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Item 1. Business

2022-03-09 compared with 2021-03-17 · 577 added, 1110 removed, 224 unchanged (88% of the section changed)

DBV Technologies is a clinical-stage

biopharmaceutical company dedicated to developing and commercializing safe, effective, and convenient therapies for patients with food allergies and other immunological conditions.

Our therapeutic approach is based on epicutaneous immunotherapy, or EPIT , our proprietary method of

delivering biologically active compounds to the immune system through intact skin using Viaskin, an epicutaneous patch (i.e., a skin patch).

We have generated significant data demonstrating that the mechanism of action of Viaskin is novel and

differentiated, as it targets specific antigen-presenting immune cells in the skin called Langerhans cells.

Langerhans cells capture the antigen and migrate to the lymph node to activate the immune system without allowing passage of the antigen into

the bloodstream, minimizing systemic exposure in the body.

We are advancing this unique technology to address areas of unmet medical need, including food allergies.

Safety is paramount to children with food allergies and their families because the

introduction of the offending allergen into an allergic childs bloodstream can cause severe and life-threatening allergic reactions, such as anaphylactic shock.

We believe Viaskin may offer a convenient, self-administered, non-invasive immunotherapy to patients.

Our most advanced product candidate is Viaskin Peanut, which has been evaluated

in nine clinical studies, including four Phase II studies and two Phase III studies, as a potential therapy for children ages four to eleven with peanut allergy.

We also have an ongoing Phase III study of Viaskin Peanut in children ages one to three

with peanut allergy.

DBV Technologies is a clinical-stage specialty biopharmaceutical company focused on changing the field of immunotherapy by developing a novel technology platform called Viaskin.

Our therapeutic approach is based on epicutaneous immunotherapy, or EPIT™, our proprietary method of delivering biologically active compounds to the immune system through intact skin using Viaskin, an epicutaneous patch (i.e., a skin patch).

We have generated significant data demonstrating that Viaskin’s mechanism of action is novel and differentiated, as it targets specific antigen-presenting immune cells in the skin, called Langerhans cells, that capture the antigen and migrate to the lymph node in order to activate the immune system without passage of the antigen into the bloodstream, minimizing systemic exposure in the body.

We are advancing this unique technology to treat patients, including infants and children, suffering from food allergies, for whom safety is paramount, since the introduction of the offending allergen into their bloodstream can cause severe or life-threatening allergic reactions, such as anaphylactic shock.

We believe Viaskin may offer convenient, self-administered, non-invasive immunotherapy to patients.

Our most advanced product candidate is Viaskin Peanut, which has been evaluated in nine clinical trials, including four Phase II trials and two Phase III trials, as a potential therapy for children ages four to eleven with peanut allergy.

We also have an ongoing Phase III trial of Viaskin Peanut in children ages one to three with peanut allergy.

We have two earlier-stage food allergy programs:

Viaskin Milk, which is in Phase II of clinical development, and Viaskin Egg, which

is in preclinical development.

Viaskin Milk, which is in Phase II of clinical development, and Viaskin Egg, which is in preclinical development.

We are also exploring potential applications of our Viaskin platform in vaccines and other immune diseases such as Eosinophilic Esophagitis, or EoE.

Our goal is to change the field of

immunotherapy by developing and commercializing safe, effective, and convenient therapies for patients with food allergies and other immunological conditions.

Our goal is to change the field of immunotherapy by developing and commercializing safe, effective, and convenient therapies for patients with food allergies and other immunological conditions.

Key elements of our strategy are:

Seek marketing approval for Viaskin Peanut in the European Union.

The European Medicines Agency, or EMA,

validated our Marketing Authorization Application, or MAA, for Viaskin Peanut in November 2020.

The validation confirmed that the submission was sufficiently complete to begin the formal

review process for Viaskin Peanut to treat peanut allergies in children ages four to eleven years.

Following the MAA validation, the EMAs Committee for Medicinal Products for Human Use, or CHMP, began their review of the application and will

provide a recommendation to the European Commission, or EC, on whether to grant a marketing authorization once their review is complete.

Seek marketing approval for Viaskin Peanut in the United States.

On August 3, 2020, we received a

Complete Response Letter, or CRL, from the U.S.

Food and Drug Administration, or FDA, regarding our Biologics License Application, or BLA, for Viaskin Peanut in children ages four to eleven.

The FDA indicated it could not approve the Viaskin Peanut

BLA in its current form and identified concerns regarding the impact of patch-site adhesion on efficacy.

The FDA indicated the need for patch modifications, and subsequently a new human factor study and supplementary clinical data to support a

modified patch.

In addition, the FDA requested additional Chemistry, Manufacturing and Controls, or CMC, data.

The FDA did not raise any safety concerns related to Viaskin Peanut.

On January 13, 2021, we received written responses from the FDA

to questions we submitted in October 2020 following the CRL.

We believe the FDA feedback provides a well-defined regulatory path forward, and we are working to advance our BLA re-submission plan based on the

FDA guidance.

Pursue the continued development of Viaskin Peanut for toddlers ages one to three.

In August 2017, we

initiated the EPIT in Toddlers with Peanut Allergy, or EPITOPE, trial, a Phase III clinical trial assessing the safety and efficacy of Viaskin Peanut for the treatment of peanut allergic

patients one to three years of age.

In September 2018, we announced that the independent Data Safety Monitoring Board, or DSMB, completed its planned safety review of Part A of the EPITOPE trial, involving two doses (100 µg and 250 µg).

The DSMB did not identify any safety concerns for patients enrolled in Part A of the trial and recommended that the trial continue as planned with the 250 µg dose selected for investigation in Part B.

We expect Part B to be fully enrolled by

the end of the first quarter of 2021.

Commercialize our Viaskin product candidates in the United States and other major markets.

broad expertise in food allergies, how they are treated and their market dynamics.

Given our teams knowledge in food allergies, and the limited number and targeted nature of food allergy healthcare providers in our target markets, we currently

intend to launch and commercialize our food allergies product candidates with our own specialty sales force or with established partners.

Pursue the continued development of Viaskin Peanut for toddlers and children with peanut allergy.

Seek marketing approval for Viaskin Peanut in the United States and the European Union

Advance the clinical development of additional Viaskin product candidates in the United States and other major markets.

Build a broad immunotherapy product pipeline with our innovative Viaskin technology platform.

leveraging our expertise in skin immunology science and believe that our Viaskin technology platform has the potential to support significant product opportunities beyond treatments for food allergies.

To support our pipeline innovation strategy, we

have completed proof-of-concept trials in the field of inflammatory and autoimmune diseases, including an investigator-sponsored study at the Childrens Hospital of

Philadelphia, or CHOP, in EoE, an inflammatory disease of the esophagus.

In collaboration with the Geneva University Hospitals, or HUG, and BioNet-Asia Co.

Ltd., or BioNet, we conducted a Phase I trial of Viaskin rPT for booster vaccination against

pertussis, our first human proof-of-concept trial in the field of boosting vaccination.

Peanut Allergy

Unmet Medical Need

Food allergies are an increasingly common and serious disorder, with epidemiologic studies demonstrating an increasing prevalence over the last two decades.

Reactions to foods in allergic patients are characterized by early onset symptoms and typically involve one or more target organs.

Presentation can vary unpredictably, from mild symptoms to severe anaphylactic reactions.

According to a paper

published in the Immunology and Allergy Clinics of North America, food allergies are responsible for 150 to 200 deaths every year in the United States.

Centers for Disease Control and Prevention reported that food allergies result in more

than 300,000 ambulatory-care visits per year among children under the age of 18.

Every three minutes a food allergy reaction sends someone to the emergency department, which is about 200,000 emergency department visits per year, and every six

minutes the reaction is one of anaphylaxis.

A recent U.S.

study indicates an increase of 350% in the number of hospitalizations of children below age 18 for diagnosis of a food allergy for the period from 2004 to 2006 as compared to the period from

1998 to 2000.

Among food allergies, peanut allergy is one of the most common, and the prevalence has increased over the past 20 years, especially in

Exposure to peanut can cause unpredictable, severe and potentially fatal allergic reactions, including anaphylaxis.

Peanut allergy affects 2.2% of all children under the age of 18 years in the United States, which is approximately

1.6 million children.

Similar percentages of affected children have been reported in Europe and Australia.

Among children with food allergies in the United States, 29% have peanut allergy, which makes it the most common food allergy in this age

Peanut allergy is more likely to result in severe reactions than most other food allergies in children, and the majority of fatal anaphylactic reactions in patients are caused by peanut allergy.

Background on Allergic Reactions

reaction represents one type of an inappropriate immune response to a foreign substance, or an allergen.

While, for most people, exposure to an allergen is relatively harmless, for others, exposure to an

allergen can provoke an allergic reaction of varying severity.

Prior to an allergic reaction occurring, an individual must be sensitized to the given allergen.

Following allergen penetration of the body via the skin or

the mucosa, for example, the eyes, respiratory or digestive tract, the immune system identifies the foreign element as dangerous and begins to produce specific antibodies against it.

Antibodies, or immunoglobulins, are substances produced by the

immune system that recognize certain foreign elements to which the body is exposed.

There are five major types of immunoglobulins, or Ig:

IgM, IgG, IgA, IgD, and IgE.

When an individual produces IgE that is directed against a specific allergen (e.g.

peanut protein), that individual is said to be sensitized and potentially clinically allergic.

Upon re-exposure to the allergen, the now sensitized immune system is ready to react.

IgE specifically directed

against that allergen interacts with cells in the body, resulting in the release of substances that lead to the signs and symptoms of an allergic reaction such as redness, hives, itching, swelling, shortness of breath, vomiting, and cardiac

Reactions vary in duration and intensity, but occur reliably upon exposure to an allergen for an allergic individual, and reactions may progress if not treated.

The most severe allergic reaction is anaphylaxis, which has been defined as

a severe, potentially fatal, systemic allergic reaction occurring suddenly after contact with an allergen.

If not treated quickly by epinephrine injection, anaphylaxis may progress to shock causing a rapid drop in blood pressure, loss of

consciousness and possibly death within a few minutes.

Longer-term Impact of Allergic Reactions

While anaphylaxis is the most severe allergic reaction to food, patients also suffer from a lower quality of life.

Symptoms tend to disappear within hours of

exposure but, in some cases, can continue to affect patients for several days.

Reactions can include, but are not limited to, skin discomfort, hay fever-like symptoms, impaired lung function and gastrointestinal complications, such as sustained

bloating, nausea, vomiting and diarrhea.

In some cases, food allergies can lead to chronic diseases such as failure to thrive in children and EoE.

addition, recent studies suggest that patients with food allergies are especially at risk for experiencing significant disruption to their daily life.

Food allergies are not only a physical disability;

they are often associated with psychological

traumas, including fear of eating, antisocial behavior and anxiety.

In the case of pediatric patients, food allergies also have a significant impact on their caretakers.

Based on our 2017 survey conducted of 500 parents with peanut-allergic children

between the ages of 3 and 14 years, 73% of parents were most concerned with accidental exposure to peanuts in their childs daily life, 60% reported stress in their daily lives due to their childs peanut allergy, and 67% believed their

childs allergy made it harder to be a parent.

Peanut allergy is one of the most common food allergies globally with an overall prevalence across all age groups of approximately 1%, which increases up to 2% in the pediatric population.

Based on a 2018 publication, an estimated 2.2% of the pediatric population in the United States, approximately 1.6 million children, is allergic to peanuts.

This reflects an increasing prevalence, as has been shown by several epidemiologic studies, including a cross-sectional survey-based study in the United States in which the prevalence of peanut allergy more than tripled between 1997 and 2008 from 0.4% to 1.4%.

Studies indicate that most children do not outgrow their peanut allergy, with resolution occurring in only about 20% of young children, making this allergy a life-long affliction in most cases.

Clinically, peanut allergy is characterized by rapid onset of symptoms which are triggered by the release of mediators from mast cells and basophils and typically involves one or more target organs.

Presentation and severity of allergic reactions are unpredictable and may vary from mild to severe (anaphylaxis) within populations and within individuals over time.

In the case of peanut allergy, all individuals are therefore considered at risk for severe allergic reactions, irrespective of their past history.

Current Challenges in the Management of Peanut Allergy Patients

Current management options for peanut-allergic patients are limited.

In peanut allergy, both children and caregivers experience anxiety related to the fear of

accidental ingestion and fear of allergic reactions.

Patients, health care professionals, caregivers, and society overall are dissatisfied with current management options.

Peanut allergy patients most often manage their allergy through strict avoidance of peanut;

however, strict avoidance is very difficult to achieve, especially

for children.

In fact, 39% of peanut allergy patients experience an accidental exposure within a year of diagnosis.

Some foods can contain hidden traces of allergens, labeling is often deceptive, and contamination of allergen-free foods occurs

For example, according to a paper published in the Journal of Allergy and Clinical Immunology, or JACI, it is estimated that accidental exposure to peanuts in peanut allergic patients occurs once every three to five years and the annual

incidence of accidental ingestion is between 15% and 40%.

Any oral exposure to peanut has the potential to result in a severe reaction.

Epinephrine, also

known as adrenaline, is the first-line treatment for anaphylactic reactions, most commonly administered by intramuscular injection.

Epinephrine is available for self/caregiver auto injection in various proprietary forms.

Allergic patients are

instructed by their physicians on how to recognize the symptoms of anaphylaxis, how and when to use their autoinjector, and how to always have an autoinjector readily available.

Epinephrine injections help relieve the symptoms of anaphylaxis, but they do not treat or help address the underlying causes of the allergic disease.

Current Peanut Allergy Treatments and their Limitations

Allergen immunotherapy refers to a treatment approach that involves repeated administration an allergen in an attempt to decrease reactivity in allergic

It is currently recognized by the World Health Organization, or WHO, as the preferred therapeutic treatment for allergies.

Desensitization therapy is widely used in respiratory

(inhalant) allergies and allergies to insect bites/stings (venom), and can also be performed for medication allergy.

For inhalant and venom allergies,

treatment is traditionally performed by subcutaneous injections of increasing doses of the allergen at regular intervals under the supervision of a physician.

Currently, oral and sublingual immunotherapy are used by some allergists to desensitize patients with food allergies.

Both approaches expose the immune system

to increasing amounts of allergen either through powder that is ingested or serum that is administered under the tongue until the patient can be exposed to a pre-determined amount of food without

experiencing an allergic reaction.

The FDA approved the first treatment for peanut allergy, Palforzia, an oral immunotherapy, in January 2020.

Palforzia uses a formulation of peanut flour for oral administration intended to desensitize the patient

The standard of care for the management of peanut allergy is strict allergen avoidance and the use of epinephrine in case of an allergic reaction.

However, since peanut is a common ingredient in many foods, strict avoidance is difficult to achieve, and accidental exposures in peanut-allergic children remains a common issue.

The estimated rate of accidental peanut exposure in peanut-allergic children is estimated to be 12.4% per year, with approximately 40% of children experiencing an accidental exposure within 3 years of diagnosis.

In addition, the constant vigilance required to avoid allergen exposure can affect the quality of life of peanut-allergic children and their parents/caregivers.

Daily family activities and social events are negatively impacted by the anxiety and fear of accidental peanut ingestion.

According to a 2020 publication, a recent survey conducted across eight European countries reported high rates of frustration, stress and isolation in peanut-allergic individuals and their caregivers.

The current management of peanut allergy has significant limitations and highlights the need for safe and effective treatments that can induce clinical desensitization (i.e., increased tolerance to peanut allergen), thus minimizing the risk of reaction due to accidental ingestion.

Current and Emerging Peanut Allergy Treatments

Several non-specific and allergen-specific treatment approaches are in various stages of clinical development for the treatment of peanut allergy.

Food allergen-specific approaches include epicutaneous immunotherapy, or EPIT, oral immunotherapy, or OIT, (both with and without adjunctive therapies), and sublingual immunotherapy, or SLIT.

EPIT is an emerging therapeutic approach to food allergy that utilizes the unique immune properties of the skin to deliver allergen directly to antigen-presenting cells in the epidermis and dermis to initiate desensitization.

Although efficacious, peanut OIT may not be suitable or a preferred option for all children with peanut allergy because of its relatively high rate of systemic side effects and the limitations the treatment places on activities of daily living, including exercise, and unpredictability of tolerance in the setting of intercurrent illness.

A proprietary form of OIT, Palforzia, was recently approved in the US and the European Union for the treatment of peanut allergy in children aged 4–17 years.

SLIT for peanut allergy has demonstrated evidence of clinical success, with a more satisfactory side effect profile compared to OIT.

Despite the evident interest of clinicians to further evaluate these treatment procedures, OIT and SLIT may not be applicable across all ages and risk categories of peanut-allergic children and adults.

There remains an unmet need for additional therapies for patients with peanut allergy.

In most other therapeutic areas, healthcare providers,

patients and their families have several treatment options, and they are able to choose the treatment that best fits their needs.

For example, in the case of respiratory allergies, symptomatic and maintenance allergy treatments, such as

antihistamines, bronchodilators and corticosteroids, are available and all among the most widely used treatments in the world.

Furthermore, in a third-party study of 200 peanut-allergic children, children expressed a preference for a patch treatment

option over an oral treatment option, mainly due to perceived difficulty of oral therapy administration and fear of ingesting peanuts.

Our clinical trials of Viaskin Peanut did not require restrictions to daily activities or require peanut

We believe Viaskin Peanut has distinct product attributes that may be important to patients with peanut allergy, their families and the allergists who treat them, and we believe they want and deserve multiple therapeutic options with

distinct product profiles.

In most other therapeutic areas, healthcare providers, patients and their families have several treatment options, and they are able to choose the treatment that best fits their needs.

For example, in the case of respiratory allergies, symptomatic and maintenance allergy treatments, such as antihistamines, bronchodilators and corticosteroids, are available and all among the most widely used treatments in the world.

Our Viaskin Technology Platform

Over the last decade, we have developed an innovative immunotherapy technology platform, with the potential for sustained therapeutic effect, by delivering

biologically active compounds, including antigens, via intact skin.

Epicutaneous, also known as on the skin, immunotherapy, or EPIT, exposes tolerance-promoting immune cells in the skin to an adhesive dermal patch containing a small (micrograms)

dose of food protein.

Over the last decade, we have developed an innovative immunotherapy technology platform, with the potential for sustained therapeutic effect, by delivering biologically active compounds, including antigens, via intact skin.

Epicutaneous, also known as on the skin, immunotherapy, or EPIT, exposes tolerance-promoting immune cells in the skin to an adhesive dermal patch containing a small (micrograms) dose of food protein.

This technology platform, which we call Viaskin, is an innovative approach to potentially treating food allergy.

In EPIT, intact skin is exposed to allergen via the Viaskin technology using a patch that contains

microgram amounts of food protein.

In EPIT, intact skin is exposed to allergen via the Viaskin technology using a patch that contains microgram amounts of food protein.

Allergen applied via EPIT is captured in the superficial layers of the skin by Langerhans cells, as well as dermal dendritic cells, thus limiting exposure to the bloodstream.

In experimental models, EPIT induced a

population of regulatory T cells, or Tregs, with specific properties that resulted in suppression of allergic symptoms and protection against further sensitizations.

EPIT-induced epigenetic modifications favored a Treg-mediated immune response and a

downregulated Th2 response and may play a role in the sustainability of effect.

Based on our trials and research, we believe that EPIT has the potential to provide all of the intended benefits of a disease-modifying treatment in allergy, while

avoiding severe or life-threatening allergic reactions.

The key elements of the Viaskin patch mechanism of action, which are illustrated below, are the

Containing a dry layer of allergen in its center, the patch is positioned on intact skin, without prior

The condensation chamber formed between the skin and the center of the patch creates hyperhydration of the skin

and an accumulation of water.

In experimental models, EPIT induced a population of regulatory T cells, or Tregs, with specific properties that resulted in suppression of allergic

symptoms and protection against further sensitizations.

EPIT-induced epigenetic modifications favored a Treg-mediated immune response and a downregulated Th2 response and may play a role in the sustainability of effect.

