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Item 1. Business

2024-03-28 compared with 2023-03-16 · 517 added, 388 removed, 839 unchanged (52% of the section changed)

We are a late-stage clinical biopharmaceutical company focused on the development of novel therapeutics for a broad range of cancer indications.

Our product candidates currently include galinpepimut-S, or GPS, a peptide immunotherapy directed against the Wilms tumor 1, or WT1, antigen, and GFH009, a highly selective small molecule cyclin-dependent kinase 9, or CDK9, inhibitor.

Our product candidates currently include galinpepimut-S, or GPS, a peptide immunotherapy directed against the Wilms tumor 1, or WT1, antigen, and SLS009 (formerly, GFH009), a highly selective small molecule cyclin-dependent kinase 9, or CDK9, inhibitor.

Galinpepimut-S

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Food and Drug Administration, or the FDA.

The primary endpoint of the REGAL study is overall survival.

We plan to enroll approximately 125 to 140 patients at approximately 95 clinical sites in North America, Europe and Asia with a planned interim safety, efficacy and futility analysis after 60 events (deaths).

Under our 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 60 events (deaths) per the protocol will occur by the end of 2023 or early 2024 and the final analysis after 80 events will occur by the end of 2024.

Because these analyses are event driven, they may occur at a different time than currently expected.

The primary endpoint of the REGAL study is overall survival, or OS.

We planned to enroll approximately 125 to 140 patients at approximately 95 clinical sites in North America, Europe and Asia with a planned interim safety, efficacy and futility analysis after 60 events (deaths).

In March 2024, we announced the completion of enrollment.

Under our current assumptions with respect to 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 60 events (deaths) per the protocol will occur in the first half of 2024 and the final analysis after 80 events will occur by the end of 2024.

Because these analyses are event driven, they are difficult to predict with any certainty and may occur at a different time than currently expected.

In December 2020, we entered into an exclusive license agreement with 3D Medicines Inc., or 3D Medicines, 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 mainland China, Hong Kong, Macau and Taiwan, which we refer to as Greater China.

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

In November 2022, we announced that we have agreed with 3D Medicines for 3D Medicines to participate in the REGAL study through the inclusion of approximately 20 patients from mainland China.

Such participation by 3D Medicines will trigger two development milestone payments totaling $13.0 million, which we expect to receive in the first half of 2023.

If the REGAL study meets its primary endpoint for efficacy and the Chinese regulatory authorities determine that the REGAL data is sufficient for approval in China, GPS could potentially reach the market in Greater China much earlier than we and 3D Medicines had anticipated when we entered into the license agreement in December 2020.

As of March 15, 2023, we have received an aggregate of $10.5 million in upfront and milestone payments under our license agreement with 3D Medicines and a total of $191.5 million in potential future development, regulatory and sales milestones, not including future royalties, remains under the license agreement, which milestones are variable in nature and not under our control.

In November 2022, we announced that we had agreed with 3D Medicines for 3D Medicines to participate in the REGAL study through the inclusion of approximately 20 patients from mainland China.

Although the REGAL study has completed enrollment as announced in March 2024, in accordance with the predetermined statistical analysis plan, 3D Medicines may still enroll patients in mainland China.

The timing of such participation and patient enrollment by 3D Medicines, if at all, cannot be predicted with certainty.

In December 2023, we announced that we had commenced a binding arbitration proceeding against 3D Medicines to resolve a dispute regarding, among other things, the trigger and payment of relevant milestone payments due to us under the 3D Medicines Agreement.

Legal Proceedings .

As of March 15, 2024, we have received an aggregate of $10.5 million in upfront and milestone payments under our license agreement with 3D Medicines, or the 3D Medicines Agreement, and a total of $191.5 million in potential future development, regulatory and sales milestones, not including future royalties, remains under the license agreement, which milestones are variable in nature and not under our control.

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, pembrolizumab (Keytruda ® ).

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We plan to present final data from this study at a medical conference in the first half of 2023.

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 November 2023, additional immunobiological and clinical data from the

study was presented at the International Gynecologic Cancer Society 2023 Annual Global Meeting which showed a correlation between immune response and progression free survival, or PFS.

In February 2020, a Phase 1 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.

Enrollment of a target total of 10 evaluable patients was completed at the end of 2022.

We expect to report topline data from this study in the first half of 2023.

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.

On March 31, 2022, we entered into an exclusive license agreement, or the GFH009 Agreement, with GenFleet that grants rights to us for the development and commercialization of GFH009, a highly selective small molecule CDK9 inhibitor, across all therapeutic and diagnostic uses worldwide, except for Greater China.

CDK9 activity has been shown to correlate negatively with overall survival in a number of cancer types, including hematologic cancers, such as AML and lymphomas, as well as solid cancers, such as osteosarcoma, pediatric soft tissue sarcomas, melanoma, endometrial, lung, prostate, breast and ovarian.

As demonstrated in preclinical and clinical data, to date, GFH009’s high selectivity has the potential to reduce toxicity as compared to older CDK9 inhibitors and other next-generation CDK9 inhibitors currently in clinical development and to potentially be more efficacious.

