What changed in this filing

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Item 1. Business

2022-03-31 compared with 2021-03-23 · 478 added, 407 removed, 648 unchanged (58% of the section changed)

We are a late-stage clinical biopharmaceutical company focused on developing novel cancer immunotherapeutics for a broad range of cancer indications.

Our product candidates currently include galinpepimut-S and nelipepimut-S.

Galinpepimut-S, or GPS

Our lead product candidate, galinpepimut-S, or GPS, is a cancer immunotherapeutic agent licensed from Memorial Sloan Kettering Cancer Center, or MSK, that targets the Wilms tumor 1, or WT1, protein, which is present in 20 or more cancer types.

Our product candidates currently include galinpepimut-S, or GPS, and nelipepimut-S, or NPS.

Galinpepimut-S

Our lead product candidate, GPS, is a cancer immunotherapeutic agent licensed from Memorial Sloan Kettering Cancer Center, or MSK, that targets the Wilms tumor 1, or WT1, protein, which is present in 20 or more cancer types.

Based on its mechanism of action as a directly immunizing agent, GPS has potential as a monotherapy or in combination with other immunotherapeutic agents to address a broad spectrum of hematologic, or blood, cancers and solid tumor indications.

In January 2020, we commenced in the United States a Phase 3 clinical trial, the REGAL study, for GPS monotherapy in patients with acute myeloid leukemia, or AML, in the maintenance setting after achievement of second complete remission, or CRem2, following successful completion of second-line antileukemic therapy.

In January 2020, we commenced in the United States a Phase 3 clinical trial, the REGAL study, for GPS monotherapy in patients with acute myeloid leukemia, or AML, in the maintenance setting after achievement of second complete remission, or CR2, following successful completion of second-line antileukemic therapy.

We expect this study will be used as the basis for submission of a Biologics License Application, or BLA, subject to a statistically significant and clinically meaningful data outcome and agreement with the U.S.

Food & Drug Administration, or the FDA.

In the second half of 2020, we received approval from each of the French and German regulatory authorities to advance the REGAL study in France and Germany, respectively.

We expect approvals from additional European health authorities in early 2021 which will allow us to expand AML patient enrollment for the REGAL study in Europe.

We plan to enroll approximately 116 patients at up to approximately 135 clinical sites primarily in the United States and Europe with a planned interim safety and futility analysis after 80 events (deaths) which we anticipate will take place in the first half of 2022, provided that the ongoing COVID-19 pandemic does not significantly adversely impact our projected timeline for enrollment.

We plan to enroll approximately 116 patients at up to approximately 85 clinical sites in the United States, Europe and Asia with a planned interim safety and futility analysis after 80 events (deaths).

Under our current planning assumptions, which take into account our best estimates of potential delays due to COVID-19, we believe that we will complete enrollment for the REGAL study in late 2022 or early in the first quarter of 2023.

Based upon these current assumptions with respect to completion of enrollment and the estimated survival times for both the treated and control groups in the study, we believe, after discussions with our external statisticians and experts, that the planned interim analysis after 80 events (deaths) per the protocol will occur by the end of the first half of 2023, provided that our statistical assumptions and assumptions regarding the impact of COVID-19 on the operations of our clinical sites as well as the duration of the pandemic remain unchanged.

Because this analysis is event driven, it may occur at a different time than currently expected.

In December 2020, we entered into an exclusive license agreement with 3D Medicines Inc., a China-based biopharmaceutical company developing next-generation immuno-oncology drugs, for the development and commercialization of GPS, as well as the Company’s next generation heptavalent immunotherapeutic GPS+, which is at preclinical stage, across all therapeutic and diagnostic uses in the Greater China territory (mainland China, Hong Kong, Macau and Taiwan).

We have retained sole rights to GPS and GPS+ outside of the Greater China area.

In January 2022, we announced that an IND application filed by 3D Medicines to initiate the first clinical trial in China for 3D189, also known as GPS, has been accepted by China’s National Medical Products Administration (“NMPA”).

The IND is for a small Phase I clinical trial investigating safety.

On March 30, 2022, the IND was approved by the NMPA triggering a $1.0 million milestone payment to the Company which is expected to be received in the second quarter of 2022.

In December 2018, pursuant to a Clinical Trial Collaboration and Supply Agreement, we initiated a Phase 1/2 multi-arm "basket" type clinical study of GPS in combination with Merck & Co., Inc.’s anti-PD-1 therapy, Keytruda® (pembrolizumab).

The tumor type currently being studied is ovarian cancer (second or third line).

We reported initial data from this study in December 2020 and we expect to report further clinical and immunobiological data by the end of the first half of 2021.

We, together with Merck, have determined not to pursue the following indications as part of the basket study:

colorectal cancer, triple negative breast cancer, small cell lung cancer, or SCLC, or AML, and we are exploring other additional potential indications to investigate in the study.

In 2020, we, together with Merck determined to focus on ovarian cancer (second or third line).

We reported updated clinical and initial immune response data from this study in June 2021.

In February 2022 we reported that we had completed enrollment of 17 evaluable patients in this study.

Data from 15 of the 17 evaluable patients is expected to be examined by mid-2022, with final data analysis for all evaluable patients expected by the end of 2022.

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In February 2020, a Phase I open-label investigator-sponsored clinical trial of GPS, in combination with Bristol-Myers Squibb’s anti-PD-1 therapy, nivolumab (Opdivo ® ), in patients with malignant pleural mesothelioma, or MPM, who harbor relapsed or refractory disease after having received frontline standard of care multimodality therapy was commenced at MSK.

In December 2020, we announced initial data from this study and we expect to report further clinical and immunobiological data by the end of the first half of 2021.

In June 2021, we announced updated data from this study.

Completion of enrollment of a target total of 10 evaluable patients is expected during the second half of 2022.

We expect to report additional clinical and immune response data in the first half of 2022.

GPS was granted Orphan Drug Product Designations from the FDA, as well as Orphan Medicinal Product Designations from the European Medicines Agency, or EMA, for GPS in AML, MPM, and multiple myeloma, or MM, as well as Fast Track Designation for AML, MPM, and MM from the FDA.

Nelipepimut-S or NPS

Nelipepimut-S, or NPS, is a cancer immunotherapy targeting the human epidermal growth factor receptor 2, or HER2, expressing cancers.

Data presented in 2018 from a Phase 2b clinical trial of the combination of trastuzumab (Herceptin®) plus NPS in HER2 low expressing (1+ or 2+ per immunohistochemistry, or IHC) breast cancer patients in the adjuvant setting to prevent recurrences showed a clinically and statistically significant improvement in the disease-free survival, or DFS, rate for the TNBC cohort at 24 months for patients treated with NPS plus trastuzumab of 92.6% compared to 70.2% for those treated with trastuzumab alone.

Following discussions with the FDA and based upon written feedback from the FDA and on the totality of clinical, safety and translational NPS data to date, we have finalized the design and plan for a Phase 3 registration-enabling study of NPS in combination with trastuzumab for the treatment of patients with TNBC in the adjuvant setting after standard treatment.

If successful, we believe this study may be considered as the basis for a BLA submission to the FDA.

We are seeking out-licensing opportunities to fund and conduct the future clinical development of NPS in order to maximize the potential of the program and we do not plan to conduct and fund a Phase 3 program for NPS on our own.

FBP-targeting bivalent vaccine (GALE-301/-302)

In order to prioritize development of our core assets, we determined to cease development of GALE-301 and GALE-302, cancer immunotherapies that target the E39 peptide derived from the folate binding protein, or FBP, which were licensed in from The Henry M.

Jackson Foundation, or HJF, and the MD Anderson Cancer Center, or MDACC.

We entered into a Termination Agreement with HJF and MDACC in February 2021.

Nelipepimut-S

NPS is a cancer immunotherapy targeting the human epidermal growth factor receptor 2, or HER2, expressing cancers.

Data presented in 2018 from a Phase 2b clinical trial of the combination of trastuzumab (Herceptin ® ) plus NPS in HER2 low expressing (1+ or 2+ per immunohistochemistry, or IHC) breast cancer patients in the adjuvant setting to prevent recurrences showed a clinically and statistically significant improvement in the disease-free survival, or DFS, rate for the cohort of patients with triple negative breast cancer, or TNBC, at 24 months for patients treated with NPS plus trastuzumab of 92.6% compared to 70.2% for those treated with trastuzumab alone.

Since 2018, largely based on this data, we have been seeking out-licensing opportunities to fund and conduct the future clinical development of NPS in TNBC in order to maximize the potential of the program as we do not plan to conduct and fund a Phase 3 program for NPS on our own.

After extensive effort, we have concluded that continued efforts to outlicense NPS for further development for breast cancer are unlikely to result in a licensing transaction commensurate with the value of the asset which we believe is due to the changing market for breast cancer therapies, the scope, cost and timeline for a Phase 3 trial which would satisfy regulatory requirements for the TNBC indication and the failure, in 2016, of the Phase 3 clinical trial of monotherapy NPS in breast cancer.

As we continue our out-licensing strategy, we are now focusing on the potential for NPS in other cancer indications.

The chart below summarizes the current status of our clinical development pipeline:

Recent Developments

Subsequent to December 31, 2020, we received $3.0 million of gross proceeds from the exercise of 830,200 warrants to acquire shares of common stock at a weighted average exercise price of $3.61.

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Merger of SELLAS Life Sciences Group Ltd.

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We refer to this business combination throughout this annual report on Form 10-K as the Merger.

Immediately after the Merger, the former Private SELLAS shareholders owned approximately 67.5% of our fully diluted common stock, and the pre-Merger shareholders owned the remaining approximately 32.5%.

As a result of the Merger, our business is now substantially comprised of the business of Private SELLAS, and although we are considered the legal acquiror of Private SELLAS, for accounting purposes, Private SELLAS is considered to have acquired our company in the Merger.

Consequently, the Merger is accounted for as a reverse acquisition.

Upon completion of the Merger, we changed our name from “Galena Biopharma, Inc.” to “SELLAS Life Sciences Group, Inc.,” our common stock began trading on The Nasdaq Capital Market, or Nasdaq, under a new ticker symbol “SLS” on January 2, 2018 and our financial statements became those of Private SELLAS.

As a result of the Merger, our business is now substantially comprised of the business of Private SELLAS, and our financial statements became those of Private SELLAS.

As used in this annual report on Form 10-K, the words “we,” “us,” “our,” the “Company,” and “SELLAS” refer to SELLAS Life Sciences Group, Inc.

and its consolidated subsidiaries following completion of the Merger.

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The Cancer Immunotherapy Industry

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Cancer immunotherapy is an important and rapidly emerging field, which has led to exciting new clinical research studies and garnered the attention of investors, biotechnology and pharmaceutical companies, regulatory agencies, payors and hospital systems, cancer patients and their families and the general public at large.

According to a January 2020 report by Kelly Scientific Publications, cancer immunotherapy drugs have already captured nearly 50% of the overall oncology drugs market in 2019, generating about $75 billion in that year alone and are forecast to surpass $115 billion in 2023.

Additionally, an October 2019 Allied Market Research report on the estimated entire market value of oncology drugs (of any type) suggests that cancer immunotherapies could represent up to 77% of that total value by 2023.

According to a report published in September 2018, it was projected that approximately 70% of the 2019 immunotherapy market would be comprised of checkpoint inhibitors (~30% of the market share), immune synapse co-stimulators and bispecific monoclonal antibodies (~40% of the market share), as well as approximately 30% of other immunotherapies, including chimeric antigen receptor (CAR) T-cell therapies and other cell-based modalities (e.g., ex vivo modified natural killer or NK cells).

It is predicted that the checkpoint inhibitor market share will decrease slightly by 2023, reaching a 27% value (from a 30% value in 2019), as novel therapies, including peptide cancer active immunizers (vaccines) such as our product candidates, GPS and NPS, and cell-based therapies, advance into regulatory approvals and use in the cancer market.

According to a January 2021 report by Kelly Scientific Publications, cancer immunotherapy drugs have captured nearly 50% of the overall oncology drugs market, generating approximately $75 billion in 2019 and are forecasted to surpass $143 billion in 2025.

A July 2021 Allied Market Research has estimated that the global cancer immunotherapy market could reach $309.6 billion by 2030, growing at a compound annual growth rate, or CAGR, of 14.1%.

The global immunotherapy market is currently comprised of bi-specific monoclonal antibodies and immune response co-stimulators, checkpoint inhibitors, and other immunotherapies including chimeric antigen receptor (CAR) T-cell therapies, other cell-based modalities and novel therapies.

It is predicted that the checkpoint inhibitor market share will decrease slightly by 2023, from approximately 30% in 2019 to approximately 27% value, as novel therapies, including peptide cancer active immunizers (vaccines) such as our product candidates, GPS and NPS, and cell-based therapies, advance into regulatory approvals and use in the cancer market.

With respect to the market for AML, a June 2021 report from Delvelnsight estimates a global market size of $5.09 billion by the end of 2030, with a CAGR of 21.85% from 2018 to 2030.

The total number of newly diagnosed patients with AML per year in the United States is approximately 20,050 (2022 epidemiological data:

American Cancer Society).

It is estimated that the number of adult patients of any age with AML in the United States per year who successfully enter into CRem2, the indication of our REGAL study, is approximately 2,000 patients and approximately 4,700 patients outside of the United States in the rest of the world, or ROW, while the number of patients who achieve first complete remission, or CRem1, is estimated to be approximately 16,400 patients in the United States and approximately 38,100 patients ROW.

The number of patients potentially eligible for GPS maintenance therapy after achievement of CRem2 status is approximately 1,200 patients in the United States and approximately 2,800 patients ROW.

It is estimated that the number of adult patients of any age with AML in the United States per year who successfully enter into CR2, the indication of our REGAL study, is approximately 2,000 patients and approximately 4,700 patients outside of the United States in the rest of the world, or ROW, while the number of patients who achieve first complete remission, or CR1, is estimated to be approximately 16,400 patients in the United States and approximately 38,100 patients ROW.

The number of patients potentially eligible for GPS maintenance therapy after achievement of CR2 status is approximately 1,200 patients in the United States and approximately 2,800 patients ROW.

Products/Pipeline

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A 2009 pilot project regarding the prioritization of cancer antigens (substances that evoke an immune response) conducted by the National Cancer Institute, or NCI, a division of the National Institutes of Health, or NIH, ranked the WT1 protein as a top priority for immunotherapy.

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WT1 is a protein that resides in the cell’s nucleus and participates in the process of cancer formation and progression.

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WT1 appears in large amounts ( i.e.

, becomes “overexpressed”) in numerous hematological malignancies, including AML, MM and chronic myeloid leukemia, as well as in many solid malignancies such as MPM, gastrointestinal cancers (such as colorectal cancer), glioblastoma multiforme, TNBC, ovarian cancer and SCLC.

Mechanism of Action in Immune System

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Each CTL typically destroys one WT1-positive cancer cell, but they have been shown to be able to kill up to 10 to 20 WT1-positive cancer cells.

Further, with respect to the activation of CD4 cells, we believe that CD4 cells are stimulated to produce WT1-specific, helper T cells, which are able to in turn activate CTLs and B cells.

Further, with respect to the activation of CD4 cells, we believe that CD4 cells are stimulated to produce WT1-specific helper T cells, which are able, in turn, to activate CTLs and B cells.

The B-cells “helped” by the helper T cells produce antibodies to specific WT1 epitopes.

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, natural killer cells) that are not as widely understood.

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The following diagram illustrate GPS’ mechanism of action:

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This process activates the CD4 and CD8 cells and sensitizes them to the key 25 epitopes of WT1, thus initiating the process of short- and long-term T-cell-mediated immunity against WT1.

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The following table summarizes the key features of GPS:

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adverse/immunosuppressive tumor

micro-environment, or TME The GPS monotherapy clinical studies are in the setting of complete remission, or CRem, and minimal residual disease, or MRD, whereby no bulky or measurable tumor deposits exist.

This is typically seen after successful frontline therapy in select cancer types for which such debulking standard therapies exist ( e.g.

, AML or MPM).

micro-environment, or TME The GPS monotherapy clinical studies are in the setting of complete remission, or CR, and minimal residual disease, or MRD, whereby no bulky or measurable tumor deposits exist.

This is typically seen after successful frontline therapy in select cancer types for which such debulking standard therapies exist (e.g., AML or MPM).

In these settings, the tumor micro-environment, or TME, is substantially absent.

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candidate patient population GPS has activity across multiple HLA types that could allow treatment of a vast majority of global patient populations harboring WT1-positive malignancies.

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Potential Key Differentiators

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• potentially applicable to 20 or more cancer types worldwide and the vast majority of HLA types;

• CRem or MRD status (after initial tumor debulking with preceding standard therapy) is the preferred setting for GPS monotherapy;

• CR or MRD status (after initial tumor debulking with preceding standard therapy) is the preferred setting for GPS monotherapy;

• not directly competitive with current clinical standard of care therapies, but rather believed to complement them in the maintenance setting;

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• positive Phase 2 clinical data on effectiveness (based on overall survival, or OS, in AML and progression-free survival, or PFS, in MM) with good tolerability and a favorable safety profile.

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Development Program for GPS

GPS has the potential as a monotherapy or in combination with other immunotherapeutic agents to address a broad spectrum of hematologic, or blood, cancers and solid tumor indications.