Based on our trials and research, we believe that EPIT has the potential to provide all of the intended benefits of a disease-modifying treatment in allergy, while avoiding severe or life-threatening allergic reactions.

The key elements of the Viaskin patch mechanism of action, which are illustrated below, are the following:

Containing a dry layer of allergen in its center, the patch is positioned on intact skin, without prior preparation.

The condensation chamber formed between the skin and the center of the patch creates hyperhydration of the skin and an accumulation of water.

The accumulation of water solubilizes the allergen.

Due to this condensation chamber, the epidermis becomes more

permeable allowing passage of the allergen into the epidermis.

Due to this condensation chamber, the epidermis becomes more permeable allowing passage of the allergen into the epidermis.

Once in the epidermis, the allergen is captured by a population of highly specialized cells:

3 unchanged sentences

Our product development strategy is based on leveraging Viaskin’s scientific profile.

We select our target product candidates with the aim to address

allergies that have high unmet medical needs.

We select our target product candidates with the aim to address allergies that have high unmet medical needs.

The following table summarizes the current development status of our product candidates:

US FDA Breakthrough Therapy and Fast Track designation in children.

US FDA Fast Track designation in pediatric patients two and older.

Viaskin Peanut for children ages 4-11

Our lead product candidate, Viaskin Peanut, has completed a global Phase III development program for the treatment of peanut allergic patients four to 11 years

The program comprised the following studies:

PEPITES ( P eanut EPIT E fficacy and

S afety Study) , a randomized, placebo-controlled pivotal Phase III trial investigating the safety and efficacy of Viaskin Peanut 250 µg in 356 patients after 12 months of treatment.

REALISE (REAL Life Use and Safety of EPIT), a randomized, placebo-controlled Phase III trial designed to

generate safety data after six months of blinded treatment, as well as to evaluate the use of Viaskin Peanut 250 µg in routine clinical practice.

PEOPLE ( P EPITES OP en L abel

E xtension S tudy) , a long-term, open-label extension trial of Viaskin Peanut 250 µg.

In the PEOPLE trial, patients who were randomized and received active treatment during PEPITES received Viaskin

Peanut 250 µg for two additional years, while patients who received placebo during PEPITES will be treated with Viaskin Peanut 250 µg for three years.

The results from PEPITES and REALISE formed the basis for our regulatory submission in the United States, a Biologics License Application, or BLA, for the use

of Viaskin Peanut in peanut allergic patients four to 11 years of age.

The results from PEPITES, REALISE and PEOPLE formed the basis for our regulatory

submission in the European Union, a Marketing Authorization Application, or MAA, for the use of Viaskin Peanut in peanut allergic patients four to 11 years of age.

United States Regulatory Status

Viaskin Peanut has

obtained fast track designation and breakthrough therapy designation in children from the FDA, which are regulatory designations intended to expedite or facilitate the process of reviewing new drugs and biological products that are intended to treat

a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

2019, we announced the submission of a BLA to the FDA for Viaskin Peanut for the treatment of peanut allergy in children four to 11 years of age.

October 2019, we announced the FDAs acceptance for review of our BLA for Viaskin Peanut, with a target action date, provided by the FDA, of August 5, 2020.

In February 2020, we announced that the FDA had announced an Allergenic Products Advisory Committee meeting to be held on May 15, 2020 to discuss the BLA

for Viaskin Peanut.

Our lead product candidate, Viaskin Peanut, has completed a global Phase III development program for the treatment of peanut allergic patients four to 11 years of age.

The program comprised the following clinical trials:

fficacy and S

, a randomized, placebo-controlled pivotal Phase III trial investigating the safety and efficacy of Viaskin Peanut 250 µg in 356 patients after 12 months of treatment.

REALISE (REAL Life Use and Safety of EPIT),

a randomized, placebo-controlled Phase III trial designed to generate safety data after six months of blinded treatment, as well as to evaluate the use of Viaskin Peanut 250 µg in routine clinical practice.

, a long-term, open-label extension trial of Viaskin Peanut 250 µg.

In the PEOPLE trial, patients who were randomized and received active treatment during PEPITES received Viaskin Peanut 250 µg for two additional years, while patients who received placebo during PEPITES were treated with Viaskin Peanut 250 µg for three years.

The results from PEPITES and REALISE formed the basis for our 2019 regulatory submission in the United States, a Biologics License Application, or BLA, for the use of Viaskin Peanut in peanut-allergic patients four to 11 years of age.

The results from PEPITES, REALISE and PEOPLE formed the basis for our 2020 regulatory submission in the European Union, a Marketing Authorization Application, or MAA, for the use of Viaskin Peanut in peanut- allergic patients four to 11 years of age.

United States Regulatory History and Current Status

Viaskin Peanut has obtained fast track designation and breakthrough therapy designation in children from the FDA, which are regulatory designations intended to expedite or facilitate the process of reviewing new drugs and biological products that are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

In August 2019, we announced the submission of a BLA to the FDA for Viaskin Peanut for the treatment of peanut allergy in children four to 11 years of age.

In October 2019, we announced the FDA’s acceptance for review of our BLA for Viaskin Peanut, with a target action date, provided by the FDA, of August 5, 2020.

In February 2020, the FDA announced an Allergenic Products Advisory Committee meeting to be held on May 15, 2020 to discuss the BLA for Viaskin Peanut.

On March 16, 2020, we announced that the FDA had informed us that during its ongoing review of our BLA for Viaskin Peanut, it had identified questions regarding efficacy, including the impact of patch-site adhesion.

Therefore, the Advisory Committee meeting to discuss the BLA originally scheduled on May 15, 2020 was cancelled.

On August 3, 2020, we received

a Complete Response Letter, or CRL, from the FDA in which the FDA indicated it could not approve the Viaskin Peanut BLA in its current form.

The FDA identified concerns regarding the impact of patch-site adhesion on efficacy and indicated the need

for patch modifications, and subsequently a new human factor study.

In August 2020, we received a Complete Response Letter, or CRL, in which the FDA indicated it could not approve the Viaskin Peanut BLA in its current form.

The FDA identified concerns regarding the impact of patch-site adhesion on efficacy and indicated the need for patch modifications, and subsequently a new human factor study.

The FDA also indicated that supplementary clinical data would need to be generated to support the modified patch.

In addition, the FDA requested additional Chemistry, Manufacturing

and Controls, or CMC, data.

In addition, the FDA requested additional Chemistry, Manufacturing and Controls, or CMC, data.

The FDA did not raise any safety concerns related to Viaskin Peanut.

On January 13, 2021, we received written responses

from the FDA to questions provided in the Type A meeting request we submitted in October 2020 following the CRL.

We believe the FDA feedback provides a well-defined regulatory path forward.

In exchanges with the FDA, we proposed potential

resolutions to two main concerns identified by the FDA in the CRL:

the impact of patch adhesion and the need for patch modifications.

The FDA agreed with our position that a modified Viaskin Peanut patch should not be considered as a new product

entity provided the occlusion chamber of the current Viaskin Peanut patch and the peanut protein dose of 250 µg (approximately 1/1000 one peanut) remains unchanged and performs in the same way it has performed previously.

confirm the consistency of efficacy data between the existing and a modified patch, FDA has requested an assessment comparing the uptake of allergen (peanut protein) between the patches in peanut allergic children ages

The FDA also recommended conducting a 6-month, well-controlled safety and adhesion trial to assess a modified Viaskin Peanut patch in the intended patient

On March 11, 2021, we announced that we had commenced a trial in healthy adult volunteers to evaluate the adhesion of five modified

Viaskin Peanut patches in order to identify the one or two best-performing patches.

expect that this trial will be completed by the end of March.

We intend to advance those patches selected for use in an allergen uptake, or protein transport, trial and adhesion and safety trial,

and we intend to submit the protocols for these trials to the FDA for review and comments in the second quarter of 2021 before initiating the trials.

We will address details about a new human factor, or HF, validation trial and additional CMC data

in subsequent interactions with the FDA.

European Union Regulatory Status

On November 2, 2020, we announced that our Marketing Authorization Application, or MAA, for Viaskin Peanut had been validated by the European Medicines

Agency, or EMA.

The validation of the MAA confirmed that the submission was sufficiently complete to begin the formal review process for Viaskin Peanut to treat peanut allergies in children ages 4 to 11 years.

Following the MAA validation, the

EMAs Committee for Medicinal Products for Human Use, or CHMP, will review the application and provide a recommendation to the European Commission, or EC, on whether to grant a marketing authorization.

On March 11, 2021, we announced that

we had received the EMAs Day 120 questions, which were consistent with both our expectations and pre-filing conversations with the EMA.

In January 2021, we received written responses from the FDA to questions provided in the Type A meeting request we submitted in October 2020 following the CRL.

The FDA agreed with our position that a modified Viaskin Peanut patch should not be considered as a new product entity provided the occlusion chamber of the current Viaskin Peanut patch and the peanut protein dose of 250 µg (approximately 1/1,000 of one peanut) remains unchanged and performs in the same way it has performed previously.

In order to confirm the consistency of efficacy data between the existing and a modified patch, FDA requested an assessment comparing the uptake of allergen (peanut protein) between the patches in peanut allergic children ages 4-11.

We named that assessment EQUAL, which stands for Equivalence in Uptake of Allergen.

The FDA also recommended conducting a 6-month, well-controlled safety and adhesion trial to assess a modified Viaskin Peanut patch in the intended patient population.

We later named this clinical trial STAMP, which stands for Safety, Tolerability, and Adhesion of Modified Patches.

Based on the January 2021 FDA feedback, we defined three parallel workstreams:

Identify a modified Viaskin patch (which we call mVP).

Generate the 6-month safety and adhesion clinical data FDA requested via STAMP, which we expected to be the longest component of the mVP clinical plan.

We prioritized the STAMP protocol submission so we could begin the clinical trial as soon as possible.

Demonstrate the equivalence in allergen uptake between the current and modified patches in the intended patient population via EQUAL.

The complexity of EQUAL hinged on the lack of established

clinical and regulatory criteria to characterize allergen uptake via an epicutaneous patch.

To support those exchanges, we outlined our proposed approach to demonstrate allergen uptake equivalence between the two patches, and allotted time to generate informative data through two additional Phase I clinical trials in healthy adult volunteers:

PREQUAL, a Phase I trial with adult healthy volunteers to optimize the allergen sample collection methodologies and validate the assays we intend to use in EQUAL.

The data collection phase of the trial is complete, and the data analysis phase is ongoing.

‘EQUAL in adults,’ a second Phase I trial with adult healthy volunteers to compare the allergen uptake of cVP and mVP.

In March 2021, we commenced CHAMP (Comparison of adHesion Among Modified Patches), a Phase I trial in healthy adult volunteers to evaluate the adhesion of five modified Viaskin Peanut patches.

We completed CHAMP in the second quarter of 2021.

All modified Viaskin Peanut patches demonstrated better adhesion performance as compared to the then-current Viaskin Peanut patch, and based on the results of CHAMP, we then selected two modified patches that performed best out of the five modified patches studied for further development.

We then selected the circular patch for further development, which is approximately 50% larger in size relative to the current patch and circular in shape.

In May 2021, we submitted our proposed STAMP protocol to the FDA, and on October 14, 2021, we received an Advice/Information Request letter from the FDA.

In this letter, the FDA requested a stepwise approach to the modified Viaskin patch development program and provided partial feedback on the STAMP protocol.

Specifically, the FDA requested that we conduct allergen uptake comparison trials (i.e., ‘EQUAL in Adults,’ EQUAL), and submit the allergen uptake comparison data for FDA review and feedback prior to starting the STAMP study.

The FDA’s explanation was that the results from the allergen uptake trials might affect the design of the STAMP study.

After careful review of the FDA’s information requests, in December 2021, we decided not to pursue the sequential approach to the development plans for Viaskin Peanut as requested by the FDA in the October 2021 feedback.

We estimated that the FDA’s newly proposed sequential approach would require at least five rounds of exchanges that necessitate FDA alignment prior to initiating STAMP, the 6-month safety and adhesion study.

As such, in December 2021, we announced we plan to initiate a pivotal Phase III placebo-controlled efficacy trial for a modified Viaskin Peanut patch (mVP) in children in the intended patient population.

The clinical trial will also include updates to the Instructions for Use (IFU).

We consider this approach the most straightforward to potentially demonstrate effectiveness, safety, and improved in vivo adhesion of the modified Viaskin Peanut system.

The FDA has confirmed our change in strategy is agreeable via oral and written exchanges.

The protocol for the new Phase III pivotal study of the modified Viaskin Peanut (mVP) patch was completed at the end of February 2022 and has been prepared for FDA submission.

We are currently engaged in discussions with FDA in preparation for protocol submission and review.

We expect to complete protocol submission following further alignment with FDA.

European Union Regulatory History and Current Status

In November 2020, we announced that our Marketing Authorization Application, or MAA, for Viaskin Peanut had been validated by the European Medicines Agency, or EMA.

The validation of the MAA confirmed that the submission was sufficiently complete to begin the formal review process for Viaskin Peanut to treat peanut allergies in children ages four to 11 years.

Following the MAA validation, the EMA’s Committee for Medicinal Products for Human Use, or CHMP, will review the application and provide a recommendation to the European Commission, or EC, on whether to grant a marketing authorization.

On March 11, 2021, we announced that we had received the EMA’s Day 120 questions, which were consistent with both our expectations and pre- filing conversations with the EMA.

We did not receive questions about the impact of adhesion on efficacy.

PEPITES ( P eanut EPIT E fficacy and S afety Study)

In December 2015, we initiated a pivotal Phase III trial designed to evaluate the safety and efficacy of Viaskin Peanut 250 µg in children four to 11

years of age suffering from peanut allergy.

PEPITES was a global, randomized 2:1, double-blind, placebo-controlled Phase III trial, in which 356 pediatric peanut-allergic patients were treated with Viaskin Peanut 250 µg or placebo for 12

On August 2, 2021, we announced we had received from the EMA the Day 180 list of outstanding issues, which is an established part of the prescribed EMA review process.

It is a letter that is meant to include any remaining

questions or objections at that stage in the process.

The EMA indicated many of their objections and major objections from the Day 120 list of questions had been answered.

One major objection remained at Day 180.

The Major Objection questioned the limitations of the data, for example, the clinical relevance and effect size supported by a single pivotal study.

On December 20, 2021, we announced we had withdrawn the MAA for Viaskin Peanut and formally notified the EMA of our decision.

The initial filing was supported by data from a single, placebo-controlled Phase III pivotal trial known as PEPITES (V712-301).

The decision to withdraw was based on the view of CHMP that the data available to date from a single pivotal clinical trial were not sufficient to preclude a Major Objection at Day 180 in the review cycle.

We believe data from a second Viaskin Peanut pivotal clinical trial will support a more robust path for licensure of Viaskin Peanut in the EU.

We intend to resubmit the MAA when that data set is available.

fficacy and S

In December 2015, we initiated a pivotal Phase III trial designed to evaluate the safety and efficacy of Viaskin Peanut 250 m

g in children four to 11 years of age suffering from peanut allergy.

PEPITES was a global, randomized 2:1, double-blind, placebo-controlled Phase III trial, in which 356 pediatric peanut-allergic patients were treated with Viaskin Peanut 250 m

g or placebo for 12 months.

A new patch was applied each day, and after 2 weeks, each patch was worn for 24 hours.

During the trial, patients sensitivity to peanut protein was assessed using a double-blind, placebo-controlled food challenge, or DBPCFC, at

baseline and again after 12 months of treatment.

The DBPCFC was halted once the patient exhibited an objective symptom, as described on a pre-specified scale, thus establishing a subjects peanut

reactivity level, also known as the patients eliciting dose, or ED.

During the trial, patients’ sensitivity to peanut protein was assessed using a double-blind, placebo-controlled food challenge, or DBPCFC, at baseline and again after 12 months of treatment.

The DBPCFC was halted once the patient exhibited an objective symptom, as described on a pre-specified scale, thus establishing a subject’s peanut reactivity level, also known as the patient’s eliciting dose, or ED.

The median baseline reactive dose in PEPITES was 100 mg at baseline.

The primary responder analysis was conducted after 12 months of treatment.

For patients with a baseline peanut protein ED

equal to or less than 10 mg, a responder was defined as a patient with a peanut protein ED equal to or greater than 300 mg of peanut protein after 12 months of treatment.

For patients with a baseline ED greater than 10 mg, a responder was defined as

a patient with a peanut protein ED equal to or greater than 1,000 mg of peanut protein after 12 months of treatment.

Secondary endpoints included the change from baseline of mean and median cumulative reactive dose of peanut protein, or CRD, which

is used to establish the total quantity of peanut protein consumed during the DBPCFC.

For patients with a baseline peanut protein ED equal to or less than 10 mg, a responder was defined as a patient with a peanut protein ED equal to or greater than 300 mg of peanut protein after 12 months of treatment.

For patients with a baseline ED greater than 10 mg, a responder was defined as a patient with a peanut protein ED equal to or greater than 1,000 mg of peanut protein after 12 months of treatment.

Secondary endpoints included the change from baseline of mean and median cumulative reactive dose of peanut protein, or CRD, which is used to establish the total quantity of peanut protein consumed during the DBPCFC.

Serological markers were also measured at baseline, three, six and 12 months to characterize the immunological changes observed in patients.

Results of PEPITES Trial

In October 2017, we announced topline results from PEPITES, in which we observed a statistically significant response with a favorable tolerability profile,

with (based on responder definitions above) 35.3% of patients responding to Viaskin Peanut 250 µg after 12 months of treatment as compared to 13.6% of patients in the placebo arm (difference in response rates = 21.7%;

In October 2017, we announced topline results from PEPITES, in which we observed a statistically significant response with a favorable tolerability profile, with (based on “responder” definitions above) 35.3% of patients

responding to Viaskin Peanut 250 m

g after 12 months of treatment as compared to 13.6% of patients in the placebo arm (difference in response rates = 21.7%;

95% CI = 12.4%—29.8%).

However, the primary endpoint, which evaluated the 95% CI in the difference in response rates between the active and placebo arms, did not reach the 15% lower bound of the CI that was proposed in the studys Statistical

Analysis Plan submitted to the FDA.

Detailed results were published in The Journal of the American Medical Association in February 2019.

With respect to CRD, a key secondary endpoint which measures threshold reactivity during the DBPCFC, we observed that at

month 12, patients treated with Viaskin Peanut 250 µg and placebo reached a mean CRD of 906 mg (median 444 mg) and 361 mg (median 144 mg) of peanut protein, respectively.

Patients in the active and placebo arms entered the study at

similar sensitivity levels;

With respect to CRD, a key secondary endpoint which measures threshold reactivity during the DBPCFC, we observed that at month 12, patients treated with Viaskin Peanut 250 m

g and placebo reached a mean CRD of 906 mg (median 444 mg) and 361 mg (median 144 mg) of peanut protein, respectively.

Patients in the active and placebo arms entered the trial at similar sensitivity levels;

mean CRD at baseline was 211.7 mg (median 144 mg) in the Viaskin Peanut arm and 212.5 mg (median 144 mg) in the placebo arm.

A difference in the CRD was observed between Viaskin Peanut and placebo (nominal p-value < 0.001) following 12 months of treatment.

Exploratory analyses showed that changes in peanut-specific biomarkers, including immunoglobulin E, orIgE, and

immunoglobulin G4, orIgG4, support the immunomodulatory effect with Viaskin Peanut.

The median observed increase from baseline in peanut-specific IgE was greater in the Viaskin Peanut group vs placebo group, respectively, at month 3 (70.1 kilounits

of antibody per liter, or kUA/L vs.

Exploratory analyses showed that changes in peanut-specific biomarkers, including immunoglobulin E, orIgE, and immunoglobulin G4, orIgG4, support the immunomodulatory effect with Viaskin Peanut.

The median observed increase from baseline in peanut-specific IgE was greater in the Viaskin Peanut group vs placebo group, respectively, at month 3 (70.1 kilounits of antibody per liter, or kUA/L vs.

