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Item 1. Business

2025-04-11 compared with 2024-03-07 · 406 added, 356 removed, 642 unchanged (54% of the section changed)

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We are advancing this unique technology to treat 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.

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

Our most advanced product candidate is Viaskin Peanut, which has been evaluated as a potential therapy for children with peanut allergy in eleven clinical trials, including four Phase 2 trials and four completed Phase 3 trials.

We also have an ongoing Phase 3 trial of Viaskin Peanut in children ages four to seven with peanut allergy, as well as two planned Phase 3 supplementary safety studies, one in peanut-allergic children ages four through seven, and one in peanut-allergic toddlers, ages one through three.

We have earlier-stage food allergy programs including Viaskin Milk, which is in Phase 2 of clinical development for Cow’s Milk Allergy and Eosinophilic Esophagitis, or EoE.

We also have an ongoing Phase 3 trial of Viaskin Peanut in children ages four to seven with peanut allergy, as well as one planned Phase 3 supplementary safety studies, in peanut-allergic toddlers, ages one through three.

We have earlier-stage food allergy programs including Viaskin Milk and 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.

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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.

Clinically, an allergic reaction to peanut 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.

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

Current Challenges in the Management of Peanut Allergy Patients

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.

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

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

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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 ® , is approved in the US and the European Union for the treatment of peanut allergy in children aged 4–17 years.

A proprietary form

of OIT, Palforzia®, is approved in the US and the European Union for the treatment of peanut allergy in children aged 1–17 years.

Xolair® (omalizumab), an anti-immunoglobulin E (IgE) antibody was recently approved by the FDA for the reduction of allergic reactions, including anaphylaxis, that may occur with accidental exposure to one or more foods in adult and pediatric patients aged 1 year and older with IgE-mediated food allergy.

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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 antigen, such as food protein.

technology platform, which we call Viaskin, is an innovative approach to potentially treating immunological disorders, with a primary focus on food allergy.

This technology platform, which we call Viaskin, is an innovative approach to potentially treating immunological disorders, with a primary focus on food allergy.

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

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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:

Based on our trials and research, we believe that EPIT has the potential to provide 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, illustrated below, are the following:

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

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

Program and Indication Trial Phase 2 Phase 3

VIAKSKIN® Peanut Patch

(DBV712) - Peanut Allergy

Ages 4-11 years

OLE extension to PEPITES (completed)

Ages 4-11 years

Ages 4-7 years

OLE extension to EPITOPE (Year 2 of OLE completed)

COMFORT Toddlers:

Ages 1-3 years

VIASKIN® Milk Patch (DBV135)

– Cow’s Milk Allergy (CMA)

Ages 2-17 years

VIASKIN® Milk Patch (DBV135)

– Eosinophilic Esophagitis (EoE)

Ages 4-17 years

Complete Ongoing Planned

◦ Phase I and Phase IIb tri als of Viaskin Peanut are not included here.

EPIT=epicutaneous immunotherapy;

PEPITES=Peanut EPIT Efficacy and Safety Study;

PEOPLE=PEPITES Open Label Extension Study;

REALISE=Real Life Use and Safety of EPIT;

VITESSE=Viaskin Peanut Immunotherapy Trial to Evaluate Safety, Simplicity and Efficacy;

EPITOPE=EPIT in Toddlers with Peanut Allergy;

EPOPEX=EPITOPE Open Label Extension Study.

Viaskin Peanut

Our lead product candidate, Viaskin Peanut 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.

We are pursuing two distinct clinical development programs for Viaskin Peanut with two versions of the patch:

• The original square patch (previously called cVP) for toddlers ages 1 - 3 years with peanut allergy.

• A modified circular patch (previously called mVP) for children 4 - 7 years with peanut allergy.

We also have a large supporting dataset from clinical trials of the original square patch in children ages 4 - 11 with peanut allergy.

Viaskin Peanut for Children ages 1-3

Our lead product candidate, Viaskin Peanut, has completed a global Phase 3 development program for the treatment of peanut allergic patients four to 11 years of age.

We are developing Viaskin Peanut for the treatment of peanut allergy in toddlers one to three years of age, given the high unmet need and absence of approved treatments for this population.

This program is independent from the Viaskin Peanut Program in 4-7-year-olds and uses the cVP (original patch).

The Viaskin Peanut program for toddlers comprises three Phase 3 clinical trials, with the intent for the trials to support a future BLA submission in this age group:

• EPITOPE (EPIT in Toddlers with Peanut Allergy), a randomized, two-part, pivotal Phase 3 clinical trial assessing the safety and efficacy of Viaskin Peanut for the treatment of peanut-allergic toddlers one to three years of age;

• COMFORT Toddlers (Characterization of the Optimal Management of Food allergy Relief and Treatment), a supplemental safety study to bring the (total) number of subjects on active therapy close to 600 in total when combined with EPITOPE;

• EPOPEX (Phase 3 Open-Label Extension to the EPITOPE Trial), a follow-up of the EPITOPE study to evaluate the long-term efficacy and safety of Viaskin Peanut in very young children.

In June 2022, we announced positive topline results from EPITOPE, which enrolled 362 subjects ages 1 to 3 years, of which 244 and 118 were in the active and placebo arms, respectively.

Enrollment was balanced for age and baseline disease characteristics between the active and placebo treatment arms.

The median subject baseline eliciting dose (ED) was 100 mg in each treatment arm.

A double-blind, placebo-controlled food challenge (DBPCFC) was administered at baseline and month 12 to determine a subject’s ED at each timepoint.

A treatment responder was defined as either a subject with a baseline ED ≤10 mg who reached an ED ≥300 mg of peanut protein at month 12, or a subject with a baseline ED >10 mg and ≤300 mg who reached an ED ≥1,000 mg of peanut protein at month 12.

Viaskin Peanut demonstrated a statistically significant treatment effect (p<0.001), with 67.0% of subjects in the Viaskin Peanut arm meeting the treatment responder criteria after 12 months, as compared to 33.5% of subjects in the placebo arm (difference in response rates = 33.4%;

95% the lower bound of the 95% confidence interval (CI) for the difference in response rates between the active and placebo groups was 22.4%, exceeding the predefined threshold of 15%);

left hand side chart.

In addition, the proportion of subjects achieving an ED of ≥1000 mg (equivalent to approximately three peanuts) after one year of treatment with Viaskin Peanut 250 μg (VP250) was significantly increased relative to placebo (64.2% versus 29.6%;

p<0.001, right hand side chart).

† Responder definition = If eliciting dose (ED) ≤10 mg at baseline, a subject is deemed a responder if ED ≥300 mg at M12.

Alternatively, if ED >10 mg and <300 mg at baseline, a subject was deemed a responder if ED ≥1000 mg at M12.

The EPITOPE safety results were generally consistent with the safety profile of Viaskin Peanut 250 μg observed in children with peanut allergy ages 4 years and older in prior clinical trials.

No imbalance in the overall adverse event (AE) rate was observed in the trial between the active and placebo arms.

Overall, 21 subjects (8.6%) in the Viaskin Peanut arm and three subjects (2.5%) in the placebo arm experienced a serious adverse event (SAE).

Only one of the SAEs (0.4%), which was mild periorbital edema (swelling around the eye) in the Viaskin Peanut arm, was deemed related to treatment.

The most commonly reported adverse events were skin reactions localized to the administration site, the majority of which were mild to moderate in nature.

Fifty-five subjects (22.5%) in the Viaskin Peanut arm experienced an application site reaction that was assessed as severe by an investigator compared with 10 subjects (8.5%) in the placebo arm.

Based on investigators’ reported observations from examinations of the skin at each study visit, using the skin grading systems defined in the protocol, the severity of administration site skin reactions following patch application decreased throughout the course of the 12-month treatment period.

Four (1.6%) subjects in the Viaskin Peanut arm experienced an anaphylactic reaction determined to be related to, or possibly related to, treatment.

Among these anaphylactic reactions, three resolved with a single dose of epinephrine and one resolved without epinephrine.

All anaphylactic reactions were mild to moderate in severity and were characterized mainly by skin and respiratory symptoms.

Eight subjects (3.3%) in the Viaskin Peanut arm discontinued due to adverse events.

In the 12-month treatment period, the trial completion rate was 84.8% and was balanced between the Viaskin Peanut and placebo arms.

Mean subject compliance to daily patch treatment was above 95% in both the active and placebo arms.

On May 10, 2023, the New England Journal of Medicine (“NEJM”) published results from the EPITOPE phase 3 clinical study that demonstrated EPIT with Viaskin Peanut was statistically superior to placebo in desensitizing children to peanut exposure by increasing the peanut dose that triggers allergic symptoms.

As stated in an accompanying editorial piece, these data are seen as “very good news” for toddlers with peanut allergy, as there are currently no approved treatment options for peanut-allergic children under the age of 4 years.

Interim Results from Open-label Extension to EPITOPE Study (EPOPEX)

Following the 12-month treatment period of EPITOPE, eligible subjects could opt to enroll in the open-label, extension (“OLE”) study for up to three years of active total treatment.

This ongoing, open label extension to EPITOPE is known as EPOPEX and is evaluating the long-term clinical benefit of Viaskin Peanut in subjects who completed the Phase 3 EPITOPE trial.

Subjects randomized to active treatment in EPITOPE could receive an additional two-years of treatment in the OLE and subjects randomized to placebo in EPITOPE cross-over to receive three years of active treatment with annual double-blind placebo-controlled food challenges (DBPCFC) and safety assessments.

266 eligible EPITOPE participants enrolled in EPOPEX.

244 underwent the month-24 DBPCFC (n=166 subjects treated with Viaskin Peanut 250 μg for 24 months);

78 subjects originally randomized to the placebo arm of EPITOPE who crossed-over and received active treatment with Viaskin Peanut for one year in the OLE.