We are currently exploring the potential role for GPS in both monotherapy and combination therapy environments:

We are currently exploring the potential role for GPS in both monotherapy and in combination therapy with checkpoint inhibitors such as PD-1 inhibitors as set forth in the table below:

Program Status

GPS Monotherapy

Phase 2 clinical trials of GPS as monotherapy for AML, MPM and MM have been completed.

In January 2020, we commenced the Phase 3 clinical trial of GPS in AML, also known as the REGAL study.

The pivotal Phase 3 REGAL study is a 1:1 randomized, open-label study comparing GPS monotherapy in the maintenance setting to investigators’ choice of best available treatment in AML patients who have achieved hematologic complete remission, with or without thrombocytopenia (CRem2/CRem2p), after second-line antileukemic therapy and who are deemed ineligible for or unable to undergo allogeneic stem-cell transplantation.

The study is expected to enroll approximately 116 patients across up to approximately 135 clinical sites primarily in the United States and Europe.

The primary endpoint is overall survival, or OS , from the time of study entry.

The Phase 2 study in AML CRem2 patients, which is the same indication as the Phase 3 REGAL study, showed a median OS of 21.0 months, at a median follow-up of 30.8 months, in patients receiving GPS compared to 5.4 months in contemporaneously treated patients with best standard therapy.

See data set forth in “- AML Clinical Data.”

• Registrational Phase 3 REGAL open-label randomized clinical trial in AML patients who have achieved hematologic complete remission, with or without thrombocytopenia (CR2/CR2p), after second-line antileukemic therapy and who are deemed ineligible for, or unable to undergo, allogeneic stem-cell transplantation

• Phase 1 clinical trial of 3D189 (GPS) in China (our licensee, 3D Medicines is the sponsor)

IND has been filed

• Phase 1 clinical trial in patients with hematologic and thoracic malignancies with no demonstrable residual/recurrent disease after debulking therapy

final data reported

• Phase 2 clinical trial in patients with AML with first complete remission (CR1) patients

final data reported

• Phase 2 clinical trial in patients with high-risk MDS or AML patients with ≥2 lines of prior therapy (CR2)

final data reported

• Phase 2 clinical trial in MM patients

final data reported

• Phase 2 randomized, double-blind, placebo-controlled clinical trial in MPM patients

final data reported

GPS Combination Therapy

◦ Combination basket study:

In December 2018, we initiated a Phase 1/2 multi-arm "basket" type clinical trial of GPS in combination with the anti-PD-1 therapy pembrolizumab (Keytruda) in collaboration with a Merck & Co., Inc., Kenilworth, N.J., U.S.

• Phase 1/2 clinical trial of GPS in combination with the anti-PD-1 therapy pembrolizumab (Keytruda) in ovarian cancer (second or third line) in collaboration with a Merck & Co., Inc., Kenilworth, N.J., U.S.

subsidiary (known as MSD outside the United States and Canada), or Merck

The purpose of the basket trial is to determine if the administration of GPS in combination with pembrolizumab has the potential to demonstrate clinical activity in the presence of macroscopic disease, where monotherapy with either agent would have a more limited effect.

◦ Mesothelioma :

A Phase I open-label investigator-sponsored clinical trial of GPS, in combination with Bristol-Myers Squibb’s anti-PD-1 therapy, nivolumab (Opdivo®), in patients with MPM who harbor relapsed or refractory disease after having received frontline standard of care multimodality therapy was commenced in February 2020 at MSK.

The study drug is being provided by us and Bristol-Myers Squibb.

The principal investigator for the study is Dr.

Zauderer, MD, Co-Director, Mesothelioma Program and Associate Attending Physician in the Thoracic Oncology Service, Department of Medicine at MSK.

The purpose of the trial is to determine if the administration of GPS in combination with nivolumab has the potential to demonstrate antitumor immune responses and meaningful clinical activity in the presence of macroscopic disease in MPM patients.

The study will also investigate the tolerability of the combination, evaluate the immunogenicity of the two agents administered together, by CD4+ and CD8+ T-lymphocytes (both peripherally and at the tumor site), and gauge the degree of clinical benefit by assessment of the overall response rate with the combination in comparison with that reported with nivolumab alone in historical comparable patient populations.

In a randomized, controlled, blinded Phase 2 clinical trial in MPM patients completed in 2017, GPS monotherapy given as maintenance after first line tumor-debulking multimodality treatment demonstrated meaningful clinical activity with median survival of 22.8 months vs.

18.3 months in the control group (N=41) and with associated sustained immune responses (both CD4+ and CD8+) against the WT1 antigen while adverse events were mainly comprised of low grade reactions at the site of the injection.

Targeted Indications

Enrollment complete;

data expected in 1H 2022

• Phase I open-label investigator-sponsored clinical trial of GPS, in combination with Bristol-Myers Squibb’s anti-PD-1 therapy, nivolumab (Opdivo), in patients with MPM who harbor relapsed or refractory disease after having received frontline standard of care multimodality therapy

• Phase 1/pilot open-label, non-randomized clinical trial of GPS in combination with nivolumab in patients with WT1-expressing (WT1+) recurrent ovarian, fallopian tube or primary peritoneal cancer who were in second or greater clinical remission (after their successful first or subsequent “salvage” therapy)

final data reported

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GPS Monotherapy for Acute Myeloid Leukemia (AML)

Current AML Treatment Therapies

AML is an aggressive and highly lethal blood cancer characterized by the rapid growth of abnormal white blood cells that build up in the bone marrow and interfere with the production of normal blood cells.

AML is an aggressive and potentially lethal blood cancer characterized by the rapid growth of abnormal white blood cells that build up in the bone marrow and interfere with the production of normal blood cells.

Its symptoms include fatigue, shortness of breath, bruising and bleeding, and increased risk of infection.

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AML most commonly affects adults, and its incidence increases with age.

Until recently, the overall treatment landscape for AML had remained static for decades, as numerous targeted and antiproliferative agents were unsuccessful in providing meaningful long-term clinical benefits, including increments in survival.

In recent years, additional drugs have been approved and current standard treatments include chemotherapy (including the fixed-combination of chemotherapy Vyxeos), hypomethylating agents, or HMAs, drugs that target mutations of the isocitrate dehydrogenase, type-1 and -2 proteins and the FMS-like tyrosine-protein kinase, FLT3, proteins in patients whose disease harbors these genetic aberrations, the B-cell lymphoma 2 inhibitor venetoclax (typically in combination with chemotherapy or HMAs), the CD33-targeting antibody-drug conjugate gemtuxumab osogamicin, and the sonic hedgehog signaling inhibitor glasdegib.

Select patients could also undergo an allogeneic hematopoietic, or blood-forming, stem cell transplant, or allo-HSCT.

The effect of newer agents on overall survival has not yet been confirmed in large controlled clinical trials.

One of the fundamental goals of therapy for AML, both in the upfront and salvage settings, is for the patient to achieve a state of complete remission, or CRem.

CRem is defined per consensus criteria by the European Leukemia Net, whereby the hematologic and clinical features of the disease are no longer detected.

In the first line setting, once AML patients achieve a status of first CRem (CRem1) they have two options for a meaningful long-term benefit:

allo-HSCT and maintenance therapy with the oral form of the HMA azacytidine, which was recently approved for use by the FDA.

In the second line setting, i.e., in AML patients who have relapsed and are receiving salvage antileukemic therapy, we are not aware of any therapies, other than allo-HSCT , that have shown through rigorous blinded, randomized, controlled clinical trials to offer a meaningful long-term benefit (either relapse-free or overall survival) when used as maintenance after patients achieve a status of CRem2.

Once the disease relapses after second-line therapy, patients have limited options which currently include off-label administration of HMAs, venetoclax in combination with either HMAs or low-dose cytarabine or investigational agents in the context of a Phase 1/2 clinical trial.

No third-line therapies have shown demonstrable clinical impact to date in AML patients after their second relapse and eventually AML patients in second relapse generally succumb to AML or complications associated with it.

We believe that there is a significant unmet medical need for a clinically safe and effective therapy as maintenance after AML patients achieve CRem2 status following successful second-line (salvage) therapies, as a large significant proportion of these patients are ineligible for or unable to undergo allo-HSCT.

The AML indication was chosen for first-in-human clinical studies of GPS for the following reasons:

• AML presents a clinical setting in which CRem status (specifically CRem2) can be achieved with standard antileukemic therapy;

• the high degree of unmet medical need in recurrent/relapsed AML and the absence of an effective maintenance therapy over the decades after salvage re-induction until and immediately after achievement of CRem2 status, especially considering that most patients in this clinical scenario are older than 60 years of age;

We chose AML, for which we have been granted Fast Track and Orphan Drug designations by the FDA, as our lead indication for GPS for the reasons outlined below:

• AML presents a clinical setting in which complete remission status (specifically CR1 and/or CR2) can be achieved with standard antileukemic therapy;

• the high degree of unmet medical need in recurrent/relapsed AML and the absence of an effective maintenance therapy over the decades after salvage re-induction until and immediately after achievement of CR2 status, especially considering that most patients in this clinical scenario are older than 60 years of age;

• the almost universal expression of WT1 in leukemic blasts, which are AML’s replicating malignant cells, as well as leukemic stem cells, or LSCs, cells that are or become extremely resistant to standard chemotherapy or targeted agent approaches and which can be realistically eradicated only with immunotherapy methods (including allo-HSCT).

LSCs have been shown to be susceptible to targeting by cytotoxic T cells (CD8 and CD4 cells) stimulated against leukemia-associated antigens and we predicted this would be the case for GPS;

LSCs have been shown to be susceptible to targeting by cytotoxic T cells (CD8 and CD4 cells) stimulated against leukemia-associated antigens and we believe this will be the case for GPS;

• the fact that WT1 has been associated with the actual development of leukemia;

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• early evidence that human immunocytes sensitized ex-vivo to peptides contained in GPS were able to recognize naturally presented WT1 peptides on the surface of several leukemia cell lines;

• early anecdotal (at the time) clinical data showing antileukemic activity of WT1 monovalent vaccines in the CRem1 maintenance setting in Japanese population (albeit restricted to HLA-A*2401 type), as well as a dendritic cell vaccine in the Netherlands (independent of HLA haplotype) in the same setting;

• early anecdotal (at the time) clinical data showing antileukemic activity of WT1 monovalent vaccines in the CR1 maintenance setting in the Japanese population (albeit restricted to HLA-A*2401 type), as well as a dendritic cell vaccine in the Netherlands (independent of HLA haplotype) in the same setting;

• a predictive assumption of very low to negligible degree of clinical toxicity with a WT1-targeted immunotherapy such as GPS, due to the fact that WT1 in normal, non-cancerous, tissues is both expressed at extremely low levels and limited in number of organs and tissues, but also due to the fact that WT1 fragments, or peptide epitopes, in normal cells are presented to host APCs in a different manner than are WT1 fragments produced in cancer cells;

of note, WT1 expression in normal tissues of adults is limited to the podocyte layer of the glomerulus (kidney), Sertoli cells (testis), granulosa cells (ovary), decidual cells (uterus), mesothelial cells (peritoneum, pleura), mammary duct and lobule (breast), and blood-forming (hematopoietic) progenitor cells (CD34+ cells in the bone marrow);

• the advent of modern immunotherapeutics in cancer and the promise of an innovative, off-the-shelf potentially effective, low adverse event burden immunotherapy to prevent or delay relapse in patients once they achieve CRem status in AML, a disease that has historically been associated with dearth of deep and sustained responses to checkpoint inhibitors.

GPS has been granted Fast Track and Orphan Drug designations by the FDA for the treatment of AML.

AML Clinical Data

In an initial pilot clinical trial in AML, a total of nine adult patients of all ages with de novo AML were treated with upfront standard chemotherapy and were able to achieve their first complete remission, or CRem1.

• the advent of modern immunotherapeutics in cancer and the promise of an innovative, off-the-shelf potentially effective, low adverse event burden immunotherapy to prevent or delay relapse in patients once they achieve complete remission status in AML, a disease that has historically been associated with dearth of deep and sustained responses to checkpoint inhibitors;

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• evidence from our completed Phase 1 and Phase 2 clinical trials that administration of GPS can lead to extended relapse free survival and overall survival especially in patients who demonstrated clear WT1 specific CD4 and/or CD8 immune response to GPS administration.

Furthermore, we believe that there is a significant unmet medical need for a clinically safe and effective therapy as maintenance after AML patients achieve CR1 and/or CR2 status following successful first-line or, second-line (salvage) therapies, as a significant percentage of these patients are ineligible for, or unable to undergo, allo-HSCT.

Current AML Treatment Therapies

Select patients could also undergo an allogeneic hematopoietic, or blood-forming, stem cell transplant, or allo-HSCT.

The potential effect of newer agents on overall survival has not yet been confirmed in large controlled clinical trials.

One of the fundamental goals of therapy for AML, both in the upfront and salvage settings, is for the patient to achieve a state of complete remission.

Complete remission is defined per consensus criteria by the European Leukemia Net, whereby the hematologic and clinical features of the disease are no longer detected.

In the first line setting, once AML patients achieve a status of first complete remission (CR1) they have two options for a meaningful long-term benefit:

allo-HSCT and maintenance therapy with the oral form of the HMA azacytidine, which was recently approved for use by the FDA.

In the second line setting, i.e., in AML patients who have relapsed and are receiving salvage antileukemic therapy, we are not aware of any therapies, other than allo-HSCT, that have shown through rigorous blinded, randomized, controlled clinical trials to offer a meaningful long-term benefit (either relapse-free or overall survival) when used as maintenance after patients achieve a status of CR2.

Our Clinical Data in AML CR1 and CR2 Patients

In an initial pilot clinical trial in AML, a total of nine adult patients of all ages with de novo AML were treated with upfront standard chemotherapy and were able to achieve CR1.

Administration of GPS resulted in a median OS that was at least 35 months from the time of GPS administration.

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Of the eight patients tested for immunologic response, seven, or 87.5%, demonstrated a WT1-specific immune response.

In a subsequent Phase 2 clinical trial in AML, a total of 22 adult patients of all ages with de novo AML were treated with upfront standard chemotherapy and were able to achieve CRem1.

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In a subsequent Phase 2 clinical trial in AML, a total of 22 adult patients of all ages with de novo AML were treated with upfront standard chemotherapy and were able to achieve CR1.

Most patients also received one to four cycles of “consolidation” chemotherapy per standard AML treatment guidelines.

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An actual OS rate of 47.4% was demonstrated at three years post-GPS treatment, exceeding historical published data of OS of 20% to 25% by 2.4- to 1.9-fold (or 240% to 190%), respectively.

GPS administration was also shown to improve OS in comparison to historical data in patients in CRem1.

GPS administration was also shown to improve OS in comparison to historical data in patients in CR1.

Administration of GPS resulted in a median OS that was poised to exceed 67.6 months from the time of initial AML diagnosis in patients of all ages, which represents a substantial improvement compared to best standard therapy.

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In this study, the patients’ median age was 64 years old.

Importantly, a preplanned subgroup analysis for the cohort of 13 patients within the clinical trial who were 60 years of age or older demonstrated a median OS of 35.3 months from time of initial diagnosis.

Comparable historical populations have a median OS ranging from 9.5 to 16.8 months from initial diagnosis, which represents a 2.25 to 3.75-fold improvement in OS associated with GPS therapy in the CR1 maintenance setting as contrasted to these historical cohorts of broadly comparable patients.

The most frequent toxicities were mild to moderate local skin reactions and inflammation, as well as fatigue, which were self-limited and responded to local supportive measures and analgesics.

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The results showed a trend in improved clinical outcomes in patients who mounted an immune response with GPS compared to those patients who did not.

Comparable historical populations have a median OS ranging from 9.5 to 15.8 months from initial diagnosis, which represents a 2.25 to 3.75-fold improvement in OS associated with GPS therapy in the CRem1 maintenance setting as contrasted to these historical cohorts of broadly comparable patients.

An additional Phase 2 clinical trial of GPS was performed at the H.

Lee Moffitt Cancer Center & Research Institute, or Moffitt.

This Phase 2 trial included 10 AML patients who had received first-line therapy for their disease, who then experienced relapse and were subsequently treated with second-line chemotherapy and achieved a CRem2.

This group of patients had a more advanced disease in comparison to those treated in the Phase 2 clinical trial in CRem1 patients discussed above, and typically demonstrated a historical OS of less than ~8 months, even with post-CRem2 allo-HSCT.

In the Moffitt trial, the efficacy of GPS (measured as median OS, from the time of achievement of CRem2 until death from any cause) was compared with that of “watchful waiting” in a cohort of 15 contemporaneously treated (but not matched by randomization) broadly comparable patients treated by the same clinical team at Moffitt.

Initial data, at a median follow-up of 19.3 months, showed that GPS administration resulted in a median OS of 16.3 months (495 days) compared to 5.4 months (165 days) from the time of achievement of CRem2.

This group of patients had a more advanced disease in comparison to those treated in the Phase 2 clinical trial in CR1 patients discussed above, and typically demonstrated a historical OS of less than ~8 months, even with post-CR2 allo-HSCT.

In the Moffitt trial, the efficacy of GPS (measured as median OS, from the time of achievement of CR2 until death from any cause) was compared with that of “watchful waiting” in a cohort of 15 contemporaneously treated (but not matched by randomization) broadly comparable patients treated by the same clinical team at Moffitt.

This was a statistically significant difference (p=0.0175).

Two of 14 AML patients demonstrated relapse-free survival of more than one year.

Both of these patients were in CRem2 at time of GPS administration, with duration of their second remission exceeding duration of their CRem1, strongly suggesting a potential benefit based on immune response mechanisms.

