What changed in this filing

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Item 1. Business

2024-03-07 compared with 2023-03-02 · 352 added, 257 removed, 646 unchanged (49% of the section changed)

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

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

We also have an ongoing Phase 3 trial of Viaskin Peanut in children ages four to seven with peanut allergy.

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.

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

Presentation and

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

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.

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

In addition, the constant vigilance required to avoid allergen exposure can affect the quality of life of peanut-allergic children

and their parents/caregivers.

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

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

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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.

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.

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

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

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

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

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.

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

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

Allergen applied via EPIT is captured in the superficial layers of the skin by specialized antigen presenting cells (Langerhans cells within the epidermis), as well as dermal dendritic cells, thus limiting exposure to the bloodstream.

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

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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.

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:

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Langerhans cells.

These cells can take the protein at the surface of the skin, process it and present its epitopes to the lymphocytes in the lymph nodes.

These cells can capture the protein at the surface of the skin, process it and present its epitopes to the T-lymphocytes in the lymph nodes.

Langerhans cells in the epidermis capturing peanut allergen (depicted in green) within the stratum corneum (the outermost layer of the skin) following solubilization of allergen and permeation into the skin after Viaskin patch application.

Our Product Candidates

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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.

The program comprised the following clinical trials:

PEPITES ( P eanut EPIT E fficacy and S afety 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.

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.

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 (PEPITES OP en L abel E xtension S tudy) , a long-term, open-label extension trial of Viaskin Peanut 250 µg.

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

PEOPLE (PEP IT ES O Pen L abel Ext e nsion 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.

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

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United States Regulatory History

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

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.

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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,

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.

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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 cVP and mVP.

‘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.

CHAMP in the second quarter of 2021.

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

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

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), and submit the allergen uptake comparison data for FDA review and feedback prior to starting the STAMP study.

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.

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

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

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.

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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.

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 ( Pe anut EPIT Ef ficacy and Sa fety Study)

PEPITES ( Pea nut EPIT Eff icacy and Saf ety 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 2 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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For patients with a baseline peanut protein ED equal to or less than 10 mg, a responder was defined as a patient with a peanut protein ED equal to or greater than 300 mg of peanut protein after 12 months of treatment.

For patients with a baseline ED greater than

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

For patients with a baseline ED greater than 10 mg but less than or equal to 300 mg, a responder was defined as a patient with a peanut protein ED equal to or greater than 1,000 mg of peanut protein after 12 months of treatment.

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

Serological markers were also measured at baseline, three, six and

12 months to characterize the immunological changes observed in patients.

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

Results of PEPITES Trial

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However, the primary endpoint, which evaluated the 95% CI in the difference in response rates between the active and placebo arms, did not reach the 15% lower bound of the CI that was proposed in the study’s Statistical Analysis Plan submitted to the FDA.

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

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

906 mg (median 444 mg) and 361 mg (median 144 mg) of peanut protein, respectively.

The clinical relevance of this is not known.

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

With respect to CRD, a key secondary endpoint which measures threshold reactivity during the DBPCFC, we observed that at month 12, patients treated with Viaskin Peanut 250 µg or placebo reached a mean CRD of 906 mg (median 444 mg) and 361 mg (median 144 mg) of peanut protein, respectively.

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

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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.

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

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

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

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

Median peanut-specific IgG4 were observed to increase over time in

the Viaskin Peanut group (change from baseline at month 3:

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

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

The change from baseline in

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

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

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

PEPITES Immunological Responses

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

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

28% in placebo) at 12 months.

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

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.

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

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

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

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

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0.8% placebo group).

Ten cases in eight Viaskin Peanut

patients (3.4%) of possibly or probably treatment-related anaphylaxis occurred, and all were classified as mild or moderate without evidence of cardiovascular, neurologic, or respiratory compromise.

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

Following the completion of PEPITES, all patients were eligible to enroll in PEOPLE ( Open-Label Follow-Up Study of the PEPITES Study to Evaluate the Long-term Efficacy and Safety of Viaskin Peanut ), a long-term, open-label extension trial of Peanut 250 µg in children.