9.8 kUA/L) and month 6 (27.4 kUA/L vs.

However, at month 12, peanut-specific IgE levels were observed to return to near baseline in

both groups (1.1 kUA/L vs.

Median peanut-specific IgG4 were observed to increase over time in the Viaskin Peanut group (change from baseline

However, at month 12, peanut-specific IgE levels were observed to return to near baseline in both groups (1.1 kUA/L vs.

Median peanut-specific IgG4 were observed to increase over time in the Viaskin Peanut group (change from baseline at month 3:

3.27 mg/L), while levels remained unchanged from baseline in the placebo group.

The change from baseline in peanut-specific IgG4 was greater at all

time points with Viaskin Peanut vs placebo, and the groups were observed to be highly distinguished by this marker, given a flat trend in the placebo arm.

These changes are consistent with trends that have been observed with other forms of

immunotherapy such as for venom and inhalant allergies.

The change from baseline in peanut-specific IgG4 was greater at all time points with Viaskin Peanut vs placebo, and the groups were observed to be highly distinguished by this marker, given a flat trend in the placebo arm.

These changes are consistent with trends that have been observed with other forms of immunotherapy such as for venom and inhalant allergies.

PEPITES Immunological Responses

In a post-hoc analysis, the majority of patients on Viaskin Peanut exhibited an

increased ED compared to the placebo group (62.6% in active vs.

In a post-hoc analysis, the majority of patients on Viaskin Peanut exhibited an increased ED compared to the placebo group (62.6% in active vs.

28% in placebo) at 12 months.

An additional post-hoc analysis showed that 53.1% of patients treated with Viaskin Peanut increased their baseline

ED from 100 mg or less to 300 mg or more, compared to 19% in the placebo group.

Based on this analysis, we believe that increasing the ED should translate to a reduction in the risk of reaction to accidental peanut exposures, as it will take a

higher ingestion quantity to trigger a reaction.

Indeed, based on quantitative risk analysis, or QRA, modeling from Baumert et al using national databases of consumption and contamination amounts, this improvement in ED from £ 100 mg to ³ 300 mg is predicted to reduce the risk of an allergic reaction due to accidental peanut exposure through a group of common contaminated packaged foods by

An additional post-hoc analysis showed that 53.1% of patients treated with Viaskin Peanut increased their baseline ED from 100 mg or less to 300 mg or more, compared to 19% in the placebo group.

Based on this analysis, we believe that increasing the ED should translate to a reduction in the risk of reaction to accidental peanut exposures, as it will take a higher ingestion quantity to trigger a reaction.

Indeed, based on quantitative risk analysis, or QRA, modeling from Baumert et al using national databases of consumption and contamination amounts, this improvement in ED from ≤100 mg to ≥300 mg is predicted to reduce the risk of an allergic reaction due to accidental peanut exposure through a group of common contaminated packaged foods by over 95%.

A favorable safety and tolerability profile was observed with Viaskin Peanut.

Treatment adherence was high (98.5%), and

similar discontinuation rates between treatment groups were reported, with 89.9% of patients completing the trial.

There was a low discontinuation rate due to treatment-emergent adverse events, or TEAEs, (1.7%), and the overall rate of TEAEs,

regardless of relatedness to the treatment, was comparable between treatment and placebo groups, at 95.4% and 89.0%, respectively.

The most commonly reported TEAEs were

mild to moderate application-site reactions that decreased after month 1 in both frequency and severity.

There were no treatment-related gastrointestinal adverse events or cases of eosinophilic

esophagitis in this trial.

Treatment adherence was high (98.5%), and similar discontinuation rates between treatment groups were reported, with 89.9% of patients completing the trial.

There was a low discontinuation rate due to treatment-emergent adverse events, or TEAEs, (1.7%), and the overall rate of TEAEs, regardless of relatedness to the treatment, was comparable between treatment and placebo groups, at 95.4% and 89.0%, respectively.

The most commonly reported TEAEs were mild to moderate application-site reactions that decreased after month one in both frequency and severity.

There were no treatment-related gastrointestinal adverse events or cases of eosinophilic esophagitis in this trial.

There were no cases of severe anaphylaxis in the trial.

SAEs were balanced between the Viaskin Peanut and placebo group, at

SAEs were balanced between the Viaskin Peanut and placebo group, at 4.2% vs.

5.1%, respectively.

Four SAEs reported in three Viaskin Peanut patients (1.3%) were determined by the investigator as possibly or probably related to treatment.

A low rate of treatment-related epinephrine use was reported (2.9% treatment

A low rate of treatment-related epinephrine use was reported (2.9% treatment group vs.

0.8% placebo group).

Ten cases in eight Viaskin Peanut patients (3.4%) of possibly or probably treatment-related anaphylaxis occurred, and all were classified as mild or moderate without evidence of cardiovascular, neurologic, or

respiratory compromise.

Ten cases in eight Viaskin Peanut patients (3.4%) of possibly or probably treatment-related anaphylaxis occurred, and all were classified as mild or

moderate without evidence of cardiovascular, neurologic, or respiratory compromise.

Six of these ten cases were treated with epinephrine, and five of the eight patients continued on Viaskin Peanut in the trial.

Following the completion of PEPITES, all patients were eligible to enroll in PEOPLE ( Open-Label Follow-Up Study of

the PEPITES Study to Evaluate the Long-term Efficacy and Safety of Viaskin Peanut ), a long-term, open-label extension trial of Peanut 250 µg in children.

In the PEOPLE trial, patients who were randomized and received active treatment

during PEPITES received Viaskin Peanut 250 µg for two additional years, while patients who previously received placebo during PEPITES will be treated with Viaskin Peanut 250 µg for three years.

In August 2017, we announced the completion

of enrollment of the PEOPLE trial, with 298 (92%) patients who completed PEPITES enrolling in this follow-up trial.

PEOPLE ( P EPITES OP en L abel E xtension S tudy)

In January 2020, we announced positive topline results of the three-year, open-label extension of our Phase III PEPITES trial, or PEOPLE trial, evaluating the

long-term efficacy and safety of investigational Viaskin Peanut in peanut-allergic children ages 4 to 11 years.

The results demonstrated long-term clinical benefit as shown by an increase in eliciting dose, or ED, which may decrease the chance of

reacting to an accidental peanut exposure.

The PEOPLE trial is an ongoing open-label extension study evaluating the long-term safety, tolerability and

efficacy of Viaskin Peanut 250 µg in patients who have completed the Phase III PEPITES trial.

Of the 213 patients who were randomized in the active treatment arm of PEPITES and completed the 12-month

trial, 198 patients opted to enter the PEOPLE study (safety population).

Of these patients, 148 were considered completers after 36 months and 141 patients completed all treatment according to the study protocol without major deviations.

data were analyzed from these 141 patients (per-protocol).

Topline results from PEOPLE support the long-term

tolerability and clinical benefit of Viaskin Peanut, demonstrating desensitization over 36 months of treatment, with 75.9% (107/141) of patients increasing their ED from baseline.

After 36 months, 51.8% (73/141) of patients reached an ED of at least

1,000 mg peanut protein, an increase relative to Month 12, 40.4% (57/141).

Following the completion of PEPITES, all patients were eligible to enroll in PEOPLE ( Open-Label Follow-Up Study of the PEPITES Study to Evaluate the Long-term Efficacy and Safety of Viaskin Peanut

), a long-term, open-label extension trial of Peanut 250 µg in children.

In the PEOPLE trial, patients who were randomized and received active treatment during PEPITES received Viaskin Peanut 250 µg for two additional years, while patients who previously received placebo during PEPITES will be treated with Viaskin Peanut 250 µg for three years.

In August 2017, we announced the completion of enrollment of the PEOPLE trial, with 298 (92%) patients who completed PEPITES enrolling in this follow-up trial.

In January 2020, we announced positive topline results of the three-year, open-label extension of our Phase III PEPITES trial, or PEOPLE trial, evaluating the long-term efficacy and safety of investigational Viaskin Peanut in peanut-allergic children ages four to 11 years.

The results demonstrated long-term clinical benefit as shown by an increase in eliciting dose, or ED, which may decrease the chance of reacting to an accidental peanut exposure.

The PEOPLE trial is an ongoing open-label extension study evaluating the long-term safety, tolerability and efficacy of Viaskin Peanut 250 µg in patients who have completed the Phase III PEPITES trial.

Of the 213 patients who were randomized in the active treatment arm of PEPITES and completed the 12-month trial, 198 patients opted to enter the PEOPLE clinical trial (safety population).

Of these patients, 148 were considered completers after 36 months and 141 patients completed all treatment according to the clinical trialprotocol without major deviations.

Efficacy data were analyzed from these 141 patients (per-protocol).

Topline results from PEOPLE support the long-term tolerability and clinical benefit of Viaskin Peanut, demonstrating desensitization over 36 months of treatment, with 75.9% (107/141) of patients increasing their ED from baseline.

After 36 months, 51.8% (73/141) of patients reached an ED of at least 1,000 mg peanut protein, an increase of 40.4% (57/141) relative to Month 12.

In addition, 13.5% (19/141) of patients completed the food challenge without meeting stopping criteria at 36 months (cumulative dose of 5,444 mg).

At Month 36, the mean

cumulative reactive dose (CRD) was 1,768.8 mg (median 944 mg) compared to 223.8 mg (median 144 mg) at baseline.

The safety profile of Viaskin Peanut was consistent with that observed in the clinical program to date in

over 1,000 patients.

At Month 36, the mean cumulative reactive dose (CRD) was 1,768.8 mg (median 944 mg) compared to 223.8 mg (median 144 mg) at baseline.

The safety profile of Viaskin Peanut was consistent with that observed in the clinical program to date in over 1,000 patients.

During the PEOPLE trial, the most common adverse events were mild to moderate skin reactions localized to the administration site, and there was no epinephrine use deemed related to treatment.

No treatment related serious

adverse events were reported.

No treatment related serious adverse events were reported.

One patient experienced one case of mild anaphylaxis that was determined by the investigator to be possibly related to treatment and resolved without treatment.

Treatment compliance remained high throughout the trial at

a mean of 98% over three years of treatment.

compliance remained high throughout the trial at a mean of 98% over three years of treatment.

Low discontinuations due to adverse events were observed, with two children discontinuing the trial due to treatment- related TEAEs during PEOPLE.

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All participants who reached an ED ≥1,000 mg at Month 36 were eligible to continue the trial for two additional months without treatment while maintaining a peanut-free diet.

A further double-blind placebo-controlled food challenge to determine

ED was administered at the end of this period (Month 38).

The analysis showed that

77.8% (14/18) of the children who completed the oral food challenge at

Month 38 maintained desensitization with an ED ³ 1,000 mg.

A further double-blind placebo-controlled food challenge to determine ED was administered at the end of this period (Month 38).

The analysis showed that 77.8% (14/18) of the children who completed the oral food challenge at Month 38 maintained desensitization with an ED ≥ 1,000 mg.

REALISE (REAL Life Use and Safety of EPIT)

In November 2016, we initiated a Phase III trial in peanut-allergic children 4 to 11 years of age designed to assess the use and safety of Viaskin

Peanut 250 µg in routine clinical practice.

REALISE is a multicenter, randomized 3:1, double-blind, placebo-controlled Phase III trial, in which pediatric peanut allergic patients were treated with Viaskin Peanut 250 µg or placebo for

In November 2016, we initiated a Phase III trial in peanut-allergic children four to 11 years of age designed to assess the use and safety of Viaskin Peanut 250 µg in routine clinical practice.

REALISE is a multicenter, randomized 3:1, double-blind, placebo-controlled Phase III trial, in which pediatric peanut allergic patients were treated with Viaskin Peanut 250 µg or placebo for six months.

Treatment course with Viaskin Peanut consists of a daily application of the patch on the backs of the patients.

No DBPCFCs were required for

entry or during the trial, in order to replicate routine clinical practice.

Patients in the study were selected, as per clinical practice, based on a well-documented medical history of IgE-mediated reactions

to peanut, including children with a history of severe anaphylaxis, along with skin and serum test results highly predictive of peanut allergy.

As no DBPCFCs were required, the primary endpoint of the study is safety as measured by adverse events,

treatment-emergent adverse events and serious adverse events after six

months of blinded treatment.

Secondary endpoints included evolution of

peanut-specific serological markers over time, including IgE, IgG and skin prick test wheal.

Exploratory criteria also included scores from patients Food Allergy Quality of Life Questionnaire, or FAQLQ, and the Food Allergy Independent

Measure, FAIM.

No DBPCFCs were required for entry or during the trial, in order to replicate routine clinical practice.

Patients in the clinical trial were selected, as per clinical practice, based on a well-documented medical history of IgE-mediated reactions to peanut, including children with a history of severe anaphylaxis, along with skin and serum test results highly predictive of peanut allergy.

As no DBPCFCs were required, the primary endpoint of the clinical trial is safety as measured by adverse events, treatment-emergent adverse events and serious adverse events after six months of blinded treatment.

Secondary endpoints included evolution of peanut-specific serological markers over time, including IgE, IgG and skin prick test wheal.

Exploratory criteria also included scores from patients’ Food Allergy Quality of Life Questionnaire, or FAQLQ, and the Food Allergy Independent Measure, FAIM.

In March 2017, we announced the completion of enrollment in REALISE, which randomized 393 patients in 32 centers across North America.

After the initial blinded six-month period, 97.5% of patients in both the placebo and active arms opted into an

open-label portion of the study, which will continue monitoring patients for a total of 36 months of active treatment.

After the initial blinded six-month period, 97.5% of patients in both the placebo and active arms opted into an open-label portion of the study, which continued monitoring patients for a total of 36 months of active treatment.

Results of REALISE Trial

Results from the 6-month blinded portion of this trial were comparable with outcomes from previous studies of

Viaskin Peanut 250 µg.

Results from the 6-month blinded portion of this trial were comparable with outcomes from previous trials of Viaskin Peanut 250 µg.

The most commonly reported adverse events were local application site reactions, which were mostly mild and moderate in nature.

No imbalance in SAEs was observed in the trial, with three cases in three patients in the

active arm (1.0%) and two cases in two patients in the placebo arm (2.0%).

No imbalance in SAEs was observed in the trial, with three cases in three patients in the active arm (1.0%) and two cases in two patients in the placebo arm (2.0%).

One case in one patient in the active arm was qualified by the investigator as moderate anaphylaxis probably related to treatment.

The patient responded to standard

outpatient therapy.

The patient responded to standard outpatient therapy.

In the six-month blinded period, the discontinuation rate was 2.5%, with a 1.0% dropout related to adverse events.

The mean patient compliance was above 95%.

In November 2021, long-term results of from REALISE, including the safety of Viaskin Peanut over three years and potential impact on health-related quality of life (HRQL), were presented at the American College of Allergy, Asthma & Immunology (ACAAI) Annual Scientific Meeting.

Viaskin Peanut for Children ages 1-3

We are also developing Viaskin Peanut for the treatment of peanut allergy in toddlers one to three years of age.

In August 2017, we initiated Part A of the

EPITOPE (EPIT ®

in Toddlers with Peanut Allergy) trial of Viaskin

EPITOPE is a two-part, pivotal Phase III clinical trial assessing the safety and efficacy of Viaskin Peanut 250 µg for the treatment of

peanut-allergic toddlers one to three years of age.

In September 2018, we announced that the independent data safety and monitoring board, or DSMB,

completed its review of Part A of EPITOPE and recommended that the dose of Viaskin Peanut 250 µg be evaluated in Part B.

In August 2017, we initiated Part A of the EPITOPE (EPIT ®

in Toddlers with Peanut Allergy) trial of Viaskin Peanut.

EPITOPE is a two-part, pivotal Phase III clinical trial assessing the safety and efficacy of Viaskin Peanut 250 µg for the treatment of peanut-allergic toddlers one to three years of age.

In September 2018, we announced that the independent data safety and monitoring board, or DSMB, completed its review of Part A of EPITOPE and recommended that the dose of Viaskin Peanut 250 µg be evaluated in Part B.

On October 26, 2018, we announced that the first patient was enrolled in Part B of EPITOPE.

On June 26, 2020, we announced that in Part A, patients in both treatment arms showed consistent treatment effect after 12 months of therapy, as assessed

by a double-blind placebo- controlled food challenge and biomarker results.

On June 26, 2020, we announced that in Part A, patients in both treatment arms showed consistent treatment effect after 12 months of therapy, as assessed by a double-blind placebo-controlled food challenge and biomarker results.

Part A subjects were not included in Part B and the efficacy analyses from Part A were not statistically powered to demonstrate superiority of either dose versus placebo.

These results validate the ongoing investigation of the 250 µg dose in this age group, which is the dose being studied in Part B of the study.

We expect Part B of EPITOPE to be fully enrolled in by the end of the first quarter of 2021.

Our second product candidate, Viaskin Milk,

is in development for the treatment of cows milk protein allergy, or CMPA, in children two to 17 years of age, and received fast track designation from the FDA in September 2016.

In November 2014, we initiated a multi-center, double-blind,

placebo-controlled, randomized Phase I/II dose-finding trial to study the safety and efficacy of Viaskin Milk in 198 patients with Immunoglobulin E, or IgE, mediated CMPA, which we refer to as the Milk Efficacy and Safety, or MILES, trial.

(Milk Efficacy and Safety) study was designed to determine a safe and effective dose in two age groups:

These results validate the ongoing investigation of the 250 µg dose in this age group, which is the dose being studied in Part B of the study.

Enrollment of Part B of EPITOPE was complete in first quarter of 2021, and top-line results are expected mid-year

Our second product candidate, Viaskin Milk, is in development for the treatment of cow’s milk protein allergy, or CMPA, in children two to 17 years of age, and received fast track designation from the FDA in September 2016.

In November 2014, we initiated a multi-center, double-blind, placebo-controlled, randomized Phase I/II dose-finding trial to study the safety and efficacy of Viaskin Milk in 198 patients with Immunoglobulin E, or IgE, mediated CMPA, which we refer to as the Milk Efficacy and Safety, or MILES, trial.

The MILES (Milk Efficacy and Safety) clinical trial was designed to determine a safe and effective dose in two age groups:

children ages two to 11 and adolescents ages 12 to 17.

In June 2015, we announced completion of Part A of the MILES study, or Phase I, for which

the DSMB recommended to continue the study as planned and did not raise any safety concerns, and we launched Part B, or Phase II, in October 2015.

February 2018, we announced topline results from Part B of the MILES study.

Following analyses of the data, the 300 µg dose of Viaskin Milk was identified as the dose with the greatest observed clinical activity for children (intent-to-treat, or ITT, p=0.042).

We believe these results support further advancement of the Viaskin Milk program, and we intend to discuss findings with regulatory

authorities to determine the design of future studies

In June 2015, we announced completion of Part A of the MILES study, or Phase I, for which the DSMB recommended to continue the trial as planned and did not raise any safety concerns, and we launched Part B, or Phase II, in October 2015.

In February 2018, we announced topline results from Part B of the MILES study.

Following analyses of the data, the 300 µg dose of Viaskin Milk was identified as the dose with the greatest observed clinical activity for children (intent-to-treat, or ITT, p=0.042).

We believe these results support further advancement of the Viaskin Milk program, and we intend to discuss findings with regulatory authorities to determine the design of future clinical trials

Viaskin Egg & Other Applications

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Preclinical development for Viaskin Egg commenced in the first half of 2015.

In addition to our development programs in food allergies, we have also

explored the use of our Viaskin technology for the treatment of inflammatory and autoimmune diseases with high unmet medical need.

Human proof-of-concept trials have

been conducted with Viaskin in EoE and as a booster vaccination against Bordetella pertussis, or whooping cough, in healthy adults.

Our other earlier stage research programs include vaccination for respiratory syncytial virus, as well as potential

treatments for Crohns disease, celiac disease and type I diabetes.