Final data, at a median follow-up of 30.8 months, showed a median OS of 21.0 months in patients receiving GPS therapy compared to 5.4 months in the AML CRem2 patients treated with best standard care.

This is a statistically significant difference (p-value < 0.02).

Both of these patients were in CR2 at time of GPS administration, with duration of their second remission exceeding duration of their CR1, strongly suggesting a potential benefit based on immune response mechanisms.

Final data, at a median follow-up of 30.8 months, showed a median OS of 21.0 months in patients receiving GPS therapy compared to 5.4 months in the AML CR2 patients treated with best standard care resulting in a statistically significant difference (p-value < 0.02).

GPS was well-tolerated in this clinical trial.

AML Phase 3 Clinical Trial

In January 2020, we commenced a Phase 3 pivotal registration-enabling study for GPS in AML patients in second complete remission, including those in complete remission with incomplete platelet recovery.

This study, which we refer to as the REGAL study, is a 1:1 randomized, open-label study comparing GPS in the maintenance setting to investigators’ choice of best available treatment, or BAT, in adult AML patients (age >18 years) who have achieved their second hematologic (morphological) complete remission, with or without thrombocytopenia (CRem2/CRem2p;

with “p” designating platelets), after second-line antileukemic therapy and who are deemed ineligible for or unable to undergo allo-HSCT.

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Phase 3 REGAL Clinical Trial

Building on the Phase 2 study in AML CR2 patients, which showed a median OS of 21.0 months, at a median follow-up of 30.8 months, in patients receiving GPS compared to 5.4 months in contemporaneously treated patients with best standard therapy, in January 2020, we commenced a Phase 3 pivotal registration-enabling study for GPS in AML patients in CR2, including those in complete remission with incomplete platelet recovery.

The primary endpoint is OS and secondary endpoints include leukemia-free survival rates of achievement of MRD negativity, and antigen-specific T-cell immune response dynamics over time.

We expect this study will be used as the basis for a BLA submission, subject to a statistically significant and clinically meaningful data outcome and agreement with the FDA.

In the second half of 2020, we received approval from each of the French and German regulatory authorities to advance the REGAL study in France and Germany, respectively.

We expect approvals from additional European health authorities in early 2021 which will allow us to expand AML patient enrollment for the REGAL study in Europe.

The REGAL study is expected to enroll approximately 116 patients at up to approximately 135 clinical sites primarily in the United States and Europe.

We believe that the COVID-19 pandemic has impacted the timeline for the REGAL study.

Since we commenced the study in 2020, we have been initiating sites in United States and the European Union.

However, since the onset of the COVID-19 pandemic, we have observed that, at certain times and in certain instances, clinical site initiations and patient enrollment have been delayed, likely due to prioritization of hospital resources towards the pandemic.

Clinicians and patients may not have been able to comply with clinical trial protocols if quarantines impeded patient movement or interrupted operations at sites.

Certain newly initiated sites have taken longer than expected to be fully operational.

Additionally, several European Union countries in which we plan to initiate clinical sites, including Germany, France, and Italy, continue to impose restrictions in response to the continued surge in coronavirus cases throughout the European Union.

We believe that these factors have had and could continue to have an impact on the projected timeline for enrollment of patients in the REGAL study.

We have taken several steps to mitigate these actual and potential delays, including increasing the number of clinical sites from 50 to up to approximately 135, increasing the number of European Union and other countries in which sites were or will be initiated, allocating additional resources, including additional CROs and internal personnel, to the REGAL study.

The study will have a single planned interim safety and futility analysis after 80 events (deaths).

Based upon our current assumptions, including with respect to continuing impact of COVID-19, we believe that this analysis will occur in the first half of 2022, provided that our assumptions regarding COVID-19, including the duration thereof and the availability and uptake of vaccines, especially in Europe, remain unchanged.

The REGAL study is expected to enroll approximately 116 patients at up to approximately 85 clinical sites in the United States, Europe and Asia.

The COVID-19 pandemic has impacted the timeline for the REGAL study over the past two years.

Since we commenced the study in 2020, we have been initiating sites in the United States, Europe and, beginning in 2022, Asia.

However, since the onset of the COVID-19 pandemic, we have observed that, at certain times and in certain instances, clinical site initiations, patient screening and patient enrollment have been delayed.

These delays are likely due to many reasons, which have been changing and evolving as the COVID-19 pandemic itself has evolved, including the prioritization of hospital resources towards the care of patients with COVID-19, delays in reviews and approvals by independent institutional review boards, or IRBs, and/or ethics committees at clinical sites, the challenges for clinicians and patients to comply with clinical trial protocols due to quarantines impeding patient movement or interrupting operations at sites, restrictions on travel and, most recently, inadequate staffing at clinical sites, supply chain-related delays, and materials shortages.

Throughout the United States, Europe and Asia, newly initiated sites have taken longer than expected to become fully operational and begin enrolling patients.

We have taken several steps to mitigate these actual and potential delays, including increasing the number of clinical sites from 50 to up to approximately 85, increasing the number of additional countries, both in Europe and Asia, in which sites were or will be initiated, allocating additional resources, including additional CROs and internal personnel, to the REGAL study, and making certain changes to the protocol for the study.

We are continuing to monitor each clinical site through our CROs as well as conducting direct outreach to investigators and study staff through site visits, investigator meetings and other modes of communication.

The protocol specifies that the study will have a planned interim safety and futility analysis after 80 events (deaths).

In addition, the charter for the Independent Data Monitoring Committee, or IDMC, for the REGAL study provides that the IDMC will conduct safety and efficacy analyses at earlier points in the clinical trial.

Based upon these current assumptions with respect to completion of enrollment and the estimated survival times for both the treated and control groups, we believe, after discussions with our external statisticians and experts, that the planned interim analysis after 80 events per the protocol will occur by the end of the first half of 2023, provided that our assumptions regarding the impact of COVID-19 on the operations of our clinical sites as well as the duration of the pandemic remain unchanged.

Because this analysis is event driven, it may become available at different times than currently expected.

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The key features and schema of this study are shown in the following graphic:

GPS Monotherapy in Other Indications

Expanded Access Program

At the request of several investigators, we are planning to institute an Expanded Access Program that would allow qualified physicians who desire to treat with AML patients who do not meet currently required study entry criteria for the ongoing REGAL trial with GPS.

This access will be provided on a case by case basis to patients in the U.S.

and, potentially, Germany.

Patients treated under the Expanded Access Program will not be considered participants in the REGAL study.

We expect the program to commence in the second quarter of 2022.

It is expected that the physician selected patients will be patients in CR1 who underwent a bone marrow transplant while being positive for the minimal residual disease (MRD+).

The most common cause of early mortality in AML patients in CR1 is relapse.

There is a high relapse rate among transplanted AML patients who enter a transplant in CR1, especially among those who are MRD+.

Approximately 30% of those patients relapse within 6 months post-transplant, and approximately 35% within 8 months post-transplant, eventually reaching approximately 50% of patients by year 2 post-transplant.

At this time, there is no standard of care for maintenance after the transplant.

Most antileukemic agents have a severe myelosuppressive effect and, as such, would be counter-productive in the post-transplant setting as they could delay engraftment resulting in both increased toxicity and lower efficacy (due to limiting graft versus leukemia effect).

Attempts at maintenance with less myelosuppressive agents have a questionable track record.

HMAs, the most studied class of drugs in this setting, have failed to show any benefit in a controlled clinical trial, while increasing toxicity.

Molecularly targeted therapies (FLT3-ITD, IDH1m and IDH2m) appear to have more potential in the transplant setting but require the presence of targetable mutations.

Therefore, a non-myelosuppressive immunotherapy that does not depend on targetable mutations may be an important advancement in an area of high unmet medical need.

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In our Phase 2 study of GPS in AML CR1 patients, GPS has shown activity (as assessed by median leukemia free survival and median overall survival since the time of initial diagnosis versus historical controls) in these patients after standard induction chemotherapy, as well as one to four post-CR1 cycles of administration of further ‘consolidation’ chemotherapeutic regimen, after the completion of which they received GPS as ‘maintenance’.

We believe that there is theoretical rationale for cytocidal activity by CTLs after GPS therapy against leukemic stem cells as well, which are especially resistant to either chemotherapy or HMAs.

Phase 1 clinical trial of 3D189 in China

In January 2022, an IND application to initiate the first clinical trial in China for 3D189 (GPS) was accepted by China’s National Medical Products Administration, or NMPA.

The IND, for a small Phase I clinical trial investigating safety, was submitted by our partner in China, 3D Medicines Inc., or 3D Medicines.

3D Medicines expects to initiate this Phase 1 clinical trial by mid-2022 and will be responsible for all expenses related to executing the trial in China.

On March 30, 2022, the IND was approved by the NMPA triggering a $1.0 million milestone payment to the Company which is expected to be received in the second quarter of 2022.

The current clinical development plan provides for initiation of a Phase II clinical trial following receipt of satisfactory safety data from the Phase I study;

the initiation of the Phase II study will also trigger a milestone payment to us which we expect to receive by the end of 2022.

Potential for GPS Monotherapy in Post-Transplant Patients

In June 2021, a peer-reviewed article was published in the journal, Bone Marrow Transplantation , which included a comprehensive retrospective analysis of survival outcomes in 4,280 AML patients treated in more than 450 blood and marrow transplant centers worldwide between 2007 and 2015.

The analysis demonstrates the high unmet medical need to extend survival in AML patients.

The published analysis shows that even among patients eligible to receive a bone marrow transplant, considered to be the only potential curative therapy in AML, less than half of the patients are alive five years after initial diagnosis.

The analysis highlights the importance of the presence of MRD, with patients who harbored MRD at the time of transplant having only 34%-37% probability of surviving five years.

In our completed Phase 2 study of AML CR1 patients, OS for patients treated with GPS was 48.5 months from the time of enrollment in the study (67.6 months from initial AML diagnosis).

The retrospective analysis of the pooled outcomes for AML patients who underwent a transplant in the article published in Bone Marrow Transplantation indicates that the median OS from the time of transplant is approximately 26 months.

We believe that there is strong scientific rationale for consideration of a study in the post-transplantation setting and we are exploring the feasibility of such a clinical trial.

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GPS Combination Therapy with Checkpoint Inhibitors

Phase 1/2 Clinical Trial of GPS in Combination with Pembrolizumab

In December 2018, we, in collaboration with Merck, initiated a Phase 1/2 open-label, non-comparative, multicenter, multi-arm clinical trial of GPS in combination with pembrolizumab in patients with WT1-positive advanced cancers, including both hematologic malignancies and solid tumors.

The purpose of the study is to determine if the administration of GPS in combination with pembrolizumab has the potential to demonstrate clinical activity in the presence of macroscopic disease, where monotherapy with either agent would have a more limited effect.

The negative influence of TME factors on the immune response is predicted to be mitigated by PD1 inhibition (by pembrolizumab), thus allowing the patients’ own immune cells to invade and destroy cancerous growth deposits specifically sensitized against WT1 (by concomitantly-administered GPS).

The endpoints of the study include safety, immunobiological response, overall response rate (as measured by “response evaluation criteria in solid tumors”, or RECIST), progression free survival and overall survival and other analyses of interest.

We, together with Merck, have determined to focus on 2nd or 3rd line WT1(+) relapsed or refractory ovarian metastatic cancer as the primary indication for the study.

Ovarian cancer represents an intriguing opportunity to study both the clinical and immunologic effects of GPS in this solid tumor.

Additionally, therapeutic targeting of WT1 through immune pathways has largely not been pursued by others to date for this indication and ovarian cancer remains “incurable” once it advances and becomes disseminated, even in the face of significant advances in the field.

Ovarian cancer was chosen as a target indication for the following reasons:

• ovarian cancer presents a clinical setting whereby MRD status can be achieved with standard upfront therapy both immediately after first line therapy, but also after effective debulking of the “first relapse.” The latter subgroup of patients (after successful second line treatment/first salvage, lacking demonstrable macroscopic residual disease) would be optimal candidates for GPS therapy, as no standard maintenance therapy exists for such patients and the subsequent relapse patterns and metrics are known and predictable;

• the high levels of expression of WT1 in ovarian cancer cells.

In fact, WT1 expression is so frequent that pathologists routinely use immunohistochemical stains for WT1 (with a standardized convention for describing expression and determining as “positive” or “negative”) to help distinguish epithelial ovarian cancers from other tumors;

• preliminary evidence, in a previous study of GPS with nivolumab in ovarian cancer, that WT1 expression may be linked to prognosis in ovarian cancer and that it may play an anti-apoptotic role in ovarian cancer cell lines;

• the high degree of unmet medical need in ovarian cancer patients after first (or subsequent) successful “salvage” debulking therapy and the absence of effective therapies for such patients;

• a predictive assumption of very low to negligible degree of clinical toxicity with a WT1-targeted immunotherapy such as GPS due to the fact that WT1 in normal, non-cancerous tissues is both expressed at extremely low levels and limited in number of organs and tissues, but also due to the fact that WT1 fragments, or peptide epitopes, in normal cells are presented to host APCs in a different manner than are WT1 fragments produced in cancer cells.

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Epithelial cancer of the ovary, or ovarian cancer, is a relatively common gynecologic cancer that develops insidiously, and hence is associated with vague or no symptoms that would urge patients to seek medical attention.

Not surprisingly, most women with ovarian cancer present with advanced (at least locally or regionally, and often systemically spread) disease.

Ovarian cancer is managed with initial surgical resection followed by platinum-based chemotherapy.

During the past decade, incremental advances in chemotherapy, and the introduction of targeted therapies (such as poly-ADP-ribose polymerase inhibitors and several others) and specially formulated compounds (such as liposomal anthracyclines) have resulted in improved survival and in more effective treatment of relapsed disease.

In addition, a better understanding of genetic risk factors, along with aggressive screening, has permitted a tailored approach to preventive strategies, such as bilateral salpingo-oophorectomy in selected women along in specific patient populations genetically predisposed to this cancer (such as those harboring genetic alterations of the BRCA gene family).

Although a complete clinical remission following initial chemotherapy can be anticipated for many patients, a review of “second-look” laparotomy, when it was often performed as a matter of routine care, indicates that less than 50% of patients are actually free of disease.

Furthermore, nearly half of patients with a negative “second-look” procedure relapse and require additional treatment.

Many patients will achieve a CR2 clinical response with additional chemotherapy.

However, almost all patients will relapse after a short remission interval of nine to 11 months, with median overall survival of nine to 12 months.

Effective strategies, such as introduction of novel immunotherapies, to prolong remission or to prevent relapse are required, as subsequent remissions are of progressively shorter duration until chemotherapy resistance broadly develops, leading to eventual disease-related demise.

In December 2020, we announced that the first set of evaluable patients (n = 8) in the study, diagnosed with metastatic ovarian cancer, demonstrated a disease control rate, or DCR, which is the sum of overall response rate and rate of stable disease, of 87.5% with a median follow-up of 9.4 weeks.

At the first assessment time-point of 6 weeks post-therapy initiation, 100% of the patients were free of disease progression.

Using a validated immunohistochemistry (IHC) assay during the screening period, the rate of WT1 positivity in this ovarian cancer patient population was approximately 70%.

Six of the eight evaluable patients are continuing to receive GPS plus pembrolizumab.

In June 2021, we reported data and immune response profiles for 11 evaluable patients.

The 11 patients had each received at least three GPS doses, the last of which was combined with pembrolizumab, and were evaluated for clinical responses;

three of the 11 patients were also evaluated for immune responses.

Of the 11 patients, 66.7% were refractory to or had failed their second-line therapies and 33.3% failed third-line or later therapy.

All 11 patients were resistant to the standard of care platinum-based therapy.

The DCR for the 11 patients was 63.6% at a median follow-up of 15.4 weeks, with median PFS at the time of follow-up analysis of 11.8 weeks.

The landmark PFS rate by log-rank analysis at six months (26 weeks) was 33%.

The rate of WT1 positivity, measured using the IHC assay, was 63.6%.

The safety profile of the GPS-pembrolizumab combination was similar to that seen with pembrolizumab alone, with the addition of only low-grade, temporary local reactions at the GPS injection site, consistent with previously performed clinical studies with GPS.

In addition, we also reported immunobiological data.

CD8+ and CD4+ T-lymphocytes were isolated from peripheral blood mononuclear cells from three patients from whom samples had been collected both at baseline and at the time of the sixth GPS dose (i.e., 18 weeks after starting investigational therapy).

The T-cells were assayed ex-vivo for immune responses against the pool of the four peptides that comprise GPS using the validated assay intracellular cytokine staining with fluorescence-activated single cell sorting (ICS-FACS) (Scorpion Biological Services, San Antonio, Texas), with appropriate positive and negative controls.

A total of five cytokine “channels” were used for the analysis (i.e., interferon-g, TNF-a, interleukin-2, CD107a and MIP-1b).

The peptide re-challenge incubation period was seven days.

At the 18-week time point versus pre-vaccination baseline, the assay demonstrated a relative increase in WT1-specific T-lymphocyte frequencies in peripheral blood averaging +242 percent (range:

+104 to +385 percent across five cytokines) for CD8+ and +80.5 percent (range:

+1 to +174 percent) for CD4+.

There was also evidence of polyfunctional T-cell activation (increases in secretion of >2 cytokines) in two out of three patients (66 percent).

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On February 1, 2022, we announced the completion of enrollment in the study.