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

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

PEOPLE ( PE PITES Ope n La bel Ex tension St udy)

In January 2020, we announced positive topline results of the three-year, open-label extension of our Phase 3 PEPITES trial, or PEOPLE trial, evaluating the long-term efficacy and safety of investigational Viaskin Peanut in peanut-allergic children ages four to 11 years.

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

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

Following the completion of PEPITES, all eligible subjects were invited to enroll in PEOPLE ( Open-Label Follow-Up Study of the PEPITES Study to Evaluate the Long-term Efficacy and Safety of Viaskin Peanut ), a long-term, open-label extension trial of Peanut 250 µg in children.

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

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

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

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.

The last patient visit of the PEOPLE trial occurred on October 12, 2022.

In January 2020, we announced positive topline results up to Year 3 from the open-label extension of our Phase 3 PEPITES trial, or PEOPLE trial, evaluating the long-term efficacy and safety of investigational Viaskin Peanut in peanut-allergic children ages four to 11 years.

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

The PEOPLE trial, which 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.

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.

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

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

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

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

The last patient last visit of the PEOPLE trial occurred on October 12, 2022.

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

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

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

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

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

Topline results from Year 3 of PEOPLE support the long-term tolerability and clinical benefit of Viaskin Peanut, demonstrating desensitization over 36 months of treatment, with 75.9% (107/141) of patients increasing their ED from baseline.

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

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

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

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

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.

J Allergy Clin Immunol.

2020;146:863-874).

The safety profile of Viaskin Peanut was consistent with that observed in the clinical program to date in over 1,000 study participants aged 4-11 years old.

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

No treatment related serious adverse events were reported.

One patient experienced one case of mild anaphylaxis that was

determined by the investigator to be possibly related to treatment and resolved without treatment.

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

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

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In November 2016, we initiated a Phase 3 trial in peanut-allergic children four to 11 years of age designed to assess the use and safety of Viaskin Peanut 250 µg in routine clinical practice.

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

REALISE was a multicenter, randomized 3:1, double-blind, placebo-controlled Phase 3 trial, in which pediatric peanut allergic subjects were treated with Viaskin Peanut 250 µg or placebo for six months, followed by an open-label extension period in which all participants were offered up to 36 months total of active treatment.

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

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

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

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

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

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

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

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

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

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

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

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

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

Results of REALISE Trial

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

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

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

The patient responded to standard outpatient therapy.

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

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

The subject responded to standard outpatient therapy.

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

The mean patient compliance was above 95%.

The mean participant compliance was above 95%.

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

Viaskin Peanut for Children ages 1-3

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

In August 2017, we initiated Part A of the EPITOPE (EPIT in Toddlers with Peanut Allergy) trial of Viaskin

EPITOPE is a two-part, pivotal Phase 3 clinical trial assessing the safety and efficacy of Viaskin Peanut 250 µg for the treatment of peanut-allergic toddlers one to three years of age.

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 patient was enrolled in Part B of EPITOPE.

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

On 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 being studied in Part B of the study.

Enrollment of Part B of EPITOPE was complete in first quarter of 2021.

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.

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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 who reached an ED ≥1,000 mg of peanut protein at month 12.

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.

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

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

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.

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

We plan to present full EPITOPE trial results at future medical congresses as well as submit them for publication in a peer-reviewed journal.

In addition, we intend to further analyze the data from EPITOPE and explore regulatory pathways for Viaskin Peanut in children ages 1 to 3 years, given the high unmet need and absence of approved treatments for this vulnerable population.

We initiated the EPOPEX trial, which is an ongoing open-label extension study evaluating the long-term clinical benefit and safety of Viaskin Peanut 250 m g in subjects who have completed the Phase III EPITOPE trial.

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.

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 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 Viaskin Peanut patch in children ages 4-7 years with peanut allergy in two Phase III clinical trials with the intent for the trials to support a future BLA submission.

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)/Ethics Committee (EC) approval.

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.

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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.

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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.

We expect to initiate patient screening in Q1 2023 with the last patient screened in 1H 2024 and topline results are anticipated in 1H 2025.

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

We plan to initiate a separate safety study in approximately 275 additional subjects, randomized 3:1 active versus placebo.