Following receipt of the CRL from the FDA in August 2020, we scaled down our

Viaskin Egg and other clinical and pre-clinical programs in order to enable us to focus on the regulatory and clinical advancement of Viaskin Peanut in the United States and the European Union.

In addition to our development programs in food allergies, we have also explored the use of our Viaskin technology for the treatment of inflammatory and autoimmune diseases with high unmet medical need.

Human proof-of-concept trials have been conducted with Viaskin in EoE and as a booster vaccination against Bordetella pertussis, or whooping cough, in healthy adults.

Our other earlier stage research programs include vaccination for respiratory syncytial virus, as well as potential treatments for Crohn’s disease, celiac disease and type I diabetes.

Following receipt of the CRL from the FDA in August 2020, we scaled down our Viaskin Egg and other clinical and pre-clinical programs in order to enable us to focus on the regulatory and clinical advancement of Viaskin Peanut in the United States and the European Union.

Diagnostic Tool Development

In an effort to continue

diversifying our product candidate pipeline, we are also exploring the use of our technology platform in the development of diagnostic tools for food allergies.

In May 2016, we announced our

entry into an exclusive global collaboration with Nestlé

Health Science to develop MAG1C, a ready-to-use and

standardized atopy patch test tool for the diagnosis of CMPA in infants and toddlers.

Under the terms of the exclusive collaboration, we are responsible for leading the development activities of MAG1C up through a

pivotal Phase III clinical program, and if the appropriate regulatory approvals are received, Nestlé

Health Science will support the commercialization

of MAG1C globally.

We are eligible to receive up to 100.0 million in potential development, clinical, regulatory and commercial milestones, inclusive of a non-refundable upfront payment of

10.0 million that we received in July 2016.

In an effort to continue diversifying our product candidate pipeline, we are also exploring the use of our technology platform in the development of diagnostic tools for food allergies.

In May 2016, we announced our entry into an exclusive global collaboration with Nestlé Health Science to develop MAG1C, a ready-to-use and standardized atopy patch test tool for the diagnosis of CMPA in infants and toddlers.

Under the terms of the

exclusive collaboration, we are responsible for leading the development activities of MAG1C up through a pivotal Phase III clinical program, and if the appropriate regulatory approvals are received, Nestlé Health Science will support the commercialization of MAG1C globally.

We are eligible to receive up to €100.0 million in potential development, clinical, regulatory and commercial milestones, inclusive of a non-refundable upfront payment of €10.0 million that we received in July 2016.

We are currently conducting a Phase II clinical trial of MAG1C.

We may explore selective

collaborations with parties who have relevant clinical and commercial expertise in other geographies, including certain European countries, and indications outside of food allergies.

We may explore selective collaborations with parties who have relevant clinical and commercial expertise in other geographies, including certain European countries, and indications outside of food allergies.

Potential Biomarker Applications

We are continuing to

explore other cellular mechanisms modulated by EPIT , such as biomarkers, in collaboration with Mount Sinai Hospital in the United States and Commissariat à

lÉnergie

Atomique et aux Énergies Alternatives, or CEA, in France.

We believe that with improved knowledge about the evolution of immunological biomarkers and epigenetic modulation, we may be able to determine the level of patient response earlier

during treatment, ensure follow-up and measure tolerance maintained once treatment is completed.

At the 2016 EAACI meeting in Vienna, Austria, we presented initial findings from some of these collaborations,

which suggest that proprietary biomarker modeling may be used to help monitor patient responses to Viaskin Peanut.

We are continuing to explore other cellular mechanisms modulated by EPIT™, such as biomarkers, in collaboration with Mount Sinai Hospital in the United States and Commissariat à l’Énergie Atomique et aux Énergies Alternatives, or CEA, in France.

We believe that with improved knowledge about the evolution of immunological biomarkers and epigenetic modulation, we may be able to determine the level of patient response earlier during treatment, ensure follow-up and measure tolerance maintained once treatment is completed.

At the 2016 EAACI meeting in Vienna, Austria, we presented initial findings from some of these collaborations, which suggest that proprietary biomarker modeling may be used to help monitor patient responses to Viaskin Peanut.

Additional research is being performed to further strengthen the results of these early findings.

Manufacturing and Supply

Our Proprietary Viaskin

We have engineered a proprietary manufacturing technology for Viaskin patch, which is designed to comply with the most stringent

pharmaceutical production standards, including those promulgated by the FDA, in order to enable Viaskin to deliver proteins via intact skin.

This novel pharmaceutical process, which was fully developed by us, uses an electrospray to spray

homogeneous, thin, dry protein layers onto the Viaskin patch.

This process sprays a liquid solution of electrically charged proteins onto the patchs backing, which is then turned into a dry solid charged particle, which remains stuck onto the patchs backing.

It deposits very small

and precise quantities of the active substance, devoid of adjuvants.

Our Proprietary Viaskin Technology

We have engineered a proprietary manufacturing technology for Viaskin patch, which is designed to comply with the most stringent pharmaceutical production standards, including those promulgated by the FDA, in order to enable Viaskin to deliver proteins via intact skin.

This novel pharmaceutical process, which was fully developed by us, uses an electrospray to spray homogeneous, thin, dry protein layers onto the Viaskin patch.

This process sprays a liquid solution of electrically charged proteins onto the patch’s backing, which is then turned into dry solid charged layers, which remain stuck onto the patch’s backing.

It deposits very small and precise quantities of the active substance, devoid of adjuvants.

The patch can then be stored at room temperature.

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The principles of the Viaskin electrospray technology are the following:

Constant liquid flows from a capillary and is subjected to a high voltage electric field.

With our electrospray machine, we can transform these electrically charged liquid droplets into dry solid charged

particles, and then drive them along the electric field lines onto the patchs backing.

When the electric field lines are directed toward the grounded Viaskin patch, they force the dry particles to go

directly to and only onto the patch.

A constant flow of liquid in a capillary is subjected to a high voltage electric field.

With our electrospray machine, we can transform these electrically charged liquid droplets into dry solid layers, deposited onto the patch’s backing.

The electric field directs particles precisely toward the Viaskin patch’s backing.

With Viaskin manufacturing technology, we believe we can achieve:

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Viaskin is a Highly Scalable Manufacturing Technology

We currently rely on a contract manufacturer, Sanofi, to manufacture the active pharmaceutical ingredients used in our Viaskin product candidates, such as

peanut protein extract.

We currently rely on a contract manufacturer, Sanofi, to manufacture the active pharmaceutical ingredients used in our Viaskin product candidates, such as peanut protein extract.

Our manufacturing machine then uses an electrospray technology to deposit the active pharmaceutical ingredient onto the Viaskin patch.

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ES GEN4.0 (2017 & 2020)

To be used for commercial products

Scalable to produce more patches annually

We believe our proprietary Viaskin manufacturing technology creates high barriers to entry to our line of business,

particularly in the engineering and manufacturing of our Viaskin product candidates.

We design, develop and build our manufacturing tools, and contract third- party manufacturers to operate it.

We have entered into an agreement with a contract

manufacturer, FAREVA, to manufacture clinical and commercial batches of Viaskin Peanut patches.

To be used for clinical batches and commercial products Scalable to produce more patches annually

We believe our proprietary Viaskin manufacturing technology creates high barriers to entry to our line of business, particularly in the engineering and manufacturing of our Viaskin product candidates.

We have designed, developed, and built our manufacturing tools, and contract third- party manufacturers to operate it.

We have entered into an agreement with a contract manufacturer, FAREVA, to manufacture clinical and commercial batches of Viaskin Peanut patches.

Intellectual Property

Our patent portfolio includes pending patent applications and issued patents in the United States and in foreign countries.

To date, all patents directed at

the Viaskin electrostatic patch, as well as food allergen desensitization methods, have been issued in the major markets, including in particular the United States, Europe, Canada and Australia.

The diagram below represents our categories of patents

or patent applications:

To date, all patents directed at the Viaskin electrostatic patch, as well as food allergen desensitization methods, have been issued in the major markets, including in particular the United States, Europe, Canada and Australia.

These patents and applications generally fall into four broad categories:

patents and patent applications we co-own with AP-HP and the Université

de Paris-Descartes relating to the Viaskin electrostatic patch and its use, half of which may expire as early as 2022;

patents and patent applications which we own relating to our electrospray method of manufacturing the Viaskin

electrostatic patch, which may expire as early as 2029;

patents and patent applications we co-own with AP-HP and the Université

de Paris-Descartes relating to the treatment of peanut allergies using our Viaskin patch technology, which may expire as early as 2028;

a variety of other patent applications that we own or co-own relating,

for example, to prophylactic uses of the Viaskin patch technology and to treatment of other indications using the Viaskin patch technology.

The term of a U.S.

patent may be eligible for patent term extension under the Hatch-Waxman Act to account for at least some of the time the drug or device is

under development and regulatory review.

With regard to a drug or device for which FDA approval is the first permitted marketing of the active ingredient, the Hatch-Waxman Act allows for extension of the term of one U.S.

The extended patent

term cannot exceed the shorter of five years beyond the non-extended expiration of the patent or 14 years from the date of the FDA approval of the drug or device.

Some foreign jurisdictions have analogous

patent term extension provisions that allow for extension of the term of a patent that covers a device approved by the applicable foreign regulatory agency.

In the future, if and when a Viaskin electrostatic patch receives FDA approval, we expect to

apply for a patent term extension on

the patent that we believe will provide the best exclusivity position if extended.

We also has extensive know-how and trade secrets covering part of the

Viaskin patch manufacturing method using electrospray technology

patents and patent applications we co-own with AP-HP and the Université de Paris-Descartes relating to the Viaskin electrostatic patch and its use, half of which may expire as early as 2022;

patents and patent applications which we own relating to our electrospray method of manufacturing the Viaskin electrostatic patch, which may expire as early as 2029;

patents and patent applications we co-own with AP-HP and the Université de Paris-Descartes relating to the treatment of peanut allergies using our Viaskin patch technology, which may expire as early as 2028;

a variety of other patent applications that we own or co-own relating, for example, to prophylactic uses of the Viaskin patch technology and to treatment of other indications using the Viaskin patch technology.

Patent Term Restoration and Marketing Exclusivity

Depending upon the timing, duration, and specifics of the FDA approval of our product candidates, some of our U.S.

patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.

The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product development and the FDA regulatory review process.

However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.

The patent term restoration period is generally one-half the time between the effective date of an IND and the submission date of

a BLA plus the time between the submission date of a BLA and the approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence.

Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent.

PTO, in consultation with the FDA, reviews and

approves the application for any patent term extension or restoration.

In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant BLA.

Some foreign jurisdictions have analogous patent term extension provisions that allow for extension of the term of a patent that covers a device approved by the applicable foreign regulatory agency.

In the future, if a Viaskin patch receives FDA approval, we expect to apply for a patent term extension on the patent that we believe will provide the best exclusivity position if extended.

We also have extensive know-how and trade secrets covering part of the Viaskin patch manufacturing method using electrospray technology.

An abbreviated approval pathway for biological products shown to be similar to, or interchangeable with, an FDA-licensed reference biological product was created by the Biologics Price Competition and Innovation Act of 2009, or BPCIA.

Biosimilarity, which requires that the biological product be highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there be no clinically meaningful differences between the product and the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical trial or trials.

Interchangeability requires that a biological product be biosimilar to the reference product and the product can be expected to produce the same clinical results as the reference product in any given patient and, for products administered multiple times, the product and the reference product may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biological product.

A reference biological product is granted twelve years of exclusivity from the time of first licensure of the product, and the FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure.

“First licensure” typically means the initial date the particular product at issue was licensed in the United States.

This does not include a supplement for the biological product or a subsequent application by the same sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a change that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength, unless that change is a modification to the structure of the biological product and such modification changes its safety, purity, or potency.

Whether a subsequent application, if approved, warrants exclusivity as the “first licensure” of a biological product is determined on a case-by-case basis with data submitted by the sponsor.

Pediatric exclusivity is another type of regulatory market exclusivity in the United States.

Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms.

This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial.

In the European Union, article 14 (11) of the regulation (EC) No.

726/2004 provides that, without prejudice to the law on the protection of industrial and commercial property, medicinal products for human use which have been authorized in accordance with the provisions of this regulation shall benefit from an eight-year period of data protection and a ten-year period of marketing protection, in which connection the latter period shall be extended to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Co-Ownership Agreement

AP-HP and Université

de Paris-Descartes

In December 2008, we entered into an assignment, development and co-ownership agreement with AP-HP and Université

Paris-Descartes, or UPD, by which we agreed to terms of co-ownership with AP-HP and UPD of certain U.S.

foreign patents and patent applications, referred to herein as the shared patents.

AP-HP and Université de Paris-Descartes

In December 2008, we entered into an assignment, development and co-ownership agreement with AP-HP and Université Paris-Descartes, or UPD, by which we agreed to terms of co-ownership with AP-HP and UPD of certain U.S.

and foreign patents and patent applications, referred to herein as the shared patents.

We, and any licensees or sublicensees that we designate, have the exclusive right to commercial uses of the shared patents.

AP-HP and UPD agreed to use the shared patents only for internal research purposes and not to license the shared patents to any third party.

Upon commercialization of any product covered by the shared patents,

which we expect would include our Viaskin product candidates, we will be obligated to pay AP-HP and UPD a percentage of net sales as a royalty.

This royalty is in the low single digits and varies depending on

the particular patent used in the product.

Additionally, if we license any of the shared patents to a third party and a licensee commercializes products covered by such shared patents, we will be obligated to pay

AP-HP and UPD a percentage in the low single digits of the money that we receive from our licensee.

sell any of our product candidates covered by the shared patents within 30 months from the date we first market such product candidates, AP-HP may, upon six months notice and subject to certain

exceptions, convert our exclusive right to the commercial use of the shared patents to a non-exclusive right.

party may terminate the license in the event of another partys substantial breach which remains uncured after six months of receiving written notice of such breach.

The agreement will also terminate in the event we cease operations or are

subject to a dissolution or bankruptcy proceedings.

Absent early termination, the agreement will automatically terminate upon the expiration of the last

shared patent.

Upon commercialization of any product covered by the shared patents, which we expect would include our Viaskin product candidates, we will be obligated to pay AP-HP and UPD a percentage of net sales as a royalty.

This royalty is in the low single digits and varies depending on the particular patent used in the product.

Additionally, if we license any of the shared patents to a third party and a licensee commercializes products covered by such shared patents, we will be obligated to pay AP-HP and UPD a percentage in the low single digits of the money that we receive from our licensee.

If we do not sell any of our product candidates covered by the shared patents within 30 months from the date we first market such product candidates, AP-HP may, upon six months’ notice and subject to certain exceptions, convert our exclusive right to the commercial use of the shared patents to a non-exclusive right.

Any party may terminate the license in the event of another party’s substantial breach which remains uncured after six months of receiving written notice of such breach.

The agreement will also terminate in the event we cease operations or are subject to a dissolution or bankruptcy proceedings.

Absent early termination, the agreement will automatically terminate upon the expiration of the last shared patent.

In the event the agreement is terminated, we would no longer have the exclusive right to commercial use of the shared patents, though we would retain our shared ownership rights.

In addition, our ownership stake in certain jointly

made improvements covered by the shared patents would survive termination of the agreement.

In addition, our ownership stake in certain jointly made improvements covered by the shared patents would survive termination of the agreement.

The longest lived patent rights licensed to us under the agreement are currently expected to expire in 2029.

The biotechnology and pharmaceutical

industries are highly competitive and subject to significant and rapid technological change as researchers learn more about diseases and develop new technologies and treatments.

Significant competitive factors in the pharmaceutical industry include

product efficacy and safety;

The biotechnology and pharmaceutical industries are highly competitive and subject to significant and rapid change as researchers learn more about diseases and develop new technologies and treatments.

Differentiating competitive factors in the pharmaceutical industry include product efficacy and safety;

quality and breadth of an organization’s technology;

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timing and scope of regulatory approvals;

government reimbursement

rates for, and the average selling price of, products;

government reimbursement rates for, and the average selling price of, products;

the availability of raw materials and qualified manufacturing capacity;

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intellectual property and patent rights and their protection;

and sales and

marketing capabilities.

Our competitors may succeed in obtaining FDA or other regulatory approvals for their product candidates more rapidly than we are

able to do, which could place us at a significant competitive disadvantage or deny us marketing exclusivity rights.

and sales and marketing capabilities.

Our competitors may succeed in obtaining FDA or other regulatory approvals for their product candidates more rapidly than we are able to do, which could place us at a significant competitive disadvantage.

Market acceptance of our product candidates will depend on a number of factors, including:

(1) potential advantages over

existing or alternative therapies or tests;

(2) the actual or perceived safety of similar classes of products;

(3) the effectiveness of sales, marketing, and distribution capabilities;

and (4) the scope of any approval provided by the

FDA or foreign regulatory authorities.

Although we believe our product candidates possess attractive attributes, we cannot assure you that our product

candidate will achieve regulatory or market acceptance, or that we will be able to compete effectively in the

biopharmaceutical drug markets.

If our product candidate fail to gain regulatory approvals and acceptance in their intended markets, we may not generate meaningful revenues or achieve

profitability.

There are numerous competitors on the market for the therapeutic treatment of allergies.

Numerous structures, pharmaceutical laboratories,

biotechnology companies, institutions, universities and other research entities are actively involved in the discovery, research, development and marketing of therapeutic responses to treat allergies.

There are competitors in the food allergy space

that have greater resources and experience in terms of clinical development, management, manufacturing, marketing and research than us.

In the case of

food allergies, we are aware of several academic studies that are currently being conducted in major centers and hospitals worldwide.

These studies are evaluating sublingual, subcutaneous, intranasal or other forms of desensitization or products

using synthetic allergens, denatured allergens or combinations of medicines or methods, or medicines using traditional methods such as Chinese herbs.

We are not aware of any pharmaceutical development in conjunction with these academic efforts at

We expect studies combining other methods of immunotherapy, such as OIT, with anti-IgE treatments will

be conducted.

These types of co-administrations may significantly improve the safety of specific immunotherapies administered orally or subcutaneously, and may become significant competitors with our products.

To our knowledge, other pharmaceutical and biotechnology companies are also seeking to develop food allergy treatments, although many are in the

discovery or preclinical stages.

For example, Aimmune Therapeutics, Inc., or Aimmune, received FDA approval of its OIT product candidate, Palforzia, in peanut allergic patients in January 2020.

Palforzia uses a formulation of peanut flour for oral

administration intended for oral desensitization to peanut.

We are also aware of other companies developing OIT product candidates, as well as other companies that are working on recombinant peanut proteins capable of initiating an attenuated immune

response of using subcutaneous administration.

In February 2020, Aimmune announced the licensing of exclusive worldwide rights to Xencors XmAb ®

7195 to be developed in combination with

Aimmune also announced a clinical collaboration with Regeneron Pharmaceuticals, Inc.

and Sanofi to study Palforzia treatment with dupilumab in peanut allergic patients, and commenced a Phase II clinical trial in October 2018 under this

collaboration.

Regeneron and Sanofi are currently recruiting patients in a Phase II study of dupilumab as a monotherapy in the treatment of peanut allergic patients.

Nestlé

S.A., with whom we have an existing license and collaboration

agreement, acquired Aimmune in October 2020.

Aimmune will continue to function as a stand-alone business unit that will manage all of Nestlés global pharmaceutical business.

In August 2018, Genentech, Inc.

and Novartis Pharmaceuticals

Corporation announced that the FDA granted breakthrough designation for Xolair (omalizumab) for the prevention of severe allergic reactions following accidental exposure to one or more foods in people with allergies.

In July 2019, the National

Institute of Allergy and Infectious Diseases, or NIAID, started a Phase III clinical trial studying omalizumab as monotherapy and as adjunct therapy to multi-allergen OIT in multiple food allergies.

(1) potential advantages over existing or

alternative therapies or tests;

(2) the actual or perceived safety and efficacy of similar classes of products;

(3) the effectiveness of selling, marketing, and distribution capabilities;

and (4) the scope of any approval provided by the FDA or foreign regulatory authorities.