GFH009 is currently in a Phase 1 dose-escalating clinical trial in the United States and China.

We are evaluating both twice-a-week and once-a-week dosing regimens, and the indications are relapsed/refractory AML, chronic lymphocytic leukemia, or CLL, small lymphocytic leukemia, or SLL, and lymphoma.

The primary goal of the trial is to establish the recommended Phase 2 dose and to assess safety.

We expect enrollment in this study to be completed in the first quarter of 2023 and we expect to determine the recommended Phase 2 dose and report analyzed data from the study early in the second quarter of 2023.

Following completion of the Phase 1 clinical trial and determination of the recommended Phase 2 dose, we intend to commence a Phase 2a clinical trial of GFH009 in combination with venetoclax and azacitidine in AML patients who failed or did not respond to treatment with venetoclax and azacitidine.

The primary endpoint of the Phase 2a clinical trial, which we expect to initiate during the second quarter of 2023, will likely be complete remission (CR) rate and secondary endpoints will likely include progression free survival, or PFS, OS and proportion of patients proceeding to transplant.

We are also planning to potentially commence a Phase 2 clinical trial of GFH009 in certain solid tumors and/or lymphoma in the third quarter of 2023 and are exploring various options with respect to clinical development for GFH009 in several pediatric indications.

We reported positive topline safety and efficacy data from this study in June 2023 and positive follow-up immune response and survival data in December 2023.

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

On March 31, 2022, we entered into an exclusive license agreement, or the GenFleet Agreement, with GenFleet Therapeutics (Shanghai), Inc., or GenFleet, a clinical-stage biotechnology company developing cutting-edge therapeutics in oncology and immunology, that grants rights to us for the development and commercialization of SLS009, a highly selective small molecule CDK9 inhibitor, across all therapeutic and diagnostic uses worldwide, except for Greater China.

CDK9 activity has been shown to correlate negatively with OS in a number of cancer types, including hematologic cancers, such as AML and lymphomas, as well as solid cancers, such as osteosarcoma, pediatric soft tissue sarcomas, melanoma, endometrial, lung, prostate, breast and ovarian.

As demonstrated in preclinical and clinical data, to date, SLS009’s high selectivity has the potential to reduce toxicity as compared to older CDK9 inhibitors and other next-generation CDK9 inhibitors currently in clinical development and to potentially be more efficacious.

We completed a Phase 1 dose-escalating clinical trial in the United States and China for SLS009 in mid-2023 and reported positive safety and efficacy data for both patient cohorts, that is relapsed and/or refractory AML and refractory lymphoma.

We also established in the trial a recommended Phase 2 dose, or RP2D, of 60 mg for AML and 100 mg for lymphomas.

In the second quarter of 2023, we commenced an open label, single arm, multi-center Phase 2a clinical trial of SLS009 in combination with venetoclax and azacitidine, or aza/ven, in AML patients who failed or did not respond to treatment with venetoclax-based therapies.

The Phase 2a trial is evaluating safety, tolerability and efficacy at two dose levels, 45 mg once weekly, and 60 mg once weekly or 30 mg twice a week.

In the fourth quarter of 2023, we announced the dosing of the first patient in a Phase 1b/2 open-label, single arm trial in relapsed/refractory, or r/r, peripheral T-cell lymphoma, or PTCL, which will enroll up to 95 patients to evaluate safety and efficacy and, based on results, may serve as a registrational study.

This study is funded by GenFleet and is being conducted in China.

In March 2024, we announced positive topline data from the Phase 2a clinical trial of SLS009 in combination with aza/ven in r/r/ AML.

A total of 21 patients were enrolled in the study as of March 15, 2024:

10 in the 45 mg safety cohort and 11 in the 60 mg cohort (30 mg twice a week or 60 mg once a week).

Response rates observed in the three cohorts were 10% in the 45 mg once a week safety dose cohort (dose level below the RP2D), 20% in the 60 mg once a week dose cohort, and 50% in the 30 mg twice a week dose cohort.

Additionally, we observed strong anti-leukemic activity, which is defined as 50% or more bone marrow blast reduction in 67% of patients across all dose levels.

Median OS has not been reached in any of the cohorts and the first patient enrolled in the study who achieved a CR continues on the study and remains leukemia-free 9 months after enrollment.

During the trial, we identified potential biomarkers currently undergoing testing as predictive markers in the most recent portion of the study.

Patients with the identified biomarkers exhibited significantly higher response rates:

100% response rate at the optimal dose level (30 mg twice a week) and 57% response rate across all dose levels.

Furthermore, we have clarified the proposed biological basis and mechanism of action for SLS009 activity in patients with these biomarkers.

The relevant biomarkers are present in multiple hematologic and solid cancer indications, with a substantial proportion of patients exhibiting them in additional indications, ranging up to ~50% of patients in some indications.

SLS009 was granted ODD for AML and PTCL and Fast Track designations for r/r AML and r/r PTCL by the FDA.

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

Our overall goal is to develop multiple oncology product candidates in order to achieve marketing authorization in the United States and the rest of the world.