The additional safety data generated by this six-month study will supplement the safety data generated by the VITESSE trial, resulting in a safety database comprised of approximately 600 children ages 4 to 7 years treated with Viaskin Peanut.

The protocol design of the safety study will be submitted to the FDA and is expected to be similar to the REALISE (REAL Life Use and Safety of EPIT) safety study that we previously conducted with Viaskin Peanut in children ages 4 to 11 years.

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.

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 patients with Immunoglobulin E, or IgE, mediated CMPA, which we refer to as the Milk Efficacy and Safety, or MILES, trial.

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.

September 2016.

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:

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

Following analyses of the data, the 300 µg dose of Viaskin Milk was identified as the dose with the greatest observed clinical activity for

children (intent-to-treat, or ITT, p=0.042).

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

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

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

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

Our other earlier stage research programs have included vaccination for respiratory syncytial virus (RSV), as well as potential treatments for inflammatory bowel disease (IBD), celiac disease and type I diabetes.

Diagnostic Tool Development

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

In May 2016, we announced our entry into an exclusive global collaboration with Nestlé Health Science to develop MAG1C, a ready-to-use and standardized atopy patch test tool for the diagnosis of CMPA (non-mediated IgE) in infants and children under 2 years old.

Under the terms of the exclusive collaboration, we are responsible for leading the development activities of MAG1C up through a pivotal Phase 3 clinical program, and if the appropriate regulatory approvals are received, Nestlé Health Science will support the commercialization of MAG1C globally.

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

We are currently conducting a Phase 2 clinical trial of MAG1C.

In May 2016, we entered into a Development Collaboration and License Agreement (the “Collaboration Agreement”) with Société des Produits Nestlé S.A.

(formerly NESTEC S.A.) (“NESTEC”).

The Collaboration Agreement related to an exclusive global collaboration with Nestlé Health Science for the development and, if approved, commercialization of MAG1C, a ready-to-use and standardized atopy patch test tool for the diagnosis of CMPA (non-mediated IgE) in infants.

Under the terms of the Collaboration Agreement, the Company was responsible for leading the development activities of MAG1C up through a pivotal Phase 3 clinical program, and if the appropriate regulatory approvals were received, Nestlé Health Science would support the commercialization of MAG1C globally.

The Company was eligible to receive up to €100.0 million in potential development, clinical, regulatory and commercial milestones, including an upfront payment of €10.0 million received in July 2016.

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.

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.

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

Potential Biomarker Applications

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

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

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

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

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.

maintained once treatment is completed.

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

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

Manufacturing and Supply

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We currently rely on a single contract manufacturer to manufacture and supply the active pharmaceutical ingredients (“API”) used in our Viaskin product candidates.

On February 1, 2018, we entered to a Master API Supply Agreement with Sanofi which sets forth the terms and conditions governing the manufacture and supply of peanut, milk and egg API to be used in our Viaskin product candidates.

The agreement expires on a Viaskin product basis five years after the first date of regulatory approval of the applicable Viaskin product candidate and requires us to purchase at least 75% of our required API from Sanofi.

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

On February 1, 2018, we entered into a Master API Supply Agreement with Sanofi which sets forth the terms and conditions governing the manufacture and supply of peanut, milk and egg API to be used in our Viaskin product candidates.

The agreement expires on a Viaskin product basis five years after the first date of regulatory approval in any jurisdiction of the applicable Viaskin product candidate and requires us to purchase at least 75% of our required API from Sanofi.

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

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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.

These patents and applications generally fall into four broad categories:

two patents and patent applications relating to the Viaskin electrostatic patch and its use, half of which expired in 2022;

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

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

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.

Patent Term Restoration and Marketing Exclusivity

Patent Term Extension and Marketing Exclusivity

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

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

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

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

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

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.

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

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

PTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

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

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.

Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent, and within 60 days of the FDA’s approval of the product.

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.

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

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

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

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

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

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

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.

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

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

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

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

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

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

Co-Ownership Agreement

AP-HP and Université de Paris-Descartes

In December 2008, we entered into an assignment, development and co-ownership agreement with AP-HP and Université Paris-Descartes, or UPD (which through a merger and a name change became Université Paris Cité), by which we agreed to terms of co-ownership with AP-HP and Université Paris Cité of certain U.S.