Although we believe our product candidates possess attractive attributes, we cannot assure you that our product candidate will achieve regulatory or market acceptance, or that we will be able to compete effectively in the biopharmaceutical drug markets.

If our product candidates fail to gain regulatory approvals and acceptance in their intended markets, we may not generate meaningful revenues or achieve profitability.

Numerous pharmaceutical and biotechnology companies, universities and other research entities are actively involved in the discovery, development and commercialization of therapeutic options to treat allergies.

There are competitors in the food allergy space that have greater resources and experience than we do.

We are aware of several food allergy studies and pharmaceutical developmental efforts connected with such studies that are currently being conducted in major medical centers and hospitals worldwide.

These studies are evaluating forms of allergen desensitization treatments such as oral, or OIT;

sublingual, or SLIT;

subcutaneous, or SCIT;

or intranasal immunotherapy, synthetic or denatured allergens, medicinal herbs, or combinations of medicines or methods.

Studies combining methods of allergen immunotherapy, such as OIT, with monoclonal antibodies also are being conducted currently.

These types of co-administrations may significantly improve the safety of specific allergen immunotherapies administered orally or subcutaneously.

In addition, the use of monoclonal antibodies as monotherapy for certain food allergies, including peanut allergy, is being studied in clinical trials.

Monoclonal antibodies, used alone or in combination with allergen immunotherapy, may become significant competitors to our products.

There is one FDA- and EMA-approved treatment for peanut allergy:

Palforzia, a formulation of peanut flour developed by Aimmune Therapeutics, Inc., or Aimmune.

Nestlé S.A., with whom we have an existing license and collaboration agreement, acquired Aimmune in October 2020.

Aimmune continues to function as a stand- alone business unit that will manage all of Nestlé’s global pharmaceutical business.

Government Regulation

Government authorities in the

United States at the federal, state and local level and in other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion,

advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug and biological products, or biologics, such as our product candidates.

Generally, before a new drug or biologic can be marketed, considerable

data demonstrating its quality, safety and efficacy must be obtained, organized into a format specific to each regulatory authority, submitted for review and approved by the regulatory authority.

Government authorities in the United States at the federal, state and local level and in other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug and biological products, or biologics, such as our product candidates.

Generally, before a new drug or biologic can be marketed, considerable data demonstrating its quality, safety and efficacy must be obtained, organized into a format specific to each regulatory authority, submitted for review and approved by the regulatory authority.

Biological Product Development

In the United

States, the FDA regulates biologics under the Federal Food, Drug, and Cosmetic Act, or FDCA, and the Public Health Service Act, or PHSA, and their implementing regulations.

Biologics are also subject to

other federal, state and local statutes and regulations.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes

and regulations require the expenditure of substantial time and financial resources.

In the United States, the FDA regulates biologics under the Federal Food, Drug, and Cosmetic Act, or FDCA, and the Public Health Service Act, or PHSA, and their implementing regulations.

Biologics are also subject to other federal, state and local statutes and regulations.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

Failure to comply with the applicable U.S.

requirements at any time during the product development process, approval process or after approval, may subject an

applicant to administrative or judicial sanctions.

These sanctions could include, among other actions, the FDAs refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters, product

recalls or withdrawals from the market, product seizures, total or partial suspension of production or distribution injunctions, fines, refusals of government

contracts, restitution, disgorgement, or civil or criminal penalties.

requirements at any time during the product development process, approval process or after approval, may subject an applicant to administrative or judicial sanctions.

These sanctions could include, among other actions, the FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, untitled or warning letters, product recalls or withdrawals from the market, product seizures, total or partial suspension of production or distribution injunctions, fines, refusals of government contracts, restitution, disgorgement, or civil or criminal penalties.

Any agency or judicial enforcement action could have a material adverse effect on us.

Our product candidates must be approved by the FDA through the Biologics License Application, or BLA, process before they may be legally marketed in the

United States.

Our product candidates must be approved by the FDA through the Biologics License Application, or BLA, process before they may be legally marketed in the United States.

The process required by the FDA before a biologic may be marketed in the United States generally involves the following:

completion of extensive nonclinical, sometimes referred to as

pre-clinical laboratory tests, pre-clinical animal studies and formulation studies in accordance with applicable regulations, including the FDAs Good Laboratory

Practice, or GLP, regulations;

completion of extensive nonclinical, sometimes referred to as pre-clinical laboratory tests, pre-clinical animal studies and formulation studies in accordance with applicable regulations, including the FDA’s Good Laboratory Practice, or GLP, regulations;

submission to the FDA of an IND, which must become effective before human clinical trials may begin;

performance of adequate and well-controlled human clinical trials in accordance with applicable IND and other

clinical trial-related regulations, sometimes referred to as good clinical practices, or GCPs, to establish the safety and efficacy of the proposed product candidate for its proposed indication;

performance of adequate and well-controlled human clinical trials in accordance with applicable IND and other clinical trial-related regulations, sometimes referred to as good clinical practices, or GCPs, to establish the safety and efficacy of the proposed product candidate for its proposed indication;

submission to the FDA of a BLA;

satisfactory completion of an FDA pre-approval inspection of the

manufacturing facility or facilities where the product is produced to assess compliance with the FDAs current good manufacturing practice, or cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the

products identity, strength, quality, purity and potency;

potential FDA audit of the pre-clinical and/or clinical trial sites that

generated the data in support of the BLA;

satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the product is produced to assess compliance with the FDA’s current good manufacturing practice, or cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality, purity and potency;

potential FDA audit of the pre-clinical and/or clinical trial sites that generated the data in support of the BLA;

FDA review and approval of the BLA prior to any commercial marketing or sale of the product in the United States.

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pre-clinical and clinical.

The pre-clinical development stage generally involves laboratory evaluations of drug chemistry, formulation and stability, as well as studies

to evaluate toxicity in animals, which support subsequent clinical testing.

of the pre-clinical

studies must comply with federal regulations, including GLPs.

The sponsor must submit the results of the pre-clinical studies, together with manufacturing information, analytical data, any available clinical

data or literature and a proposed clinical protocol, to the FDA as part of the IND.

The pre-clinical development stage generally involves laboratory evaluations of drug chemistry, formulation and stability, as well as studies to evaluate toxicity in animals, which support subsequent clinical testing.

The conduct of the pre-clinical studies must comply with federal regulations, including GLPs.

The sponsor must submit the results of the pre-clinical studies, together with manufacturing information, analytical data, any available clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND.

An IND is a request for authorization from the FDA to administer an investigational drug product to humans.

The central focus of an IND submission is on the general

investigational plan and the protocol(s) for human trials.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical trials and places the IND on clinical

hold within that 30-day time period.

The central focus of an IND submission is on the general investigational plan and the protocol(s) for human trials.

The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions regarding the proposed clinical trials and places the IND on clinical hold within that 30-day time period.

In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.

The FDA may also impose clinical holds on a product

candidate at any time before or during clinical trials due to safety concerns or non-compliance.

Accordingly, we cannot be sure that submission of an IND will result in the FDA allowing clinical trials to

begin, or that, once begun, issues will not arise that could cause the trial to be suspended or terminated.

The clinical stage of development involves

the administration of the product candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial

sponsors control, in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.

trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety and assess efficacy.

protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.

Further, each clinical trial must be reviewed and approved by an independent institutional review board, or IRB, at or servicing each

institution at which the clinical trial will be conducted.

An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized

and are reasonable in relation to anticipated benefits.

The FDA may also impose clinical holds on a product candidate at any time before or during clinical trials due to safety concerns or non-compliance.

Accordingly, we cannot be sure that submission of an IND will result in the FDA allowing clinical trials to begin, or that, once begun, issues will not arise that could cause the trial to be suspended or terminated.

The clinical stage of development involves the administration of the product candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria, and the parameters to be used to monitor subject safety and assess efficacy.

Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.

Further, each clinical trial must be reviewed and approved by an independent institutional review board, or IRB, at or servicing each institution at which the clinical trial will be conducted.

An IRB is charged with protecting the welfare and rights of trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in relation to anticipated benefits.

The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative and must monitor the clinical trial until completed.

There are also requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries.

Sponsors of certain clinical trials of FDA-regulated products,

including biologics, are required to register and disclose specified clinical trial information, which is publicly available at www.clinicaltrials.gov.

Information related to the product, patient population, phase of investigation, study sites and

investigators, and other aspects of the clinical trial is then made public as part of the registration.

There are also requirements governing the reporting of ongoing clinical

trials and completed clinical trial results to public registries.

Sponsors of certain clinical trials of FDA-regulated products, including biologics, are required to register and disclose specified clinical trial information, which is publicly available at www.clinicaltrials.gov.

Information related to the product, patient population, phase of investigation, study sites and investigators, and other aspects of the clinical trial is then made public as part of the registration.

Sponsors are also obligated to disclose the results of their clinical trials after completion.

Clinical trials are generally conducted in three sequential phases that may overlap, known as Phase I, Phase II and Phase III clinical trials.

clinical trials generally involve a small number of healthy volunteers who are initially exposed to a single dose and then multiple doses of the product candidate.

The primary purpose of these clinical trials is to assess the metabolism,

pharmacologic action, side effect tolerability and safety of the product candidate and, if possible, to gain early evidence on effectiveness.

Phase II clinical trials typically involve studies in disease-affected patients to determine the dose

required to produce the desired benefits.

At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, as well as identification of possible adverse effects and safety risks and preliminary evaluation of

of the product for its intended use, its safety in use, and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product approval.

Phase III clinical trials may include comparisons with placebo and/or

other comparator treatments.

Phase I clinical trials generally involve a small number of healthy volunteers who are initially exposed to a single dose and then multiple doses of the product candidate.

The primary purpose of these clinical trials is to assess the metabolism, pharmacologic action, side effect tolerability and safety of the product candidate and, if possible, to gain early evidence on effectiveness.

Phase II clinical trials typically involve studies in disease-affected patients to determine the dose required to produce the desired benefits.

At the same time, safety and further pharmacokinetic and pharmacodynamic information is collected, as well as identification of possible adverse effects and safety risks and preliminary evaluation of efficacy.

Phase III clinical trials generally involve large numbers of patients at multiple sites, in multiple countries (from several hundred to several thousand subjects) and are designed to provide the data necessary to demonstrate the efficacy of the product for its intended use, its safety in use, and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product approval.

Phase III clinical trials may include comparisons with placebo and/or other comparator treatments.

The duration of treatment is often extended to mimic the actual use of a product during marketing.

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Post-approval trials, sometimes referred to as Phase IV clinical trials, may be conducted after initial marketing approval.

These trials are used to gain

additional experience from the treatment of patients in the intended

therapeutic indication.

In certain instances, FDA may condition approval of a BLA on

the sponsors agreement to conduct additional clinical trials to further assess the biologics safety and effectiveness after BLA approval.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and written IND safety reports must be submitted

to the FDA and the investigators for serious and unexpected

suspected adverse, findings from other studies suggesting a significant risk to humans exposed

to the drug, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important rate increase of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

I, Phase II and Phase III clinical trials may not be completed successfully within any specified period, if at all.

The FDA, the IRB, or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that

the research subjects or patients are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the

IRBs requirements or if the drug has been associated with unexpected serious harm to patients.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a

data safety monitoring board or committee.

These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication.

In certain instances, FDA may condition approval of a BLA on the sponsor’s agreement to conduct additional clinical trials to further assess the biologic’s safety and effectiveness after BLA approval.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators for serious and unexpected suspected adverse, findings from other studies suggesting a significant risk to humans exposed to the drug, findings from animal or in vitro

testing suggesting a significant risk to humans, and any clinically important rate increase of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

Phase I, Phase II and Phase III clinical trials may not be completed successfully within any specified period, if at all.

The FDA, the IRB, or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee.

This group provides authorization for whether or not a trial may move forward at designated intervals based on access to certain data from the trial.

We may also suspend or terminate a clinical trial based

on evolving business objectives and/or

competitive climate.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical

characteristics of the product candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches

of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final product.

Additionally, appropriate packaging must be selected and tested and stability studies must be

conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

We may also suspend or terminate a clinical trial based on evolving business objectives and/or competitive climate.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final product.

Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

BLA and FDA Review Process

Following trial completion, trial data is analyzed to assess safety and efficacy.

The results of pre-clinical

studies and clinical trials are then submitted to the FDA as part of a BLA, along with proposed labeling for the product and information about the manufacturing process and facilities that will be used to ensure product quality, results of

analytical testing conducted on the chemistry of the product candidate, and other relevant information.

The BLA is a request for approval to market the biologic for one or more specified indications and must contain proof of safety, purity, potency

and efficacy, which is demonstrated by extensive pre-clinical and clinical testing.

The application includes both negative or ambiguous results of pre-clinical and

clinical trials and positive findings.

The results of pre-clinical studies and clinical trials are then submitted to the FDA as part of a BLA, along with proposed labeling for the product and information about the manufacturing process and facilities that will be used to ensure product quality, results of analytical testing conducted on the chemistry of the product candidate, and other relevant information.

The BLA is a request for approval to market the biologic for one or more specified indications and must contain proof of safety, purity, potency and efficacy, which is demonstrated by extensive pre-clinical and clinical testing.

The application includes both negative or ambiguous results of pre-clinical and clinical trials and positive findings.

Data may come from company-sponsored clinical trials intended to test the safety and efficacy of a use of a product, or from a number of alternative sources, including studies initiated by investigators.

support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of the FDA.

FDA approval of a BLA must be obtained before a biologic

may be marketed in the United States.

Under the Prescription Drug User Fee Act, or PDUFA, as amended, each BLA must be accompanied by a significant user

fee, which is adjusted on an annual basis.

To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and efficacy of the investigational product to the satisfaction of the FDA.

FDA approval of a BLA must be obtained before a biologic may be marketed in the United States.

Under the Prescription Drug User Fee Act, or PDUFA, as amended, each BLA must be accompanied by a significant user fee, which is adjusted on an annual basis.

PDUFA also imposes an annual program fee for approved drugs.

Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a

small business.

Once a BLA has been accepted for filing, which occurs, if at all, sixty days after the BLAs submission, the FDAs goal is to

review BLAs within ten months of the filing date for standard review or six months of the filing date for priority review, if the application is for a product intended for a serious or life-threatening condition and the product, if approved, would

provide a significant improvement in safety or effectiveness.

Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed by a small business.

Once a BLA has been accepted for filing, which occurs, if at all, sixty days after the BLA’s submission, the FDA’s goal is to review BLAs within ten months of the filing date for standard review or six months of the filing date for priority review, if the application is for a product intended for a serious or life-threatening condition and the product, if approved, would provide a significant improvement in safety or effectiveness.

The review process is often significantly extended by FDA requests for additional information or clarification.

If not accepted for filing, the sponsor must resubmit the BLA and begin the

FDAs review process again, including the initial sixty-day review to determine if the application is sufficiently complete to permit substantive review.

After the BLA submission is accepted for filing, the FDA reviews the BLA to determine, among other things, whether the proposed product candidate is safe and

effective for its intended use, and whether the product candidate is being manufactured in accordance with cGMP to assure and preserve the product candidates identity, strength, quality, purity and potency.

The FDA may refer applications for

novel drug product candidates or drug product candidates which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as

to whether the application should be approved and under what conditions.

If not accepted for filing, the sponsor must resubmit the BLA and begin the FDA’s review process again, including the initial sixty-day

review to determine if the application is sufficiently complete to permit substantive review.

After the BLA submission is accepted for filing, the FDA reviews the BLA to determine, among other things, whether the proposed product candidate is safe and effective for its intended use, and whether the product candidate is being manufactured in accordance with cGMP to assure and preserve the product candidate’s identity, strength, quality, purity and potency.

The FDA may refer applications for novel drug product candidates or drug product candidates which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

The FDA will likely re-analyze the clinical trial data, which could result in extensive discussions between the FDA and us during the review process.

The review and evaluation of a BLA by the FDA is extensive and time consuming and may

take longer than originally planned to complete, and we may not receive a timely approval, if at all.

The review and evaluation of a BLA by the FDA is extensive and time consuming and may take longer than originally planned to complete, and we may not receive a timely approval, if at all.

Before approving a BLA, the FDA will conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMPs.

The FDA will not approve the product unless it

determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

addition, before approving a BLA, the FDA may also audit data from clinical trials to ensure compliance with GCP requirements.

After the FDA evaluates the application, manufacturing process and manufacturing facilities, it may issue an approval

letter or a Complete Response Letter.

The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

In addition, before approving a BLA, the FDA may also audit data from clinical trials to ensure compliance with GCP requirements.

After the FDA evaluates the application, manufacturing process and manufacturing facilities, it may issue an approval letter or a Complete Response Letter.

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

A Complete Response Letter indicates that the review cycle of the application is

complete and the application will not be approved in its present form.

A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form.

A Complete Response Letter usually describes all of the specific deficiencies in the BLA identified by the FDA.

The Complete Response Letter may require additional clinical data

and/or an additional pivotal Phase III clinical trial(s), and/or other significant and time-consuming requirements related to clinical trials, pre-clinical studies or manufacturing.

If a Complete Response

Letter is issued, the applicant may either resubmit the BLA, addressing all of the deficiencies identified in the letter, or withdraw the application.

Even if such data and information is submitted, the FDA may ultimately decide that the BLA does

not satisfy the criteria for approval.

The Complete Response Letter may require additional clinical data and/or an additional pivotal Phase III clinical

trial(s), and/or other significant and time-consuming requirements related to clinical trials, pre-clinical studies or manufacturing.

If a Complete Response Letter is issued, the applicant may either resubmit the BLA, addressing all of the deficiencies identified in the letter, or withdraw the application.

Even if such data and information is submitted, the FDA may ultimately decide that the BLA does not satisfy the criteria for approval.

Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.

There is no assurance that the FDA will ultimately approve a product for marketing in the United States and we may encounter significant difficulties or costs

during the review process.

If a product receives marketing

approval, the approval may be significantly limited to specific populations, severities of

allergies, and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product.

Further, the FDA may require that certain contraindications, warnings or precautions be included in the product

labeling or may condition the approval of the BLA on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct post-market testing or clinical trials and surveillance to monitor the

effects of approved products.

For example, the FDA may require Phase IV testing which involves clinical trials designed to further assess the products safety and effectiveness and may require testing and surveillance programs to monitor the

safety of approved products that have been commercialized.

There is no assurance that the FDA will ultimately approve a product for marketing in the United States and we may encounter significant difficulties or costs during the review process.

If a product receives marketing approval, the approval may be significantly limited to specific populations, severities of allergies, and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product.

Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling or may condition the approval of the BLA on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct post-market testing or clinical trials and surveillance to monitor the effects of approved products.

For example, the FDA may require Phase IV testing which involves clinical trials designed to further assess the product’s safety and effectiveness and may require testing and surveillance programs to monitor the safety of approved products that have been commercialized.

The FDA may also place other conditions on approvals including the requirement for a Risk Evaluation and Mitigation Strategy, or REMS, to assure the safe use of the product.

concludes a REMS is needed, the sponsor of the BLA must submit a proposed REMS.

If the FDA concludes a REMS is needed, the sponsor of the BLA must submit a proposed REMS.

The FDA will not approve the BLA without an approved REMS, if required.

A REMS could include medication guides, physician communication plans, or elements to assure safe

use, such as restricted distribution methods, patient registries and other risk minimization tools.

A REMS could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

Any of these limitations on approval or marketing could restrict the commercial promotion, distribution, prescription or dispensing of products.

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Review and Approval of Combination Products in the United States

Certain products may be comprised of components that would normally be regulated under different types of regulatory authorities, and frequently by different

centers at the FDA.

Certain products may be comprised of components that would normally be regulated under different types of regulatory authorities, and frequently by different centers at the FDA.

These products are known as combination products.