The total expected enrolled and evaluable number of patients is 17.

Data from 15 patients is expected to be examined by mid-2022, with final data analysis for all evaluable patients expected by the end of 2022.

We and Merck will jointly perform applicable analyses of the study, including survival, immune-biological and any other analyses of interest, to assess the safety and efficacy profile of the combination of GPS and pembrolizumab in this metastatic ovarian cancer indication.

GPS Combination Therapy with Nivolumab for MPM

A single-center, open-label, single-arm, non-randomized investigator-sponsored Phase 1 trial of concomitant administration of GPS in combination with Bristol-Myers Squibb’s anti-PD-1 therapy, nivolumab (Opdivo ® ) was initiated in February 2020 at MSK in patients with MPM who have previously received treatment with pemetrexed-based chemotherapy and have measurable disease on imaging, either due to residual disease after prior treatment or recurrent disease.

We are providing GPS and BMS is providing nivolumab for this study.

The principal investigator for the study is Dr.

Zauderer, MD, Co-Director, Mesothelioma Program and Associate Attending Physician in the Thoracic Oncology Service, Department of Medicine at MSK.

The IST is planned to accrue a minimum of 10 patients.

With approximately 3,300 cases in the United States each year, accompanied by a rising incidence in developing countries, MPM is notoriously difficult to treat and can lead to poor clinical outcomes with respect to both overall survival and progression-free survival, especially for those patients with the sarcomatoid variant who show a median overall survival of approximately 4.0 to 5.0 months.

In relapsed and refractory patients who progressed after the first line standard of care pemetrexed, a similar patient population to that in the GPS nivolumab combination trial, the common treatment regimen is vinorelbine and overall survival in those patients is reported to be between 4.5 and 6.2 months.

In patients treated with other chemotherapy regimens, such as carboplatin and irinotecan, median overall survival is reported to be approximately 7.0 months.

See GPS Monotherapy:

Completed Clinical Trials in Other Indications.

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The key features and schema of the study are shown in the Figure below:

In December 2020, we announced that the first set of evaluable patients (n = 3) had a median PFS of at least 10 weeks since therapy initiation.

In primary refractory MPM patients, any prolongation of progression-free interval greater than 8 weeks would be considered clinically meaningful, considering the current lack of effective therapies.

All patients had the epithelioid variant of MPM, a tumor which is universally expressing WT1.

GPS was found to be appropriately immunogenic, leading to the emergence of antigen (WT1)-specific CD4+ T-memory cell responses at three months post-therapy initiation.

In June 2021, we reported updated clinical data for four evaluable patients, all of whom had the MPM epithelioid and/or sarcomatoid variant and all of whom had received and progressed with, or are refractory to, frontline pemetrexed-based chemotherapy.

Average overall survival (OS) was 35.3 + 24.0 weeks with a median OS of 35.4 weeks, while average progression-free survival (PFS) was 8.8 + 4.2 weeks with a median PFS of seven weeks, both at a median follow-up of 35.4 weeks.

The safety profile of the GPS-nivolumab combination was similar to that seen with nivolumab alone, with the addition of only low-grade, temporary local reactions at the GPS injection site, consistent with previously performed clinical studies with GPS.

Additional MPM patients are currently being enrolled;

completion of study enrollment (target total n = 10) is expected during the second half of 2022.

We expect to report additional clinical and immune response data in the first half of 2022, including, potentially, an assessment of CD8+ and CD4+ T-cell responses to the WT1 peptide pool in the GPS mixture, as well as epitope spreading (ES) by testing for antibody presence (IgG’s) directed specifically against the full-length WT1 protein (intra-antigenic ES) and IgG’s presence against other key oncofetal antigens expressed in MPM (inter-antigenic epitope spreading).

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GPS Monotherapy:

Completed Clinical Trials in Other Indications

MPM is an asbestos-related cancer that forms on the protective tissues that cover many of the internal organs.

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, age and functional status).

Consequently, median survival can vary from up to at least 15 years in non-high-risk patients who achieve CRems, as defined by the International Myeloma Working Group, or IMWG, criteria, to approximately three years (from time of initial treatment) in patients with MM who achieve less than partial response, or PR, after ASCT.

Consequently, median survival can vary from up to at least 15 years in non-high-risk patients who achieve complete remission, as defined by the International Myeloma Working Group, or IMWG, criteria, to approximately three years (from time of initial treatment) in patients with MM who achieve less than partial response, or PR, after ASCT.

There are patients with MM who fare even more poorly than described above.

For example, those in the immediately aforementioned group who also have high-risk cytogenetics at baseline may survive on average less than three years.

Similarly, patients who are ineligible for ASCT and are managed only with chemotherapy and long-term IMiD maintenance (with up to nine cycles of lenalidomide) who also achieve less than CRems and remain MRD-positive demonstrate a three-year OS rate of only about 55%;

Similarly, patients who are ineligible for ASCT and are managed only with chemotherapy and long-term IMiD maintenance (with up to nine cycles of lenalidomide) who also achieve less than complete remission and remain MRD-positive demonstrate a three-year OS rate of only about 55%;

these landmark three-year OS rates decrease by approximately 40 to 50% in patients who also have high-risk cytogenetics at baseline.

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The data indicate promising clinical activity among MM patients with high-risk cytogenetics at initial diagnosis who also remain MRD(+) after successful frontline therapy (induction regimen followed by ASCT).

This subgroup of MM patients, when serially assessed per IMWG criteria, typically relapse/progress within 12 to 14 months after ASCT, even when they receive maintenance therapy with IMiDs such as thalidomide or proteasome inhibitors such as bortezomib.

Of note, 18 of the 19 patients received lenalidomide maintenance starting after the first three GPS administrations following ASCT;

This subgroup of MM patients, when serially assessed per IMWG criteria, typically relapse/progress within 12 to 14 months after ASCT, even when they receive maintenance therapy with IMiDs such as

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thalidomide or proteasome inhibitors such as bortezomib - 18 of the 19 patients received lenalidomide maintenance starting after the first three GPS administrations following ASCT;

the remaining single patient received bortezomib under the same schedule.

All patients had evidence of at least MRD after ASCT, while 15 of the 19 also had high-risk cytogenetics at diagnosis.

All patients had evidence of at least MRD (MRD+) after ASCT, while 15 of the 19 also had high-risk cytogenetics at diagnosis.

Combined, these characteristics typically result in low PFS rates that do not exceed 12 to 14 months following ASCT, even while on maintenance therapy with IMiDs or proteasome inhibitors, which are the current standards of care.

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We believe that these results offer mechanistic underpinnings for immune activation against WT1 in patients with aggressive, high-risk MM, and support the potential antimyeloma activity of GPS.

GPS Combination Therapy with PD1 blocker (nivolumab) for Ovarian Cancer

Not surprisingly, most women with ovarian cancer present with advanced (at least locally or regionally, and often systemically spread) disease.

Ovarian cancer is managed with initial surgical resection followed by platinum-based chemotherapy.

Furthermore, nearly half of patients with a negative “second-look” procedure relapse and require additional treatment.

Many patients will achieve a CRem2 clinical response with additional chemotherapy.

However, almost all patients will relapse after a short remission interval of nine to 11 months.

Ovarian cancer represents an intriguing opportunity to study both the clinical and immunologic effects of GPS in another solid tumor.

Ovarian cancer was chosen as a target indication for the following reasons:

• the high levels of expression of WT1 in ovarian cancer cells.

• preliminary evidence that WT1 expression may be linked to prognosis in ovarian cancer and that it may play an anti-apoptotic role in ovarian cancer cell lines;

• the high degree of unmet medical need in ovarian cancer patients after first (or subsequent) successful “salvage” debulking therapy and the absence of effective therapies for such patients;

GPS was studied in combination with nivolumab, a PD-1 immune checkpoint inhibitor, in an open-label, non-randomized Phase 1/pilot clinical trial, which was independently sponsored by MSK.

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GPS Combination Therapy:

Completed Clinical Trial in Ovarian Cancer

GPS was studied in combination with nivolumab in an open-label, non-randomized Phase 1/pilot clinical trial, which was independently sponsored by MSK.

The aim of the study was to evaluate the safety and efficacy of this combination in patients with WT1-expressing (WT1+) recurrent ovarian, fallopian tube or primary peritoneal cancer who were in second or greater clinical remission (after their successful first or subsequent “salvage” therapy).

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No new serious adverse events were noted during the longer follow-up period.

GPS Combination Therapy with PD1 blocker (pembrolizumab)

Given the potential immunobiologic and pharmacodynamic synergy between GPS and an immune check-point inhibitor (e.g., PD1 blocker), we entered into a Clinical Trial Collaboration and Supply Agreement with Merck (known as MSD outside the United States and Canada), to assess the efficacy and safety of GPS in combination with Merck’s anti-PD-1 therapy pembrolizumab with exploratory long-term follow-up for OS and safety and have commenced a Phase 1/2 open-label, non-comparative, multicenter, multi-arm study of patients with WT1-positive advanced cancers, including both hematologic malignancies and solid tumors.

The purpose of this “basket” trial is to determine whether the administration of GPS in combination with pembrolizumab has the potential to demonstrate clinical activity in the presence of macroscopic disease, where monotherapy with either agent would have a more limited effect.

The primary endpoints of the study are safety, overall response rate (as measured for solid tumors by “response evaluation criteria in solid tumors”, or RECIST) and achievement of morphologic CRem for hematologic cancers.

This clinical study was initiated in December 2018.

The tumor type currently being investigated is ovarian cancer (second or third line).

In December 2020, we announced that the first set of evaluable patients (n = 8) in the study, diagnosed with 2nd or 3rd line WT1(+) relapsed or refractory metastatic ovarian cancer, demonstrated a disease control rate (the sum of overall response rate and rate of stable disease) of 87.5% with a median follow-up of 9.4 weeks.

At the first assessment time-point of 6 weeks post-therapy initiation, 100% of the patients were free of disease progression.

Using a validated immunohistochemistry (IHC) assay during the screening period, the rate of WT1 positivity in this ovarian cancer patient population was approximately 70%.

Six of the eight evaluable patients are continuing to receive GPS plus pembrolizumab.

Enrollment in this arm of the study is continuing with a target of a total of 20 patients.

We expect to announce further clinical and immunobiological data by the end of the first half of 2021.

We, together with Merck, have determined not to pursue the following indications as part of the basket study:

colorectal cancer, TNBC, SCLC or AML, and we are exploring other potential additional indications to investigate in the basket study.

GPS Combination Therapy with PD1 blocker (nivolumab) for MPM

A single-center, open-label, single-arm, non-randomized investigator-sponsored Phase 1 trial of concomitant administration of GPS in combination with nivolumab was initiated in February 2020 at MSK in patients with MPM who have previously received treatment with pemetrexed-based chemotherapy and have measurable disease on imaging, either due to residual disease after prior treatment or recurrent disease.

We are providing GPS and BMS is providing nivolumab for this study.

The IST is planned to accrue a minimum of 10 patients.

Its primary objective is to determine the tolerability of the GPS plus nivolumab combination in patients with previously treated MPM who have documented progression of disease on imaging at the time of study entry, while the secondary objective is to evaluate the immunogenicity of the above combination by assessing the WT1-specific cell-mediated immune response both in peripheral blood and at the tumor site.

The key features and schema of the study are shown in the Figure below:

In December 2020, we announced that the first set of evaluable patients (n = 3) had a median PFS of at least 10 weeks since therapy initiation.

In primary refractory MPM patients, any prolongation of progression-free interval greater than 8 weeks would be considered clinically meaningful, considering the current lack of effective therapies.

All patients had the epithelioid variant of MPM, a tumor which is universally expressing WT1.

GPS was found to be appropriately immunogenic, leading to the emergence of antigen (WT1)-specific CD4+ T-memory cell responses at three months post-therapy initiation.

Additional MPM patients are currently being enrolled;

completion of study enrollment (target total n = 10) and further clinical and immunobiological data are expected by the end of the first half of 2021.

GPS Regulatory and Manufacturing

In September 2020, we received approval of our Investigational Medicinal Product Dossier, or IMPD, from the French regulatory authority, Agence Nationale de Sécurité du Médicament et des Produits de Santé, to advance in France REGAL study in AML CR2 patients.

Later in 2020, we subsequently received IMPD approval from the German health authorities.

We expect approvals from additional European health authorities in early 2021 which will allow us to expand AML patient enrollment in Europe for the REGAL study.

In late 2020, we manufactured the first of three registration batches of GPS which will be required for a BLA for GPS assuming positive data from the REGAL study.

This additional batch will be used in our GPS clinical programs and for clinical supply to 3D Medicines under the license agreement for development and commercialization in Greater China.

We have received approvals from the regulatory authorities in the United States, France, Germany, Greece, Poland, Hungary and Taiwan to commence enrollment in our Phase 3 REGAL study in those countries.

We expect to obtain regulatory approvals from additional countries in the first half of 2022.

In August 2021, we manufactured the second of three registration batches of GPS which will be required for a BLA for GPS assuming positive data from the REGAL study.

This additional batch will be used in our GPS clinical programs and for clinical supply to 3D Medicines under the license agreement for development and, potentially, commercialization in Greater China.

During the first half of 2021, the drug product manufacturing process for GPS was successfully transferred to a new CMO, Lyophilization Services of New England, Inc., or LSNE.

LSNE manufactured a new regulatory standard drug product batch which entailed further process improvements which were agreed upon by the FDA.

The new manufacturing batch met all the release criteria and, to date, has shown favorable stability data on already known long-term conditions (-20°C) as well as newly accelerated conditions (5°C and 25°C).

Both long-term and accelerated stability data are monitored to confirm that all drug product parameters are within the acceptance criteria and this optimized batch, based on the data to date, may ultimately allow for GPS to be stored in 5°C to 25°C conditions versus -20°C.

This favorable outcome would be more optimal for supply chain and logistical reasons.

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Commercial Strategy for GPS

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See “Strategic Collaborations and License Agreements.”

NPS (nelipepimut-S)

Our other cancer immunotherapy product, NPS, utilizes a targeted approach and is being developed to potentially (i) prevent secondary recurrence of HER2, low expressing breast cancer and (ii) prevent ductal carcinoma in situ, or DCIS, from becoming invasive breast cancer.

Our programs for NPS primarily target patients in the adjuvant, or after-surgery, setting who have relatively healthy immune systems but may still have residual disease.

MRD, or micrometastases, that are undetectable by current radiographic scanning technologies, can result in breast cancer recurrence.

Nelipepimut-S

Our other cancer immunotherapy product, NPS, targets HER2 expressing cancers.

The historical development program for NPS has primarily targeted patients in the adjuvant, or after-surgery, setting who have relatively healthy immune systems but may still have residual disease.

NPS is the immunodominant nonapeptide derived from the extracellular domain of the HER2 protein, a well-established and validated target for therapeutic intervention in breast and gastric carcinomas.

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These activated CTLs recognize, neutralize and destroy, through cell lysis, HER2 expressing cancer cells, including occult cancer cells and micrometastatic foci.

The nelipepimut immune response can also generate CTLs to other immunogenic peptides through inter- and intra-antigenic epitope spreading.

NPS Therapy for Breast Cancer

According to NCI, over 260,000 women in the United States are diagnosed with breast cancer annually.

While improved diagnostics and targeted therapies have decreased breast cancer mortality in the United States, metastatic breast cancer remains incurable.

Approximately 75% to 80% of breast cancer patients test positive for some increased amount of the HER2 receptor, which is associated with disease progression and decreased survival.

Only approximately 20% to 30% of all breast cancer patients have a HER2-directed, approved treatment option, i.e., trastuzumab, available after their initial standard of care.

The patients are defined as having tumors demonstrating a level of HER2 expression of 3+ by immunohistochemistry, or IHC, (HER2 IHC 3+), or HER2 IHC 2+ but also being positive by HER2 gene amplification by fluorescence in situ hybridization, or FISH.

This leaves the majority of breast cancer patients with low-to-intermediate HER2 expression by IHC (IHC 1+, 2+ by IHC) with tumors that are not HER2-amplified by FISH ineligible for targeted therapy with trastuzumab and without an effective targeted treatment option to prevent cancer recurrence.

In April 2018, we announced positive interim data from the prospective, randomized, single-blinded, controlled Phase 2b IST clinical trial of trastuzumab +/- NPS in HER2 1+/2+ breast cancer patients in the adjuvant setting to prevent recurrences.

A pre-specified interim analysis, conducted by the data safety monitoring board, or DSMB, of the efficacy and safety data for the study in an overall population of 275 patients as well as the two primary study target patient populations (node-positive and TNBC) after a median follow-up of 19 months, demonstrated:

• a clinically meaningful difference in median DFS in favor of the active arm (NPS + trastuzumab), a primary endpoint of the study, with hazard ratios of 0.67 and 0.61 in the ITT, and modified ITT, or mITT, populations (i.e., those who received at least one dose of vaccine or control) as well as a 34.9% and 39.5% reduction in relative risk of recurrence in the active versus control arms in the ITT and mITT populations, respectively;

• a clinically meaningful and also statistically significant difference between the two arms in the cohort of patients (n= 98) with TNBC, with a hazard ratio of 0.26 and a p-value of 0.023 in favor of the NPS + trastuzumab combination with a 70.4% reduction in relative risk of recurrence in the active arm versus control;

• a clinically meaningful and statistically significant difference between the two arms in favor of the combination in the cohort of patients not receiving hormonal therapy (n = 110), with a hazard ratio of 0.24 and a p-value of 0.009 with a 74.1% reduction in relative risk of recurrence in the active arm versus control;

• no notable differences between treatment arms;

• that the addition of NPS to trastuzumab did not result in any additional cardiotoxicity compared to trastuzumab alone.