AP-HP and Université Paris Cité (formerly known as Université de Paris-Descartes)

In December 2008, we entered into an assignment, development and co-ownership agreement with AP-HP and Université Paris-Descartes, which through a merger and a name change became Université Paris Cité, by which we agreed to terms of co-ownership with AP-HP and Université Paris Cité of certain U.S.

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

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

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

Any party may terminate the assignment, development and co-ownership agreement in the event of another party’s substantial breach which remains uncured after six months of receiving written notice of such breach.

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

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

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

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

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

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

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

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

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

quality and breadth of an organization’s technology;

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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subcutaneous, or SCIT;

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

oral mucosal, or OMIT;

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

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

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

acquired Aimmune in October 2020 and divested the Palforzia business to Stallergenes Greer in September 2023.

In addition, Xolair (omalizumab) is approved by the FDA for the reduction of allergic reactions including reducing the risk of anaphylaxis, that may occur with accidental exposure to one or more food allergens, including peanut.

Omalizumab is an anti-immunoglobulin E (IgE) monoclonal antibody that is administered via subcutaneous injection.

The prescribing information for both Palforzia and Xolair indicate patients should continue to avoid all foods to which they are allergic.

Government Regulation

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

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

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

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

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

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

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

The clinical stage of development involves the administration of the product candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial 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.

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.

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.

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

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

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

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

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

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

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

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

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

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.

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

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

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

Phase 2 clinical trials typically involve studies in disease-affected patients to determine the dose required to produce the desired benefits.

Phase 2 clinical trials, if Phase 1 trials do not reveal unacceptable toxicity, typically involve studies in disease-affected patients to determine the dose required to produce the desired benefits.

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

Phase 3 clinical trials generally involve large numbers of patients at multiple sites, in multiple countries (from several hundred to several thousand subjects) and are designed to provide the data necessary to demonstrate the efficacy of the product for its intended use, its safety in use, and to establish the overall benefit/risk relationship of the product and provide an adequate basis for product approval.

Phase 3 clinical trials generally involve large numbers of subjects at multiple sites, in multiple countries (from several hundred to several thousand subjects) and are designed to provide the data necessary to demonstrate the efficacy of the product candidate for its intended use, its safety in use, and to establish the overall benefit/risk relationship of the product candidate and provide an adequate basis for product approval.

Phase 3 clinical trials may include comparisons with placebo and/or other comparator treatments.

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

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

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.

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

These trials are used to gather information about a product candidate’s safety, efficacy, and optimal use from the treatment of subjects in the intended therapeutic indication.

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

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators for serious and unexpected suspected adverse, findings from other studies suggesting a significant risk to humans exposed to the drug, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important rate increase of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

Progress reports detailing the results of a clinical trial must be submitted periodically to the FDA.

Written IND safety reports must be submitted to the FDA and the investigators for serious and unexpected suspected adverse, findings from other studies suggesting a significant risk to humans exposed to the drug, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important rate increase of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, if at all.

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

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

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.

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

This group provides

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

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

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

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

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

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BLA and FDA Review Process

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

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

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

Following completion of a clinical trial, data generated from such trial is analyzed to assess safety and efficacy.

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

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

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

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

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

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

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

PDUFA also imposes an annual program fee for approved drugs.

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

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

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.

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.

whether the application should be approved and under what conditions.

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

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

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

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

The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

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

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

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

The FDA will not approve the product candidate unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and are adequate to assure consistent production of the product candidate within required specifications.

In addition, before approving a BLA, the FDA may also audit data from clinical trials to ensure compliance with GCP requirements.

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A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form.

A Complete Response Letter usually describes all of the specific deficiencies in the BLA identified by the FDA.

A Complete Response Letter usually describes the specific deficiencies in the BLA identified by the FDA.

The Complete Response Letter may require additional clinical data and/or an additional pivotal Phase 3 clinical trial(s), and/or other significant and time-consuming requirements related to clinical trials, pre-clinical studies or manufacturing.

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Even if such data and information is submitted, the FDA may ultimately decide that the BLA does not satisfy the criteria for approval.

Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.