We are particularly focused on developing better treatments for AML, the lead indication for both GPS and GFH009, which will allow us to leverage our clinical development expertise in hematology/oncology and to build a single streamlined commercial infrastructure sufficient for both of our current product candidates.

We are particularly focused on developing better treatments for AML, the lead indication for both GPS and SLS009, which will allow us to leverage our clinical development expertise in hematology/oncology and to build a single streamlined commercial infrastructure sufficient for both of our current product candidates.

Products/Pipeline

Galinpepimut-S (GPS):

Innovative WT1 Targeting Immunotherapy

GPS is a WT1-targeting peptide-based cancer immunotherapeutic being developed as a monotherapy and in combination with other therapeutic agents to treat different types of cancers that result from uninhibited tumor cell growth.

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As such, WT1 is classified as an “oncogene.” WT1 plays a key role in the development of the kidneys in fetal life, but then almost disappears from normal organs and tissues.

In a wide variety of cancers (20 or more cancer types), WT1 becomes detectable again in at least 50% of tumor pathology specimens in the cells of these cancers.

In approximately 20 cancer types, WT1

becomes detectable again in at least 50% of tumor pathology specimens in the cells of these cancers.

WT1 appears in large amounts ( i.e.

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GPS is a multi-peptide product that has been modified to enhance the degree and duration of the immune response against the WT1 protein.

The modification is based on the fact that two of the four peptides in the peptide mixture

comprising GPS are deliberately mutated in a single amino acid residue.

Two of the four peptides in the peptide mixture comprising GPS are deliberately mutated in a single amino acid residue.

These mutated peptides are recognized by the immune system as non-self entities and are therefore less likely to induce immune tolerance.

After administration of these mutated peptides, the patients become immunized against the corresponding native versions of these peptides (which are expressed by the tumor cells), and thus, are able to cross-react against them, which concept is called the heteroclitic principle.

These mutated peptides are designed using artificial intelligence (AI) to elicit strong T-cell response against both mutated peptides and naturally occurring peptides in cancer cells.

This concept is called the heteroclitic principle.

We believe that GPS has a mechanism of action that involves direct activation of the patient’s immune system specifically and solely against the WT1 protein.

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T-cells can be classified into two major subsets, CD4 cells and CD8 cells.

CD8 cells, known as killer T cells, are characterized by the expression of the CD8 protein on their cell surface that allow them to recognize, bind and kill cells infected by cancer cells.

CD8 cells, often called cytotoxic T-cells, are characterized by the expression of the CD8 protein on their cell surface.

Once activated, cytotoxic T-cells recognize, bind and kill cancer cells marked by abnormal proteins.

CD4 cells, known as helper T-cells, are critical to providing the signals necessary for sustained CD8 cell responses and are also capable of exerting direct anti-tumor activity.

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This occurs by two mechanisms:

(i) conversion of some of the activated CD8 cells to CD8 memory cells, and (ii) activation of CD4 cells and the eventual creation of CD4 terminal effective memory cells.

We believe that, with respect to the conversion of activated CD8 cells, the GPS stimulated CD8 cells transform into cytotoxic T-lymphocytes, or CTLs, which are expected to be able to attack and destroy specifically WT1-positive cancer cells.

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, in turn, to activate CTLs and B cells.

(i) conversion of some of the activated CD8 cells to memory CD8 cells, and (ii) activation of CD4 cells and the eventual creation of CD4 terminal effector memory cells.

We further believe that cytotoxic CD8 T-cells activated by GPS 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, in turn, to activate cytotoxic T-cells and B-cells.

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

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If administered on its own, GPS would rapidly degrade and would not have the opportunity to activate the immune system.

Therefore, GPS is mixed with Montanide™, a commercially available, non-specific immune adjuvant composed of a natural metabolizable oil and a very refined emulsifier, creating a dense emulsion.

Montanide is co-administered with GPS by subcutaneous injection to optimally activate cellular and humoral immune responses in vaccinated patients.

Additionally, prior to the administration of GPS, patients receive another immune adjuvant, granulocyte-macrophage colony-stimulating factor, or GM-CSF, to non-specifically stimulate and activate antigen-presenting cells, or APCs, in the vicinity of the subcutaneous injection of GPS.

Therefore, GPS is mixed with Montanide™, a commercially available, non-specific immune adjuvant composed of a natural metabolizable oil and a very refined emulsifier, creating a water in oil emulsion.

The GPS and Montanide emulsion is administered by subcutaneous injection to optimally activate cellular and humoral immune responses in vaccinated patients.

After subcutaneous injection, the WT1 peptides within GPS disperse locally underneath the injection site and at local lymph nodes and are ingested by APCs.

Digested peptide fragments are then presented on the surface of APCs to CD8 and CD4 lymphocytes while simultaneously associated on the cell membrane with major histocompatibility complexes, or MHC, human leukocyte antigen, or HLA, molecules.

Digested peptide fragments are then presented on the surface of APCs to CD8 and CD4 T-cells while simultaneously associated on the cell membrane with major histocompatibility complexes, or MHC, human leukocyte antigen, or HLA, molecules.