Based on these results, the DSMB recommended that we expeditiously seek regulatory guidance from the FDA for further development of the combination of GPS plus trastuzumab for TNBC.

In October 2018, we announced the following final data at the 26-month median follow-up of the NPS +/- trastuzumab Phase 2b trial for the TNBC cohort, which confirmed the previously reported positive data:

• clinically and statistically significant efficacy in the TNBC cohort, with a p-value of 0.013 and a 75.2% reduction in risk of relapse or death;

• clinically meaningful difference in median DFS in favor of the active arm (patients treated with NPS + trastuzumab) in the TNBC cohort at 24 months for patients of 92.6% compared to 70.2% for those treated with trastuzumab alone;

• in all HER2 low-expressing breast cancer patients, the DFS rate was also in favor of the NPS plus trastuzumab combination (89.8%) as compared to trastuzumab alone (83.8%).

The DSMB, in October 2018, unanimously concluded that the final analysis of the Phase 2b study data with a median follow-up of 26 months confirmed that TNBC patients should be the key target population for the development of trastuzumab plus NPS in the adjuvant setting in early-stage HER2 1+/2+ breast cancer patients and again recommended that we expeditiously seek regulatory guidance for further development for TNBC.

In November and December 2018 we announced the following positive data from a preplanned secondary efficacy analysis across HLA allele subgroups from the Phase 2b IST study:

• the data analysis confirmed the therapeutic potential of NPS in patients with early-stage TNBC in the adjuvant setting across HLA types A-02, -03, -24 and -26, which cover approximately 80-85% of the North American/European populations and 86-90% of Asian/Pacific basin populations;

• in the subgroup of TNBC patients with the HLA-A24+ allele type, which is highly prevalent in the Asian population, treated with the combination of NPS and trastuzumab (n=47), the p-value is 0.003 with a 90.6% relative reduction in risk of relapse or death at 24 months and a hazard ratio of 0.08 in favor of the active (combination) arm;

• TNBC patients with the HLA-A24+ allele type had a significant improvement in DFS both by log-rank and landmark (24 month) analysis despite the lowest predicted binding potential between the E75 (NPS) antigen and this HLA-type;

• a clinically meaningful and statistically significant decrease in the number of clinically detectable relapses in the TNBC cohort with the combination of trastuzumab and NPS (7.5%) versus trastuzumab alone (27.3%) (p=0.004).

In June 2019, we announced results from a preplanned analysis of immunologic responses in the TNBC cohort at the 2019 ASCO meeting.

91 of the 97 TNBC patients, 51 of whom received the combination therapy, were analyzed for immune responses, or IR, at five timepoints.

IR were evaluated ex vivo by clonal expansion of antigen NPS-specific CTLs by dextramer-staining/flow cytometry at predefined time points over three years.

In vivo IR were assessed by cutaneous delayed type hypersensitivity, or DTH, reactions periodically, by measuring the diameter of skin induration post treatment.

NPS plus trastuzumab-treated TNBC patients exhibited increases in CTL frequencies compared with baseline by 1.1-, 1.73-, and 2.86-fold at 18, 24 and 30 months, respectively.

The mean CTL frequencies in these patients increased from 29±0.1 per 10 -4 at baseline to 112±2.6% at 30 months, a 2.86-fold difference that was highly clinically indicative (p = 0.058), as compared with patients receiving trastuzumab only, whereby CTL frequencies were 20±0.1 per 10 -4 at baseline compared with 52±1.6 per 10 -4 at 30 months, a 1.6-fold non-significant difference (p=0.70).

Three patients in the combination arm recurred (5.9%) as compared with 12 (30%) in the trastuzumab-alone arm.

TNBC patients treated with NPS plus trastuzumab whose disease recurred did not mount an IR by ex vivo assessment (absolute CTL frequency change) or by in vivo DTH (no change in skin induration), while non-recurrent patients mounted both vigorous NPS-specific clonal CTL expansion and enhanced in vivo DTH.

In a Type C meeting with the FDA in late 2018, as well as subsequently during 2019, we discussed several key points of the clinical and regulatory strategy for NPS in combination with trastuzumab for TNBC, a registration-enabling Phase 3 trial design and biostatistical plan.

After having received written feedback from the FDA in February 2020, we finalized the design and plan for a Phase 3 registration-enabling study of NPS in combination with trastuzumab for the treatment of patients with TNBC in the adjuvant setting after standard treatment based upon the FDA feedback and on the totality of clinical, safety and translational NPS data to date.

The FDA indicated in its feedback that there is adequate safety information to support the use of NPS in combination with trastuzumab.

The planned Phase 3 study will be a 1:1 randomized, blinded two-arm study to evaluate the efficacy and safety of the NPS vaccine (NPS plus GM-CSF) in combination with trastuzumab vs.

GM-CSF alone as maintenance treatment in the adjuvant setting following standard-of-care therapy in patients with TNBC, defined as hormone receptor-negative, HER2 1+/2+ tumors (as assessed by immunohistochemistry tumors), at high risk of recurrence.

If successful, we believe this study may be considered as the basis for a BLA submission to the FDA.

Our second IST for NPS plus trastuzumab is a Phase 2 study in high-risk HER2 3+ breast cancer patients who are defined as patients with HER2 3+ (“classic” HER2+) breast cancer who have completed neoadjuvant therapy with an approved regimen that includes trastuzumab and who have failed to achieve a pathological complete response, meaning they have microscopic evidence of residual disease at the time of their primary surgery and are therefore at an increased risk of disease recurrence.

The protocol for this study specified that the patients also should be HLA A2+ or HLA A3+.

This multi-center, prospective, randomized, single-blinded Phase 2 clinical trial is fully enrolled with 100 patients actively participating.

The rationale for this study is based on the fact that HER2 3+ patients with high risk features are known to have higher recurrence rates than all other HER2 3+ breast cancer patients.

Eligible patients are being randomized to receive NPS + GM-CSF + trastuzumab or trastuzumab + GM-CSF alone.

The primary endpoint of the study is DFS.

Funding for this trial was awarded through the Congressionally Directed Medical Research Program, funded through the Department of Defense, via a breast cancer research program breakthrough award.

In February 2017, the DSMB reported that there were no safety concerns with the trial and the trial is not futile.

The pre-specified interim safety analysis was also completed on 50 patients and demonstrated that the combination is well tolerated with no increased cardiotoxicity associated with giving NPS in combination with trastuzumab.

The recommendation from the DSMB was to continue the HER2 3+ trial unmodified.

In January 2021, the DSMB recommended that, given the small size of the trial and in order to preserve the statistical power of the trial, the primary analysis of the trial be completed upon the completion of the three years of follow-up on every patient or until more events are collected.

We now expect the primary analysis to be completed by the end of 2021.

NPS was previously granted Fast Track designation by the FDA for the adjuvant treatment of patients with early stage breast cancer with low to intermediate HER2 expression following standard of care upfront therapy (surgery plus chemotherapy +/- radiotherapy).

NPS for Ductal Carcinoma In Situ of the Breast (DCIS)

DCIS is defined by the NCI as a noninvasive condition in which abnormal cells are found in the lining of a breast duct and have not spread outside the duct to other tissues in the breast.

DCIS is the most common type of breast neoplasm with malignant potential.

DCIS represents about 20% of breast cancer cases diagnosed annually in the United States, which translates to more than 48,000 women being newly diagnosed in 2019, according to the most recent estimates by the American Cancer Society.

In some cases, DCIS may become invasive cancer and spread to other tissues, and at this time, there is no way to know which lesions could become invasive.

The goal of therapy for DCIS is to prevent the progression of the tumor toward an invasive breast cancer.

Current treatment options for DCIS include breast-conserving surgery and radiation therapy with or without tamoxifen, breast-conserving surgery without radiation therapy, or total mastectomy with or without tamoxifen.

Considering the potential for side effects from radiation therapy and the prolonged use of hormonal blockade therapy such as tamoxifen, an alternative adjuvant therapy that would be at least equally effective in reducing progression of DCIS to an invasive breast cancer would be an attractive management option.

We are supporting a Phase 2 IST to evaluate women diagnosed with DCIS who are HLA-A2+ or A3+ positive, who express HER2 at IHC 1+, 2+, or 3+ levels, and who are pre- or post-menopausal.

This clinical study was initiated in February 2018.

Patients are being randomized to one of two arms:

NPS plus GM-CSF or GM-CSF alone.

The trial is sponsored and operationalized by the NCI, studying NPS’s potential clinical effects in earlier stage disease.

The trial has an immunological (rather than clinical) endpoint evaluating NPS peptide-specific CTL (CTL;

This immune response can also generate CTLs to other immunogenic peptides through inter- and intra-antigenic epitope spreading.

We have previously reported data for NPS in two different types of breast cancer:

• In 2018 and 2019, we announced positive data for a subset of patients with TNBC from the prospective, randomized, single-blinded, controlled Phase 2b IST clinical trial of trastuzumab +/- NPS in HER2 1+/2+ breast cancer patients in the adjuvant setting to prevent recurrences showing a clinically and statistically significant improvement in the DFS rate for the TNBC cohort at 24 months of 92.6% for patients treated with NPS plus trastuzumab compared to 70.2% for those treated with trastuzumab alone.

In early 2020, based upon FDA feedback and on the totality of clinical, safety and translational NPS data to date, we finalized the design and plan for a Phase 3 registration-enabling study of NPS in combination with trastuzumab for the treatment of patients with TNBC in the adjuvant setting after standard treatment.

• In March 2020, we reported preliminary antigen-specific immune response data from a Phase 2 IST of NPS in combination with GM-CSF which evaluated women diagnosed with, ductal carcinoma in situ of the breast, or DCIS, who are HLA-A2+ or A3+ positive, who express HER2 at IHC 1+, 2+, or 3+ levels, and who are pre- or post-menopausal.

The trial had an immunological (rather than clinical) endpoint evaluating NPS peptide-specific CTL (CTL;

CD8+ T-cell) response in vaccinated patients.

In August 2019, the Company announced the completion of enrollment in this study.

In March 2020, we reported preliminary antigen-specific immune response data from the Phase 2 trial.

The relative frequency of NPS-specific CD8 CTLs as a percentage (NPS-CTL%) was twice as large in the NPS-treated patients.

The NPS-CTL% was measured in the peripheral blood by a sensitive and specific assay using dextramer staining followed by flow cytometry, both at baseline (before vaccination or GM-CSF) and at 30 (+/-7) days after surgery.

The mean difference in NPS-CTL% increase between the active and control groups was +0.10% vs +0.05%.

The relative magnitude of change in NPS-CTL% mean values in NPS-treated patients over time was an 11-fold increase, from 0.01% at baseline to 0.11% after surgery, indicating a continued antigen-specific T-cell response post-NPS vaccination.

NPS was generally well-tolerated in the study with no drug-related unexpected serious adverse reactions.

The overall adverse event profile was consistent with previous safety data.

In December 2020 we reported updated final data, based on a 6-month follow-up, which demonstrated that CD8+ T-cell responses persist long-term post-NPS treatment, with treated patients retaining and modestly enhancing their antigen-specific immune response.

When compared to baseline (BL, prior to investigational agent administration), the relative frequency of NPS-specific CD8 CTLs as a percentage (NPS-CLT%) in peripheral blood at the 1-month and 6-month post-operative time-points increased in the NPS+GM-CSF group (n=9) by 11- and 14-fold:

0.01+0.02% [BL] vs.

0.11+0.12% [1-mo] and 0.14+0.12% [6-mo], respectively, while in the GM-CSF alone group (n=4) the NPS-CLT% in peripheral blood increased by only 2.25- and 3.75-fold:

0.04+0.07% [BL] vs.

0.09+0.15% [1-mo] and 0.15+0.03% [6-mo], respectively.

For the NPS+GM-CSF group, the differences in absolute NPS-CTL% mean values between baseline and 1- or 6-months post-vaccination were statistically significant, with p-values of 0.039 and 0.0125, respectively.

The relative change in NPS-CTL% mean values at 6 months post-vaccination was +1,300+450% for the NPS+GM-CSF group vs.

250+150% in the GM-CSF alone group, which was highly statistically significant in favor of the NPS+GM-CSF group:

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Since 2018, we have conducted an extensive global out-licensing effort for NPS to find an interested party to fund and conduct the future clinical development of NPS in order to maximize the potential of the program, with a focus on further development of NPS for breast cancer, specifically TNBC.

We do not currently plan to conduct and fund a Phase 3 program for NPS for the TNBC indication on our own.

As part of our out-licensing efforts, we engaged numerous outside advisors who assisted us in specifically targeting over 100 pharmaceutical and biotechnology companies in the United States, Europe and Asia with research and development programs in breast cancer as well as those companies developing biosimilars of trastuzumab and companies developing immunotherapies.

During this period through the end of 2021, we met with several companies who engaged in varying degrees of due diligence and negotiation, but we were ultimately unable to agree upon terms favorable to the Company which we believed were commensurate with the value of NPS.

We believe that the reason for our inability to agree upon terms which we believe are commensurate with the value of the asset was due to the changing market for breast cancer therapies, the scope, cost and timeline for a Phase 3 trial which would satisfy regulatory requirements for the TNBC indication and the failure, in 2016, of the Phase 3 clinical trial of monotherapy NPS in breast cancer.

At this point in time, we have concluded that continued efforts to outlicense NPS for further development for breast cancer are unlikely to result in a licensing transaction.

As we continue our out-licensing strategy, we are now focusing on the potential for NPS in other cancer indications.

Strategic Collaborations and License Agreements

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or (c) ten years from the first commercial sale in such country.

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Merck & Co., Inc.

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In September 2017, we entered into a clinical trial collaboration and supply agreement through a Merck subsidiary, whereby we agreed with the Merck subsidiary to collaborate on a clinical program to evaluate GPS as it is administered in combination with their PD1 blocker pembrolizumab in a Phase 1/2 clinical trial enrolling patients in up to five cancer indications, including both hematologic malignancies and solid tumors.

The Phase 1/2 clinical trial utilizes a combination of GPS plus pembrolizumab in patients with WT1+ relapsed or refractory tumors.

The study is designed to explore the combination in both solid tumor and hematological cancer indications.

This study is assessing the efficacy and safety of the combination, comparing overall response rates and immune response markers achieved with the combination compared to prespecified rates based on those seen with pembrolizumab alone in comparable patient populations.

The Phase 1/2 clinical trial was designed to explore the combination of GPS plus pembrolizumab in patients with WT1+ relapsed or refractory tumors in both solid tumor and hematological cancer indications and to assess the efficacy and safety of the combination, comparing overall response rates and immune response markers achieved with the combination compared to prespecified rates based on those seen with pembrolizumab alone in comparable patient populations.

This trial was initiated in December 2018.

In 2020, we, together with Merck determined to focus on ovarian cancer (second or third line).

We reported updated clinical and initial immune response data from this study in June 2021.

In February 2022 we reported that we had completed enrollment of 17 evaluable patients in this study.

Data from 15 of the 17 evaluable patients is expected to be examined by mid-2022, with final data analysis for all evaluable patients expected by the end of 2022.

Exclusive License Agreement with 3D Medicines Inc.

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We and 3DMed also agreed to negotiate in good faith the terms and conditions of a clinical supply agreement, a commercial supply agreement, and related quality agreements pursuant to which we will manufacture or have manufactured and supply 3DMed with all quantities of the Licensed Product necessary for 3DMed to develop and commercialize the Licensed Products in the 3DMed Territory until 3DMed has received all approvals required for 3DMed or its designated contract manufacturing organization to manufacture the Licensed Products in the 3DMed Territory.

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The 3DMed License Agreement will expire on a Licensed Product-by-Licensed Product and region-by-region basis on the date of the expiration of all of 3DMed’s payment obligations to us.

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The 3DMed License Agreement includes customary representations and warranties, covenants and indemnification obligations for a transaction of this nature.

Under the 3DMed License Agreement, we achieved regulatory milestones relating to agreement upon and completion of a technology transfer plan in March 2021 and June 2021, respectively, for $1 million each.

On March 30, 2022, the IND was approved by the NMPA triggering a $1.0 million milestone payment to the Company which is expected to be received in the second quarter of 2022.

The IND is for a small Phase I clinical trial investigating safety.

The University of Texas M.

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We do not own or operate manufacturing facilities for the production of our product candidates, nor do we have plans to develop our own manufacturing operations in the foreseeable future.

We currently depend on third-party contract manufacturers for all of our required raw materials, active pharmaceutical ingredients, and finished product candidate for our clinical trials, including manufacturers with facilities in northern Italy.

We currently depend on third-party contract manufacturers for all of our required raw materials, active pharmaceutical ingredients, and finished product candidate for our clinical trials.

We do not have any current contractual arrangements for the manufacture of commercial supplies of any product candidates.

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We plan to further evaluate these alternatives as we approach approval for the use of our product candidates for one or more indications.

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Intellectual Property

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• Patent application co-owned by us and MSK:

◦ International application under the Patent Cooperation Treaty, or PCT, system covering a heptavalent (7-peptide) immunotherapy composition and methods of use for treating, reducing the incidence of, or inducing an immune response against a WT1-expressing cancer, which is pending and, if granted in jurisdictions in the national stage, would expire in 2040.