There is no assurance that the FDA will ultimately approve a product for marketing in the United States and we may encounter significant difficulties or costs during the review process.

Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than a sponsor interprets the same data.

There is no assurance that the FDA will ultimately approve a product for marketing in the United States and a sponsor may encounter significant difficulties or costs during the review process.

If a product receives marketing approval, the approval may be significantly limited to specific populations, severities of allergies, and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product.

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two or more separate products packaged together in a single package or as a unit and comprised of drug and device products;

approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose;

a drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device or biological where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose;

any investigational drug, device, or biological packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.

Our Viaskin product candidates are combination products comprising a device for delivery of a biologic.

Our Viaskin product candidates are combination products comprising a device for delivery of a biologic product.

Under the FDCA, the FDA is charged with assigning a center with primary jurisdiction, or a lead center, for review of a combination product.

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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.

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.

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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The limitations imposed would be commensurate with the specific safety concerns presented by the product.

In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

In addition, the FDA currently requires pre-approval of promotional materials as a condition for accelerated approval, which could adversely impact the timing of the commercial launch of the product.

Fast track designation, priority review and accelerated approval do not change the standards for approval but may expedite the development or approval process.

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Following approval of a new product, a manufacturer and the approved product are subject to continuing regulation by the FDA, including, among other things, monitoring and recordkeeping activities, reporting to the applicable regulatory authorities of adverse experiences with the product, providing the regulatory authorities with updated safety and efficacy information, product sampling and distribution requirements, and complying with promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting products for uses or in patient populations that are not described in the product’s approved labeling, also known as off-label use, limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

Although physicians may prescribe legally available drugs and biologics for off-label uses, manufacturers may not market or promote

such off-label uses.

Although physicians may prescribe legally available drugs and biologics for off-label uses, manufacturers may not market or promote such off-label uses.

Modifications or enhancements to the product or its labeling or changes of the site of manufacture are often subject to the approval of the FDA and other regulators, which may or may not be received or may result in a lengthy review process.

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The handling of any controlled substances must comply with the U.S.

Controlled Substances Act and Controlled Substances

Import and Export Act.

Controlled Substances Act and Controlled Substances Import and Export Act.

Products must meet applicable child-resistant packaging requirements under the U.S.

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European Union Drug Development

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

In the European Union, or the EU, product candidates may also be 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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Clinical Trials in the EU

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

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.

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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 CTD.

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.

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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.

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 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 reference 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 Member States in which the trial is to be conducted for their review.

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

Each concerned Member State will issue a single decision on the authorization of the clinical trial including input from the national competent authority and Ethics Committee.

Each concerned EU Member State will issue a single decision on the authorization of the clinical trial including input from the national competent authority and Ethics Committee.

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

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The publication of data and documents in relation to the conduct of a clinical trial will take place in accordance with specific timelines.

The timelines are established by the EMA and are determined based on the documents and the categorization of the clinical trial.

In addition, sponsors of clinical trials may apply for deferral of publication of certain documents at the time of submission of the initial clinical trial application.

The application for deferral of publication should be based on justified grounds and include a reasoned proposed deferral period.

Applications for deferral of publication are subject to the approval of concerned EU Member States.

The extent to which on-going clinical trials will be governed by the CTR will depend on the timing at which an application for the authorization of a clinical trial is submitted and the duration of the individual clinical trial.

Sponsors can choose to submit a clinical trial application under either the CTD or the CTR until January 31, 2023.

For clinical trials in relation to which application for authorization was made on the basis of the CTD before January 31, 2022, the CTD will continue to apply on a transitional basis for three years and, if authorized, those clinical trials will be governed by the CTD until January 31, 2025.

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 clinical trial has already transitioned to the CTR framework.

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.

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.

Medicines used in clinical trials, including ATMPs, must be manufactured in accordance with the guidelines on cGMP and in a GMP licensed facility, which can be subject to GMP inspections.

Medicines used in clinical trials, including advanced therapy medicinal products, or ATMPs, must be manufactured in accordance with the guidelines on cGMP and in a GMP licensed facility, which can be subject to GMP inspections.

European Union Drug Review and Approval

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

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).

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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) advanced therapy medicinal products, or 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.