In November 2023, we announced the interim analyses from the first year of the open-label extension of EPITOPE.

These data were presented at the annual American College of Allergy, Asthma, and Immunology (ACAAI) in November 2023.

Using the same primary endpoint definition that was used in EPITOPE, 83.9% of subjects who completed the DBPCFC met the responder criteria after 24 months.

This compares to 67% of subjects after one year of therapy.

81.3% of Viaskin Peanut subjects reached an eliciting dose (ED) of ≥1000 mg (equivalent to approximately three peanuts;

central chart), relative to 64% after one-year of treatment observed in EPITOPE.

Furthermore, following an additional year of treatment, 55.9% completed the food challenge without meeting the stopping criteria (i.e., consumed the equivalent of about 12-14 peanuts).

Greenhawt et al.

EPOPEX, Efficacy and Safety of Epicutaneous Immunotherapy in Peanut-allergic Toddlers:

1-year Open-Label Extension to EPITOPE.

Oral Presentation at ACAAI Meeting Nov 2023.

† Responder definition = If eliciting dose (ED) ≤10 mg at baseline, a subject was deemed a responder if ED ≥300 mg at M12.

Alternatively, if ED >10 mg and <300 mg at baseline, subject was deemed a responder if ED ≥1000 mg at M12.

* 100 mg = Median ED at Baseline (month 0);

*125 mg = Median dose consumed at accidental consumption of peanut (Deschildre A, et al.

Clin Exp Allergy 2015;

Peanut-allergic patients in the MIRABEL survey:

characteristics, allergists’ dietary advice and lessons from real life.

‡ Number of subjects with non-missing food challenge endpoint.

Regarding safety and tolerability findings, no new safety signals were observed, and findings were generally similar to what was reported during the first year of treatment with Viaskin Peanut in EPITOPE.

Local application site reactions continued to be the most reported adverse event, with frequency decreasing during the second year of treatment.

The frequency of treatment related TEAEs also decreased in Year 2 relative to Year 1.

There were no treatment related serious TEAEs reported during the second year of treatment (versus 1% in EPITOPE).

As observed during the first year of treatment with Viaskin Peanut, no TEAEs led to permanent study treatment discontinuation.

Finally, no treatment-related anaphylactic events were observed in the second year of treatment (compared with 1.7% of participants during the first year of treatment with Viaskin Peanut in EPITOPE).

In summary, two years

of VP250 in 1-3-year-old peanut-allergic toddlers resulted in continued increases in treatment effect, beyond those observed after one year, without any new safety signals.

In placebo-treated EPITOPE participants, outcomes after 12 months of cross-over to Viaskin Peanut in EPOPEX were consistent with EPITOPE treatment results:

68.0% were responders (compared to 67% of subjects on active treatment in the first year of EPITOPE);

62.7% of subjects reached an ED ≥1000 mg (relative to 64.2% in EPITOPE);

36.5% reached an ED ≥2000 mg (relative to 37% in EPITOPE);

28.4% completed the DBPCFC without meeting stopping criteria (relative to 30.7% in EPITOPE).

There was one event of treatment-related anaphylaxis in Year 2.

We announced month 36 results in January 2025.

266 EPITOPE participants enrolled in the open label extension (EPOPEX) and 211 participants underwent the Month 36 DBPCFC (n=149 VP250;

n=62 placebo).

After three years of VP250, 83.5% of participants reached an eliciting dose (ED) of ≥1000 mg, an increase from 64.2% at month 12 (the EPITOPE study).

A similar increase was observed for participants reaching an ED of ≥2000 mg (72.7% at month 36;

37.0% at month 12;).

Those completing the DBPCFC without meeting stopping criteria increased to 68.2% at month 36 from 30.7% at month 12.

Continued reductions in DBPCFC reaction severity occurred, with 66.5% having no/mild symptoms at month 36 vs 40.2% at month 12.

No treatment-related anaphylaxis or serious treatment-related TEAEs occurred in Year 3.

Local application-site reactions occurred less frequently in Year 3 vs Years 1 and 2.

In placebo-treated EPITOPE participants, outcomes after 24 months of VP250 in the OLE were consistent with 24-month results in EPITOPE VP250 participants.

Supplemental Safety Study in Toddlers (COMFORT Toddlers)

In April 2023, we received pre-BLA Type B Meeting Written Responses from the FDA related to the Viaskin Peanut program in toddlers.

The FDA did not request an additional efficacy study in 1-3-year-olds (i.e., the Agency agreed that the primary endpoint was satisfactorily met in DBV’s Phase 3 trial EPITOPE).

There was agreement with the FDA to conduct a supplemental safety study (COMFORT Toddlers) using the original square (cVP) Viaskin Peanut patch to augment the safety data collected from EPITOPE and have close to 600 total subjects on active treatment in the controlled safety database.

On November 9, 2023, the Company submitted the protocol for its COMFORT Toddlers supplemental safety study in 1 – 3 years-old to FDA.

The Company received comments and queries to the protocol from the FDA on March 11, 2024.

On October 22, 2024, the Company announced positive regulatory updates for the Viaskin Peanut patch in the United States and Europe.

DBV has agreed to guidance provided by the FDA on a potential pathway under the Accelerated Approval Program for the Viaskin Peanut patch in toddlers ages 1 – 3 years-old.

FDA guidance for Accelerated Approval include three qualifying criteria:

1) that the product candidate treats a serious condition, 2) that the product candidate generally provides a meaningful advantage over available therapies, and 3) that the product candidate demonstrates an effect on an intermediate clinical endpoint that is reasonably likely to predict clinical benefit.

FDA confirmed that the Company has met criterion 1 and 2.

Regarding criterion 3, FDA has provided guidance and suggestion regarding the intermediate clinical endpoint, which the Company has agreed to in informal discussions with the FDA.

The Company intends to formalize the Accelerated Approval guidance provided by FDA via submission of a meeting request to confirm the general elements of the two study components:

the COMFORT Toddlers safety study, to be completed before BLA submission, and the confirmatory effectiveness study, including the third Accelerated Approval criterion regarding the intermediate clinical endpoint.

The Company expects that the confirmatory study will be initiated by the time of BLA submission and would run in parallel to commercialization in the United States, if Viaskin Peanut is approved.

The Company announced further that it has aligned with FDA on a wear time collection methodology in COMFORT Toddlers that provides a practical approach for subjects and families, is intended to generate sufficient data to support a BLA submission, and places wear time into an acceptable clinical hierarchy relative to other study endpoints.

DBV has initiated study start-up activities and plans to screen the first subject in the second quarter of 2025.

The company anticipates enrolling approximately 300 – 350 subjects on active treatment into the safety study, which would bring the total Viaskin Peanut patch safety database in toddlers to approximately 600 subjects, consistent with prior FDA guidance.

With this path forward, the BLA submission for Viaskin Peanut patch in 1 – 3 years-old under the Accelerated Approval program is anticipated to be supported by:

Positive efficacy and safety data from DBV’s previously completed EPITOPE Phase 3 Study;

Additional safety data generated in COMFORT Toddlers supplemental safety study to be initiated in the second quarter of 2025.

On December 11, 2024, the Company announced that it reached alignment with FDA on the Accelerated Approval pathway for Viaskin Peanut patch in toddlers 1-3 years-old and on key study design elements for the COMFORT Toddlers study, including study size and wear time collection methodology and analysis.

The Company announced further that FDA confirmed criteria for a post-marketing confirmatory study in toddlers 1-3 years-old and that the Company and FDA agreed that the confirmatory study will assess the effectiveness of the intended commercial Viaskin Peanut patch and will need to be initiated at the time that the BLA is submitted.

Viaskin Peanut for Children ages 4-7

We are evaluating the modified (circular) Viaskin Peanut patch in children ages 4-7 years with peanut allergy in two Phase 3 clinical trials with the intent for the trials to support a future BLA submission in this age group.

VITESSE (Viaskin Peanut Immunotherapy Trial to Evaluate Safety, Simplicity and Efficacy)

On September 7, 2022, we announced the initiation of VITESSE, a new Phase 3 pivotal study of the modified Viaskin Peanut (mVP) patch in children ages 4-7 years with peanut allergy.

We defined initiation as the submission of the trial protocol to selected study sites for subsequent Institutional Review Board (IRB) approval and Ethics Committee (EC) opinion.

On September 21, 2022, the Company announced it received from the FDA a partial clinical hold letter related to certain design elements of VITESSE.

The Company announced on December 23, 2022 that the FDA lifted the partial clinical hold.

The FDA confirmed the Company satisfactorily addressed all clinical hold issues and the VITESSE phase 3 clinical study could proceed with the revised trial protocol.

On March 7, 2023, the Company announced that the first patient was screened in the VITESSE trial.

The Company announced on September 23, 2024 that subject screening was completed in the third quarter of 2024.

Topline results are anticipated in the fourth quarter of 2025.

We enrolled a total of 654 subjects for participation in the VITESSE study, randomized 2:1 active to placebo.

The primary efficacy endpoint is the percentage of treatment responders in the active versus placebo arms at month 12.

The primary efficacy analysis includes the success criterion of the lower bound of the confidence interval of the difference in responder rates between active and placebo groups being greater than or equal to 15%.

A treatment responder is defined as either a subject with a baseline eliciting dose (ED) ≤30 mg who reaches an ED ≥300 mg of peanut protein at month 12, or a subject with a baseline ED = 100 mg who reaches an ED ≥600 mg of peanut protein at month 12.

A double-blind, placebo-controlled food challenge (DBPCFC) will be administered at baseline and month 12 to determine a subject’s ED at both timepoints.

We defined the peanut protein sensitivity inclusion criteria to align with peanut allergy patients at the greatest risk of experiencing reactions to accidental peanut ingestion and with the highest unmet need.