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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- specificity across different HLA types;

- production of both CD4 and CD8 activated cells;

- the ability to apply the heteroclitic principle, as described above, to overcome tolerance.

- activation of both CD4 and CD8 T-cells;

- enhancing immune response and overcoming tolerance (the heteroclitic principle).

Optimal T-cell engagement leading to

cancer cell destruction Immune response data from the final analysis of the Phase I clinical study of GPS in MM in 12 evaluable patients that were presented at the 44th Annual Meeting of the European Society for Blood and Marrow Transplantation, or EBMT, in 2018 (Dr.

cancer cell destruction Immune response data from the final analysis of the Phase 1 clinical study of GPS in MM in 12 evaluable patients that were presented at the 44th Annual Meeting of the European Society for Blood and Marrow Transplantation, or EBMT, in 2018 (Dr.

Kohne et al.) showed 75% frequency of either CD8+ or CD4+ responses to an all-pool mixture of WT1-derived antigens after completion of the 12 vaccinations per the study protocol.

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allogeneic, “off-the-shelf,” vialed subcutaneously administered drug that is not patient-specific;

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

• positive Phase 2 clinical data on effectiveness (based on OS in AML and PFS in MM) with good tolerability and a favorable safety profile.

Development Program for GPS

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

final data to be reported in 1H2023

• 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

Enrollment completed;

topline data expected 1H2023

final data reported

• Phase 1 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

final data reported

• Phase 1/pilot open-label, non-randomized clinical trial of GPS in combination with nivolumab in patients with WT1-expressing, or 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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In recent years, additional drugs have been approved and current standard treatments include chemotherapy (including the fixed molar ratio combination chemotherapy Vyxeos), hypomethylating agents, or HMAs, drugs that target mutations of the isocitrate dehydrogenase type-1 and -2 and the FMS-like tyrosine-protein kinase, FLT3, in patients whose disease harbors these genetic aberrations, the B-cell lymphoma 2 inhibitor venetoclax (in combination with chemotherapy or HMAs), the CD33-targeting antibody-drug conjugate gemtuzumab ozogamicin, and the sonic hedgehog signaling inhibitor glasdegib.

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

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

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.

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allo-HSCT and maintenance therapy with the oral form of the HMA azacitidine, which the FDA approved for use in the second half of 2020.

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.

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 OS) when used as maintenance after patients achieve a status of CR2.

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.

AML as lead indication for GPS Program

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:

We chose AML, for which we have been granted Fast Track and ODD 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;

chemotherapy or targeted agent approaches and which can be realistically eradicated only with immunotherapy methods (including allo-HSCT).

• 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 believe this will be the case for GPS;

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• 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;

• 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.

• evidence from our completed Phase 1 and Phase 2 clinical trials that administration of GPS can lead to extended relapse free survival and OS 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.

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In this study, specifically for patients who were 60 years and older (n=5), median OS was at least 33 months from the time of GPS administration or approximately 43 months from the time of initial AML diagnosis.

The mean time of follow-up was 30 months from the time of diagnosis at the time of this analysis for all patients.

The mean time of follow-up was 30 months from the time of diagnosis

at the time of this analysis for all patients.

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

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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.

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.

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 or later hematologic (morphological) complete remission, with or without thrombocytopenia, after second-line antileukemic therapy and who are deemed ineligible for, or unable to undergo, allo-HSCT.

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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.

The REGAL study is expected to enroll approximately 125 to 140 patients at approximately 95 clinical sites in North America, Europe and Asia.

We have received approvals from the regulatory authorities in the United States, Canada, France, Germany, Greece, Poland, Hungary, Spain, Italy, Serbia, India and Taiwan to commence enrollment in our Phase 3 REGAL study at clinical sites in those countries.

The REGAL study was expected to enroll approximately 125 to 140 patients (not including potentially 20-25 patients from mainland China) at approximately 95 clinical sites in North America, Europe and Asia.

In the fourth quarter of 2023, we announced that we had exceeded our target enrollment of 105 patients (excluding the approximately 20-25 patients intended for enrollment in mainland China) and exceeded the number of patients needed for the pre-specified interim and final analyses (60/80).

In March 2024, we announced the completion of enrollment.

The protocol specifies that the study will have a planned interim safety, efficacy and futility analysis after 60 events (deaths).

In addition, the charter for the Independent Data Monitoring Committee, or IDMC, for the REGAL study provides that the IDMC may conduct risk-benefit assessments at earlier points in the clinical trial.

In December 2022, the IDMC performed its initial prespecified risk-benefit assessment of unblinded data from the study and recommended that the trial continue without modifications.

Based upon our 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 60 events per the protocol will occur by the end of 2023 or early 2024 and that the final analysis after 80 events will occur by the end of 2024.

Because these analyses are event driven, they may become available at different times than currently expected.

The IDMC has met several times to perform these prespecified risk-benefit assessments of unblinded data from the study and have recommended in each instance that the trial continue without modifications.

Based upon our 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 60 events per the protocol will occur in the first half of 2024 and that the final analysis after 80 events will occur by the end of 2024.