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.

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.

Once subsequently definitively renewed, the MA shall be valid for an unlimited period.

Any authorization which is not followed by the actual placing of the

medicinal product on the EU market (for a centralized MA) or on the market of the authorizing EU Member State within three years after authorization ceases to be valid (the so-called sunset clause).

Any authorization which is not followed by the actual placing of the medicinal product on the EU market (for a centralized MA) or on the market of the authorizing EU Member State within three years after authorization ceases to be valid (the so-called sunset clause).

Innovative products that target an unmet medical need and are expected to be of major public health interest may be eligible for a number of expedited development and review programs, such as the Priority Medicines, or PRIME, scheme, which provides incentives similar to the breakthrough therapy designation in the U.S.

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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 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 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.

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.

Once the MA is obtained in all EU Member States and

study results are included in the product information, even when negative, the product is eligible for a six-month extension to the Supplementary Protection Certificate, or SPC, if any is in effect at the time of authorization or, in the case of orphan medicinal products, a two-year extension of orphan market exclusivity.

Once the MA is obtained in all EU Member States and study results are included in the product information, even when negative, the product is eligible for a six-month extension to the Supplementary Protection Certificate, or SPC, if any is in effect at the time of authorization or, in the case of orphan medicinal products, a two-year extension of orphan market exclusivity.

Data and Market Exclusivity

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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, 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.

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.

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.

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.

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Combination Products

In the EU, products that are a combination of a medicinal product and a medical device are regulated as either a medicinal product or a medical device, depending on which component has the primary mode of action.

Medical devices that incorporate a medicinal product as an integral part that has an action ancillary to the action of the medical device are regulated as medical devices in accordance with Regulation (EU) 2017/745 on Medical Devices, or MDR.

The EU regulates medical devices and medicinal products separately, and through different legislative instruments.

Products that are a combination of a medicinal product and a medical device may be regulated as either a medicinal product, a medical device or, subject to certain requirements, on the basis of both sets of rules.

The applicable requirements governing placing a drug-device combination on the EU market will vary depending on the type of drug-device combination product and on which of the components of the combination has the primary mode of action.

Drug-device combination products that form a single integral product that is not reusable and for which the action of the medicinal product is principal to that of the medical device are governed by the regulatory framework applicable to medicinal products.

However, the General Safety and Performance Requirements, or GSPRs, of Annex I to Regulation (EU) 2017/745 on Medical Devices, or MDR, will be applicable to the safety and performance of the medical device part of the product in the context of its use with the medicinal product.

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.

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.

Based on this approach, the competent authorities responsible for medicinal products will review the specific aspects of the medical devices part of the product which are relevant to the safety and efficacy of the medicinal product and the Notified Body – where applicable – will evaluate the relevant GSPRs of the device.

Drug-device combination products that form a single integral product that is not reusable and for which the action of the medicinal products is ancillary to that of the medical device are governed by the regulatory framework applicable to MDR.

However, the quality, safety and usefulness of the medicinal product must also be verified as part of the device and a scientific opinion from a national competent authority of an EU Member State or from the EMA, depending on its nature and therapeutic intention, must be sought regarding the quality and safety of the medicinal product, including the benefit or risk of its incorporation into the medical device.

Where a medical device incorporates a medicinal product as an integral part as a single use drug delivery system, it is regulated as a medicinal product.

In this case, the relevant General Safety and Performance Requirements, or GSPRs of the MDR will apply to the safety and performance of the device element.

Where the primary mode of action of the combined product comes from the medicinal product , it is regulated as a medicinal product.

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.

Other Regulatory Matters

The United Kingdom’s, or UK, withdrawal from the EU on January 31, 2020, commonly referred to as Brexit, has created significant uncertainty concerning the future relationship between the UK and the EU.

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

On December 24, 2020, the EU and UK reached an agreement in principle on the framework for their future relationship, the EU-UK Trade and Cooperation Agreement, or Agreement.

The Agreement primarily focuses on ensuring free trade between the EU and the UK in relation to goods, including medicinal products.

Although the body of the Agreement includes general terms which apply to medicinal products, greater detail on sector-specific issues is provided in an Annex to the Agreement.