◦ Applications in the United States, Australia, Canada, China, Europe, Israel, India, Japan, South Korea, Mexico and Russia covering a heptavalent (7-peptide) immunotherapy composition and methods of use for treating, reducing the incidence of, or inducing an immune response against a WT1-expressing cancer, which are pending and, if granted, are expected to expire in 2040.

• Patents and patent applications in-licensed from MSK:

◦ Composition-of-matter patents covering the WT1-A1 peptide of GPS which have issued in the United States, Canada, Australia, and several countries of the European Union, and which are expected to expire in the United States in 2026 and elsewhere in 2024;

◦ Composition-of-matter patent covering the WT1-427 long and WT1-331 long peptides of GPS issued in the United States, which is expected to expire in 2031, and patents covering the methods of use in the United States which are expected to expire in 2026;

and a patent application covering peptide conjugates of the WT1-427 long peptide or WT1-331 long peptide which, if granted, is expected to expire in 2026;

◦ Composition-of-matter patents covering the WT1-427 long peptide of GPS and WT1-331 long peptide of GPS, and methods of use, which have issued in Australia and several countries of the European Union, which are expected to expire in 2026;

◦ Composition-of-matter patent covering the WT1-427 long peptide of GPS and method of use, which has issued in Canada which is expected to expire in 2026, and composition of matter patent application covering the WT1-331 long peptide of GPS and method of use, which is pending in Canada which, if granted, is expected to expire in 2026;

◦ Composition-of-matter patents covering the WT1-427 long and WT1-331 long peptides of GPS issued in the United States, which is expected to expire in 2031, and patents covering the methods of use in the United States, and which are expected to expire in 2026;

and a patent application covering peptide conjugates of the WT1-427 long peptide or WT1-331 long peptide, and which, if granted, is expected to expire in 2026;

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◦ Composition-of-matter patent covering the WT1-427 long peptide of GPS and method of use, which has issued in Canada, and which is expected to expire in 2026, and composition of matter patent application covering the WT1-331 long peptide of GPS and method of use, which is pending in Canada and which, if granted, is expected to expire in 2026;

◦ Composition-of-matter patent covering a WT1-specific peptide issued in the United States, which is expected to expire in 2026;

◦ Composition-of-matter patent covering the WT1-122A1 long peptide of GPS in the United States which is expected to expire in 2033;

and patent application covering the WT1-122A1 long peptide of GPS and methods of use in the United States which if granted, is expected to expire in 2027;

◦ Composition-of-matter patent covering the WT1-122A1 long peptide of GPS and methods of use in several countries of the European Union, which is expected to expire in 2027, and patent applications covering the WT1-122A1 long peptide of GPS and methods of use pending in the European Union and Canada which if granted, are expected to expire in 2027;

◦ Composition-of-matter patents covering certain WT1-targeting peptides and methods of use in the United States, Australia, China, several countries of the European Union, and Japan, which are expected to expire in 2034, and patent applications covering certain WT1-targeting and methods of use pending in the United States, Australia, European Union, Canada, China, Hong Kong, and Japan which, if granted, are expected to expire in 2034;

◦ Patent applications covering methods for treating, reducing the incidence of, or inducing an immune response against a WT1-expressing cancer, using the peptides of GPS in combination with immune checkpoint inhibitors in the United States, Australia, Canada, China, Hong Kong, European Union, South Korea, and Japan which if granted, are expected to expire in 2036.

and patent application covering the WT1-122A1 long peptide of GPS and methods of use in the United States, and which if granted, is expected to expire in 2027;

◦ Composition-of-matter patents covering certain WT1-targeting peptides and methods of use in the United States, Australia, China, several countries of the European Union, and Japan, which are expected to expire in 2034, and patent applications covering certain WT1-targeting peptides and methods of use pending in the United States, Australia, European Union, Canada, China, Hong Kong, and Japan, and which, if granted, are expected to expire in 2034;

◦ Patents covering methods for treating, reducing the incidence of, or inducing an immune response against a WT1-expressing cancer, using the peptides of GPS in combination with anti-PD-1 antibody checkpoint inhibitors in the United States and Japan, and which are expected to expire in 2037 and 2036, respectively;

Patents and patent applications covering NPS:

• Patent application owned by us:

◦ International application under the PCT system and patent application in the United States covering treatment of triple-negative breast cancer using a combination of NPS and trastuzumab which, if granted, are expected to expire in 2039.

• Patent applications owned by us:

◦ Patent applications in the United States, Australia, Canada, China, Europe, Israel, South Korea, Mexico and Russia covering treatment of TNBC using a combination of NPS and trastuzumab, and which, if granted, are expected to expire in 2039.

• Patents and patent applications in-licensed from HJF:

◦ Composition-of-matter patent covering modified NPS peptides, and method patent covering method of their production, which issued in the United States which are expected to expire in 2025 and 2024, respectively;

and patent application pending in the United States covering modified NPS peptides and methods of use which, if granted, is expected to expire in 2023;

◦ Patents covering treatment of cancer expressing HER2/neu using a combination of NPS and trastuzumab, which have issued in the United States and Australia which are expected to expire in 2026;

◦ Patents covering a method of inducing protective or therapeutic immunity against breast cancer having low/intermediate HER2 expression, which have issued in the United States, Australia, Canada, certain countries in the European Union, Japan, South Korea, and Mexico which are expected to expire in 2028;

and patent applications covering a method of inducing protective or therapeutic immunity against breast cancer having low/intermediate HER2/neu expression pending in the United States, China, European Union, Hong Kong, Japan, and South Korea which, if granted, are expected to expire in 2028.

◦ Composition-of-matter patent covering modified NPS peptides, and method patent covering method of their production, and which issued in the United States which are expected to expire in 2025 and 2024, respectively;

and patent application pending in the United States covering modified NPS peptides and methods of use, and which, if granted, is expected to expire in 2023;

◦ Patents covering treatment of cancer expressing HER2/neu using a combination of NPS and trastuzumab, which have issued in the United States and Australia, and which are expected to expire in 2026;

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and patent applications covering a method of inducing protective or therapeutic immunity against breast cancer having low/intermediate HER2/neu expression pending in the United States, China, European Union, Hong Kong, Japan, and South Korea, and which, if granted, are expected to expire in 2028.

Cancer immunotherapy has become a significant growth area for the biopharmaceutical industry, attracting large pharmaceutical companies as well as small niche players.

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and Pfizer, Inc.

Most of these companies, either alone or together with their collaborative partners, have substantially greater financial resources than we do.

Most of these companies, either alone or together with their collaborative partners, have substantially greater resources than we do.

Companies developing novel products with similar indications to those we are pursuing are expected to influence our ability to penetrate and maintain market share.

Principal competitors for our AML indication broadly include both companies with currently approved products in AML, such as AbbVie/Genentech (the holders of rights to VENCLEXTA), Agios Pharmaceuticals, Inc./Servier (the holder of U.S.

rights to TIBSOVO), Novartis AG (the holder of rights to RYDAPT), Astellas Pharmaceuticals (the holder of rights to XOSPATA), BMS (the holder of rights to ONUREG/VIDAZA and IDHIFA), Otsuka Pharmaceutical Co., Ltd.

(the holder of rights to DACOGEN), among others, as well as those with front-line chemotherapy drugs and maintenance therapies such as Jazz Pharmaceuticals, Inc.

(the holder of rights to VYXEOS), BMS (the holder of rights to ONUREG), Pfizer, Inc.

(the holder of rights to VYXEOS), Pfizer, Inc.

(the holder of rights to MYLOTARG and DAURISMO), among others, as well as companies with drugs currently in development for AML, such as Daiichi Sankyo (the holder of rights to quizartinib/licensed in Japan under the name VANFLYTA), Karyopharm Therapeutics, Inc.

(the holder of rights to XPOVIO), Pfizer, Inc./AROG Pharmaceuticals, LLC (the holders of rights to crenolanib), Novartis AG (the holder of rights to MBG453), Johnson & Johnson/Janssen Pharmaceuticals, Inc.

(the holder of rights to XPOVIO), Pfizer, Inc./AROG Pharmaceuticals, LLC (the holders of rights to crenolanib), Novartis AG (the holder of rights to sabatolimab, or MBG453), Johnson & Johnson/Janssen Pharmaceuticals, Inc.

(the holder of rights to cusatuzumab, or ARGX-110/JNJ-4550), Gilead Sciences, Inc.

(the holder of rights to magrolimab, or Hu5F9 G4), Actinium Pharmaceuticals, Inc.

(the holder of rights to [131]-iodine-apamistamab) and Rafael Pharmaceuticals, Inc.

(the holder of rights to devimistat) , among others.

Companies currently engaged in the clinical development of AML therapies with an immunological/immuno-modulatory mechanism of action include Pfizer, Inc./EMD Serono (the holders of rights to BAVENCIO), BMS (the holder of rights to YERVOY) MacroGenics, Inc./Les Laboratoires Servier, SA (the holders of rights to flotetuzumab, or MGD006), Celyad Oncology SA (the holder of rights to CYAD-01), Fortress Biotech, Inc, (the holder of rights to CNDO-109), Glycostem Therapeutics BV (the holder of rights to oNKord), iCell Gene Therapeutics, LLC (the holder of rights to CLL-CD33 Compound CAR T-cell), among others.

(the holder of rights to [131]-iodine-apamistamab), Syndax (the holder of rights to SNDX-5613), Aptose Biosciences (the holder of rights to HM43239), among others.

Companies currently engaged in the clinical development of AML therapies with an immunological/immuno-modulatory mechanism of action include Pfizer, Inc./EMD Serono (the holders of rights to BAVENCIO), BMS (the holder of rights to YERVOY) MacroGenics, Inc./Les Laboratoires Servier, SA (the holders of rights to flotetuzumab, or MGD006), ImmunoGen (the holder of rights to IMGN632), Celyad Oncology SA (the holder of rights to CYAD-01), Fortress Biotech, Inc, (the holder of rights to CNDO-109), Glycostem Therapeutics BV (the holder of rights to oNKord), iCell Gene Therapeutics, LLC (the holder of rights to CLL-CD33 Compound CAR T-cell), among others.

Companies currently engaged in the clinical development of WT1-targeting vaccines (not specifically for AML) include Otsuka Pharmaceutical Co., Ltd.

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(the holder of rights to DSP-7888)/ade-gramotide/nelatimotide).

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For patients with early stage breast cancer, adjuvant therapy is often given to prevent recurrence and increase the chance of long-term DFS.

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Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for our current product candidates or any other future product candidate, which could result in our competitors establishing a strong market position before we are able to enter the market.

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Government Regulation

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• submission to the FDA of an IND application, which must become effective before clinical trials may begin and must be updated annually or when significant changes are made;

• approval by an independent Institutional Review Board, or IRB, or ethics committee at each clinical site before the trial is begun;

• approval by an IRB, or ethics committee at each clinical site before the trial is begun;

• performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCP, and other clinical-trial related regulations to establish the safety, purity and potency of the investigational biologic product candidate for its proposed indication;

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The testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for our current or future product candidates will be granted on a timely basis, if at all.

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Preclinical studies

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Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives.

Some studies also include oversight by an independent DSMB organized by the clinical trial sponsor, which provides authorization for whether or not a clinical trial may move forward at designated check points based on access to certain data from the clinical trial and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

Information about certain clinical trials, including details of the protocol and eventually study results, also must be submitted within specific timeframes to the National Institutes of Health for public dissemination on the ClinicalTrials.gov data registry.

Some studies also include oversight by an independent data safety monitoring board, or DSMB, organized by the clinical trial sponsor, which provides authorization for whether or not a clinical trial may move forward at designated check points based on access to certain data from the clinical trial and may halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy.

Information about certain clinical trials, including details of the protocol and eventually study results, also must be submitted within specific timeframes to the NIH for public dissemination on the ClinicalTrials.gov data registry.

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

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Competitors may use this publicly available information to gain knowledge regarding the progress of development programs.

Failure to timely register a covered clinical study or to submit study results as provided for in the law can give rise to civil monetary penalties and also prevent the non-compliant party from receiving future grant funds from the federal government.

The NIH Final Rule on ClinicalTrials.gov registration and reporting requirements became effective in 2017, and both NIH and FDA have recently begun enforcing those requirements against non-compliant clinical trial sponsors.

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For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap.

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The FDA 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 clinical protocol, cGCP, or other IRB 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 clinical protocol, GCP, or other IRB requirements or if the drug has been associated with unexpected serious harm to patients.

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

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

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BLA Submission and Review by the FDA

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These fees are typically increased annually, but exemptions and waivers may be available under certain circumstances (such as a waiver for the first human drug application submitted by a qualifying small business and exemptions for orphan products).

Once a BLA has been submitted, the FDA’s goal is to review the application within ten months after it accepts the application for filing, or, if the application relates to an unmet medical need in a serious or life-threatening indication, six months after the FDA accepts the application for filing.

This FDA review typically takes twelve months from the date the BLA is submitted to the FDA (for a standard review) and eight months from the date the BLA is submitted (for a “priority review”) because the FDA has approximately two months, or 60 days, after BLA submission to make a “filing” decision.

Furthermore, the review process is often significantly extended by FDA requests for additional information or clarification after the BLA has been accepted for filing.

The FDA may also request additional information rather than accept a BLA for filing.

In this event, the application must be resubmitted with the additional information.

The FDA reviews all BLAs submitted to determine if they are substantially complete before it accepts them for filing and may request additional information rather than accepting an BLA for filing.

The FDA must make a decision on accepting a BLA for filing within 60 days of receipt and must inform the sponsor by the 74th day after the FDA’s receipt of the submission whether the application is sufficiently complete to permit substantive review.

The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information.

In this event, the BLA must be resubmitted with the additional information requested by the agency.

The resubmitted application is also subject to review before the FDA accepts it for filing.

After a BLA is accepted for filing, the FDA reviews it to determine, among other things, whether the product is safe, pure and potent and the facility in which it is manufactured, processed, packed, or held meets standards designed to assure the product’s continued safety, purity and potency.

Once a BLA is accepted for filing, the FDA’s goal is to review the application within ten months after it accepts the application for filing, or, if the application meets the criteria for “priority review”, six months after the FDA accepts the application for filing.

The review process is often significantly extended by FDA requests for additional information or clarification after the BLA has been accepted for filing.

During the review process, the FDA reviews the BLA to determine, among other things, whether the product is safe, pure and potent and the facility in which it is manufactured, processed, packed, or held meets standards designed to assure the product’s continued safety, purity and potency.

The FDA may refer any BLA, including applications for novel biologic candidates which present difficult questions of safety or efficacy to an advisory committee to provide clinical insight on application review questions.

Typically, an advisory committee is a panel of independent experts, including clinicians and other scientific experts that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions.

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

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

Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured.

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Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information.

If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies as part of the review process and often will request additional testing or information.

Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

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Under the Pediatric Research Equity Act, or PREA, amendments to the FDCA, a BLA or supplement to a BLA must contain data that are adequate to assess the safety and efficacy of the product candidate for the claimed indications in all relevant pediatric populations and to support dosing and administration for each pediatric population for which the product is safe and effective.

The FDA may grant deferrals for submission of pediatric data or full or partial waivers.

The Food and Drug Administration Safety and Innovation Act, or the FDASIA, enacted in 2012, made permanent PREA to require a sponsor who is planning to submit a marketing application for a product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration to submit an initial Pediatric Study Plan, or PSP, within sixty days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 clinical trial.

The PREA requires a sponsor that is planning to submit a marketing application for a product that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration to submit an initial Pediatric Study Plan, or PSP, within sixty days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 clinical trial.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including trial objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

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The FDA may not grant approval on a timely basis, or at all, and we may encounter difficulties or unanticipated costs in our efforts to secure necessary governmental approvals, which could delay or preclude us from marketing its products.

After the FDA evaluates a BLA and conducts inspections of manufacturing facilities where the investigational product and/or its drug substance will be produced, the FDA may issue an approval letter or a Complete Response Letter.

After the FDA evaluates a BLA and conducts inspections of the manufacturing facilities where the investigational product and/or its drug substance will be produced, the FDA may issue an approval letter or a Complete Response Letter, or CRL.

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

A Complete Response Letter indicates that the review cycle of the application is complete and the application is not ready for approval.

A Complete Response Letter generally outlines the deficiencies in the submission and may require substantial additional testing, information or clarification for FDA to reconsider the application.

A CRL indicates that the review cycle of the application is complete and the application is not ready for approval.

A CRL generally outlines the deficiencies in the submission and may require substantial additional testing, information or clarification for FDA to reconsider the application.

The FDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.

If a CRL is issued, the applicant may either resubmit the BLA, addressing all of the deficiencies identified in the letter, or withdraw the application.

If and when the deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the BLA, the FDA will issue an approval letter.

The FDA has committed to reviewing such resubmissions in response to an issued CRL in either two or six months depending on the type of information included.

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

If regulatory approval of a product is granted, such approval is limited to the conditions of use (e.g., patient population, indication) described in the application and may entail further limitations on the indicated uses for which such product may be marketed.

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In addition, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

Fast Track, Priority Review, Accelerated Approval, and Breakthrough Therapy Designations

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Fast Track, Priority Review, and Breakthrough Therapy Designations

A sponsor may seek approval of its product candidate under programs designed to accelerate FDA’s review and approval of new drugs and biological products that meet certain criteria.

Specifically, new drugs and biological products are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet medical needs for the condition.