Specifically, under regulations issued by the FDA, a combination product may be:

a product comprised of two or more regulated components that are physically, chemically, or otherwise combined or

mixed and produced as a single entity;

two or more separate products packaged together in a single package or as a unit and comprised of drug and device

a drug, device, or biological product packaged separately that according to its investigational plan or proposed

labeling is intended for use only with an approved individually specified drug, device or biological where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the

approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose;

any investigational drug, device, or biological packaged separately that according to its proposed labeling is

for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

Our Viaskin product candidates are combination products comprising a

device for delivery of a biologic.

a product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity;

two or more separate products packaged together in a single package or as a unit and comprised of drug and device products;

a drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device or biological where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose;

any investigational drug, device, or biological packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

Our Viaskin product candidates are combination products comprising a device for delivery of a biologic.

Under the FDCA, the FDA is charged with assigning a center with primary jurisdiction, or a lead center, for review of a combination product.

That determination is based on the primary mode of action of

the combination product, which means the mode of action expected to make the greatest contribution to the overall intended therapeutic effects.

Thus, if the primary mode of action of a device-biologic combination product is attributable to the

biologic product, that is, if it acts by means of a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, the FDA center responsible for premarket review of the biologic

product would have primary jurisdiction for the combination product.

That determination is based on the “primary mode of action” of the combination product, which means the mode of action expected to make the greatest contribution to the overall intended therapeutic effects.

Thus, if the primary mode of action of a device-biologic combination product is attributable to the biologic product, that is, if it acts by means of a virus, therapeutic serum,

toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, the FDA center responsible for premarket review of the biologic product would have primary jurisdiction for the combination product.

Expedited Development and Review Programs

The FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs and biological products that meet certain

Specifically, new drugs and biological products are eligible for fast track designation if they are intended to treat a serious or life-threatening condition and nonclinical or

clinical data demonstrate the potential to address an unmet medical need.

Fast track designation applies to the combination of the product and the specific

indication for which it is being studied.

The FDA has a fast track program that is intended to expedite or facilitate the process for reviewing new drugs and biological products that meet certain criteria.

Specifically, new drugs and biological products are eligible for fast track designation if they are intended to treat a serious or life-threatening condition and nonclinical or clinical data demonstrate the potential to address an unmet medical need.

Fast track designation applies to the combination of the product and the specific indication for which it is being studied.

The sponsor of a new drug or biologic may request the FDA to designate the drug or biologic as a fast track product concurrently with the submission of an IND or at any time before a pre-NDA meeting, and the FDA must determine if the product qualifies for fast track designation within 60 days of receipt of the sponsor’s request.

Unique to a fast track product, the FDA may consider for

review sections of the marketing application on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the

application and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application.

Any product submitted to the FDA for marketing, including under a fast track program, may be eligible for other types of FDA programs intended to expedite

development and review, such as priority review and accelerated approval.

Any product is eligible for priority review, or review within a six-month timeframe from the date a complete BLA is accepted for

filing, if it treats a serious condition and has the potential to provide a significant improvement in safety or effectiveness.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug or biological

product designated for priority review in an effort to facilitate the review.

Unique to a fast track product, the FDA may consider for review sections of the marketing application on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application.

Any product submitted to the FDA for marketing, including under a fast track program, may be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

Any product is eligible for priority review, or review within a six-month timeframe from the date a complete BLA is accepted for filing, if it treats a serious condition and has the potential to provide a significant improvement in safety or effectiveness.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug or biological product designated for priority review in an effort to facilitate the review.

Additionally, a product may be eligible for accelerated approval.

biological products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval, which means that they may be

approved on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint

other than survival or irreversible morbidity.

Drug or biological products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval, which means that they may be approved on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity.

As a condition of approval, the FDA may require that a sponsor of a drug or biological product receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

FDA concludes that a drug shown to be effective can be safely used only if distribution or use is restricted, it will require such post-marketing restrictions as it deems necessary to assure safe use of the drug, such as:

If the FDA concludes that a drug shown to be effective can be safely used only if distribution or use is restricted, it will require such post-marketing restrictions as it deems necessary to assure safe use of the drug, such as:

distribution restricted to certain facilities or physicians with special training or experience;

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The limitations imposed would be commensurate with the specific safety concerns presented by the product.

In addition, the FDA currently requires as a

condition for accelerated approval pre-approval of promotional

materials, which could adversely impact the timing of the commercial launch of the product.

Fast track designation, priority review and accelerated approval do not change the standards for

approval but may expedite the development or approval process.

In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

Fast track designation, priority review and accelerated approval do not change the standards for approval but may expedite the development or approval process.

Breakthrough Designation

The Food and Drug Administration Safety and Innovation Act, or FDASIA, amended the FDCA to require the FDA to expedite the development and review of a

breakthrough therapy.

A product can be designated as a breakthrough therapy if it is intended to treat a serious or life-threatening condition and preliminary clinical evidence indicates that it may demonstrate substantial improvement over existing

therapies on one or more clinically significant endpoints.

A sponsor may request that a product candidate be designated as a breakthrough therapy concurrently with the submission of an IND or any time before an end-of-Phase-II meeting, and the FDA must determine if the product candidate qualifies for breakthrough therapy designation within 60 days of receipt of the

sponsors request.

If so designated, the FDA shall act to expedite the development and review of the products marketing application, including by meeting with the sponsor throughout the products development, providing timely advice

to the sponsor to ensure that the development program to gather pre-clinical and clinical data is as efficient as practicable, involving senior managers and experienced review staff in a cross-disciplinary

review, assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor, and taking steps to ensure that

the design of the clinical trials is as efficient as practicable.

The Food and Drug Administration Safety and Innovation Act, or FDASIA, amended the FDCA to require the FDA to expedite the development and review of a breakthrough therapy.

A product can be designated as a breakthrough therapy if it is intended to treat a serious or life-threatening condition and preliminary clinical

evidence indicates that it may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

If so designated, the FDA shall act to expedite the development and review of the product’s marketing application, including by meeting with the sponsor throughout the product’s development, providing timely advice to the sponsor to ensure that the development program to gather pre-clinical and clinical data is as efficient as practicable, involving senior managers and experienced review staff in a cross-disciplinary review, assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor, and taking steps to ensure that the design of the clinical trials is as efficient as practicable.

Pediatric Trials

Under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA must contain data to assess the safety and efficacy of the product for the

claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

FDASIA requires that a sponsor who is planning to submit a marketing

application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan, or PSP, within sixty days of an end-of-Phase II meeting or as may be agreed between the sponsor and FDA.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to

conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial

waiver of the requirement to provide data from pediatric studies along with supporting information.

Under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA must contain data to assess the safety and efficacy of the product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

FDASIA requires that a sponsor who is planning to submit a marketing application for a drug or biological product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan, or PSP, within sixty days of an end-of-Phase II meeting or as may be agreed between the sponsor and FDA.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

FDA and the sponsor must reach agreement on the PSP.

A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the

pediatric plan need to

be considered based on data collected from nonclinical studies, early phase clinical trials, and/or other clinical

development programs.

A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from nonclinical studies, early phase clinical trials, and/or other clinical development programs.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of data or full or partial waivers.

Post-Marketing Requirements

Following approval of a

new product, a manufacturer and the approved product are subject to continuing regulation by the FDA, including, among other things, monitoring and recordkeeping activities, reporting to the

applicable regulatory authorities of adverse experiences with the product, providing the regulatory authorities with updated safety and efficacy information,

product sampling and distribution requirements, and complying with promotion and advertising requirements, which include, among others, standards for direct-to-consumer

advertising, restrictions on promoting products for uses or in patient populations that are not described in the products approved labeling, also known as off-label use, limitations on industry-sponsored

scientific and educational activities, and requirements for promotional activities involving the internet.

Although physicians may prescribe legally available drugs and biologics for off-label uses,

manufacturers may not market or promote such off-label uses.

Modifications or enhancements to the product or its labeling or changes of the site of manufacture are often subject to the approval of the FDA and

other regulators, which may or may not be received

or may result in a lengthy review process.

Following approval of a new product, a manufacturer and the approved product are subject to continuing regulation by the FDA, including, among other things, monitoring and recordkeeping activities, reporting to the applicable regulatory authorities of adverse experiences with the product, providing the regulatory authorities with updated safety and efficacy information, product sampling and distribution requirements, and complying with promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting products for uses or in patient populations that are not described in the product’s approved labeling, also known as off-label use, limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

Although physicians may prescribe legally available drugs and biologics for off-label uses, manufacturers may not market or promote such off-label uses.

Modifications or enhancements to the product or its labeling or changes of the site of manufacture are often subject to the approval of the FDA and other regulators, which may or may not be received or may result in a lengthy review process.

Prescription drug promotional materials must be submitted to the FDA in conjunction with their first use.

Any distribution of prescription drug products

and pharmaceutical samples must comply with the U.S.

Any distribution of prescription drug products and pharmaceutical samples must comply with the U.S.

Prescription Drug Marketing Act, or the PDMA, a part of the FDCA.

In the United States, once a

product is approved, its manufacture is subject to comprehensive and continuing regulation by the FDA.

In the United States, once a product is approved, its manufacture is subject to comprehensive and continuing regulation by the FDA.

The FDA regulations require that products be manufactured in specific approved facilities and in accordance with cGMP.

Moreover, the constituent

parts of a combination product retain their regulatory status, for example, as a biologic or device, and as such, we may be subject to additional requirements in the Quality System Regulation, or QSR, applicable to medical devices, such as design

controls, purchasing controls, and corrective and preventive action.

Moreover, the constituent parts of a combination product retain their regulatory status, for example, as a biologic or device, and as such, we may be subject to additional requirements in the Quality System Regulation, or QSR, applicable to medical devices, such as design controls, purchasing

controls, and corrective and preventive action.

We rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of our products in accordance with cGMP regulations.

regulations require, among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

Manufacturers and other

entities involved in the manufacture and distribution of approved products are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state

agencies for compliance with cGMP and other laws.

cGMP regulations require, among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

Manufacturers and other entities involved in the manufacture and distribution of approved products are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

These regulations also impose certain

organizational, procedural and documentation requirements with respect to manufacturing and quality assurance activities.

BLA holders using contract manufacturers, laboratories or packagers are responsible for the selection and monitoring of

qualified firms, and, in certain circumstances, qualified suppliers to these firms.

These firms and, where applicable, their suppliers are subject to inspections by the FDA at any time, and the discovery of violative conditions, including failure to

conform to cGMP, could result in enforcement actions that interrupt the operation of any such facilities or the ability to distribute products manufactured, processed or tested by them.

Discovery of problems with a product after approval may result

in restrictions on a product, manufacturer, or holder of an approved BLA, including, among other things, recall or withdrawal of the product from the market.

The FDA also may require post-approval testing, sometimes referred to as Phase IV testing, REMS and post-marketing surveillance to monitor the effects of an

approved product or place conditions on an approval that could restrict the distribution or use of the product.

Discovery of previously unknown problems with a product or the failure to comply with applicable FDA requirements can have negative

consequences, including adverse publicity, judicial or administrative enforcement, warning letters from the FDA, mandated corrective advertising or communications with doctors, and civil or criminal penalties, among others.

Newly discovered or

developed safety or effectiveness data may require changes to a products approved labeling, including the addition of new warnings and contraindications, and also may require the implementation of other risk management measures.

government requirements, including those resulting from new legislation, may be established, or the FDAs policies may change, which could delay or prevent regulatory approval of our products under development.

These regulations also impose certain organizational, procedural and documentation requirements with respect to manufacturing and quality assurance activities.

BLA holders using contract manufacturers, laboratories or packagers are responsible for the selection and monitoring of qualified firms, and, in certain circumstances, qualified suppliers to these firms.

These firms and, where applicable, their suppliers are subject to inspections by the FDA at any time, and the discovery of violative conditions, including failure to conform to cGMP, could result in enforcement actions that interrupt the operation of any such facilities or the ability to distribute products manufactured, processed or tested by them.

Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved BLA, including, among other things, recall or withdrawal of the product from the market.

The FDA also may require post-approval testing, sometimes referred to as Phase IV testing, REMS and post- marketing surveillance to monitor the effects of an approved product or place conditions on an approval that could restrict the distribution or use of the product.

Discovery of previously unknown problems with a product or the failure to comply with applicable FDA requirements can have negative consequences, including adverse publicity, judicial or administrative enforcement, warning letters from the FDA, mandated corrective advertising or communications with doctors, and civil or criminal penalties, among others.

Newly discovered or developed safety or effectiveness data may require changes to a product’s approved labeling, including the addition of new warnings and contraindications, and also may require the implementation of other risk management measures.

Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

Other Regulatory Matters

Manufacturing, sales, promotion

and other activities following product approval are also subject to regulation by numerous regulatory authorities in addition to the FDA, including, CMS, other divisions of the Department of

Health and Human Services, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational

Safety & Health Administration, the Environmental Protection Agency and state and local governments.

In the United States, sales, marketing and scientific/educational programs, among other activities, must also comply with state and federal

fraud and abuse laws, data privacy and security laws, transparency laws, and pricing and reimbursement requirements in connection with governmental payor programs, among others.

Manufacturing, sales, promotion and other activities following product approval are also subject to regulation by numerous regulatory authorities in addition to the FDA, including the Centers for Medicare & Medicaid Services, or CMS, other divisions of the Department of Health and Human Services, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments.

In the United States, sales, marketing and scientific/educational programs, among other activities, must also comply with state and federal fraud and abuse laws, data privacy and security laws, transparency laws, and pricing and reimbursement requirements in connection with governmental payor programs, among others.

The handling of any controlled substances must comply with the U.S.

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Poison Prevention Packaging Act.

Manufacturing, sales, promotion and other activities are

also potentially subject to federal and state consumer protection and unfair competition laws.

The distribution of pharmaceutical products is subject to additional requirements and regulations, including

extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

to comply with regulatory requirements subjects firms to possible legal or regulatory action.

Depending on the circumstances, failure to meet applicable regulatory requirements can result in civil, criminal and administrative penalties, damages,

fines, disgorgement, injunctions, recall or seizure of products, total or partial suspension of production, denial or withdrawal of product approvals, the exclusion from participation in federal and state healthcare programs or refusal to allow a

firm to enter into supply contracts, including government contracts, integrity obligations and individual imprisonment.

In addition, even if a firm complies with FDA and other requirements, new information regarding the safety or efficacy of a

product could lead the FDA to modify or withdraw product approval.

Manufacturing, sales, promotion and other activities are also potentially subject to federal and state consumer protection and unfair competition laws.

The distribution of pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

The failure to comply with regulatory requirements subjects firms to possible legal or regulatory action.

Depending on the circumstances, failure to meet applicable regulatory requirements can result in civil, criminal and administrative penalties, damages, fines, disgorgement, injunctions, recall or seizure of products, total or

partial suspension of production, denial or withdrawal of product approvals, the exclusion from participation in federal and state healthcare programs or refusal to allow a firm to enter into supply contracts, including government contracts, integrity obligations and individual imprisonment.

In addition, even if a firm complies with FDA and other requirements, new information regarding the safety or efficacy of a product could lead the FDA to modify or withdraw product approval.

Prohibitions or restrictions on sales or withdrawal of future products marketed by us could materially affect our business in an adverse way.

Changes in regulations, statutes or the

interpretation of existing regulations could impact our business in the future by requiring, for example:

Changes in regulations, statutes or the interpretation of existing regulations could impact our business in the future by requiring, for example:

(i) changes to our manufacturing arrangements;

(ii) additions or modifications to product labeling;

(iii) the recall or

discontinuation of our products;

(iii) the recall or discontinuation of our products;

or (iv) additional record-keeping requirements.

If any such changes were to be imposed, they could adversely affect the operation of our business.

Patent Term Restoration and Marketing Exclusivity

Depending upon the timing, duration, and specifics of the FDA approval of our product candidates, some of our U.S.

patents may be eligible for limited patent

term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.

The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for patent

term lost during product development and the FDA regulatory review process.

However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the products approval date.

The patent term restoration

period is generally one-half the time between the effective date of an IND and the submission date of a BLA plus the time between the submission date of a BLA and the approval of that application, except that

the review period is reduced by any time during which the applicant failed to exercise due diligence.

Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the

expiration of the patent.

PTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

In the future, we may apply for restoration of patent term for our currently owned or licensed

patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant BLA.

An abbreviated approval pathway for biological products shown to be similar to, or interchangeable with, an

FDA-licensed reference biological product was created by the Biologics Price Competition and Innovation Act of 2009, or BPCIA.

Biosimilarity, which requires that the biological product be highly similar to the

reference product notwithstanding minor differences in clinically inactive components and that there be no clinically meaningful differences between the product and the reference product in terms of safety, purity, and potency, can

be shown through analytical studies, animal studies, and a clinical trial or trials.

Interchangeability requires that a biological product be biosimilar to the

reference product and the product can be expected to produce the same clinical results as the reference product in any given patient and, for products administered multiple times, the product and the reference product may be alternated or switched

after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biological product.

A reference biological product is granted twelve years of exclusivity from the

time of first licensure of the product, and the FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure.

First licensure

typically means the initial date the particular product at issue was licensed in the United States.

This does not include a supplement for the biological product or a subsequent application by the same sponsor or manufacturer of the biological

product (or licensor, predecessor in interest, or other related entity) for a change that results in a new indication,

route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength, unless that change is a modification to the structure of the biological product and such

modification changes its safety, purity, or potency.

Whether a subsequent application, if approved, warrants exclusivity as the first licensure of a biological product is determined on a case-by-case basis with data submitted by the sponsor.

Pediatric exclusivity is another type of regulatory

market exclusivity in the United States.

Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms.

This six-month exclusivity, which runs from the end of other

exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued Written Request for such a trial.

European Union Drug Development

In the European

Union, our future product candidates may also be subject to extensive regulatory requirements.

In the European Union, our future product candidates may also be subject to extensive regulatory requirements.

As in the United States, medicinal products can only be marketed if a marketing authorization from the competent regulatory agencies has been obtained.

Similar to the United States, the various phases of pre-clinical and clinical research in the European Union are

subject to significant regulatory controls.

trials in the European Union, the European Union Member States have transposed and applied the provisions of the Directive differently.

Similar to the United States, the various phases of pre-clinical and clinical research in the European Union are subject to significant regulatory controls.

Although the EU Clinical Trials Directive 2001/20/EC has sought to harmonize the European Union clinical trials regulatory framework, setting out common rules for the control and authorization of clinical trials in the European Union, the European Union Member States have transposed and applied the provisions of the Directive differently.

This has led to significant variations in the Member State regimes.

To improve the current system, a new

Regulation No.

To improve the current system, a new Regulation No.

536/2014 on clinical trials on medicinal product candidates for human use, which repealed Directive 2001/20/EC, was adopted on April 16, 2014 and published in the European Official Journal on May 27, 2014.

Regulation aims at harmonizing and streamlining the clinical trials authorization process, simplifying adverse event reporting procedures, improving the supervision of clinical trials, and increasing their transparency.

The new Regulation was

published on June 16, 2014 but should only be applied in December 2021 (its entry into application will occur after the publication of a notice delivered by the European Commission on the European Union clinical trial portal and database).

The new Regulation aims at harmonizing and streamlining the clinical trials authorization process, simplifying adverse event reporting procedures, improving the supervision of clinical trials, and increasing their transparency.

The new Regulation was published on June 16, 2014 but should only be applied from January 31, 2022 (its entry into application will occur after the publication of a notice delivered by the European Commission on the European Union clinical trial portal and database).

Until then, the Clinical Trials Directive 2001/20/EC will still apply.

In addition, the transitory provisions of the new Regulation offer the sponsors the possibility to choose between the requirements of the Directive and the Regulation for one

year from the entry into application of the Regulation.

Under the current regime, before a clinical trial can be initiated, it must be approved in each

of the European Union countries where the trial is to be conducted by two distinct bodies:

In addition, the transitory provisions of the new Regulation offer the sponsors the possibility to choose between the requirements of the Directive and the Regulation for one year from the entry into application of the Regulation.