Among the changes that will now occur, Great Britain (England, Scotland and Wales) will be treated as a third country.

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

As part of the Agreement, the EU and the UK will recognize GMP inspections carried out by the other party and the acceptance of official GMP documents issued by the other party.

The Agreement also encourages, although it does not oblige, the parties to consult one another on proposals to introduce significant changes to technical regulations or inspection procedures.

Among the areas of absence of mutual recognition are batch testing and batch release.

The UK has unilaterally agreed to accept EU batch testing and batch release.

However, the EU continues to apply EU laws that require batch testing and batch release to take place in the EU territory.

This means that medicinal products that are tested and released in the UK must be retested and re-released when entering the EU market for commercial use.

Regarding marketing authorizations, Great Britain has a separate regulatory submission process, approval process and a national marketing authorization.

Northern Ireland will, however, continue to be covered by the marketing authorizations granted by the European Commission.

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

Since this date, companies established in the UK cannot use the centralized procedure and instead must follow one of the UK national authorization procedures to obtain an MA to market products in the UK.

Until December 31, 2023, MHRA may rely on a decision taken by the European Commission on the approval of a new centralized procedure marketing authorization when determining an application for a Great Britain marketing authorization.

From January 1, 2024, a new international recognition process, which will have regard to decisions made by the EMA and certain other regulatory, is anticipated to be in place.

The MHRA has also established its own decentralized or mutual recognition procedures which enable marketing authorizations approved in EU Member States through decentralized and mutual recognition procedures to be recognised in the United Kingdom or Great Britain.

Since Brexit, the MHRA has been updating various aspects of the regulatory regime for medicinal products in the UK.

These include:

introducing the Innovative Licensing and Access Procedure to accelerate the time to market and

facilitate patient access for innovative medicinal products;

updates to the UK national approval procedure, introducing a 150-day objective for assessing applications for marketing authorizations in the UK, Great Britain and Northern Ireland and a rolling review process for marketing authorization applications (rather than a consolidated full dossier submission).

It is currently unclear to what extent the UK will seek to align its regulations with the EU in the future.

The UK regulatory framework in relation to clinical trials and marketing authorization is derived from existing EU legislation (as implemented into UK law, through secondary legislation).

However, the Retained EU Law (Revocation and Reform) Bill published in late 2022 which is intended to remove all EU-derived legislation from the UK statute book by the end of 2023, may result in a divergence of approach between the EU and the UK.

UK Regulations

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 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.

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.

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

Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding marketing authorization application.

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.

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.

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.

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Third-party payors may limit coverage to specific drug products on an approved list, also known as a formulary, which might not include all of the FDA approved drugs for a particular indication.

In order to secure coverage and reimbursement for any product candidate that might be approved for sale, we may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost- effectiveness of the product candidate, in addition to the costs required to obtain FDA or other comparable regulatory approvals.

In order to secure coverage and reimbursement for any product candidate that might be approved for sale, sponsors may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost- effectiveness of the product candidate, in addition to the costs required to obtain FDA or other comparable regulatory approvals.

Whether or not we conduct such studies, our product candidates may not be considered medically necessary or cost-effective.

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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

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

For example, on June 17, 2021 the U.S.

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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.

Under current legislation the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester.

On January 2, 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, or the ATRA, which among other things, also reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

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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, 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 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.

Further, the Biden administration released an additional executive order on October 14, 2022, directing HHS to submit a report on how the Center for Medicare and Medicaid Innovation can be further leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.

It is unclear whether this executive order or similar policy initiatives will be implemented in the future.

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.

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.

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.

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For example, the European Union provides options for its Member States to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

A Member State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

An EU Member State may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market.

In France, for example, effective access to the market can be achieved either at a free price, decided by the pharmaceutical company, or with a system of cover/reimbursement with a price regulated by the authorities.

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Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor.

The intent standard under the federal Anti-Kickback Statute was amended by the ACA to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to

violate it in order to have committed a violation.