We added a 600 mg dose of peanut protein to the month 12 DBPCFC to increase the sensitivity of the efficacy assessment.

Participants will apply the modified patch (either Viaskin Peanut 250 μg or a placebo) daily for a period of 12 months.

The maximum study duration per subject is 58 weeks:

a four-week screening period, a 12-month treatment period and a two-week follow-up period.

During the screening period, subjects will undergo an initial screening visit with assessment for eligibility according to peanut skin prick test (SPT) and serum peanut IgE.

Those meeting these criteria will proceed to a peanut DBPCFC to confirm their peanut allergy and establish an entry peanut ED.

The entry DBPCFC will be 1 mg peanut protein, and will escalate up to a highest single dose of 100 mg peanut protein.

Subjects who react with an ED at or below the dose of 100 mg peanut protein are considered eligible.

At month 12, a post-treatment DBPCFC will be performed, with a starting dose of 3 mg peanut protein, escalating to a highest dose of 1,000 mg peanut protein according to the following schedule:

3, 10, 30, 100, 300, 600, 1,000 mg.

Secondary efficacy endpoints include changes in Cumulative Reactive Dose, ED and severity of allergic reaction at baseline and month 12 food challenge.

VITESSE will also evaluate the safety of the modified Viaskin Peanut patch based on overall adverse events, local site reactions and systemic allergic reactions.

The VITESSE Instructions for Use (IFU) will direct caregivers to apply one patch at approximately the same time each day, following removal of the previous day’s patch.

The updated IFU now outlines that Viaskin Peanut 250 μg is to be worn for as close to a full day as possible (i.e., 24 hours) with a minimum daily wear time of 20 hours each day.

Patch adhesion will be assessed in VITESSE to affirm the modified Viaskin Peanut patch performs adequately, which aligns with existing regulatory requirements for patch-based therapies.

In post-PCH discussions, we agreed with the FDA that a statistical test of adhesion will be included in the VITESSE statistical analysis plan and further considered patch adhesion data collection and interpretation in the context of the novel nature of the Viaskin patch platform.

Viaskin Peanut for children ages 4-11

Viaskin Peanut completed a global Phase 3 development program for the treatment of peanut allergic patients four to 11 years of age.

The program comprised of the following clinical trials:

PEPITES ( P eanut EPIT E fficacy and S afety S tudy) , a randomized, placebo-controlled pivotal Phase 3 trial investigating the safety and efficacy of Viaskin Peanut 250 µg in 356 patients after 12 months of treatment.

• PEPITES (Peanut EPIT Efficacy and Safety Study), a randomized, placebo-controlled pivotal Phase 3 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 3 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 (PEP IT ES O Pen L abel Ext e nsion Study) , a long-term, open-label extension trial of Viaskin Peanut 250 µg.

• PEOPLE (PEPITES OPen Label Extension Study), 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 up to four additional years, while patients who received placebo during PEPITES were treated with Viaskin Peanut 250 μg for up to five years.

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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

Viaskin Peanut 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.

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.

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

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 1 clinical trials in healthy adult volunteers:

PREQUAL, a Phase 1 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 1 trial with adult healthy volunteers to compare the allergen uptake of the original patch (which we call cVP) and mVP.

In March 2021, we commenced CHAMP (Comparison of adHesion Among Modified Patches), a Phase 1 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 (cVP), 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 (in terms of the surface area in contact with the skin) relative to cVP 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., ‘PREQUAL in Adults,’ PREQUAL (a Phase 1 study in healthy volunteers to optimize allergen sample collection methodologies and validate the assays DBV intended to be used in EQUAL, a second Phase 1 study that was planned (but not initiated) comparing allergen uptake following application of mVP and cVP), 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 our plan to initiate a pivotal Phase 3 placebo-controlled efficacy trial for a modified Viaskin Peanut patch (mVP) in children in the intended patient population.

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 confirmed our change in strategy was agreeable via oral and written exchanges.

In 2022, we announced the new Phase 3 pivotal study of the modified Viaskin Peanut (mVP) patch would be in younger (4-7 years old) and more sensitive children with peanut allergy.

European Union Regulatory History

In November 2020, we announced that our Marketing Authorization Application, or MAA, for Viaskin Peanut, submitted under the name “Abylqis ® ”, 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, reviews the application and provides a recommendation to the European Commission, 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.

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 17, 2021, we announced we had withdrawn the MAA for Viaskin Peanut, submitted under the name “Abylqis”, and formally notified the EMA of our decision.

The initial filing was supported by data from a single, placebo-controlled Phase 3 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.

PEPITES ( Pea nut EPIT Eff icacy and Saf ety Study)

PEPITES (Peanut EPIT Efficacy and Safety Study)

In December 2015, we initiated a pivotal Phase 3 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 3 trial, in which 356 pediatric peanut-allergic patients were treated with Viaskin Peanut 250 μg or placebo for 12 months.

A new patch was applied each day, and after 2 weeks, each patch was worn for 24 hours, plus-or-minus 4 hours.

A new patch was applied each day, and after two weeks, each patch was worn for 24 hours, plus-or-minus 4 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.

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

Response Rate (ITT) after 12 months

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

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

CRD after 12 months

Exploratory analyses showed that changes in peanut-specific biomarkers, including immunoglobulin E (IgE), and immunoglobulin G4(IgG4), support the immunomodulatory effect of Viaskin Peanut.

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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.

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.

2 unchanged sentences

28% in placebo) at 12 months.

An additional post-hoc analysis showed that 53.1% of subjects 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.

An additional post-hoc analysis showed that 53.1% of subjects 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%.

Change in Eliciting Dose after 12 months

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

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

PEOPLE ( PEP ITES Open Lab el Ext ension Stu dy)

PEOPLE (PEPITES Open Label Extension Study)

The PEOPLE trial, which was completed in October 2022, is an open-label extension study that evaluated the long-term safety, tolerability and efficacy of Viaskin Peanut 250 μg in patients who have completed the Phase 3 PEPITES trial.

2 unchanged sentences

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.

Results of the PEOPLE trial for participants receiving 3 years of active treatment were published in the Journal of Allergy and Clinical Immunology in October 2020.

Results of the PEOPLE trial for participants receiving three years of active treatment were published in the Journal of Allergy and Clinical Immunology in October 2020.

Of the 356 participants who were enrolled in PEPITES, 298 eligible participants opted to enroll in PEOPLE.

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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.

Changes in ED were maintained or improved over 3 years in the majority of subjects in the Open-label extension study (Fleischer DM, et al.

% of Subjects (N=141)

Changes in ED were maintained or improved over three years in the majority of subjects in the Open-label extension study (Fleischer DM, et al.

J Allergy Clin Immunol .

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Results of REALISE Trial

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

Results from the six-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.

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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, given the high unmet need and absence of approved treatments for this population.

This program is independent from the Viaskin Peanut Program in 4–7-year-olds and uses the cVP (original patch).

The Viaskin Peanut program for toddlers comprises three Phase 3 clinical trials, with the intent for the trials to support a future BLA submission in this age group:

EPITOPE (EPIT in Toddlers with Peanut Allergy) , a randomized, two-part, pivotal Phase 3 clinical trial assessing the safety and efficacy of Viaskin Peanut for the treatment of peanut-allergic toddlers one to three years of age.

COMFORT Toddlers ( Characterization of the Optimal Management of Food allergy Relief and Treatment), a supplemental safety study to bring the (total) number of subjects on active therapy close to 600 in total when combined with EPITOPE.

EPOPEX ( Phase 3 Open-Label Extension to the EPITOPE Trial), a follow-up of the EPITOPE study to evaluate the long-term efficacy and safety of Viaskin Peanut in very young children,

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 3 clinical trial assessing the safety and efficacy of Viaskin Peanut 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 subject was enrolled in Part B of EPITOPE.

On June 26, 2020, we announced that in Part A, subjects 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 that was studied in Part B of the study.

Enrollment of Part B of EPITOPE was completed in the first quarter of 2021.

In June 2022, we announced positive topline results from Part B of EPITOPE, which enrolled 362 subjects ages 1 to 3 years, of which 244 and 118 were in the active and placebo arms, respectively.

United States Regulatory History

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 August 2020, the Company received a Complete Response Letter (“CRL”) in which the FDA indicated it could not approve the Viaskin Peanut BLA in its then-current form.

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

In addition, the FDA indicated that supplementary clinical data would need to be generated to support the modified patch.

Finally, the FDA requested additional Chemistry, Manufacturing and Controls (“CMC”) data.

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

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

The FDA agreed with the Company’s 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 of one peanut) remains unchanged and performs in the same way it has performed previously.

In March 2021, the Company commenced CHAMP (Comparison of adHesion Among Modified Patches), a Phase 1 trial in healthy adult volunteers to evaluate the adhesion of five modified Viaskin Peanut patches to confirm consistency of efficacy data between the existing and modified patches.

The study was completed in the second quarter of 2021 and the Company selected the circular patch for further development, which is larger in size relative to the current patch and circular in shape.

In May 2021, the Company submitted a proposed protocol to the FDA for STAMP (Safety, Tolerability, and Adhesion of Modified Patches), a 6-month safety and adhesion study.

On October 14, 2021, in an Advice/Information Request letter, the FDA requested the Company conduct a stepwise, or sequential, approach to the modified Viaskin patch development program by conducting allergen uptake comparison studies (i.e., ‘EQUAL in Adults’, EQUAL) and submitting the data for FDA review and feedback prior to starting the STAMP study.

After careful review of the FDA’s information requests, the Company decided not to pursue the approach to the development plans for Viaskin Peanut as requested by the FDA.