Because these analyses are event driven, they are difficult to predict with any certainty and may become available at different times than currently expected.

We have agreed with our partner in China, 3D Medicines, for 3D Medicines to participate in the REGAL study through the inclusion of approximately 20-25 patients from mainland China.

Such participation by 3D Medicines is possible due to the increase in the target patient enrollment in the study and will trigger two development milestone payments totaling $13.0 million, which we expect to receive in the first half of 2023.

Although the REGAL study has completed enrollment as announced in March 2024, in accordance with the predetermined statistical analysis plan, 3D Medicines may still enroll patients in mainland China.

The timing of such participation and patient enrollment by 3D Medicines, if at all, cannot be predicted with certainty.

In December 2023, we announced that we had commenced a binding arbitration proceeding administered by the Hong Kong International Arbitration Centre, which proceeding will be governed by New York law as per the terms of the 3D Medicines Agreement.

We commenced the proceeding after having exhausted the dispute resolution provisions in the 3D Medicines Agreement to resolve a dispute regarding, among other things, the trigger and payment of relevant milestone payments due to us under the 3D Medicines Agreement as well as 3D Medicines' failure to use commercially reasonable best efforts to develop GPS in accordance with the terms of the agreement.

Legal Proceedings .

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

Phase 1 clinical trial of 3D189 in China

In January 2022, 3D Medicines submitted an IND application to initiate the first clinical trial in China for 3D189, also known as GPS.

The IND for the Phase 1 clinical trial, which is investigating safety, was accepted by China’s National Medical Products Administration NMPA and the trial commenced in mid-2022.

In January 2022, 3D Medicines submitted an Investigational New Drug, or IND, application to initiate the first clinical trial in China for 3D189, also known as GPS.

The IND for the Phase 1 clinical trial, which is investigating safety, was accepted by China’s National Medical Products Administration, or NMPA, and the trial commenced in mid-2022.

3D Medicines is responsible for all expenses related to executing the trial in China.

In the second quarter of 2022, we received a $1.0 million milestone payment which was triggered by the NMPA’s approval of the IND.

Enrollment in this study has been completed.

Expanded Access Program

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

Given the potential immunobiologic and pharmacodynamic synergy between GPS and an immune check-point inhibitor (e.g., PD-1 inhibitor), 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.

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.

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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.

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

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This study was the first clinical trial of GPS in a patient population harboring overt bulky disease.

growth deposits specifically sensitized against WT1 (by concomitantly-administered GPS).

The endpoints of the study were 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.

GPS has been designed as maintenance therapy in order to provide an overall survival benefit after patients reach MRD status or complete remission.

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

GPS has been designed as maintenance therapy in order to provide an OS benefit after patients reach MRD status or complete remission.

The final topline data from this study demonstrated that the combination of GPS and pembrolizumab could halt or slow down the progression in highly active disease refractory to other therapies.

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, or 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).

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

On November 10, 2022, we reported the following confirmatory topline data from 17 evaluable patients in the study.

We plan to report final data from this study at a medical conference in the first half of 2023.

• Median OS was 18.4 months compared to 13.8 months with pembrolizumab alone in a in a checkpoint inhibitor single agent study in a similar patient population treated with checkpoint inhibitor alone.

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• The safety profile of GPS in combination with pembrolizumab was similar to pembrolizumab alone, with only the addition of low-grade rapidly resolving local reactions at the GPS injection site, consistent with observations from other GPS clinical studies.

In November 2023, additional immunobiological and clinical data from the study for 16 safety and efficacy evaluable patients who had follow-up cross-sectional imaging (CT/MRI) were presented at the International Gynecologic Cancer Society 2023 Annual Global Meeting:

• WT1-specific T-cell (CD8 and CD4) immune response data showed a positive trend over time post-baseline with highest consistency and potential biomarkers for consistency being IFNγ and MIP1β.

• GPS in combination with pembrolizumab was strongly immunogenic, as evidenced by the positive T-cell responses seen post-vaccination.

◦ 42.8% of patients (6/14) achieved CD8 T-cell immune response.

◦ 85.7% of patients (12/14) achieved CD4 T-cell immune response.

• A correlation between WT1 specific T-cell immune responses (CD8 or CD4) and PFS was observed in a subset of analyzed patients with 41% longer PFS in patients with recorded immune response vs without (p=0.025).

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 Bristol-Myers Squibb is providing nivolumab for this study.

The principal investigator for the study is Dr.

based chemotherapy and have measurable disease on imaging, either due to residual disease after prior treatment or recurrent disease.

We provided GPS and Bristol-Myers Squibb provided nivolumab for this study.

The principal investigator for the study was 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.

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.

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.

The purpose of the trial was 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 also investigated the tolerability of the combination, evaluated the immunogenicity of the two agents administered together, by CD4+ and CD8+ T-lymphocytes (both peripherally and at the tumor site), and gauged 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.

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 OS and progression-free survival, especially for those patients with the sarcomatoid variant who show a median OS 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 OS 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 OS is reported to be approximately 7.0 months.