For a product candidate with Fast Track designation, the FDA may consider sections of the BLA for review on a rolling basis before the complete application is submitted if relevant criteria are met.

A Fast Track designated product candidate may also qualify for priority review, under which the FDA sets the target date for FDA action on the BLA at six months after the FDA accepts the application for filing.

Fast Track designation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinical development, in addition to the potential for rolling review once a marketing application is filed, meaning that the FDA may consider for review sections of the BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the BLA, the FDA agrees to accept sections of the BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application.

A Fast Track designated product candidate may also qualify for accelerated approval (described below) or priority review, under which the FDA sets the target date for FDA action on the BLA at six months after the FDA accepts the application for filing.

We have obtained Fast Track designation for GPS in AML, MPM, and MM, and for NPS in TNBC.

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If criteria are not met for priority review, the application is subject to the standard FDA review period of ten months after FDA accepts the application for filing.

Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.

Under the Accelerated Approval program, the FDA may approve a BLA on the basis of either a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

Post-marketing studies or completion of ongoing studies after marketing approval are generally required to verify the biologic’s clinical benefit in relationship to the surrogate endpoint or ultimate outcome in relationship to the clinical benefit.

Failure to conduct required post-approval studies, or to confirm the predicted clinical benefit of the product during post-marketing studies, would allow the FDA to withdraw approval of the drug.

In addition, a sponsor may seek FDA designation of its product candidate as a Breakthrough Therapy, if the product candidate is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the therapy may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

If the FDA designates a breakthrough therapy, it may take actions appropriate to expedite the development and review of the application.

Breakthrough designation also allows the sponsor to file sections of the BLA for review on a rolling basis.

Drugs or biologics designated as breakthrough therapies are also eligible for accelerated approval of their respective marketing applications.

Breakthrough Therapy designation provides all the features of Fast Track designation in addition to intensive guidance on an efficient development program beginning as early as Phase 1, and FDA organizational commitment to expedited development, including involvement of senior managers and experienced review and regulatory staff in a proactive, collaborative, cross-disciplinary review, where appropriate.

A drug designated as Breakthrough Therapy is also eligible for Accelerated Approval if the relevant criteria are met.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Fast Track, Priority Review and Breakthrough Therapy designations do not change the standards for approval but may expedite the development or approval process.

Fast Track, priority review and Breakthrough Therapy designations do not change the scientific or medical standards for approval or the quality of evidence necessary to support approval but may expedite the development or approval process.

Accelerated Approval

In addition, 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 from the FDA and may be approved on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit.

The FDA may also grant accelerated approval for such a drug or biologic when it has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, or IMM, and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA may require that a sponsor of a drug or biologic receiving accelerated approval perform post-marketing clinical trials to verify and describe the predicted effect on IMM or other clinical endpoint, and the product may be subject to expedited withdrawal procedures.

Drugs and biologics granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.

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For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit.

Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints.

An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug or biologic, such as an effect on IMM.

The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints, but has indicated that such endpoints generally may support accelerated approval when the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate long-term clinical benefit of a drug.

The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a drug, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly.

For example, accelerated approval has been used extensively in the development and approval of drugs and biologics for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large clinical trials to demonstrate a clinical or survival benefit.

The accelerated approval pathway is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the product candidate’s clinical benefit.

As a result, a product candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint.

Failure to conduct required post-approval studies, or to confirm the predicted clinical benefit of the product during post-marketing studies, would allow the FDA to withdraw approval of the product.

All promotional materials for product candidates being considered and approved under the accelerated approval program are subject to prior review by the FDA.

Under the Orphan Drug Act, the FDA may grant Orphan Drug Product Designation to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 individuals in the United States, or a patient population greater than 200,000 individuals in the United States and when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States for that drug or biologic.

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We have obtained Orphan Drug Product Designation in the United States for GPS in AML, MPM and MM.

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Pediatric exclusivity

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The issuance of a written request does not require the sponsor to undertake the described studies.

Reference product exclusivity for biological products

In March 2010, the Patient Protection and Affordable Care Act, or ACA, was enacted in the United States and included the Biologics Price Competition and Innovation Act of 2009, or the BPCIA.

The BPCIA amended the PHSA to create an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-licensed reference biological product.

A federal district court ruling in Texas struck down the ACA in its entirety based on constitutionality in December 2018 after the individual mandate was repealed by Congress as part of the Tax Cuts and Jobs Act, effective January 1, 2019, and in December 2019 the Fifth Circuit Court of Appeals upheld the lower court’s finding that the individual mandate in the law is unconstitutional.

However, the Fifth Circuit also reversed and remanded the case to the district court to determine if other reforms enacted as part of the ACA, but not specifically related to the individual mandate or health insurance, including the BPCIA, could be severed from the rest of the ACA so as not to be declared invalid.

On March 2, 2020, the United States Supreme Court granted the petitions for writs of certiorari to review this case and allocated one hour for oral arguments, which occurred on November 10, 2020.

A decision from the Supreme Court is expected to be issued in spring 2021.

It is unclear how this litigation and other efforts to repeal and replace the ACA will affect the implementation of that law and our business.

To date, the FDA has approved a number of biosimilars, and numerous biosimilars have been approved in Europe.

The FDA has also issued several guidance documents outlining its approach to reviewing and approving biosimilars and interchangeable biosimilars.

A biosimilar product is defined as one that is highly similar to a reference product notwithstanding minor differences in clinically inactive components and for which there are no clinically meaningful differences between the follow-on biological product and the reference product in terms of the safety, purity and potency of the product.

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

Upon licensure by the FDA, an interchangeable biosimilar may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product, although to date no such products have been approved for marketing in the United States.

The biosimilar applicant must demonstrate that its product is biosimilar based on data from (1) analytical studies showing that the biosimilar product is highly similar to the reference product;

(2) animal studies (including toxicity);

and (3) one or more clinical studies to demonstrate safety, purity and potency in one or more appropriate conditions of use for which the reference product is approved.

In addition, the applicant must show that the biosimilar and reference products have the same mechanism of action for the conditions of use on the label, route of administration, dosage and strength, and the production facility must meet standards designed to assure product safety, purity and potency.

A reference biological product is granted twelve years of data exclusivity from the time of first licensure of the product, and the first approved interchangeable biologic product will be granted an exclusivity period of up to one year after it is first commercially marketed.

If pediatric studies are performed and accepted by the FDA as responsive to a Written Request, the twelve-year exclusivity period will be extended for an additional six months.

Patent Term Restoration and Reference product exclusivity for biological products

Depending upon the timing, duration and specifics of FDA approval of the use of our product candidates, some of our United States patents may be eligible for limited patent term extension under the Hatch-Waxman Act.

The Hatch-Waxman Act permits 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 candidate’s approval date.

The patent term restoration period is generally one half of 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 product candidate is eligible for the extension and the application for extension must be made prior to expiration of the patent.

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

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

The Biologics Price Competition and Innovation Act of 2009 (BPCIA) amended the PHSA to authorize the FDA to approve similar versions of innovative biologics such as ours, which are also known as “reference biological products.” The new pathway authorized under the BPCIA allows FDA to approve, under an abbreviated application, a biological product that are demonstrated to be “biosimilar” or “interchangeable” with an FDA-licensed reference biological product.

Biosimilarity to an approved reference product requires that there be no differences in conditions of use, route of administration, dosage form, and strength, and no clinically meaningful differences between the follow-on biological product and the reference product in terms of safety, purity, and potency.

Biosimilarity is demonstrated in steps beginning with rigorous analytical studies or “fingerprinting”, in vitro studies, in vivo animal studies, and generally at least one clinical study, absent a waiver from the FDA.

The biosimilarity exercise tests the hypothesis that the investigational product and the reference product are the same.

If at any point in the stepwise biosimilarity process a significant difference is observed, then the products are not biosimilar, and the development of a standalone BLA is necessary.

In order to meet the higher hurdle of interchangeability, a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product, and for a product that is administered more than once, that the risk of switching between the reference product and biosimilar product is not greater than the risk of maintaining the patient on the reference product.

Complexities associated with the larger, and often more complex, structures of biological products, as well as the process by which such products are manufactured, pose significant hurdles to implementation that are still being evaluated by the FDA.

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Under the BPCIA, a reference biological product is granted twelve years of data exclusivity from the date of first licensure of the product, which means that the FDA is barred from approving biosimilar applications for 12 years after the reference biological product receives initial marketing approval.

In addition, 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 of the reference product.

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Following approval of a new product, the manufacturer and the approved product are subject to pervasive and continuing regulation by the FDA, including, among other things, monitoring and recordkeeping activities, reporting of adverse experiences with the product, product sampling and distribution restrictions, complying with promotion and advertising requirements, which include restrictions on promoting drugs for unapproved uses or patient populations (i.e., “off-label use”) and limitations on industry-sponsored scientific and educational activities.

The manufacturer and its product are also subject to similar post-approval requirements by regulatory authorities comparable to FDA in jurisdictions outside of the United States where the product is approved.

The manufacturer and its products are also subject to similar post-approval requirements by regulatory authorities comparable to FDA in jurisdictions outside of the United States where the products are approved.

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

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Product approvals may be withdrawn for non-compliance with regulatory standards or if problems occur following initial marketing.

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FDA regulations require that products be manufactured in specific approved facilities and in accordance with cGMPs.

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These manufacturers must comply with cGMP regulations that require, among other things, quality control and quality assurance, the maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

Manufacturers and other entities involved in the manufacture and distribution of approved drugs or biologics are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

Manufacturers and other entities involved in the manufacture and distribution of approved drugs or biologics are required to register their establishments with the FDA and certain state agencies and are subject to periodic prescheduled or unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain cGMP compliance.

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or mandated modification of promotional materials and labeling and the issuance of corrective information.

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In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, which regulates the distribution of drugs and drug samples at the federal level and sets minimum standards for the registration and regulation of drug distributors by the states.

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Many states have similar laws that apply to their state health care programs as well as private payors.

In November 2020, HHS finalized significant changes to the regulations implementing the Anti-Kickback Statute, as well as the Physician Self-Referral Law (Stark Law) and the civil monetary penalty rules regarding beneficiary inducements, with the goal of offering the health care industry more flexibility and reducing the regulatory burden associated with those fraud and abuse laws, particularly with respect to value-based arrangements among industry participants.

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The FCA imposes liability on persons who, among other things, present or cause to be presented false or fraudulent claims for payment by a federal health care program.

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In addition, there has been a recent trend of increased federal and state regulation of payments made to physicians and other healthcare providers.

The ACA, as amended by the Health Care and Education Reconciliation Act, or collectively, the Affordable Care Act, among other things, requires manufacturers of FDA-approved drugs, devices, biologics and medical supplies covered by Medicare or Medicaid to report, on an annual basis, to the U.S.

Department of Health and Human Services information related to payments or other transfers of value made by them to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

The federal Physician Payments Sunshine Act, enacted as part of the Patient Protection and Affordable Care Act of 2010 (the “ACA”) requires manufacturers of FDA-approved drugs, devices, biologics and medical supplies covered by Medicare or Medicaid to report, on an annual basis, to the U.S.

Department of Health and Human Services information related to payments or other transfers of value made by them to U.S.-licensed physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

Failure to submit required information may result in civil monetary penalties .

Certain states also mandate implementation of commercial compliance programs, impose restrictions on drug manufacturer marketing practices and/or require the tracking and reporting of gifts, compensation and other remuneration to physicians and other healthcare professionals.

Effective January 1, 2022, these reporting obligations will extend to include transfers of value made in the previous year to certain non-physician providers, including physician assistants, nurse practitioners, clinical nurse specialists, certified registered nurse anesthetists, anesthesiology assistants, and certified nurse midwives.

The federal criminal statutes enacted under HIPAA impose criminal liability for knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors, or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program;

knowingly and willfully embezzling or stealing from a healthcare benefit program;

willfully preventing, obstructing, misleading, or delaying a criminal investigation of a healthcare offense;

and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statements in connection with the delivery of or payment for healthcare benefits, items or services.

Similar to the federal Anti-Kickback Statute, a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

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We may also be subject to data privacy and security regulation by both the federal government and the states in which it conducts its business.

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Prescription drug and biologic products also must meet applicable child-resistant packaging requirements under the U.S, Poison Prevention Packaging Act.

We may also be subject to analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third party-payors, including private insurers, and may be broader in scope than their federal equivalents.

The laws of some U.S.

states and foreign jurisdictions require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government or otherwise restrict payments that may be made to healthcare providers.

In addition, certain state and foreign laws and regulations require disclosures to regulatory agencies and/or commercial purchasers with respect to certain price increases that exceed a certain level as identified in the relevant statutes, require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers, and restrict marketing practices or require disclosure of marketing expenditures and pricing information.

states also require registration of pharmaceutical sales representatives.

If our operations are found to be in violation of any of such laws or any other governmental regulations that apply to it, we may be subject to penalties, including, without limitation, civil and criminal penalties, damages, fines, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare programs and imprisonment, any of which could adversely affect our ability to operate our business and our financial results.

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Violations of these laws, or allegations of such violations, could result in fines, penalties or prosecution and have a negative impact on our business, results of operations and reputation.

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General Data Protection Regulation .

The collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the European Union, including personal health data, is subject to the European Union’s General Data Protection Regulation, or GDPR, which became effective on May 25, 2018.

The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.

The GDPR also imposes strict rules on the transfer of personal data to countries outside the European Union, including the U.S., and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.

The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.

The Company must comply with the GDPR in the performance of its clinical trials in the European Union, and relies on its CROs to implement appropriate safeguards and procedures relating to informed consent in order to ensure that trials are conducted in a manner consistent with the GDPR.

Coverage and Reimbursement

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Accordingly, decisions regarding the extent of coverage and amount of reimbursement to be provided for any of our products will be made on a payor-by-payor basis.

As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.

The United States government, state legislatures and foreign governments have shown significant interest in implementing cost containment programs to limit the growth of government-paid health care costs, including price-controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs.

Third-party payors are increasingly challenging drug prices and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy.

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

A payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.

Moreover, eligibility for reimbursement does not imply that any product will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution.

Interim payments for new products, if applicable, may also not be sufficient to cover our costs and may not be made permanent.

Payment rates may vary according to the use of the product and the clinical setting in which it is used, may be based on payments allowed for lower cost products that are already reimbursed and may be incorporated into existing payments for other services.

Net prices for products may be reduced by mandatory discounts or rebates required by third-party payors and by any future relaxation of laws that presently restrict imports of products from countries where they may be sold at lower prices than in the United States.

In the United States, third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies, but they also have their own methods and approval process apart from Medicare coverage and reimbursement determinations.

Accordingly, one third-party payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage for the product.

Accordingly, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or granted at all.

The process for determining whether a payor will cover and how much it will reimburse a product may be separate from the process of seeking approval of the product or for setting the price of the product.

Even if reimbursement is provided, market acceptance of our products may be adversely affected if the amount of payment for our products proves to be unprofitable for health care providers or less profitable than alternative treatments or if administrative burdens make our products less desirable to use.

Additionally, the United States government, state legislatures and foreign governments have shown significant interest in implementing cost containment programs to limit the growth of government-paid health care costs,

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including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs.

For example, the ACA contains provisions that may reduce the profitability of drug products through increased rebates for drugs reimbursed by Medicaid programs, extension of Medicaid rebates to Medicaid managed care plans, mandatory discounts for certain Medicare Part D beneficiaries and annual fees based on pharmaceutical companies’ share of sales to federal health care programs.

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The ACA also expanded the universe of Medicaid utilization subject to drug rebates by requiring pharmaceutical manufacturers to pay rebates on Medicaid managed care utilization and by enlarging the population potentially eligible for Medicaid drug benefits.

As another example, the 2021 Consolidated Appropriations Act signed into law on December 27, 2020 incorporated extensive healthcare provisions and amendments to existing laws, including a requirement that all manufacturers of drugs and biological products covered under Medicare Part B report the product’s average sales price (“ASP”), to the DHHS beginning on January 1, 2022, subject to enforcement via civil money penalties.

Since its enactment, there have been judicial and Congressional challenges to certain aspects of the ACA, and as a result certain sections of the ACA have not been fully implemented or effectively repealed.

In particular, in December of 2018, a Texas U.S.

District Court Judge ruled that the ACA is unconstitutional in its entirety because the individual mandate was repealed by Congress as part of the Tax Cuts and Jobs Act, effective January 1, 2019.

On December 18, 2019, the U.S.

Court of Appeals for the Fifth Circuit upheld the District Court ruling that the individual mandate was unconstitutional but remanded the case back to the District Court to determine whether other reforms enacted as part of the ACA but not specifically related to the individual mandate or health insurance could be severed from the rest of the ACA so as not to be declared invalid as well.

On March 2, 2020, the United States Supreme Court granted the petitions for writs of certiorari to review this case and allocated one hour for oral arguments, which occurred on November 10, 2020.

A decision from the Supreme Court is expected to be issued in spring 2021.

It is unclear how this litigation and other efforts to repeal and replace the ACA will impact the ACA and the pharmaceutical industry more generally.

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

The Coronavirus Aid, Relief, and Economic Security Act, or the CARES Act, which was signed into law on March 27, 2020 and was designed to provide financial support and resources to individuals and businesses affected by the COVID-19 pandemic, suspended the 2% Medicare sequester from May 1, 2020 through December 31, 2020, and extended the sequester by one year, through 2030, in order to offset the added expense of the 2020 cancellation.