The Company estimated that the FDA’s proposed sequential approach would require at least five rounds of exchanges with the FDA to achieve alignment before initiating STAMP, the 6-month safety and adhesion study.

As such, in December 2021, the Company announced its plan to initiate a pivotal Phase 3 placebo-controlled efficacy trial for a modified Viaskin Peanut patch (mVP) in children in the intended patient population.

The Company considered this approach the most straightforward to potentially demonstrate effectiveness, safety, and improved in vivo adhesion of the mVP.

Following written exchanges with the FDA, the FDA confirmed it was aligned with the Company’s change in strategy.

On September 7, 2022, the Company announced the initiation of VITESSE, a Phase 3 pivotal study of the mVP in children ages 4-7 years with peanut allergy.

On September 21, 2022, the Company announced it received from FDA a partial clinical hold letter related to certain design elements of VITESSE.

On December 23, 2022, the Company announced that the FDA lifted the partial clinical hold.

The FDA confirmed the Company satisfactorily addressed all clinical hold issues and the VITESSE phase 3 clinical study could proceed with the revised trial protocol.

On March 7, 2023, the Company announced that the first patient was screened in the VITESSE study.

The Company announced on September 23, 2024 that subject screening was completed in the third quarter of 2024.

Topline results are anticipated in the fourth quarter of 2025.

In June 2022, the Company announced positive topline results from Part B of EPITOPE, which enrolled 362 subjects ages 1-3 years, of which 244 and 118 were in the active and placebo arms respectively.

Enrollment was balanced for age and baseline disease characteristics between the active and placebo treatment arms.

The median subject baseline eliciting dose (ED) was 100 mg in each treatment arm.

A double-blind, placebo-controlled food challenge (DBPCFC) was administered at baseline and month 12 to determine a subject’s ED at each timepoint.

95% the lower bound of the 95% confidence interval (CI) for the difference in response rates between the active and placebo groups was 22.4%, exceeding the predefined threshold of 15%);

left hand side chart.

In addition, the proportion of subjects achieving an ED of ≥1000 mg (equivalent to approximately three peanuts) after one year of treatment with Viaskin Peanut 250 µg (VP250) was significantly increased relative to placebo (64.2% versus 29.6%;

p<0.001, right hand side chart)

† Responder definition = If eliciting dose (ED) ≤10 mg at baseline, a subject is deemed a responder if ED ≥300 mg at M12.

Alternatively, if ED >10 mg and <300 mg at baseline, a subject was deemed a responder if ED ≥1000 mg at M12.

The EPITOPE safety results were generally consistent with the safety profile of Viaskin Peanut 250 µg observed in children with peanut allergy ages 4 years and older in prior clinical trials.

No imbalance in the overall adverse event (AE) rate was observed in the trial between the active and placebo arms.

Overall, 21 subjects (8.6%) in the Viaskin Peanut arm and 3 subjects (2.5%) in the placebo arm experienced a serious adverse event (SAE).

Only 1 of the SAEs (0.4%), which was mild periorbital edema (swelling around the eye) in the Viaskin Peanut arm, was deemed related to treatment.

The most commonly reported adverse events were skin reactions localized to the administration site, the majority of which were mild to moderate in nature.

Fifty-five subjects (22.5%) in the Viaskin Peanut arm experienced an application site reaction that was assessed as severe by an investigator compared with 10 subjects (8.5%) in the placebo arm.

Four (1.6%) subjects in the Viaskin Peanut arm experienced an anaphylactic reaction determined to be related to, or possibly related to, treatment.

Among these anaphylactic reactions, 3 resolved with a single dose of epinephrine and 1 resolved without epinephrine.

All anaphylactic reactions were mild to moderate in severity and were characterized mainly by skin and respiratory symptoms.

Eight subjects (3.3%) in the Viaskin Peanut arm discontinued due to adverse events.

In the 12-month treatment period, the trial completion rate was 84.8% and was balanced between the Viaskin Peanut and placebo arms.

Mean subject compliance to daily patch treatment was above 95% in both the active and placebo arms.

In May 2023, the EPITOPE trial results were published in the New England Journal of Medicine with an accompanying editorial article from Alkis Togias titled “Good News for Toddlers with Peanut Allergies.” The EPITOPE primary data were also presented as an oral presentation at the American College of Allergy, Asthma and Immunology (ACAAI) in November 2022 .

We anticipate to perform additional analyses of the data collected from EPITOPE for further potential publication opportunities.

Supplemental Safety Study in Toddlers (COMFORT Toddlers)

In April 2023, we received pre-BLA Type B Meeting Written Responses from the FDA related to the Viaskin Peanut program in toddlers.

The FDA did not request an additional efficacy study in 1-3-year-olds (i.e., the Agency agreed that the primary endpoint was satisfactorily met in DBV’s Phase 3 trial EPITOPE).

agreement with the FDA to conduct a supplemental safety study (COMFORT Toddlers) using the original square (cVP) Viaskin ™ Peanut patch to augment the safety data collected from EPITOPE and have close to 600 total subjects on active treatment in the controlled safety database.

In July 2023, we received Type C Meeting Written Responses from the FDA regarding key study design elements for the COMFORT Toddlers supplemental safety study.

In summary, COMFORT Toddlers will be a 6-month Double-Blind, Placebo-Controlled (DBPC) study involving approximately 400 toddlers, aged 1 through 3 years, randomized at a 3:1 ratio (active to placebo) with a 12-month open-label extension.

Subsequently, in October 2023, we received feedback from the FDA addressing the remaining protocol design elements for COMFORT Toddlers.

This feedback included language simplification for how the product should be used (i.e., where each epicutaneous system is intended to be worn for a full day (24 hours)).

Furthermore, the key inclusion criteria for the COMFORT Toddlers study will be based on a Double-Blind, Placebo-Controlled Food Challenge (DBPCFC) performed at entry.

Recruiting a study population close to EPITOPE is critical for the future BLA and aligning with the intended patient population if Viaskin Peanut is approved.

We believe that an entry DBPCFC represents the best way to ensure that the optimal study population (i.e., as close to EPITOPE as possible) is enrolled.

The revised protocol design of the safety study was submitted to the FDA in Q4 2023.

Interim Results from Open-label Extension to EPITOPE Study (EPOPEX)

Following the 12-month treatment period of EPITOPE, eligible subjects could opt to enroll in the open-label, extension (“OLE”) study for up to three years of active total treatment.

This ongoing, open label extension to EPITOPE is known as EPOPEX and is evaluating the long-term clinical benefit of Viaskin Peanut in subjects who completed the Phase 3 EPITOPE trial.

Subjects randomized to active treatment in EPITOPE could receive an additional 2-years of treatment in the OLE and subjects randomized to placebo in EPITOPE cross-over to receive 3 years of active treatment with annual double-blind placebo-controlled food challenges (DBPCFC) and safety assessments.

266 eligible EPITOPE participants enrolled in EPOPEX;

244 underwent the Month-24 DBPCFC (n=166 subjects treated with Viaskin Peanut 250 µg for 24 months);

78 subjects originally randomized to the placebo arm of EPITOPE who crossed-over and received active treatment with Viaskin Peanut for 1 year in the OLE.

In November 2023, we announced the interim analyses from the first year of the open-label extension of EPITOPE.

These data were presented at the annual American College of Allergy, Asthma, and Immunology (ACAAI) in November 2023.

Using the same primary endpoint definition that was used in EPITOPE, 83.9% of subjects who completed the DBPCFC met the responder criteria after 24 months.

This compares to 67% of subjects after one year of therapy.

81.3% of Viaskin Peanut subjects reached an eliciting dose (ED) of ≥1000 mg (equivalent to

approximately 3 peanuts;

central chart), relative to 64% after 1-year of treatment observed in EPITOPE.

Furthermore, following an additional year of treatment, 55.9% completed the food challenge without meeting the stopping criteria (i.e., consumed the equivalent of about 12-14 peanuts).

Greenhawt et al.

EPOPEX, Efficacy and Safety of Epicutaneous Immunotherapy in Peanut-allergic Toddlers:

1-year Open-Label Extension to EPITOPE.

Oral Presentation at ACAAI Meeting Nov 2023.

Responder definition = If eliciting dose (ED) ≤10 mg at baseline, a subject was deemed a responder if ED ≥300 mg at M12.

Alternatively, if ED >10 mg and <300 mg at baseline, subject was deemed a responder if ED ≥1000 mg at M12.

100 mg = Median ED at Baseline (Month 0);

*125 mg = Median dose consumed at accidental consumption of peanut (Deschildre A, et al.

Clin Exp Allergy 2015;

Peanut-allergic patients in the MIRABEL survey:

characteristics, allergists’ dietary advice and lessons from real life.

Number of subjects with non-missing food challenge endpoint.

Local application site reactions continued to be the most reported adverse event, with frequency decreasing during the 2 nd year of treatment.

The frequency of treatment related TEAEs also decreased in year 2 relative to year 1.

There were no treatment related serious TEAEs reported during the 2 nd year of treatment (versus 1% in EPITOPE).

As observed during the first year of treatment with Viaskin Peanut, no TEAEs led to permanent study treatment discontinuation.

Finally, no treatment-related anaphylactic events were observed in the second year of treatment (compared with 1.7% of participants during the first year of treatment with Viaskin Peanut in EPITOPE).

In summary, two years of VP250 in 1-3-year-old peanut-allergic toddlers resulted in continued increases in treatment effect, beyond those observed after one year, without any new safety signals.

In placebo-treated EPITOPE participants, outcomes after 12 months of cross-over to Viaskin Peanut in EPOPEX were consistent with EPITOPE treatment results:

68.0% were responders (compared to 67% of subjects on active treatment in the first year of EPITOPE);

62.7% of subjects reached an ED ≥1000 mg (relative to 64.2% in EPITOPE);

36.5% reached an ED ≥2000 mg (relative to 37% in EPITOPE);

28.4% completed the DBPCFC without meeting stopping criteria (relative to 30.7% in EPITOPE).