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.

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Completed Clinical Trials in Other Indications.

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.

Study enrollment (target total n=10) was completed at the end of 2022.

We expect to report final topline data for this study in the first half of 2023.

In June 2023, we reported positive topline safety and efficacy data from the study:

• Nine of the 10 patients enrolled received at least three doses of GPS, with the third GPS dose given in combination with nivolumab.

• All enrolled patients had either received and progressed with or were refractory to frontline pemetrexed-based chemotherapy.

• Median OS in patients who received the combination therapy (9/10 patients) was 70.3 weeks (17.6 months) and 54.1 weeks (13.5 months) for all 10 patients (nine patients with combination therapy and one GPS only patient).

Median OS for patients who entered the study as Stage IV patients was 62.3 weeks (15.6 months).

OS was calculated as the time from cessation of the most recent previous therapy until confirmed death or most recent data update for patients who still alive.

• Median PFS for all patients was 11.9 weeks.

• DCR was 30% with three patients achieving stable disease per RECIST criteria with the tumor volume decrease of up to 17%.

• As expected in this high-risk advanced cancer population, all patients experienced adverse events, unrelated and related.

Seven out of 10 patients (70%) had treatment related toxicities and six (60%) had nivolumab related toxicities.

Grade 3, or G3, and higher toxicities were observed in three patients (30%).

None of the G3 and higher toxicities were related to GPS.

GPS related toxicities were observed in three patients (30%), all were Grade 1, or G1, and included G1 skin induration at the site of injection/injection site reaction and/or fatigue in two patients and G1 dizziness and non-cardiac chest pain, each in one patient.

• Of the 10 evaluable patients, eight were male and two were female, with a median age of 69 years.

Sixty percent of entered the study as Stage III or IV patients.

Initial tumor stages were I (one patient), II (three patients), III (two patients) and IV (four patients).

• All patients had MPM epithelioid and/or sarcomatoid variant, a tumor which universally expresses WT1.

In December 2023, we reported positive follow-up immune response and survival data:

• The median OS among patients who did not have an immune response to GPS was 9.0 months;

the median OS for patients who had an immune response to GPS was 27.8 months, which was more than three times longer (208.3% increase) than for those patients without an immune response.

Among the nine evaluable patients, four patients had a CD4+ immune response (44.4%) and three patients had a CD8+ immune response (33.3%) to GPS.

Three patients had both CD4+ and CD8+ immune responses (33.3%).

• Among patients who had a full immune response (both CD4+ and CD8+) to GPS, two patients achieved an objective response (66.7%), while among the patients who did not have an immune response to GPS one patient achieved an objective response (14.3%).

GPS Monotherapy:

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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 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.

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.

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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.

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

Despite significant therapeutic advances in the management of MM, the prognosis of patients with high-risk cytogenetics at the time of diagnosis remains quite poor, even when they successfully complete an ASCT, particularly if such patients continue to have evidence of MRD.

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Information on the primary endpoint of this clinical trial, which was the safety of repeated GPS administrations, for a total of six doses, in combination with seven infusions of nivolumab was presented at the American Society of Clinical Oncology, or ASCO, 2018 annual meeting (O’Cearbhaill RE, et al).

The secondary endpoint of the study was immune response, and the exploratory endpoints included landmark one-year PFS rate compared to historical controls and correlative analyses between clinical and immune responses.

immune responses.

Exploratory efficacy interim data from this pilot trial showed that GPS, when combined with a PD-1 inhibitor, in this case nivolumab, demonstrated PFS of 64% at one year in an intent to treat the group of 11 evaluable patients with WT1+ ovarian cancer in second or greater remission.

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The most common adverse events were Grade 1 or 2, including fatigue and injection site reactions.

Dose limiting toxicity was observed in one patient, following the

second dose of the combination.

Dose limiting toxicity was observed in one patient, following the second dose of the combination.

No additional adverse event burden was observed for the combination as compared to nivolumab monotherapy.

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

GFH009 is a next generation highly selective CDK9 inhibitor which we in-licensed from GenFleet in March 2022.

Highly Selective Next Generation CDK9 Inhibitor

SLS009 is a next generation highly selective CDK9 inhibitor which we in-licensed from GenFleet in March 2022.

We have worldwide development and commercialization rights, except for Greater China.

See Strategic Collaborations and License Agreements - Exclusive License Agreement with GenFleet Therapeutics (Shanghai), Inc.

CDK9 activity has been shown to correlate negatively with overall survival in several cancer types, including hematologic cancers, such as AML and lymphomas, as well as solid cancers, such as osteosarcoma, pediatric soft tissue sarcomas, melanoma, endometrial, lung, prostate, breast and ovarian cancer.

CDK9 activity has been shown to correlate negatively with OS in several cancer types, including hematologic cancers, such as AML and lymphomas, as well as solid cancers, such as osteosarcoma, pediatric soft tissue sarcomas, melanoma, endometrial, lung, prostate, breast and ovarian cancer.

Mechanism of Action

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These first-generation drug candidates showed some clinical activity but had significant toxicity due to low specificity.