Under the current regime, before a clinical trial can be initiated, it must be approved in each of the European Union countries where the trial is to be conducted by two distinct bodies:

the National Competent Authority, or NCA, and one or more Ethics Committees, or Ecs.

Under the current regime all suspected unexpected serious adverse

reactions, or SUSARs, to the investigated drug that occur during the clinical trial have to be reported to the NCA and ECs of the Member State where they occurred.

As a result of the ongoing COVID-19 pandemic, the regulatory authorities in various countries (including the Agence

nationale de sécurité

du médicament et des produits de santé

, or ANSM, in France) have published general recommendations and set up transitional measures during the first wave of the epidemic aimed at guaranteeing the

continuity of drug development while ensuring the safety of clinical trial participants.

Under the current regime all suspected unexpected serious adverse reactions, or SUSARs, to the investigated drug that occur during the clinical trial have to be reported to the NCA and Ecs of the Member State where they occurred.

As a result of the ongoing COVID-19 pandemic, the regulatory authorities in various countries (including the Agence nationale de sécurité du médicament et des produits de santé

, or ANSM, in France) have published general recommendations and set up transitional measures during the first wave of the epidemic aimed at guaranteeing the continuity of drug development while ensuring the safety of clinical trial participants.

The transitional measures may be reactivated depending on the evolution of the healthcare context and the needs identified for the various research sites.

Finally, a proposal for a Regulation on Health Technology Assessment (HTA) was adopted in first reading on June 22, 2021.

The purpose of this proposal for a Regulation is to establish a permanent and viable European cooperation on the common clinical evaluation of new medicines (and certain new medical devices).

Member States will be able to use common HTA methods, procedures and tools across the European Union.

The Regulation will facilitate the exchange of information with health technology developers on their development plans for a given health technology.

Through HTA, national health authorities will be able to make informed

decisions about pricing or reimbursement of health technologies that remain within the national competence of Member States (see section 1.2.9.3 below).

European Union Drug Review and Approval

In the European

Economic Area, or EEA, which is comprised of the 27 Member States of the European Union plus Norway, Iceland and Liechtenstein, medicinal products can only be commercialized after obtaining a Marketing Authorization, or MA (though there are other

cases of regulatory authorizations derogating from the MA system which are exceptional and do not currently apply to us).

In the European Economic Area, or EEA, which is comprised of the 27 Member States of the European Union plus Norway, Iceland and Liechtenstein, medicinal products can only be commercialized after obtaining a Marketing Authorization, or MA (though there are other cases of regulatory authorizations derogating from the MA system which are exceptional and do not currently apply to us).

There are four types of marketing authorizations procedures.

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The Centralized Procedure:

an MA is issued by the European Commission through the Centralized Procedure, based on

the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency, or EMA, and is valid throughout the entire territory of the EEA.

The Centralized Procedure is mandatory for certain types of products, such

as biotechnology medicinal products, orphan medicinal products, and medicinal products containing a new active substance indicated for the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and viral diseases.

Centralized Procedure is optional for products containing a new active substance not yet authorized in the EEA on the date on which Regulation No.

726/2004 enters into force or for products that constitute a significant therapeutic, scientific

or technical innovation or which are in the interest of public health in the European Union.

The Mutual Recognition Procedure is mandatory when a product has already been authorized for marketing in a

Member State of the EEA, known as the reference Member State, or RMS.

an MA is issued by the European Commission through the Centralized Procedure, based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency, or EMA, and is valid throughout the entire territory of the EEA.

The Centralized Procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, and medicinal products containing a new active substance indicated for the treatment of AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and viral diseases.

The Centralized Procedure is optional for products containing a new active substance not yet authorized in the EEA on the date on which Regulation No.

726/2004 enters into force or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the European Union.

The Mutual Recognition Procedure is mandatory when a product has already been authorized for marketing in a Member State of the EEA, known as the reference Member State, or RMS.

This National MA needs to be recognized by the other Member States through the Mutual Recognition Procedure.

The Decentralized Procedure:

when the product has not received a National MA in any Member State at the time of

application, it can be approved simultaneously in various Member States through the Decentralized Procedure.

Under the Decentralized Procedure an identical dossier is submitted to the competent authorities of each of the Member States in which the

MA is sought, one of which is selected by the applicant as the Reference Member State, or RMS.

The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics, or SPC, and a draft of the labeling

and package leaflet, which are sent to the other Member States (referred to as the Concerned Member States, or CMSs) for their approval.

If the CMSs raise no objections, based on a potential serious risk to public health, to the assessment, SPC,

labeling, or packaging proposed by the RMS, the product is subsequently granted a national MA in all the Member States (i.e.

in the RMS and the CMSs).

when the product has not received a National MA in any Member State at the time of application, it can be approved simultaneously in various Member States through the Decentralized Procedure.

Under the Decentralized Procedure an identical dossier is submitted to the competent authorities of each of the Member States in which the MA is sought, one of which is selected by the applicant as the Reference Member State, or RMS.

The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics, or SPC, and a draft of the labeling and package leaflet, which are sent to the other Member States (referred to as the Concerned Member States) for their approval.

If the Concerned Member States raise no objections, based on a potential serious risk to public health, to the assessment, SPC, labeling, or packaging proposed by the RMS, the product is subsequently granted a national MA in all the Member States (i.e.

in the RMS and the Concerned Member States).

For the registration of a medicinal product in only one Member State of the European Union, the applicant must use the national procedure.

National marketing

authorizations are issued by the competent authorities of the EEA Member States (e.g., for France, ANSM) and only cover their respective territories.

They are available for products that are not covered by the compulsory scope of Community

Under the above described procedures, before granting the MA, the EMA or the competent authorities of the Member States of the EEA make an

assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

The EEA currently

consists of the 27 Member States of the European Union as well as Norway, Iceland and Liechtenstein.

The pharmaceutical legislation of the European Union

is no longer applicable in the United Kingdom as of January 1, 2021.

An Economic and Trade Partnership Agreement was concluded between the European

Union and the United Kingdom on December 24, 2020.

National marketing authorizations are issued by the competent authorities of the EEA Member States (e.g., for France, ANSM) and only cover their respective territories.

They are available for products that are not covered by the compulsory scope of Community procedures.

Under the above described procedures, before granting the MA, the EMA or the competent authorities of the Member States of the EEA make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

The EEA currently consists of the 27 Member States of the European Union as well as Norway, Iceland and Liechtenstein.

The pharmaceutical legislation of the European Union is no longer applicable in the United Kingdom as of January 1, 2021.

An Economic and Trade Partnership Agreement was concluded between the European Union and the United Kingdom on December 24, 2020.

To date, this agreement does not provide for a principle of mutual recognition (i.e.

the marketing authorization of a drug obtained in the European Union is not recognized in the United

Kingdom, and vice versa).

the marketing authorization of a drug obtained in the European Union is not recognized in the United Kingdom, and vice versa).

However, the Agreement does contain facilitation and cooperation arrangements, including an annex dedicated to medicinal products ( Annex TBT-2 on Medicinal Products

meantime, regulatory authorities (such as the EMA at the European Union level or the ANSM in France) have published

recommendations intended for

industrial stakeholders likely to be affected by Brexit, pending eventual technical agreements.

Many aspects related to the development, marketing and commercialization of drugs (including drug manufacturing and supply chain) have been and are

expected to continue to be impacted by Brexit.

In the meantime, regulatory authorities (such as the EMA at the European Union level or the ANSM in France) have published recommendations intended for industrial stakeholders likely to be affected by Brexit, pending eventual technical agreements.

Many aspects related to the development, marketing and commercialization of drugs (including drug manufacturing and supply chain) have been and are expected to continue to be impacted by Brexit.

Other Regulatory Matters

French Regulatory Framework

In the European Union

pending the effectiveness of Regulation No.

In the European Union—pending the effectiveness of Regulation No.

536/2014—the regulation governing clinical trials is currently based on European Directive No.

2001/20/EC of April 4, 2001 with respect to the implementation of good clinical practices in

the conduct of clinical trials on medicinal products for human use.

2001/20/EC of April 4, 2001 with respect to the implementation of good clinical practices in the conduct of clinical trials on medicinal products for human use.

Each European Union Member State had to transpose this Directive into national law by eventually adapting it to its own regulatory framework.

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2001/20/EC has been transposed by Act No.

2004-806 of August 9, 2004

relative to the public health policy and Decree No.

2004-806 of August 9, 2004 relative to the public health policy and Decree No.

2006-477, April 26, 2006, modifying chapter I, Title II, Book I of the first part of the Code of Public Health dedicated to biomedical research.

This regulation replaces the notification procedure arising from the Huriet-Sérusclat Act of December 20, 1988.

The Act of August 9, 2004 was notably amended by the Act of March 5, 2012

and by the ordinance of June 16, 2016, which mostly aims at (i) adapting the provisions relating to clinical research to the new European Regulation No.

536/2014, (ii) a better response coordination among Ethical Research Committees

in charge of reviewing research agreements and (iii) harmonizing data protection provisions with the latest legislative developments (Jardé

1121-4 of the Public Health Code, as amended by the Ordinance of June 16, 2016, establishes a system

of prior authorization issued by the ANSM and/or of a favorable opinion of a competent Ethical Research Committee, depending on the type of clinical trial.

Since the entry into force of the Jardé

Act, the competent Ethical Research Committee

is selected randomly among available committees having the required jurisdiction to review the project by drawing lots (article L.1123-6 of the Public Health Code as amended by Law No.

December 7, 2020).

This regulation replaces the notification procedure arising from the Huriet-Sérusclat Act of December 20, 1988.

The Act of August 9, 2004 was notably amended by the Act of March 5, 2012 and by the ordinance of June 16, 2016, which mostly aims at (i) adapting the provisions relating to clinical research to the new European Regulation No.

536/2014, (ii) a better response coordination among Ethical Research Committees in charge of reviewing research agreements and (iii) harmonizing data protection provisions with the latest legislative developments (Jardé Act).

1121-4 of the Public Health Code, as amended by the Ordinance of June 16, 2016, establishes a system of prior authorization issued by the ANSM and/or of a favorable opinion of a competent Ethical Research Committee, depending on the type of clinical trial.

Since the entry into force of the Jardé Act, the competent Ethical Research Committee is selected randomly among available committees having the required jurisdiction to review the project by drawing lots (article L.1123-6 of the Public Health Code as amended by Law No.

2020-1525 of December 7, 2020).

On the basis of Article L.

1123-7 of the same code, the Ethical Research Committee shall deliver its opinion on the researchs conditions of validity, particularly with respect to

participant protection, their information and how they collect informed consent, as well as the projects general relevance, the satisfactory nature of the assessment of benefits and risks and the adequacy between the objectives pursued and the

means implemented.

The ANSM, after submission of the complete file containing not only information on the clinical protocol, but also specific product data and its quality control, as well as results of

pre-clinical studies may inform the sponsor that it objects to the implementation of the research.

The sponsor can then modify the contents of his research project and submit this amended or supplemented

request to the ANSM.

1123-7 of the same code, the Ethical Research Committee shall deliver its opinion on the research’s conditions of validity, particularly with respect to participant protection, their information and how they collect informed consent, as well as the project’s general relevance, the satisfactory nature of the assessment of benefits and risks and the adequacy between the objectives pursued and the means implemented.

The ANSM, after submission of the complete file containing not only information on the clinical protocol, but also specific product data and its quality control, as well as results of pre-clinical studies may inform the sponsor that it objects to the implementation of the research.

The sponsor can then modify the contents of his research project and submit this amended or supplemented request to the ANSM.

If the sponsor does not alter the content of its request, the request is considered rejected.

Under the terms of the Decree of

April 26, 2006 (as modified by Decree No.

Under the terms of the Decree of April 26, 2006 (as modified by Decree No.

2016-1537 of November 16, 2016), the time limit for the examination of a request for authorization cannot exceed 60 days from the receipt of the complete file (Article R.1123-32 of the Public Health Code).

Finally, under Article L.

1123-11, in the event of risk to public health or if the ANSM considers that the conditions in which the

research is implemented no longer correspond to the conditions indicated in the request for authorization or does not comply with the provisions of the Public Health Code, it may at any time request changes to procedures for the realization of

research, and suspend or ban this research.

As of October 15, 2018, the ANSM has implemented a fast-track system for the authorization of clinical trials (Fast Track), which will reduce the time required to process applications for

authorization of clinical trials for medicines (for sponsors who meet the eligibility criteria) and for innovative therapy medicines, or ITMs, as of February 18, 2019.

Fast Track 1, Access to Innovation, provides for a maximum

review time of 40 days for trials of new medicines and 110 days for ITMs.

1123-11, in the event of risk to public health or if the ANSM considers that the conditions in which the research is implemented no longer correspond to the conditions indicated in the request for authorization or does not comply with the provisions of

the Public Health Code, it may at any time request changes to procedures for the realization of research, and suspend or ban this research.

As of October 15, 2018, the ANSM has implemented a fast-track system for the authorization of clinical trials (“Fast Track”), which will reduce the time required to process applications for authorization of clinical trials for medicines (for sponsors who meet the eligibility criteria) and for innovative therapy medicines, or ITMs, as of February 18, 2019.

Fast Track 1, “Access to Innovation”, provides for a maximum review time of 40 days for trials of new medicines and 110 days for ITMs.

Fast Track 2, “Development Support”, provides for a maximum review time of 25 days for trials of new medicines and 60 days for ITMs.

The decision of November 24, 2006 sets the rules for Good Clinical Practice, or GCP, for biomedical research on medicines for human use provided for in

The decision of November 24, 2006 sets the rules for Good Clinical Practice, or GCP, for biomedical research on medicines for human use provided for in Article L.

1121-3 of the Public Health Code.

The purpose of Good Clinical Practice is to ensure both the reliability of data arising from clinical trials and the protection of persons participating in these

clinical trials.

The purpose of Good Clinical Practice is to ensure both the reliability of data arising from clinical trials and the protection of persons participating in these clinical trials.

GCPs shall apply to all clinical trials, including pharmacokinetics, bioavailability and bioequivalence studies in healthy volunteers and Phase II to IV clinical trials.

Personal data collected during clinical trials must be reported to the French data protection authority, and

kept in the record of processing activities held by the data processor pursuant to the Regulation 2016/679 of April 27, 2016 (GDPR), French Act No.

78-17 of January 6, 1978, concerning

computing, files and freedoms, and its implementing legislation.

Personal data collected during clinical trials must be reported to the French data protection authority, and kept in the record of processing activities held by the data processor pursuant to the Regulation 2016/679 of April 27, 2016 (GDPR), French Act No.

78-17 of January 6, 1978, concerning computing, files and freedoms, and its implementing legislation.

However, for certain types of research, the formalism is lightened if the data processing is carried out in compliance with one of the reference methodologies (RM) in force.

particular, the data controller who wishes to implement one or more processing operations in compliance with one of these reference methodologies must send the CNIL a declaration attesting to this compliance for each reference methodology applicable

to its projects.

On the other hand, if the study does not fall within the scope of these reference methodologies, the sponsor is obliged to submit a research authorization request to the CNIL.

According to the aforementioned regulations, patients

have, among others, a right to their data and a right of rectification of such data, as the case may be.

Regarding transfers of personal data between the

European Union and the United States, the European Court of Justice has (i) invalidated the data protection shield known as the Privacy Shield, but (ii) held the European Commissions standard contractual clauses regarding

personal data transfers to be valid (as set forth in Commission Decision 2010/87/EU of February 5, 2010, amended in 2016) in the Schrems II decision of July 16, 2020 (CJUE, July 16, 2020,

French Pharmaceutical Company Status

By official letters of the ANSM dated August 23, 2017 and June 4, 2019, the Company has been granted by the ANSM the status of pharmaceutical

establishment ( établissement pharmaceutique ) solely for the purpose of conducting quality control and release activities for its future therapeutic patches on the Bagneux site.

Obtaining the pharmaceutical establishment

license, either as distributor exploitant or as manufacturer, requires the submission of a request electronic file via the dedicated platform (mandatory since January 1, 2020) specific to each of the two qualifications with the

ANSM, which only grants it after review of this file and evaluation, usually after verification that the company has adequate premises, the necessary personnel and an adapted structure with satisfactory procedures for carrying out the proposed

pharmaceutical activities.

In order to simplify the procedures for authorizing pharmaceutical companies manufacturing new and/or innovative medicines to

operate in France, the ANSM has introduced a new procedure to reduce the time required to process an application from 90 to 60 days.

We currently entrust

CMOs with the manufacturing of clinical batches and intend to continue relying on CMOs for the production of the first commercial batches.

In particular, the data controller who wishes to implement one or more processing operations in compliance with one of these RM must send the CNIL a declaration attesting to this compliance for each RM applicable to its projects.

On the other hand, if the study does not fall within the scope of these RM , the sponsor is obliged to submit a research authorization request to the CNIL.

According to the aforementioned regulations, patients have, among others, a right to their data and a right of rectification of such data, as the case may be.

Regarding transfers of personal data between the European Union and the United States, the European Court of Justice has (i) invalidated the data protection shield known as the “Privacy Shield”, but (ii) held the European Commission’s standard contractual clauses regarding personal data transfers to be valid (as set forth in Commission Decision 2010/87/EU of February 5, 2010, amended in 2016) in the “Schrems II” decision of July 16, 2020 (CJUE, July 16, 2020, C-311/18).

Reimbursement

Significant uncertainty exists as

to the coverage and reimbursement status of any product candidates for which we or our collaborators obtain regulatory approval.

Sales of our products will depend, in part, on the extent to which our products, once approved, will be covered and

reimbursed by third-party payors, such as government health programs, commercial insurance and managed healthcare organizations.

Significant uncertainty exists as to the coverage and reimbursement status of any product candidates for which we or our collaborators obtain regulatory approval.

Sales of our products will depend, in part, on the extent to which our products, once approved, will be covered and reimbursed by third-party payors, such as government health programs, commercial insurance and managed healthcare organizations.

These third-party payors are increasingly reducing reimbursements for medical products and services.

The process for

determining whether a third-party payor will provide coverage for a drug product typically is separate from the process for setting the price of a drug product or for establishing the reimbursement rate that a payor will pay for the drug product

once coverage is approved.

The process for determining whether a third-party payor will provide coverage for a drug product typically is separate from the process for setting the price of a drug product or for establishing the reimbursement rate that a payor will pay for the drug product once coverage is approved.

Third-party payors may limit coverage to specific drug products on an approved list, also known as a formulary, which might not include all of the FDA approved drugs for a particular indication.

In order to secure coverage and reimbursement for any product candidate that might be approved for sale, we may need to conduct expensive pharmacoeconomic

studies in order to demonstrate the medical necessity and cost-effectiveness of the product candidate, in addition to the costs required to obtain FDA or other comparable regulatory approvals.

Whether or not we conduct such studies, our product

candidates may not be considered medically necessary or cost-effective.

A third-party payors decision to provide coverage for a drug product does not imply that an adequate

reimbursement rate will be approved.

Further, one payors determination to provide coverage for a product does not assure that other payors will also provide coverage, and adequate

reimbursement, for the product.

In order to secure coverage and reimbursement for any product candidate that might be approved for sale, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost- effectiveness of the product candidate, in addition to the costs required to obtain FDA or other comparable regulatory approvals.

Whether or not we conduct such studies, our product candidates may not be considered medically necessary or cost-effective.

A third-party payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved.

Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage, and adequate reimbursement, for the product.

Third party reimbursement may not be sufficient to enable us to maintain price levels high enough to realize an appropriate return on our investment in product development.

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government, state legislatures and foreign governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products.

of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results.

Decreases in third-party reimbursement for our product

candidate or a decision by a third-party payor to not cover our product candidate could reduce physician usage of the product candidate and have a material adverse effect on our sales, results of operations and financial condition.

Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit our net revenue and results.

Decreases in third-party reimbursement for our product candidate or a decision by a third-party payor to not cover our product candidate could reduce physician usage of the product candidate and have a material adverse effect on our sales, results of operations and financial condition.