There was 1 event of treatment-related anaphylaxis in Year 2.

We anticipate communicating the results of the Year Two results as a manuscript that is currently in preparation.

In addition, We anticipate that Month 36 results will become available in the second half of 2024 and we anticipate additional analyses of that data will be performed.

Viaskin Peanut for Children ages 4-7

We will evaluate the modified (circular) Viaskin Peanut patch in children ages 4-7 years with peanut allergy in two Phase 3 clinical trials with the intent for the trials to support a future BLA submission in this age group.

VITESSE (Viaskin Peanut Immunotherapy Trial to Evaluate Safety, Simplicity and Efficacy)

On September 7, 2022, we announced the initiation of VITESSE, a new Phase 3 pivotal study of the modified Viaskin Peanut (mVP) patch in children ages 4-7 years with peanut allergy.

We defined initiation as the submission of the trial protocol to selected study sites for subsequent Institutional Review Board (IRB) approval and Ethics Committee (EC) opinion.

On September 21, 2022, we announced we had received feedback from the FDA in the form of a partial clinical hold on VITESSE.

In the partial clinical hold letter, the FDA specified changes to elements of the VITESSE protocol, acknowledging the intent for the trial to support a future BLA submission.

In the following months, we engaged with the FDA to address the feedback provided in the partial clinical hold letter and to finalize the VITESSE protocol.

In addition, we continued internal preparations for VITESSE and conducted certain site assessment and start-up activities for prompt study launch once the partial clinical hold was lifted.

On December 23, 2022, we announced the FDA lifted the partial clinical hold and confirmed we satisfactorily addressed all clinical hold issues.

The FDA stated that VITESSE may proceed with the revised trial protocol.

On March 7, 2023, the Company announced screening of the first subject in VITESSE.

Screening of the last subject was anticipated in the first half of 2024, and topline results are anticipated in the first half of 2025.

We expect to enroll 600 subjects for participation in the VITESSE study, randomized 2:1 active to placebo.

The primary efficacy endpoint is the percentage of treatment responders in the active versus placebo arms at month 12.

A double-blind, placebo-controlled food challenge (DBPCFC) will be administered at baseline and month 12 to determine a subject’s ED at both timepoints.

We added a 600 mg dose of peanut protein to the month 12 DBPCFC to increase the sensitivity of the efficacy assessment.

Participants will apply the modified patch (either Viaskin Peanut 250 µg or a placebo) daily for a period of 12 months.

The maximum study duration per subject is 58 weeks:

a four-week screening period, a 12-month treatment period and a two-week follow-up period.

During the screening period, subjects will undergo an initial screening visit with assessment for eligibility according to peanut skin prick test (SPT) and serum peanut IgE.

Those meeting these criteria will proceed to a peanut DBPCFC to confirm their peanut allergy and establish an entry peanut ED.

The entry DBPCFC will be 1 mg peanut protein, and will escalate up to a highest single dose of 100 mg peanut protein.

Subjects who react with an ED at or below the dose of 100 mg peanut protein are considered eligible.

At month 12, a post-treatment DBPCFC will be performed, with a starting dose of 3 mg peanut protein, escalating to a highest dose of 1,000 mg peanut protein according to the following schedule:

3, 10, 30, 100, 300, 600, 1,000 mg.

Secondary efficacy endpoints include changes in Cumulative Reactive Dose, ED and severity of allergic reaction at baseline and month 12 food challenge.

VITESSE will also evaluate the safety of the modified Viaskin Peanut patch based on overall adverse events, local site reactions and systemic allergic reactions.

The VITESSE Instructions for Use (IFU) will direct caregivers to apply one patch at approximately the same time each day, following removal of the previous day’s patch.

The updated IFU now outlines that Viaskin Peanut 250 µg is to be worn for as close to a full day as possible (i.e., 24 hours) with a minimum daily wear time of 20 hours each day.

Patch adhesion will be assessed in VITESSE to affirm the modified Viaskin Peanut patch performs adequately, which aligns with existing regulatory requirements for patch-based therapies.

We initiated subject screening for VITESSE in Q1 2023 (the first subject was screened in February 2023 and randomized in March) and anticipate that the last patient will be screened by Q3 2024.

Supplemental Safety Study in children ages 4-7 years with peanut allergy

In 2024, we plan to initiate a supplemental safety study (COMFORT Children) in peanut-allergic children aged 4-7 years.

COMFORT Children comprises a 6-month, randomized, double-blind, placebo-controlled period followed by a 12-month, open-label, single-arm active treatment period.

The additional safety data generated by the 6-month DBPC study will supplement the safety data generated by the VITESSE trial, resulting in a controlled safety database close to 600 children (total) aged 4 to 7 years treated with Viaskin Peanut.

In July 2023, we received Type C Meeting Written Responses from the FDA regarding key study design elements for COMFORT Children.

In summary, there was an agreement with the Agency that COMFORT Children will be a Double-Blind, Placebo-Controlled study involving approximately 270 children, randomized at a 3:1 ratio (active to placebo).

Participation will not necessitate a food challenge, and patch adhesion data will be generated using the same approach as previously agreed upon with the FDA for the VITESSE phase 3 study.

Subsequently, in October 2023, we received feedback from the FDA addressing the remaining protocol design elements for COMFORT Children.

This feedback included language simplification for how Viaskin should be used.

Furthermore, the key inclusion criteria for the COMFORT Children study will be based on a physician-diagnosed peanut allergy, peanut-specific IgE and a Skin Prick Test (with no requirement for a DBPCFC).

The revised protocol design of the safety study was submitted to the FDA in Q4 2023.

COMFORT Children is anticipated to be initiated towards the end of VITESSE enrollment.

We intend that enrollment of the COMFORT Children safety study will be strategically timed to avoid competition with the VITESSE study for the same subjects.

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

September 2016.

On April 19, 2023, the Company outlined the regulatory pathway for Viaskin Peanut in children 1-3 years old after the FDA confirmed in written responses to the Company’s Pre-BLA meeting request that the Company’s EPITOPE phase 3 study met the pre-specified criteria for success for the primary endpoint and did not request any additional efficacy study in this age group.

The FDA required additional safety data to augment the safety data collected from EPITOPE in support of a BLA.

On July 31, 2023, the Company announced receipt of feedback from FDA on two supplemental safety studies, COMFORT Children and COMFORT Toddlers.

On November 9, 2023, the Company submitted the protocol for its COMFORT Toddlers supplemental safety study in 1 – 3 years-old to FDA.

The Company received comments and queries to the protocol from the FDA on March 11, 2024.

On July 30, 2024, the Company announced that it and the FDA had been engaged in ongoing dialogue since May 2023 on the COMFORT Toddlers supplemental safety study in 1 – 3 years-old with a peanut allergy.

Since March 2024, much of the dialogue between DBV and FDA regarding the COMFORT Toddlers supplemental study had focused on patch wear-time experience, including how prescribers would advise parents and caregivers to manage day-to-day variability in patch wear time.

The Company proposed an approach, informed by the EPITOPE efficacy data, that focuses on the user experience during the first 90-days of treatment.

The Company submitted to the FDA draft labeling for Section 2 – Dosing and Administration, for a potential Viaskin Peanut Prescribing Information (PI), along with comprehensive supportive data and analyses.

Within the first 90-days of treatment (excluding the lead-in dosing period) it is possible to identify those patients who are likely to have a robust clinical efficacy response based on patch wear time experience (i.e., “Label-in” patients).

The proposed PI recommends continuation of treatment for these patients.

With the same 90-day approach, patients less likely to have a robust clinical efficacy response,

identified by their patch wear-time experience, would be identified as “Label-out” patients.

In these instances, the PI would recommend a shared decision-making process, between the health care provider and the parent or caregiver, to determine whether treatment should be discontinued.

The Company also announced on November 9, 2023, 2-year results from the ongoing phase 3 open-label extension to the EPITOPE trial, EPOPEX, of Viaskin Peanut in toddlers.

On October 22, 2024, the Company announced positive regulatory updates for the Viaskin Peanut patch in the United States and Europe.

DBV has agreed to guidance provided by the FDA on a potential pathway under the Accelerated Approval Program for the Viaskin Peanut patch in toddlers ages 1 – 3 years-old.

FDA guidance for Accelerated Approval include three qualifying criteria:

FDA confirmed that the Company has met criterion 1 and 2.

Regarding criterion 3, FDA has provided guidance and suggestion regarding the intermediate clinical endpoint, which the Company has agreed to in informal discussions with the FDA.

The Company intends to formalize the Accelerated Approval guidance provided by FDA via submission of a meeting request to confirm the general elements of the two study components:

The Company expects that the confirmatory study will be initiated by the time of BLA submission and would run in parallel to commercialization in the United States, if Viaskin Peanut is approved.

DBV has initiated study start-up activities and plans to screen the first subject in the second quarter of 2025.

With this path forward, the BLA submission for Viaskin Peanut patch in 1 – 3 years-old under the Accelerated Approval program is anticipated to be supported by:

Positive efficacy and safety data from DBV’s previously completed EPITOPE Phase 3 Study;

Additional safety data generated in COMFORT Toddlers supplemental safety study to be initiated in the second quarter of 2025.

The Company submitted the protocol for its COMFORT Children supplemental safety study in ages 4-through-7-years-old to the FDA on November 29, 2023.

On October 22, 2024, the Company announced further that the COMFORT Children safety study is expected to be initiated in the second quarter of 2025.