Next generation CDK9 inhibitors, including GFH009, have potential for higher specificity for CDK9 and lack of binding to other CDKs, potentially resulting in less toxicity and more consistent clinical activity.

Next generation CDK9 inhibitors, including SLS009, have potential for higher specificity for CDK9 and lack of binding to other CDKs, potentially resulting in less toxicity and more consistent clinical activity.

Key Attributes

Higher selectivity :

In preclinical studies, GFH009 has demonstrated higher selectivity for CDK9 than other members of the human kinome when compared to other non-oral CDK9 inhibitors currently in active clinical development in the United States for hematological cancers, including AZD-4573 being developed by AstraZeneca and BAY-1251152 (now VIP152) being developed by Vincerx Pharma.

GFH009 has been shown to block activity of fewer kinases, other than CDK9, than these competing development candidates, as.

In preclinical studies, SLS009 has demonstrated higher selectivity for CDK9 than other members of the human kinome when compared to other non-oral CDK9 inhibitors currently in active clinical development in the United States for hematological cancers, including AZD-4573 being developed by AstraZeneca and enitociclib (VIP152) being developed by Vincerx Pharma.

The human kinome is a set of all 538 kinases, which are enzymes that play essential functions by catalyzing protein phosphorylation.

SLS009 has been shown to block activity of fewer kinases, other than CDK9, than these competing development candidates which, as demonstrated in clinical trials, has resulted in a better safety profile with fewer treatment related adverse events.

Higher anti-cancer activity:

The preclinical data below is a comparison of GFH009 and an exact molecular copy of VIP152 (shown in the graphs as GFC002).

The top table shows the maximal inhibitory concentration, which is the amount of drug that is needed to inhibit survival of cancer cells, across different cell lines of cancer in vitro.

Across multiple cancer cell line histologies, a smaller concentration of GFH009 is needed to achieve the same inhibitory effect as compared to the exact molecular copy of VIP152.

In a mouse AML xenograft model, the lowest tumor growth and the highest AML cell killing was achieved by GHF009.

In this mouse model, there was significantly more toxicity, including weight loss, observed with VIP152 treated mice.

GFH009 IC50 (72h)

The preclinical data below is a comparison of SLS009 and an exact molecular copy of enitociclib (VIP152) (shown in the graphs as GFC002).

The top table shows the maximal inhibitory concentration, which is the amount of drug that is needed to inhibit survival of cancer cells, across different cell lines of cancer in

Across multiple cancer cell line histologies, a smaller concentration of SLS009 is needed to achieve the same inhibitory effect as compared to the exact molecular copy of enitociclib (VIP152).

In a mouse AML xenograft model, the lowest tumor growth and the highest AML cell killing was achieved by SLS009.

In this mouse model, there was significantly more toxicity, including weight loss, observed with enitocliclib (VIP152) treated mice.

SLS009 IC50 (72h)

VIP152 IC50 (72h)

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Pharmacokinetic, or PK, Data:

Initial PK data observed from the ongoing Phase 1 trial are shown below.

PK data observed from the completed Phase 1 trial are shown below.

PK data show the relationship between the dosing regimen and the body’s exposure to a drug as indicated by the concentration time curve.

An important component of the mechanism of CDK9 inhibition in cancer is to achieve very high concentration immediately which then shuts down the cancer cell and leads to apoptosis, while quickly ramping down so that there is not apoptosis of neutrophils.

The PK curves observed at the 2.5 mg and 4.5 mg dose levels of the Phase 1 study are very similar:

there is quick ramp up to 500–600 ng/mL which drops to half of that within an hour, and another half in the next hour, resulting in enough time for fast metabolizing cancer cells to enter apoptosis but not enough time for neutrophils to become apoptotic.

In contrast, for VIP152, elimination half-life was reported as three to nine hours.

We believe that this difference in PK may account for the differences in safety outcomes between VIP152 and GFH009.

PK analyses were made for both twice a week dosing regimen (BIW cohorts) and once a week dosing regimen (QW cohorts).

The PK analysis result showed that after intravenous infusion of 2.5 mg (N=1), 4.5 mg (N=5), 9 mg (N=8), 15 mg (N=11), 22.5 mg (N=7), 30 mg (N=8), and 40 mg (N=3) of SLS009 twice a week (BIW, administered on the first and second days of each week for one hour), the plasma concentration reached peak at the end of the infusion.

The exposure parameters (C max and AUC) of SLS009 increased in an approximately proportional manner in the dose range 2.5 mg to 40 mg.

The PK profiles in single and repeated administration were comparable.

After intravenous infusion of 30 mg (N=7), 45 mg (N=8), and 60 mg (N=9) of SLS009 once a week (QW, administered on the first day of each week for four hours), the plasma concentration-time profiles were comparable to those of BIW administration, indicating a similar characterization of distribution and metabolism.

The plasma concentration reached peak at the end of the infusion.

The exposure parameters (C max and AUC) of SLS009 increased in an approximately proportional manner with the dose range 30 mg~60 mg.

After QW administration, there was no obvious accumulation of SLS009.