Moreover, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act;

federal civil and criminal false claims laws, including the federal civil False Claims Act, which impose penalties and provide for civil whistleblower or qui tam actions, and civil monetary penalty laws, which prohibit, among other things, knowingly presenting, or causing to be presented, claims for payment from Medicare, Medicaid, or other third-party payors that are false or fraudulent, or making a false statement or record material to payment of a false claim or avoiding, decreasing, or concealing an obligation to pay money to the federal government, including for example, providing inaccurate billing or coding information to customers or promoting a product off-label;

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.

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the federal Physician Payments Sunshine Act, enacted as part of the ACA, which requires applicable manufacturers of covered drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to track and annually report to CMS payments and other transfers of value provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals and information regarding certain ownership and investment interests held by physicians or their immediate family members;

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and its implementing regulations, which imposes certain requirements on covered entities and their business associates, and their covered subcontractors, relating to the privacy, security and transmission of individually identifiable health information;

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;

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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and state and foreign laws governing the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect as HIPAA, thus complicating compliance efforts.

Outside the United States, interactions between pharmaceutical companies and health care professionals are also governed by strict laws, such as national anti-bribery laws of EU Member States, national sunshine rules and regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct.

Outside the United States, interactions between pharmaceutical companies and healthcare professionals are also governed by strict laws, such as national anti-bribery laws of EU Member States, national sunshine rules and regulations, industry self-regulation codes of conduct and physicians’ codes of professional conduct.

Failure to comply with these requirements could result in administrative penalties, fines or imprisonment, reputational risk and public reprimands.

Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws will involve substantial costs.

It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and

abuse or other healthcare laws.

If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant administrative, civil, and/or criminal penalties, damages, fines, disgorgement, individual imprisonment, exclusion from government funded healthcare programs, such as Medicare and Medicaid, or comparable foreign programs, integrity obligations, contractual damages, reputational harm, diminished profits and future earnings, and the curtailment or restructuring of our operations.

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.

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.

Data Privacy and Security

We are subject to stringent and evolving United States and foreign laws, regulations, rules, contractual obligations, policies and other obligations related to data privacy and security, including the European Union’s General Data Protection Regulation ((EU) 2016/679), or GDPR, and the United Kingdom’s General Data Protection Regulation, or UK GDPR.

We are subject to stringent and evolving United States and foreign laws, regulations, rules, contractual obligations, policies and other obligations related to data privacy and security, including the EU’s General Data Protection Regulation ((EU) 2016/679), or GDPR, and the UK’s General Data Protection Regulation, or UK GDPR.

New privacy rules are being enacted in the United States and globally, and existing ones are being expanded, updated and strengthened.

The collection and use of personal health data in the EEA is governed by the GDPR, which became effective on May 25, 2018.

The GDPR applies to any company established in the EEA and to companies established outside the EEA that process personal data in connection with the offering of goods or services to data subjects in the EU or the monitoring of the behavior of data subjects in the European Union.

The GDPR enhances data protection obligations for controllers and processors of personal data, including stringent requirements relating to the consent of data subjects, expanded disclosures about how personal data is used, requirements to conduct privacy impact assessments for high-risk processing, limitations on retention of personal data and mandatory data breach notification and privacy by design requirements, and creates direct obligations on service providers acting as data processors.

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

Following the United Kingdom’s withdrawal and the expiration of the transition period, from January 31, 2020, companies doing business in the EU and the UK will be obliged to comply with both the GDPR and the UK GDPR.

Following the UK’s withdrawal and the expiration of the transition period, from January 31, 2020, companies doing business in the EU and the UK will be obliged to comply with both the GDPR and the UK GDPR.

On June 28, 2021, the European Commission adopted an adequacy decision permitting flows of personal data between the EU and the UK to continue without additional requirements.

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The relationship between the UK and the EU in relation to certain aspects of data protection law remains unclear, and it is unclear how UK data protection laws and regulations will develop in the medium to longer term, and how data transfers to and from the UK will be regulated in the long term.

Employees and Human Capital Resources

As of December 31, 2023, we had 104 full-time employees, including approximately 23 with M.D.

degrees, and 1 part-time employee.

Of these employees, 29 employees are engaged in research and development, clinical development and operations, medical affairs, and biostatistics activities and 26 employees are engaged in general and administrative activities.

We consider the relationship with our employees to be good.

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

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.

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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.

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.

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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