On March 24, 2025, the Company announced that in a Written Responses Only to the Company’s Type D IND meeting request the FDA agreed with the Company’s proposal that the safety exposure data from the VITESSE Phase 3 study for Viaskin peanut patch in 4 – 7-year-olds will be sufficient to support a BLA filing in this age group.

As a result, the COMFORT Children supplemental safety study will no longer be required and the Company will not conduct the study.

The Company will utilize the safety data from the VITESSE participants randomized to active treatment as well as placebo-crossover participants in the VITESSE Open Label Extension (OLE).

Accordingly, the Company plans to submit a BLA in the first half of 2026 and anticipates potentially accelerating the product launch by approximately one year, subject to FDA approval.

The confirmatory study will include a double-blind, placebo-controlled food challenge (DBPCFC) and will use the same statistical criteria for success (i.e., lower bound of the 95% CI > 15%) as used in the EPITOPE Phase 3 efficacy study.

Adhesion data for the post-marketing confirmatory study will be collected in a similar manner relative to the COMFORT Toddlers study.

The Company expects these data will further support the importance of average daily wear time in the use of the Viaskin Peanut patch as it relates to efficacy and labeling.

European Union Regulatory History

In November 2020, we announced that our Marketing Authorization Application, or MAA, for Viaskin Peanut, submitted under the name “Abylqis®”, 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.

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 identified 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 17, 2021, we announced we had withdrawn the MAA for Viaskin Peanut, submitted under the name “Abylqis”, and formally notified the EMA of our decision.

On October 22, 2024, the Company announced it received scientific advice from EMA on an indication for ages 1 – 7 years-old in Europe.

The Company sought scientific advice from EMA regarding the components of a MAA for the Viaskin Peanut patch.

Previous advice obtained from two local country regulatory health authorities indicated a potential path for a 1 – 7 year-old registration with one patch, the modified patch.

The EMA recently confirmed through scientific advice that the completed EPITOPE study in 1 – 3 years-old, and a positive VITESSE study in 4 – 7 years-old, could constitute an MAA submission for a 1 – 7 years-old indication for peanut allergy patients using the modified patch, along with a new safety study in toddlers ages 1 – 3 years-old with the modified patch.

Timing for the initiation of this new safety study to satisfy the important EU market is currently being planned.

The Company intends to resubmit the MAA when that data set is available.

In November 2014, we initiated a multi-center, double-blind, placebo-controlled, randomized Phase 1/2 dose-finding trial to study the safety and efficacy of Viaskin Milk in 198 subjects 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.

children ages 2 to 11 and adolescents ages 12 to 17.

In June 2015, we announced completion of Part A of the MILES study, or Phase 1, 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 2, in October 2015.

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On October 30, 2023, the Company and NESTEC entered into a Mutual Termination Letter Agreement terminating the Collaboration Agreement.

Each party remains responsible for its own costs and expenses related to its respective wind-down activities.

Each party remained responsible for its own costs and expenses related to its respective wind-down activities.

Any and all licenses and sublicenses, granted by either party to the other party under the Collaboration Agreement, including, without limitation, any licenses to intellectual property, were revoked and terminated.

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We are continuing to explore other cellular mechanisms modulated by EPIT, such as biomarkers, in collaboration with external companies and academic institutions in both the United States and EU.

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.

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We have also entered into a Commercial Supply Agreement, dated January 13, 2020, as amended (the “Commercial Supply Agreement”), with FAREVA setting forth the terms and conditions for the manufacture and supply of commercial batches of Viaskin Peanut by FAREVA.

We have agreed with FAREVA to delay implementation of the Commercial Supply Agreement through December 31, 2024, unless we, at our option, decide to reinstate the Commercial Supply Agreement sooner.

We previously agreed with FAREVA to delay implementation of the Commercial Supply Agreement.

Intellectual Property

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

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

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

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

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

These patents and applications generally fall into five broad categories:

patents, which we own, relating to the Viaskin electrostatic patch and its use, which expired in 2022;

patents, which we co-own with with Assistance Publique-Hôpitaux de Paris, or AP-HP, and Université Paris Cité (formerly Université de Paris-Descartes,and prior to that, Université de Paris, prior to merger and name change), relating to the Viaskin electrostatic patch and its use, which expired in 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 Assistance-Publique-Hôpitaux de Paris, or AP-HP, and the Université Paris Cité (formerly Université de Paris-Descartes, prior to merger and name change) relating to the treatment of peanut, milk, egg, and other allergies using our Viaskin patch technology, which may expire as early as 2028;

design patents and patent applications, which we own relating to various components of the Viaskin patch, which may expire as early as 2038;

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.

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

• design patents and patent applications, which we own relating to various designs of components of the Viaskin patch, which may expire as early as 2032;

• 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, and to other technologies.

Patent Term Extension and Marketing Exclusivity

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

Accordingly, if the remaining patent term has fourteen (14) or more years after the FDA approval date, the patent would not be eligible for any patent extension.

Accordingly, if the remaining patent term has fourteen (14) or more years after the FDA approval date, the patent would not be eligible for any patent term extension.

The amount of time by which a patent term may be extended is generally one-half the time between the effective date of an IND submission and the submission date of a BLA plus the time between the submission date of a BLA and the FDA’s approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence.

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Patent and Trademark Office, or USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension.

In the future, we may apply for extension 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.

In the future, we may apply for extension of patent term for our currently owned or licensed patents to add patent term beyond its then-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.

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 for that product if extended.

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, which can be shown through analytical studies, animal studies, and a clinical trial or trials.

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 biological product and the reference product in terms of safety, purity, and potency, which 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.

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

“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.

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

Absent early termination, the assignment, development and co-ownership agreement will automatically terminate upon the expiration of the last shared patent.

Absent early termination, the assignment, development and co-ownership agreement will automatically terminate upon the expiration cancellation, or abandonment 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, or depending on, at least one of the shared patents would survive termination of the agreement.

The longest-lived patent rights under the agreement are currently expected to expire in 2031, absent patent term extension.

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

quality and breadth of an

organization’s technology;

quality and breadth of an organization’s technology;

skill of an organization’s employees and its ability to recruit and retain key employees;

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oral mucosal, or OMIT;

and cutaneuos or intranasal immunotherapy, synthetic, denatured allergens, small molecule inhibitors, or combinations of medicines or methods.

cutaneous and intranasal, or INT immunotherapy, synthetic, denatured allergens, small molecule inhibitors, or combinations of medicines or methods.

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

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

There is one treatment for peanut allergy approved by the FDA and the European Commission:

There is one treatment for peanut allergy in children 1 to 17 years of age approved by the FDA and the European Commission:

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

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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 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 regulatory 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.

Accordingly, we cannot be sure that submission of an original IND submission 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 disease-affected subjects 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.

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

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

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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.

There are also requirements governing the reporting of ongoing clinical trials and completed clinical trial results to the IRB’s, health authorities and public registries (such as clinicaltrials.gov).

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

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

Generally, the FDA requires two adequate and well-controlled Phase 3 clinical trials for approval of a BLA.

Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.

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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 product has been associated with unexpected serious harm to subjects or patients.

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 and/or protocol or if the product has been associated with unexpected serious harm to subjects or 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.

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PDUFA also imposes an annual program fee for approved drugs.

Fee waivers or reductions may be 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 such BLA within ten months of the filing date for standard review or six months of the filing date for priority review (if granted by the FDA), 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 may be available in certain circumstances, including a waiver of the application fee for the first application filed by a small business or for certain products with an Orphan Drug Designation.

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

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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.

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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.

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.

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.

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.

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:

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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

Breakthrough Therapy 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.

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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.

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.

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European Union Drug Development

In the European Union, or the EU, product candidates may also be subject to extensive regulatory requirements.

In the European Union, or the EU, product candidates are also subject to extensive regulatory requirements.

Approval from the competent authorities of EU Member States must be obtained before commencing clinical trials.

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Similar to the United States, the various phases of pre-clinical and clinical research in the EU are subject to significant regulatory controls.

Certain preclinical (also termed “non-clinical”) data is required in order to enable clinical trials and later to be used in a dossier for a marketing authorization application.

The requisite amount of preclinical data enables the design of a clinical trial, from Phase 1 (first-in-human clinical trials) through to Phases 2 and 3, which are quality, safety and efficacy studies.

During all phases of clinical development, national competent authorities of EU Member States and other comparable regulatory authorities require extensive monitoring and auditing of all clinical activities, clinical data and clinical trial investigators.

In the EU, clinical trials are governed by the Clinical Trials Regulation (EU) No 536/2014, or CTR, which entered into application on January 31, 2022, repealing and replacing the Clinical Trials Directive 2001/20, or

Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations governing clinical trials, including the Good Clinical Practice Directive 2005/28.

Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical or biological substances.

Non-clinical studies must be conducted in compliance with the principles of good laboratory practice, as set forth in EU Directive 2004/10/EC.

In particular, non-clinical studies, both in vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies.

These GLP standards reflect the Organization for Economic Co-operation and Development requirements.

Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Conference on Harmonization, or ICH, guidelines on GCPs, as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

In the EU, clinical trials are governed by the Clinical Trials Regulation (EU) No.

536/2014, or CTR, which entered into application on January 31, 2022, repealing and replacing the Clinical Trials Directive 2001/20, or CTD.

The CTR is intended to harmonize and streamline clinical trial authorizations, simplify adverse-event reporting procedures, improve the supervision of clinical trials and increase transparency.

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Since January 31, 2023, the use of CTIS has become mandatory for all clinical trial sponsors submitting initial applications for the approval of their clinical trials in the EU.

The CTR also establishes a single set of documents to be prepared and submitted for the application including, among other things, a copy of the trial protocol and an investigational medicinal product dossier containing information about the manufacture and quality of the medicinal product under investigation, as well as simplified reporting procedures for clinical trial sponsors.