For example, the ACA, enacted in March 2010, has significantly impacted the health care industry.

The ACA was expansive health reform legislation designed to

expand coverage for the uninsured while at the same time containing overall healthcare costs enhance remedies against fraud and abuse, add new transparency requirements for health care and health insurance industries, impose new taxes and fees on

the health industry and impose additional health policy reforms, and other changes.

With regard to biopharmaceutical products, among other things, the ACA expanded and increased industry rebates for drugs covered under Medicaid programs and made

changes to the coverage requirements under the Medicare Part D program.

The ACA was expansive health reform legislation designed to expand coverage for the uninsured while at the same time containing overall healthcare costs enhance remedies against fraud and abuse, add new transparency requirements for health care and health insurance industries, impose new taxes and fees on the health industry and impose additional health policy reforms, and other changes.

With regard to biopharmaceutical products, among other things, the ACA expanded and increased industry rebates for drugs covered under Medicaid programs and made changes to the coverage requirements under the Medicare Part D program.

However, there have been executive, judicial and Congressional challenges to certain aspects of the ACA.

While Congress has not passed comprehensive repeal legislation, several bills affecting the implementation of certain taxes under the ACA have been signed

For example, on December 22, 2017, President Trump signed into law The Tax Cuts and Jobs Act of 2017, or Tax Act, which included a provision repealing the individual mandate to maintain health insurance coverage under the ACA,

effective January 1, 2019.

In addition, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated Cadillac tax on high-cost employer-sponsored

health coverage and medical device tax and, effective January 1, 2021, also eliminated the health insurer tax.

On December 14, 2018, a U.S.

District Court Judge in the Northern District of Texas ruled that the individual mandate is a

critical and inseverable feature of the ACA, and because it was repealed as part of the Tax Act, the remaining provisions of the ACA are invalid as well.

Additionally, on December 18, 2019, the U.S.

Court of Appeals for the 5th Circuit upheld

the District Court ruling that the individual mandate was unconstitutional and remanded the case back to the District Court to determine whether the remaining provisions of the ACA are invalid as well.

Supreme Court is currently reviewing

the case, although it is unknown when a decision will be made.

Further, although the U.S.

Supreme Court has not yet ruled on the constitutionality of the ACA, on January 28, 2021, President Biden issued an executive order to initiate a special

enrollment period from February 15, 2021 through May 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructs certain governmental agencies to review and reconsider their

existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to

health insurance coverage through Medicaid or the ACA.

It is unclear how the Supreme Court ruling, other such litigation, and the healthcare reform measures of the Biden administration will impact the ACA.

We continue to evaluate how the ACA and

recent efforts to limit the implementation of the ACA will impact our business.

In addition, other legislative changes have been proposed and adopted in

the United States since the ACA was enacted.

While Congress has not passed comprehensive repeal legislation, several bills affecting the implementation of certain taxes under the ACA have been signed into law.

In addition, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated “Cadillac” tax on high-cost employer-sponsored health coverage and medical device tax and, effective January 1, 2021, also eliminated the health insurer tax.

On June 17, 2021 the U.S.

Supreme Court dismissed a challenge on procedural grounds that argued the ACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.

Thus, the ACA will remain in effect in its current form.

Prior to the U.S.

Supreme Court ruling, on January 28, 2021, President Biden issued an executive order that initiated a special enrollment period for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

It is possible that the ACA will be subject to judicial or Congressional challenges in the future.

It is unclear how such challenges and the healthcare reform measures of the Biden administration will impact the ACA.

In addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted.

On August 2, 2011, the Budget Control Act of 2011 among other things, created measures for spending reductions by Congress.

The Joint Select Committee on Deficit Reduction was tasked with

recommending to Congress proposals in spending reductions.

Because they did not achieve a targeted deficit reduction of at least $1.2 trillion for fiscal years 2012 through 2021, it triggered the legislations automatic reduction to several

government programs.

This includes aggregate reductions to Medicare payments to providers of up to 2% per

fiscal year, which went into effect in April 2013 and will stay in effect through 2030 with the exception of a temporary suspension from May 1, 2020 through March 31, 2021 unless

additional Congressional action is taken.

On January 2, 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, or the ATRA, which among other things, also reduced Medicare payments to several providers, including

hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

We expect that additional federal healthcare reform measures

will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, and in turn could significantly reduce the projected value of certain development projects and

reduce our profitability.

Additionally, in the United States, there have been several recent Congressional inquiries and federal and state legislative

activity designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

At the federal level,

the Trump administration used several means to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives.

For example, on July 24, 2020 and September 13, 2020, the Trump

administration announced several executive orders related to prescription drug pricing that seek to implement several of the administrations proposals.

As a result, the FDA released a final rule on September 24, 2020, effective

November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from

pharmaceutical manufacturers to plan sponsors under Medicare Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed by the Biden administration

from January 1, 2022 to January 1, 2023 in response to ongoing litigation.

The rule also creates a new safe harbor for price reductions reflected at the

point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also

been delayed pending review by the Biden administration until March 22, 2021.

On November 20, 2020, CMS issued an interim final rule implementing the Trump administrations Most Favored Nation executive order, which would tie Medicare

Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effective January 1, 2021.

On December 28, 2020, the U.S.

District Court in Northern California issued a nationwide

preliminary injunction against implementation of the interim final rule.

It is unclear whether the Biden administration will work to reverse these measures or pursue similar policy initiatives.

At the state level, legislatures have increasingly

passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure

and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

Additional legislative proposals to reform healthcare and government insurance programs, along with the trend toward managed

healthcare in the United States, could influence the purchase of medicines and reduce demand and prices for our products, if approved.

The Joint Select Committee on Deficit Reduction was tasked with recommending to Congress proposals in spending reductions.

Because they did not achieve a targeted deficit reduction of at least $1.2 trillion for fiscal years 2012 through 2021, it triggered the legislation’s automatic reduction to several government programs.

This includes aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments, including the Infrastructure Investment and Jobs Act, will stay in effect through 2031 with the exception of a temporary suspension from May 1, 2020 through March 31, 2022 unless additional Congressional action is taken.

Under current legislation the actual reduction in Medicare payments will vary from 1% in 2022 to up to 3% in the final fiscal year of this sequester.

On January 2, 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, or the ATRA, which among other things, also reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

We expect that additional federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that

federal and state governments will pay for healthcare products and services, and in turn could significantly reduce the projected value of certain development projects and reduce our profitability.

Additionally, in the United States, there have been several recent Congressional inquiries and federal and state legislative activity designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

At the federal level, the Trump administration used several means to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives.

For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing that seek to implement several of the administration’s proposals.

As a result, the FDA concurrently released a final rule and guidance in September 2020, providing pathways for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020, the U.S.

Department of Health and Human Services, or HHS, finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Medicare Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed until January 1, 2023.

On November 20, 2020, CMS issued an interim final rule implementing the Trump administration’s Most Favored Nation executive order, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effective January 1, 2021.

As a result of litigation challenging the Most Favored Nation model, on December 27, 2021, CMS published a final rule that rescinded the Most Favored Nation model interim final rule.

In July 2021, the Biden administration released an executive order “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on September 9, 2021, HHS released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.

No legislation or administrative actions have been finalized to implement these principles.

It is unclear whether these or similar policy initiatives will be implemented in the future.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

Additional legislative proposals to reform healthcare and government insurance programs, along with the trend toward managed healthcare in the United States, could influence the purchase of medicines and reduce demand and prices for our products, if approved.

This could harm our or our collaborators’ ability to market any products and generate revenues.

containment measures that healthcare payors and providers are instituting and the effect of further healthcare reform could significantly reduce potential revenues from the sale of any of our product candidates approved in the future, and could

cause an increase in our compliance, manufacturing, or other operating expenses.

Cost containment measures that healthcare payors and providers are instituting and the effect of further healthcare reform could significantly reduce potential revenues from the sale of any of our product candidates approved in the future, and could cause an increase in our compliance, manufacturing, or other operating expenses.

It is also possible that additional governmental action will be taken in response to the COVID-19 pandemic.

In addition, in some foreign countries, the proposed pricing for a drug must be approved before it may be lawfully marketed.

The requirements governing drug

pricing vary widely from country to country.

For example, the European Union provides options for its Member States to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control

the prices of medicinal products for human use.

A Member State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product

on the market.

In France, for example, effective access to the market can be achieved either at a free price, decided by

the pharmaceutical company, or with a system of cover/reimbursement with a price regulated by the authorities.

In this case, the future products must be included, for coverage by hospitals, on the list of proprietary medicinal products approved for

use by local authorities and various public services (known as the Liste Collectivités ) (Article L.

5123-2 of the Public Health Code) or included on the list of proprietary medicinal

products reimbursable to insured persons (known as the Liste Sécurité

Sociale ) for reimbursement by the Social Security system (Article L.

The requirements governing drug pricing vary widely from country to country.

A Member State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

In France, for example, effective access to the market can be achieved either at a free price, decided by the pharmaceutical company, or with a system of cover/reimbursement with a price regulated by the authorities.

In this case, the future products must be included, for coverage by hospitals, on the list of proprietary medicinal

products approved for use by local authorities and various public services (known as the “ Liste Collectivités

”) (Article L.

5123-2 of the Public Health Code) or included on the list of proprietary medicinal products reimbursable to insured persons (known as the “ Liste Sécurité Sociale

”) for reimbursement by the Social Security system (Article L.

162-17 of the Social Security Code).

Indeed, in France, the manufacturers price excluding tax of medicines reimbursable to insured persons (registered on the Social Security List) is

the subject of a multi-year agreement negotiated between each pharmaceutical company and the Economic Committee for Health Products, or CEPS (failing this, by unilateral decision of the CEPS).

A framework agreement has been concluded between LEEM

(the trade union representing the pharmaceutical industries) and CEPS.

The last framework agreement was signed on December 31, 2015 and will remain in force until July 31, 2020.

In addition, the transfer prices of medicines on the Sus List

and the Retrocession List are also set by agreement between the operating laboratory and the CEPS.

There can be no assurance that any country that has

price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates.

Historically, products launched in the European Union do not follow price

structures of the United States and generally tend to be significantly lower.

Indeed, in France, the manufacturer’s price excluding tax of medicines reimbursable to insured persons (registered on the Social Security List) is the subject of a multi-year agreement negotiated between each pharmaceutical company and the Economic Committee for Health Products, or CEPS (failing this, by unilateral decision of the CEPS).

A framework agreement has been concluded between LEEM (the trade union representing the pharmaceutical industries) and CEPS.

The last framework agreement was signed on March 5, 2021 and has a three-year term.

In addition, the transfer prices of medicines on the Sus List and the Retrocession List are also set by agreement between the operating laboratory and the CEPS.

There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our product candidates.

Historically, products launched in the European Union do not follow price structures of the United States and generally tend to be significantly lower.

Other Healthcare Laws and Compliance Requirements

Our business operations in the United States and our arrangements with clinical investigators, healthcare providers, consultants, third-party payors and

patients may expose us to broadly applicable federal, state, and foreign fraud and abuse and other healthcare laws.

These laws may impact, among other things, our research, proposed sales, marketing and education programs of our product candidates

that obtain marketing approval.

Our business operations in the United States and our arrangements with clinical investigators, healthcare providers, consultants, third-party payors and patients may expose us to broadly applicable federal, state, and foreign fraud and abuse and other healthcare laws.

These laws may impact, among other things, our research, proposed sales, marketing and education programs of our product candidates that obtain marketing approval.

The healthcare laws and regulations that may affect our ability to operate include, among others:

the federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully

soliciting, receiving, offering or paying remuneration (including any kickback, bribe or rebate), directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, lease,

order, or recommendation of, an item, good, facility or service reimbursable under a federal healthcare program, such as the Medicare and Medicaid programs.

Although there are a number of statutory exceptions and regulatory safe harbors protecting

some common activities from prosecution, the exceptions and safe harbors are drawn narrowly.

Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny if

they do not qualify for an exception or safe harbor.

The intent standard under the federal Anti-Kickback Statute was amended by the ACA to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or

specific intent to violate it in order to have committed a violation.

Moreover, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent

claim for purposes of the federal civil False Claims Act;

federal civil and criminal false claims laws, including the federal civil False Claims Act, which impose

penalties and provide for civil whistleblower or qui tam actions, and civil monetary penalty laws, which prohibit, among other things, knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other third-party

payers that are false or fraudulent, or making a false statement or record material to payment of a false claim or avoiding, decreasing, or concealing an obligation to pay money to the federal government, including for example, providing inaccurate

billing or coding information to customers or promoting a product off-label;

HIPAA, which created additional federal criminal statutes that prohibit knowingly and willfully executing or

attempting to execute a scheme to defraud any healthcare benefit program, knowingly and willfully falsifying, concealing or covering up a material fact or making false statements relating to healthcare matters, knowingly and willfully embezzling or

stealing from a healthcare benefit program, or willfully obstructing a criminal investigation of a healthcare offense.

Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific

intent to violate it to have committed a violation;

the federal Physician Payments Sunshine Act, enacted as part of the ACA, which requires applicable manufacturers

of covered drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Childrens Health Insurance Program, with specific exceptions, to track and annually report to CMS payments and other

transfers of value provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals and certain ownership and investment interests held by physicians or their immediate family members

in applicable manufacturers and group purchasing organizations, and, beginning in 2022, will require applicable manufacturers to report information regarding payments and other transfers of value provided in the previous year to physician

assistants, nurse practitioners, clinical nurse specialists, certified registered nurse anesthetists, anesthesiologist assistants, and certified nurse midwives;

HIPAA, as amended by the HITECH Act, and its implementing regulations, which imposes certain requirements on

covered entities and their business associates, and their covered subcontractors, relating to the privacy, security and transmission of individually identifiable health information;

state, local and foreign law equivalents of each of the above federal laws, such as state anti-kickback and false

claims laws which may apply to items or services reimbursed by any third-party payor, including commercial insurers;

state and local marketing and/or transparency laws applicable to manufacturers that may be broader in scope than the federal

requirements;

the federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and willfully soliciting, receiving, offering or paying remuneration (including any kickback, bribe or rebate), directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, lease, order, or recommendation of, an item, good, facility or service reimbursable under a federal healthcare program, such as the Medicare and Medicaid programs.

Although there are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly.

Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor.

The intent standard under the federal Anti-Kickback Statute was amended by the ACA to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Moreover, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act;

federal civil and criminal false claims laws, including the federal civil False Claims Act, which impose penalties and provide for civil whistleblower or qui tam actions, and civil monetary penalty laws, which prohibit, among other things, knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other third-party payors that are false or fraudulent, or making a false statement or record material to payment of a false claim or avoiding, decreasing, or concealing an obligation to pay money to the federal government, including for example, providing inaccurate billing or coding information to customers or promoting a product off-label;

HIPAA, which created additional federal criminal statutes that prohibit knowingly and willfully executing or attempting to execute a scheme to defraud any healthcare benefit program, knowingly and willfully falsifying, concealing or covering up a material fact or making false statements relating to healthcare matters, knowingly and willfully embezzling or stealing from a healthcare benefit program,

or willfully obstructing a criminal investigation of a healthcare offense.

Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it to have committed a violation;

the federal Physician Payments Sunshine Act, enacted as part of the ACA, which requires applicable manufacturers of covered drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to track and annually report to CMS payments and other transfers of value provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals and information regarding certain ownership and investment interests held by physicians or their immediate family members;

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and its implementing regulations, which imposes certain requirements on covered entities and their business associates, and their covered subcontractors, relating to the privacy, security and transmission of individually identifiable health information;

state, local and foreign law equivalents of each of the above federal laws, such as state anti- kickback and false claims laws which may apply to items or services reimbursed by any third- party payor, including commercial insurers;

state and local marketing and/or transparency laws applicable to manufacturers that may be broader in scope than the federal requirements;

state laws that require biopharmaceutical companies to comply with the biopharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government;

state and local laws

that require licensure or registration by pharmaceutical sales representatives;

state and local laws that require licensure or registration by pharmaceutical sales representatives;

state laws that require disclosure of information related to drug pricing;

and state and foreign laws governing the privacy and security of health information in certain

circumstances, many of which differ from each other in significant ways and may not have the same effect as HIPAA, thus complicating compliance efforts.

and state and foreign laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect as HIPAA, thus complicating compliance efforts.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws will involve substantial costs.

It is possible

that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws.

If our operations are found to be in

violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant administrative, civil, and/or criminal penalties, damages, fines, disgorgement, individual imprisonment, exclusion from

government funded healthcare programs, such as Medicare and Medicaid, integrity obligations, contractual damages, reputational harm, diminished profits and future earnings, and the curtailment or restructuring of our operations.

If the physicians or

other healthcare providers or entities with whom we expect to do business are found to be not in compliance with applicable laws, they may be subject to significant administrative, civil, and/or criminal sanctions, including individual imprisonment

and exclusion from government funded healthcare programs.

Within the European Union, there are also national anti-corruption procedures and specific

rules on ethics.

As of December 31, 2020, we had 141 full-time employees and 1part-time employee, including around 20 with M.D.

It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws.

If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant administrative, civil, and/or criminal penalties, damages, fines, disgorgement, individual imprisonment, exclusion from government funded healthcare programs, such as Medicare and Medicaid, integrity obligations, contractual damages, reputational harm, diminished profits and future earnings, and the curtailment or restructuring of our operations.

If the physicians or other healthcare providers or entities with whom we expect to do business are found to be not in compliance with applicable laws, they may be subject to significant administrative, civil, and/or criminal sanctions, including individual imprisonment and exclusion from government funded healthcare programs.

Within the European Union, there are also national anti-corruption procedures and specific rules on ethics.

As of December 31, 2021, we had 92 full-time employees, including around 24 with M.D.

degrees, and no part-time employees.

Of these employees, 4 employees are engaged in research and development activities and 27 employees are engaged in general and administrative activities.

We consider the relationship with our employees to be good.

Our human capital

resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.

The principal purposes of our equity incentive plans are to attract, retain and motivate selected

employees, consultants and directors through the granting of equity-based compensation awards.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.

The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants and directors through the granting of equity-based compensation awards.

Corporate Information

Our legal and commercial name is DBV Technologies S.A.

We were incorporated as a société

par actions simplifiée (S.A.S.) under the

laws of the French Republic on March 29, 2002 for a period of 99 years and subsequently converted on March 13, 2003 into a société

We are registered at the Nanterre Commerce and Companies Register under the

number 441 772 522.

We were incorporated as a société par actions simplifiée (S.A.S.)

under the laws of the French Republic on March 29, 2002 for a period of 99 years and subsequently converted on March 13, 2003 into a société anonyme

We are registered at the Nanterre Commerce and Companies Register under the number 441 772 522.

Our principal executive offices are located at 177-181 avenue Pierre Brossolette, 92120 Montrouge, France, and our telephone number is +33 1 55 42 78 78.

Our agent for service of process in

the United States is Cogency Global Inc.

Our agent for service of process in the United States is Cogency Global Inc.

Available Information

Our website address is http://www.dbvtechnologies.com.

We make available on our website, free of charge, our Annual Report on

Form 10-K, our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K and any amendments to those

reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the

Securities and Exchange Commission, or the SEC.

Our website address is http://www.dbv-technologies.com

We make available on our website, free of charge, our Annual Reports on Form 10-K, our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange Commission, or the SEC.

The SEC maintains a website that contains reports, proxy and information statements and other information regarding our filings at www.sec.gov.

The information found on our website is not

incorporated by reference into this Annual Report on Form 10-K or any other report we file with or furnish to the SEC.

Information contained on or accessible through our website is not a part of our Annual Report on Form 10-K, and the inclusion of our website address in this Annual Report on Form 10-K is an inactive textual reference only.

The information found on our website is not incorporated by reference into this Annual Report on Form 10-K or any other report we file with or furnish to the SEC.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business