The 2021 Consolidated Appropriations Act was subsequently signed into law on December 27, 2020 and extends the CARES Act suspension period to March 31, 2021.

On June 17, 2021, the U.S.

Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

In addition, various legislative changes have been proposed and adopted since the ACA was enacted.

These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year pursuant to the Budget Control Act of 2011, which began in 2013 and will remain in effect through 2030 unless additional Congressional action is taken, with the exception of a temporary suspension by Congress of the 2% cut in Medicare payments from May 1, 2020 through June 30, 2022 (a 1% sequester will apply from April 1, 2022 through June 30, 2022) due to the COVID-19 pandemic.

In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further 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.

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003, or the MMA, established the Medicare Part D program to provide a voluntary prescription drug benefit to Medicare beneficiaries.

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government agencies, the manufacturer must extend discounts to entities eligible to participate in the 340B drug pricing program.

The maximum amount that a manufacturer may charge a 340B covered entity for a given product is the AMP reduced by the rebate amount paid by the manufacturer to Medicaid for each unit of that product.

The maximum amount that a manufacturer may charge a 340B covered entity for a

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given product is the AMP reduced by the rebate amount paid by the manufacturer to Medicaid for each unit of that product.

As of 2010, the ACA expanded the types of entities eligible to receive discounted 340B pricing, although, under the current state of the law, with the exception of children’s hospitals, these newly eligible entities will not be eligible to receive discounted 340B pricing on orphan drugs.

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Moreover, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products.

In March 2020, the Trump administration sent “principles” for drug pricing to Congress, calling for legislation that would, among other things, cap Medicare Part D beneficiary out-of-pocket pharmacy expenses, provide an option to cap Medicare Part D beneficiary monthly out-of-pocket expenses, and place limits on pharmaceutical price increases.

In addition, the Trump administration previously released a “Blueprint” to lower drug prices and reduce out of pocket costs of drugs that contained proposals to increase manufacturer competition, increase the negotiating power of certain federal healthcare programs, incentivize manufacturers to lower the list price of their products and reduce the out-of-pocket costs of drug products paid by consumers.

HHS has solicited feedback on some of these measures and has implemented others under its existing authority.

For example, in September 2020, the FDA finalized a rulemaking to establish a system whereby state governmental entities could lawfully import and distribute prescription drugs sourced from Canada.

Those new regulations became effective on November 30, 2020, although the impact of such future programs is uncertain and lawsuits have been filed challenging the government’s authority to promulgate them.

While some of these and other measures may require additional authorization to become effective, Congress and the Trump administration have each indicated that they will continue to seek new legislative and/or administrative measures to control drug costs.

For example, on July 24, 2020, President Trump announced four executive orders related to prescription drug pricing that attempt to implement several of the Administration’s proposals, including a policy that would tie Medicare Part B drug prices to international drug prices;

one that directed HHS to finalize the Canadian drug importation proposed rule previously issued by HHS (which has since been finalized, as noted above) and made other changes allowing for personal importation of drugs from Canada;

one that directed HHS to finalize the rulemaking process on modifying the anti-kickback law safe harbors for plans, pharmacies, and pharmaceutical benefit managers after HHS confirms that the action is not projected to increase federal spending, Medicare beneficiary premiums, or patients’ total out-of-pocket costs (which HHS finalized in November 2020);

and one that reduces costs of insulin and epinephrine auto-injectors to patients of federally qualified health centers.

President Trump also issued another executive order on September 13, 2020 that directed HHS to undertake rulemaking in order to test an international reference pricing model for prescription drug products, which was also implemented by HHS and then challenged in federal court by industry groups in December 2020.

The probability of success of these newly announced policies and their impact on the U.S.

prescription drug marketplace is unknown.

There are likely to be continued political and legal challenges associated with implementing these reforms as they are currently envisioned, notwithstanding the January 20, 2021 transition to a new presidential administration.

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.

For example, the 2021 Consolidated Appropriations Act signed into law on December 27, 2020 incorporated extensive healthcare provisions and amendments to existing laws, including new requirements for (1) all manufacturers of drugs and biological products covered under Medicare Part B to report the product’s average sales price (“ASP”), to the DHHS beginning on January 1, 2022, subject to enforcement via civil money penalties, (2) certain Medicare plans to develop tools to display Medicare Part D prescription drug benefit information in real time, and (3) for group and health insurance issuers to report information on pharmacy benefit and drug costs to the Secretaries of Health and Human Services, Labor and the Treasury.

In addition, the Biden Administration, has indicated that lowering prescription drug prices is a priority.

For example, in July 2021, President Biden issued a sweeping executive order on promoting competition in the American economy that includes several mandates pertaining to the pharmaceutical and health care insurance industries.

Among other things, the executive order directs the FDA to work towards implementing a system for importing drugs from Canada (following on a Trump administration notice-and-comment rulemaking on Canadian drug importation that was finalized in October 2020).

The Biden order also called on HHS to release a comprehensive plan to combat high prescription drug prices, and it includes several directives regarding the Federal Trade Commission’s oversight of potentially anticompetitive practices within the pharmaceutical industry.

The drug pricing plan released by HHS in September 2021 in response to the executive order makes clear that the Biden Administration supports aggressive action to address rising drug prices, including allowing HHS to negotiate the cost of Medicare Part B and D drugs, but such significant changes will require either new legislation to be passed by Congress or time-consuming administrative actions.

Any future measures will require authorization through additional legislation or regulation to become effective, and it is uncertain whether Congress or the new Biden administration will seek new legislative and/or administrative measures to control drug costs.

We expect that federal, state and local governments in the United States will continue to consider legislation directed at lowering the total cost of health care.

In December 2020, the U.S.

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Some countries may require additional studies that compare the cost-effectiveness of our product candidate to currently available therapies (so called health technology assessment, or HTA) in order to obtain reimbursement or pricing approval.

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 medicines.

For example, the European Union provides options for its member states to restrict the range of medicinal

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products for which their national health insurance systems provide reimbursement and to control the prices of medicines.

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

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There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any of our products.

Historically, products launched in the European Union do not follow price structures of the United States and generally tend to by significantly lower.

Historically, products launched in the European Union do not follow price structures of the United States and generally tend to be priced significantly lower.

Foreign Regulation

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Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.

It is not yet clear how the United Kingdom’s withdrawal from the European Union, which took place on January 31, 2020, will affect the approval of medicinal products in the United Kingdom.

Certain countries outside of the United States have processes that require the submission of a clinical trial application much like an IND prior to the commencement of human clinical trials.

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Once the CTA is approved in accordance with a country’s requirements, clinical trials may proceed in that country.

clinical trials legislation currently is undergoing a transition process mainly aimed at harmonizing and streamlining clinical-trial authorization, simplifying adverse-event reporting procedures, improving the supervision of clinical trials and increasing their transparency.

Specifically, in April 2014, the new Clinical Trials Regulation, (E.U.) No 536/2014 (Clinical Trials Regulation) was adopted and it is anticipated to come into application in late 2020 or early 2021.

The Clinical Trials Regulation will be directly applicable in all the E.U.

Member States, repealing the current Clinical Trials Directive 2001/20/EC.

Conduct of all clinical trials performed in the European Union will continue to be bound by currently applicable provisions until the new Clinical Trials Regulation becomes applicable.

The extent to which ongoing clinical trials will be governed by the Clinical Trials Regulation will depend on when the Clinical Trials Regulation becomes applicable and on the duration of the individual clinical trial.

If a clinical trial continues for more than three years from the day on which the Clinical Trials Regulation becomes applicable the Clinical Trials Regulation will at that time begin to apply to the clinical trial.

The requirements and processes governing the conduct of clinical trials, product licensing, pricing and reimbursement in Europe vary from country to country, even though there is already some degree of legal harmonization in the E.U.

member states resulting from the national implementation of underlying E.U.

Under the EU’s new Clinical Trials Regulation, which took effect in January 2022, there will be a centralized application procedure where one EU Member State’s competent authority takes the lead in reviewing part I of the application, which contains scientific and medicinal product documentation, and the other national authorities only have limited involvement.

Part II, which contains the national and patient-level documentation, will be assessed individually by each EU Member State.

Any substantial changes to the trial protocol or other information submitted with the CTA must be notified to or approved by the relevant competent authorities and ethics committees.

Medicines used in clinical trials must be manufactured in accordance with good manufacturing practices.

Other national and EU-wide regulatory requirements may also apply.

member states resulting from the national implementation of underlying EU legislation.

In all cases, the clinical trials are conducted in accordance with GCP and other applicable regulatory requirements.

To obtain regulatory approval of a new drug or medicinal product in the European Union, a sponsor must obtain approval of a marketing authorization application.

The way in which a medicinal product can be approved in the European Union depends on the nature of the medicinal product.

To obtain regulatory approval of a new drug or medicinal product in the EU, a sponsor must obtain approval of a marketing authorization application.

The way in which a medicinal product can be approved in the EU depends on the nature of the medicinal product.

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The centralized procedure results in a single marketing authorization granted by the European Commission that is valid across the European Union, as well as in Iceland, Liechtenstein and Norway.

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In this circumstance, EMA ensures that the evaluation for the opinion of the CHMP is completed within 150 days, excluding clock stops, and the opinion issued thereafter.

There are also two other possible routes to authorize medicinal products in several E.U.

countries, which are available for investigational medicinal products for which the centralized procedure is not obligatory:

There are also two other possible routes to authorize medicinal products in several EU countries, which are available for investigational medicinal products for which the centralized procedure is not obligatory:

the decentralized procedure and the mutual recognition procedure, or MRP.

Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one E.U.

country of medicinal products that have not yet been authorized in any E.U.

country and that do not fall within the mandatory scope of the centralized procedure.

Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one EU country of medicinal products that have not yet been authorized in any EU country and that do not fall within the mandatory scope of the centralized procedure.

The MRP is applicable to the majority of conventional medicinal products, and is based on the principle of recognition of an already existing national marketing authorization by one or more member states.

The characteristic of the MRP is that the procedure builds on an already existing marketing authorization in an E.U.

member state which is used as reference in order to obtain marketing authorizations in other E.U.

member states.

In the MRP, a marketing authorization for a drug already exists in one or more member states of the E.U.

and subsequently marketing authorization applications are made in other European Union member states by referring to the initial marketing authorization.

The characteristic of the MRP is that the procedure builds on an already existing marketing authorization in an EU member state which is used as reference in order to obtain marketing authorizations in other EU member states.

In the MRP, a marketing authorization for a drug already exists in one or more member states of the EU and subsequently marketing authorization applications are made in other EU member states by referring to the initial marketing authorization.

The member state in which the marketing authorization was first granted will then act as the reference member state.

The member states where the marketing authorization is subsequently applied for act as concerned member states.

The MRP is based on the principle of the mutual recognition by E.U.

member states of their respective national marketing authorizations.

The MRP is based on the principle of the mutual recognition by EU member states of their respective national marketing authorizations.

Based on a marketing authorization in the reference member state, the applicant may apply for marketing authorizations in other member states.

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National marketing authorizations shall be granted within 30 days after acknowledgement of the agreement.

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Should any Member State refuse to recognize the marketing authorization by the reference member state, on the grounds of potential serious risk to public health, the issue will be referred to a coordination group.

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As in the centralized procedure, this process entails consulting various European Commission Directorates General and the Standing Committee on Human Medicinal Products or Veterinary Medicinal Products, as appropriate.

In the E.U., new chemical entities, sometimes referred to as new active substances, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

The data exclusivity, if granted, prevents regulatory authorities in the E.U.

from referencing the innovator’s data to assess a generic or biosimilar application for eight years, after which generic marketing authorization can be submitted, and the innovator’s data may be referenced, but not approved for two years.

The overall ten-year period can be extended to a maximum of 11 years if, during the first eight years of those 10 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 determined to bring a significant clinical benefit in comparison with currently approved therapies.

In the EU, new chemical entities, sometimes referred to as new active substances, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

The data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic or biosimilar application for eight years, after which generic marketing authorization can be submitted, and the innovator’s data may be referenced, but not approved for two years.

The overall ten-year period can 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 determined to bring a significant clinical benefit in comparison with currently approved therapies.

The criteria for designating an orphan medicinal product in the European Union are similar in principle to those in the United States.

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If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension of clinical trials, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

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Health Care Reform in the U.S.

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FDA and other regulatory authority policies may change and additional government regulations may be enacted that could prevent, limit or delay regulatory approval of our drug candidates.

For example, in December 2016, the 21st Century Cures Act, or Cures Act, was signed into law.

The Cures Act, among other things, is intended to modernize the regulation of drugs and devices and to spur innovation, but its ultimate implementation is uncertain.

In addition, in August 2017, the FDA Reauthorization Act was signed into law, which reauthorized the FDA’s user fee programs and included additional drug and device provisions that build on the Cures Act.

For example in August 2017, the FDA Reauthorization Act was signed into law, which reauthorized the FDA’s user fee programs and included additional drug and device provisions that build on the Cures Act enacted in December 2016.

The next cycle of Congressional reauthorization for FDA’s prescription drug, biologic, and medical device user fee programs must be completed by mid-2022 and that periodic must-pass legislation is typically used as a vehicle to implement federal policy changes or other substantive amendments to the FDCA.

If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we otherwise may have obtained and we may not achieve or sustain profitability, which would adversely affect our business, prospects, financial condition and results of operations.

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Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medical products and services, implementing reductions in Medicare and other health care funding and applying new payment methodologies.

For example, in March 2010, the ACA was enacted, which, among other things, increased the minimum Medicaid rebates owed by most manufacturers under the Medicaid Drug Rebate Program;

introduced a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;

extended the Medicaid Drug Rebate Program to utilization of prescriptions of individuals enrolled in Medicaid managed care plans;

imposed mandatory discounts for certain Medicare Part D beneficiaries as a condition for manufacturers’ outpatient drugs coverage under Medicare Part D;

and established a Center for Medicare Innovation at the US Centers for Medicare and Medicaid Services, or CMS, to test innovative payment and service delivery models to lower Medicare and Medicaid spending.

The uncertainty related to the Affordable Care Act and the Trump Administration’s regulatory and executive actions pertaining to drug costs and drug pricing matters is described above under “Coverage, Pricing, and Reimbursement.”

Other legislative changes have been proposed and adopted in the United States since the Affordable Care Act that may affect health care expenditures.

For example, on December 20, 2019, President Trump signed the Further Consolidated Appropriations Act for 2020 into law (P.L.

116-94) that includes a piece of bipartisan legislation called the Creating and Restoring Equal Access to Equivalent Samples Act of 2019 or the “CREATES Act.” The CREATES Act aims to address the concern articulated by both the FDA and others in the industry that some brand manufacturers have improperly restricted the distribution of their products, including by invoking the existence of a REMS for certain products, to deny generic and biosimilar product developers access to samples of brand products.

In addition to the sweeping reforms contained in the ACA (summarized above in the section entitled “Coverage and Reimbursement”), other legislative changes have been proposed and adopted in the United States that may affect health care expenditures.

For example, the 2020 Further Consolidated Appropriations Act (P.L.

116-94) included a piece of bipartisan legislation called the Creating and Restoring Equal Access to Equivalent Samples Act of 2019 or the “CREATES Act.” The CREATES Act aims to address the concern articulated by both the FDA and others in the industry that some brand manufacturers have improperly restricted the distribution of their products, including by invoking the existence of a REMS for certain products, to deny generic and biosimilar product developers access to samples of brand products.

Because generic and biosimilar product developers need samples to conduct certain comparative testing required by the FDA, some have attributed the inability to timely obtain samples as a cause of delay in the entry of generic and biosimilar products.

To remedy this concern, the CREATES Act establishes a private cause of action that permits a generic or biosimilar product developer to sue the brand manufacturer to compel it to furnish the necessary samples on “commercially reasonable, market-based terms.” Whether and how generic and biosimilar product developments will use this new pathway, as well as the likely outcome of any legal challenges to provisions of the CREATES Act, remain highly uncertain and its potential effects on our future commercial products are unknown.

The Consolidated Appropriations Act, 2021, signed into law by President Trump on December 27, 2020 also includes, among other things, a new requirement for patent information to be submitted to the FDA and published in a “Purple Book” that contains detailed information about each FDA-licensed biological product, analogous to the Orange Book that provides information about approved small-molecule drug products and their patent and exclusivity information under the Hatch-Waxman Amendments.

In addition, the next cycle of Congressional reauthorization for FDA’s prescription drug, biologic, and medical device user fee programs must be completed by mid-2022 and that periodic must-pass legislation is typically used as a vehicle to implement federal policy changes or other substantive amendments to the FDCA.

The Consolidated Appropriations Act of 2021 also includes, among other things, a new requirement for patent information to be submitted to the FDA and published in a “Purple Book” that contains detailed information about each FDA-licensed biological product, analogous to the Orange Book that provides information about approved small-molecule drug products and their patent and exclusivity information under the Hatch-Waxman Amendments.

We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative or executive action, either in the United States or abroad.

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Moreover, if we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, our therapeutic candidates may lose any marketing approval that may have been obtained and we may not achieve or sustain profitability, which would adversely affect our business.

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Corporate Information

Our principal executive offices are located at 7 Times Square, Suite 2503, New York, NY 10036, and our phone number is (646) 200-5278.

Our website address is www.sellaslife.com.

Our website address is www.sellaslifesciences.com.

We do not incorporate the information on our website into this annual report on Form 10-K, and you should not consider such information part of this annual report on Form 10-K.

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What changed 10-K

Item 1. Business