The CTR also establishes a single set of documents to be prepared and submitted for the application including, among other things, a copy of the trial protocol and an Investigational Medicinal Product Dossier (“IMPD”)containing information about the manufacture and quality of the medicinal product under investigation, as well as simplified reporting procedures for clinical trial sponsors.

A harmonized procedure for the assessment of applications for clinical trials has been introduced and is divided into two parts.

Part I assessment is led by the competent authorities of a reporting EU Member State selected by the trial sponsor and relates to clinical trial aspects that are considered to be scientifically harmonized across EU Member States.

This assessment is then submitted to the competent authorities of all the concerned EU Member States in which the trial is to be conducted for their review.

Part I assessment is led by the competent authorities of a reference EU Member State selected by the trial sponsor and relates to clinical trial aspects that are considered to be scientifically harmonized across EU Member States.

This assessment is then submitted to the competent authorities of all concerned EU Member States in which the trial is to be conducted for their review.

Part II is assessed separately by the competent authorities and Ethics Committees in each concerned EU Member State.

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Individual EU Member States, therefore, retain the power to authorize the conduct of clinical trials in their territory.

The CTR establishes a general principle according to which information contained in CTIS shall be made publicly accessible unless confidentiality is justified on grounds of necessary to protect personal data, or commercially confidential information, necessary to protect confidential communications between EU Member States in relation to the preparation of an assessment report, or necessary to ensure effective supervision of the conduct of a clinical trial by EU Member States.

trial by EU Member States.

The confidentiality exception may be overruled if there is an overriding public interest in disclosure.

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The timelines are established by the European Medicines Agency, or EMA, and are determined based on the documents and the categorization of the clinical trial.

The CTR includes a three-year transition period.

The extent to which on-going clinical trials will be governed by the CTR varies.

For clinical trials in relation to which an application for approval was made on the basis of the CTD before January 31, 2023, the CTD will continue to apply on a transitional basis until January 31, 2025.

By that date, all ongoing trials will become subject to the provisions of the CTR.

The CTR will apply to clinical trials from an earlier date if the related clinical trial application was made on the basis of the CTR or if the clinical trial has already transitioned to the CTR framework before January 31, 2025.

The CTR foresaw a three-year transition period that ended on January 31, 2025.

Since this date, all new or ongoing trials are subject to the provisions of the CTR.

In all cases, clinical trials must be conducted in accordance with GCP and the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

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In the European Economic Area, or EEA, which is comprised of the 27 Member States of the EU plus Norway, Iceland and Liechtenstein, medicinal products can only be commercialized after obtaining a Marketing Authorization, or MA.

To obtain a MA for a product in the EEA, an applicant must submit a Marketing Authorization Application, or MAA either under a centralized procedure administered by the EMA or one of the procedures administered by competent authorities in the EU Member States (decentralized procedure, national procedure or mutual recognition procedure).

To obtain a MA for a product in the EU, an applicant must submit a Marketing Authorization Application, or MAA either under a centralized procedure administered by the EMA or one of the procedures administered by competent authorities of EU Member States (decentralized procedure, national procedure or mutual recognition procedure).

An MA may be granted only to an applicant established in the EU.

The centralized procedure provides for the grant of a single MA by the European Commission that is valid for all EU Member States.

Pursuant to Regulation (EC) No 726/2004, the centralized procedure is compulsory for specific products, including for (i) medicinal products derived from biotechnological processes, (ii) products designated as orphan medicinal products, (iii) ATMPs, and (iv) products with a new active substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto immune and other immune dysfunctions and viral diseases.

The centralized procedure provides for the grant of a single MA by the European Commission that is valid throughout the EEA.Pursuant to Regulation (EC) No.

726/2004, the centralized procedure is compulsory for specific products, including for (i) medicinal products derived from biotechnological processes, (ii) products designated as orphan medicinal products, (iii) ATMPs, and (iv) products with a new active substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto immune and other immune dysfunctions and viral diseases.

For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, authorization through the centralized procedure is optional on related approval.

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The MA may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the EMA or by the competent authority of the EU Member State in which the original MA was granted.

To support the application, the MA holder must provide the EMA or the competent authority with a consolidated version of the eCTD (Common Technical Document) providing up-to-date data concerning the quality, safety and efficacy of the product, including all variations introduced

since the MA was granted, at least nine months before the MA ceases to be valid.

The European Commission or the competent authorities of the EU Member States may decide on justified grounds relating to pharmacovigilance, to proceed with one further five-year renewal period for the MA.

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Pediatric Development

In the EU, Regulation (EC) No 1901/2006 provides that all MAAs for new medicinal products have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan, or PIP, agreed with the EMA’s Pediatric Committee, or PDCO.

In the EU, Regulation (EC) No.

1901/2006 provides that all MAAs for new medicinal products have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan, or PIP, agreed with the EMA’s Pediatric Committee, or PDCO.

The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the medicinal product for which the MA is being sought.

The PDCO can grant a deferral of the obligation to implement some or all of the measures provided in the PIP until

there are sufficient data to demonstrate the efficacy and safety of the product in adults.

The PDCO can grant a deferral of the obligation to implement some or all of the measures provided in the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults.

Further, the obligation to provide pediatric clinical trial data can be waived by the PDCO when these data are not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients.

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Upon receiving an MA, innovative medicinal products are generally entitled to receive eight years of data exclusivity and 10 years of market exclusivity.

Data exclusivity prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic application or biosimilar application for eight years from the date of authorization of the innovative product, after which a generic or biosimilar MAA can be submitted, and the innovator’s data may be referenced.

Data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic application or biosimilar application for eight years from the date of authorization of the innovative product, after which a generic or biosimilar MAA can be submitted, and the innovator’s data may be referenced.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial MA of the reference product in the EU.

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In the EU, the advertising and promotion of medicinal products are subject to both EU and EU Member States’ laws governing promotion of medicinal products, interactions with physicians and other healthcare professionals, misleading and comparative advertising and unfair commercial practices.

Although general requirements for advertising and promotion of medicinal products are established under EU legislation, the details are governed by

regulations in individual EU Member States and can differ from one country to another.

For example, applicable laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics, or SmPC, as approved by the competent authorities in connection with an MA.

The SmPC is the document that provides information to physicians concerning the safe and effective use of the product.

Although general requirements for advertising and promotion of medicinal products are established under EU legislation, the details are governed by regulations in individual EU Member States and can differ from one country to another.

For example, applicable laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics, or SmPC, which may require approval by the competent national authorities in connection with an MA.

The SmPC is the document that provides information to physicians and other healthcare professionals concerning the safe and effective use of the product.

Promotional activity that does not comply with the SmPC is considered off-label and is prohibited in the EU.

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In these circumstances, an MAA must be submitted to the competent authorities responsible for evaluating the safety and effectiveness of medicinal products.

As part of the MAA, the applicant must also submit, where available, the results of the assessment of the conformity of the medical device part of the product with the MDR contained in the manufacturer’s EU Declaration of Conformity of the device or the relevant Certificate of Conformity issued by a Notified Body.

EU Declaration of Conformity of the device or the relevant Certificate of Conformity issued by a Notified Body.

If the MAA does not include the results of the conformity assessment, and where the conformity assessment of the device, if used separately, requires the involvement of a Notified Body, the competent authorities must require the applicant to provide a Notified Body Opinion on the conformity of the device with the relevant GSPRs.

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In this case, the medicinal product should also be compliant with regulation (EU) 2017/745 and particularly the Article 117.

This article requires a Notified Body opinion on the conformity of the device part to the relevant General Safety and Performance Requirements, or GSPRs of the MDR.

Unless an express waiver is granted by the applicable Notified Body, Article 117 requires a Notified Body opinion on the conformity of the device part to the relevant General Safety and Performance Requirements, or GSPRs of the MDR.

Other Regulatory Matters

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The United Kingdom’s, or UK, withdrawal from the EU on January 31, 2020, commonly referred to as Brexit, has changed the regulatory relationship between the UK and the EU.

The Medicines and Healthcare products Regulatory Agency, or MHRA, is now the UK’s standalone regulator for medicinal products and medical

Great Britain (England, Scotland and Wales) is now a third country to the EU.

Northern Ireland will, with regard to EU regulations, continue to follow the EU regulatory rules for now.

The Medicines and Healthcare products Regulatory Agency, or MHRA, is now the UK’s standalone regulator for medicinal products and medical devices.

The United Kingdom is now a third country to the EU.

The UK regulatory framework in relation to clinical trials is governed by the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended, which is derived from the CTD, as implemented into UK national law through secondary legislation.

On January 17, 2022, the MHRA launched an eight-week consultation on reframing the UK legislation for clinical trials, and which aimed to streamline clinical trials approvals, enable innovation, enhance clinical trials transparency, enable greater risk proportionality, and promote patient and public involvement in clinical trials.

The UK Government published its response to the consultation on March 21, 2023 confirming that it would bring forward changes to the legislation.

These resulting legislative amendments will determine how closely the UK regulations will align with the CTR.

The UK Government published its response to the consultation on March 21, 2023 confirming that it would bring forward changes to the legislation and such changes were laid in parliament on December 12, 2024.

These resulting legislative amendments will, if implemented in their current form, bring the United Kingdom into closer alignment with the CTR.

In October 2023, the MHRA announced a new Notification Scheme for clinical trials which enables a more streamlined and risk-proportionate approach to initial clinical trial applications for Phase 4 and low-risk Phase 3 clinical trial applications.

Marketing authorizations in the UK are governed by the Human Medicines Regulations (SI 2012/1916), as amended.

Since January 1, 2021, an applicant for the EU centralized procedure marketing authorization can no longer be established in the UK.

As a result, since this date, companies established in the UK cannot use the EU centralized procedure and instead must follow one of the UK national authorization procedures or one of the remaining post-Brexit international cooperation procedures to obtain an marketing authorization to market products in the UK.

All existing EU marketing authorizations for centrally authorized products were automatically converted or grandfathered into UK marketing authorization, effective in Great Britain only, free of charge on January 1, 2021, unless the marketing authorization holder opted-out of this possibility.

Northern Ireland currently remains within the scope of EU authorizations in relation to centrally authorized medicinal products.

Accordingly, until the Windsor Framework is implemented in Northern Ireland on January 1, 2025, products falling within the scope of the EU centralized procedure can only be authorized through UK national authorization procedures in Great Britain.

The MHRA has also introduced changes to national marketing authorization procedures.

This includes introduction of procedures to prioritize access to new medicines that will benefit patients, including a 150-day assessment route, a rolling review procedure and the International Recognition Procedures which entered into application on January 1, 2024.

Since January 1, 2024, the MHRA may also rely on the International Recognition Procedure, or IRP, when reviewing certain types of marketing authorization applications.

This procedure is available for applicants for marketing authorization who have already received an authorization for the same product from a reference regulator.

These include the FDA, the EMA, and national competent authorities of individual EEA countries.

A positive opinion from the EMA and CHMP, or a positive end of procedure outcome from the mutual recognition or decentralized procedures are considered to be authorizations for the purposes of the IRP.

Marketing authorizations in the United Kingdom are governed by the Human Medicines Regulations (SI 2012/1916), as amended.

Since January 1, 2021, an applicant for the EU’s centralized procedure marketing authorization can no longer be established in the United Kingdom.

As a result, since this date, companies established in the United Kingdom cannot use the EU’s centralized procedure.

In order to obtain a United Kingdom MA to commercialize products in the United Kingdom, an applicant must be established in the United Kingdom and must follow one of the United Kingdom national authorization procedures or one of the remaining post-Brexit international cooperation procedures.

Applications are governed by the Human Medicines Regulations (SI 2012/1916) and are made electronically through the MHRA Submissions Portal.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, a 150-day assessment (subject to clock-stops) and a rolling review procedure.

The rolling-review procedure permits the separate or joint submission of quality, non-clinical, and clinical data to the MHRA which can be reviewed on a rolling basis.

After an application under the rolling-review procedure has been validated, the decision should be received within 100 days (subject to clock-stops).

In addition, since January 1, 2024, the MHRA may rely on the International Recognition Procedure (“IRP”), when reviewing certain types of MAAs.

Pursuant to the IRP, the MHRA will take into account the expertise and decision-making of trusted regulatory partners (e.g., the regulatory in Australia, Canada, Switzerland, Singapore, Japan, the U.S.A.

The MHRA will conduct a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust.

The IRP allows medicinal products approved by such trusted regulatory partners that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update a MA in the United Kingdom.

Applications should be decided within a maximum of 60 days if there are no major objections identified that cannot be resolved within such 60 day period and the approval from the trusted regulatory partner selected has been granted within the previous 2 years or if there are such major objections identified or such approval hasn’t been granted within the previous 2 years within 110 days.

Applicants can submit initial MAAs to the IRP but the procedure can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals.

All existing marketing authorizations of the EU for centrally authorized products were automatically converted or grandfathered into the United Kingdom’s marketing authorization, effective in Great Britain only, free of charge on January 1, 2021, unless the marketing authorization holder opted-out of this possibility.

Northern Ireland remained within the scope of authorizations of the EU in relation to centrally authorized medicinal products until January 1, 2025.

However, on January 1, 2025, a new arrangement as part of the so-called “Windsor Framework” came into effect and reintegrated Northern Ireland under the regulatory authority of the MHRA with respect to medicinal products.

The Windsor Framework removes EU licensing processes and EU labeling and serialization requirements in relation to Northern Ireland and introduces a UK-wide licensing process for medicines.

There is no pre-marketing authorization orphan designation for medicinal products in the UK.

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The criteria are essentially the same as those in the EU, but have been tailored for the market.

This includes the criterion that prevalence of the condition in Great Britain, rather than the EU, must not be more than five in 10,000.

This includes the criterion that prevalence of the condition in the UK, rather than the EU, must not be more than five in 10,000.

Upon the grant of a marketing authorization with orphan status, the medicinal product will benefit from up to 10 years of market exclusivity from similar products in the approved orphan indication.

The start of this market exclusivity period will be set from the date of first approval of the product in Great Britain.

The start of this market exclusivity period will be set from the date of first approval of the product in the UK.

Reimbursement and Reform

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.

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.

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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.

Coverage policies and third-party reimbursement rates may change at any time.

Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

The containment of healthcare costs has become a priority of federal and state governments, and the prices of drugs have been a focus in this effort.

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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.

For example, 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.

On August 16, 2022, President Biden signed the Inflation Reduction Act of 2022, or IRA, into law, which, among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

However, there have been executive, judicial and Congressional challenges and amendments to certain aspects of the ACA.

For example, on August 16, 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law, which, among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in ACA marketplaces through plan year 2025.

The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program.

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.

It is unclear how such challenges and the healthcare reform measures of the second Trump administration will impact the ACA.

In addition, other legislative changes have been proposed and adopted in the United States since the ACA was enacted.

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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.

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 until 2032, 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.

We expect that additional federal healthcare reform measures will be adopted in the future, particularly given the recent change in administration, 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, 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, the U.S.

Department of Health and Human Services, or 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.

In addition, the IRA, among other things, (i) directs HHS to negotiate the price of certain high-expenditure, single-source drugs and biologics covered under Medicare, and subject drug manufacturers to civil monetary penalties and a potential excise tax by offering a price that is not equal to or less than the negotiated “maximum fair price” for such drugs and biologics under the law, and (ii) imposes rebates with respect to certain drugs and biologics covered under Medicare Part B or Medicare Part D to penalize price increases that outpace inflation.

These provisions take effect progressively starting in fiscal year 2023.

On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges.

It is currently unclear how the IRA will be implemented but is likely to have a significant impact on the pharmaceutical industry.

In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act.

At the federal level, the IRA, among other things, (i) directs the U.S.

Department of Health and Human Services, or HHS, to negotiate the price of certain high-expenditure, single-source biologics that have been on the market for at least 11 years covered under Medicare, and subject drug manufacturers to civil monetary penalties and a potential excise tax by offering a price that is not equal to or less than the negotiated “maximum fair price” for such drugs and biologics under the law, or the “Medicare Drug Price Negotiation Program”, and (ii) imposes rebates with respect to certain drugs and biologics covered under Medicare Part B or Medicare Part D to penalize price increases that outpace inflation.

These provisions began to take effect progressively starting in fiscal year 2023.

On August 15, 2024, HHS announced the agreed-upon prices of the first ten drugs that were subject to price negotiations, although the Medicare Drug Price Negotiation Program is currently subject to legal challenges.

On January 17, 2025, HHS selected 15 additional products covered under Part D for price negotiation in 2025.

Each year thereafter more Part B and Part D products will become subject to the Medicare Drug Price Negotiation Program.

On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

While march-in rights have not previously been exercised, it isuncertain if that will continue under the new framework.

While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.

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.

Additional health reform measures may continue and affect our business in unknown ways, particularly given the recent change in administration.

The current Trump administration is pursuing policies to reduce regulations and expenditures across government including at HHS, the FDA, CMS and related agencies.

These actions, presently directed by executive orders or memoranda from the Office of Management and Budget, may propose policy changes that create additional uncertainty for our business.

These actions may include, for example, directives to reduce agency workforce, rescinding a Biden administration executive order tasking the Center for Medicare and Medicaid Innovation, or CMMI, to consider new payment and healthcare models to limit drug spending and eliminating the Biden administration’s executive order that directed HHS to establishing an AI task force and developing a strategic plan, and directing certain federal agencies to enforce existing law regarding hospital and price plan transparency and by standardizing prices across hospitals and health plans.

Additionally, in its June 2024 decision in Loper Bright Enterprises v.

Raimondo, or Loper Bright, the U.S.

Supreme Court overturned the longstanding Chevron doctrine, under which courts were required to give deference to regulatory agencies’ reasonable interpretations of ambiguous federal statutes.

The Loper Bright decision could result in additional legal challenges to current regulations and guidance issued by federal agencies applicable to our operations, including those issued by the FDA.

Congress may introduce and ultimately pass health care related legislation that could impact the drug approval process and make changes to the Medicare Drug Price Negotiation Program created under the IRA.

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.

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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.

• 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;

• the federal Health Insurance Portability and Accountability Act of 1996, or 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;

federal Health Insurance Portability and Accountability Act of 1996, or 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;

• 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;

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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, or comparable foreign programs, integrity obligations, contractual damages, reputational harm, diminished profits and future earnings, and the curtailment or

restructuring of our operations.

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, or comparable foreign programs, 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.

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The GDPR also imposes strict rules on the transfer of personal data outside of the EEA to countries that do not ensure an adequate level of protection, such as the U.S.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the EEA Member States may result in fines up to 20 million Euros or 4% of a company’s global annual revenues for the preceding financial year, whichever is higher.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the EEA Member States may result in fines up to €20 million or 4% of a company’s global annual revenues for the preceding financial year, whichever is higher.

Moreover, the GDPR grants data subjects the right to claim compensation for damages resulting from infringement of the GDPR.

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As of December 31, 2024, we had 109 full-time employees, including approximately 25 with M.D.

degrees, and 1 part-time employee.

degrees, and one part-time employee.

Most of these employees, are engaged in research and development, clinical development and operations, medical affairs, and biostatistics activities.

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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.

We are registered at the Nanterre Commerce and Companies Register under the number 441 772 522.

Our principal executive offices are located at 107 Av.

de la République, 92320 Châtillon , 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.

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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