Comparison of twice a week and once a week dosing regimens is shown below.

Pharmacodynamic, or PD, Data:

The graphs below show certain correlative pharmacodynamic data from the ongoing Phase 1 study.

The graphs below show certain correlative pharmacodynamic data from the completed Phase 1 study.

At higher dose levels, a pattern of drug induced decreases in two biomarkers commonly used for assessing pharmacodynamics of CDK9 inhibitors, MCL1 and MYC, is seen.

These data are important in that we believe they demonstrate that GFH009 is translating CDK9 inhibition into a meaningful suppression of cancer associated proteins.

These data are important in that we believe they demonstrate that SLS009 is translating CDK9 inhibition into a meaningful suppression of cancer associated proteins.

MCL1 is a key antiapoptotic protein which is difficult to inhibit directly.

It is postulated that CDK9 inhibitors can indirectly inhibit MCL1.

We believe that these PD data demonstrate that GFH009 does inhibit MCL1.

We believe that these PD data demonstrate that SLS009 does inhibit MCL1.

MYC is a key driver in many cancers, both hematological and solid tumors.

We believe that the data presented below demonstrate meaningful MYC suppression.

Efficacy in venetoclax resistant disease:

Venetoclax, in combination with hypomethylating agents, is a key component of treatment for AML across all patient categories, especially older patients, who are the vast majority of AML patients.

We believe that GFH009 has potential as a treatment option for AML patients who are resistant or refractory to venetoclax.

To our knowledge, as of March 31, 2023, GFH009 is the only CDK9 inhibitor for which a complete response as monotherapy in r/r AML has been reported.

We believe that SLS009 has potential as a treatment option for AML patients who are r/r to venetoclax.

We observed in the Phase 1 study that a r/r AML patient achieved a complete response and four additional r/r AML patients achieved greater than or equal to 50% decrease in bone marrow blasts which includes patients who had prior treatment with venetoclax.

To our knowledge, as of March 1, 2024, SLS009 is the only CDK9 inhibitor for which a complete response as monotherapy in r/r AML has been reported.

See Phase 1 Clinical Trial.

We have also observed in the Phase 1 study two additional r/r AML patients with greater than or equal to 50% decrease in bone marrow leukemic blasts.

Each of these three patients had prior treatment with venetoclax.

Phase 1 Clinical Trial

GFH009 is currently in a Phase 1 dose-escalating clinical trial in the United States and China.

We expect to complete enrollment of this study in the first quarter of 2023.

In the study, we are evaluating both twice-a-week and once-a-week dosing, and the indications are relapsed/refractory, or r/r, AML, chronic lymphocytic leukemia, or CLL, small lymphocytic leukemia, or SLL, and lymphoma.

The primary goal of the trial is to establish the recommended Phase 2 dose and to assess safety.

We expect to report analyzed data from this study and the recommended Phase 2 dose early in the second quarter of 2023.

We announced in December 2022 data to date from this study.

As of December 2022, a total of 57 patients were enrolled in the study, including 31 with r/r lymphoma and 26 with r/r AML.

All enrolled patients were heavily pretreated with up to six lines of previous therapy.

The dose escalating trial was originally planned at fixed per patient doses ranging from 2.5 mg to 30 mg, administered as 30-minute infusions twice a week.

The initial design was based on expected toxicities observed in previously published trials with other CDK9 inhibitors, which were primarily severe neutropenias.

However, the lack of observed severe toxicities, even at the highest dose level of 30 mg, provided the opportunity to both further escalate the dose levels, and to explore a more patient friendly once a week dosing regimen without sacrificing efficacy.

New dosing regimens added to the trial were 40 mg administered twice per week and 30 mg, 45 mg and 60 mg administered once a week.

At December 2022, apparent efficacy was noted without significant toxicities at multiple dose levels ranging from 9 mg to 30 mg, suggesting a broad therapeutic window, which is a key trait for high combination potential.

Stable disease (SD) was maintained in certain patients for more than 8 months and one patient on treatment in December 2022 had maintained SD for more than a year, which suggests a favorable safety profile with potential for prolonged treatment.

Selective Preliminary GFH009 Monotherapy Efficacy Data in r/r AML Group at December 2022:

• One patient had a confirmed CR and was MRD negative after failing azacitidine–venetoclax treatment

• One patient continued on treatment for three months

• Two patients had blast count decreases of ≥50% in bone marrow (both r/r on azacitidine- venetoclax treatment)

Selective Preliminary GFH009 Monotherapy Efficacy Data in r/r Lymphoma Group at December 2022:

• Two patients had partial response (PR)

• Four patients achieved SD with one maintaining SD for over a year while still continuing GFH009 monotherapy

The PK profile of GFH009 showed dose proportional concentrations with a biphasic profile of rapid initial tissue distribution followed by slower elimination from tissues.

There were no apparent time-dependent changes in volume of distribution or clearance.

Initial PD studies have shown clear reductions in two known biomarkers of CDK9 activity, MCL‐1 and MYC.

In the data reported in December 2022, biomarker response was observed in 97.6% of analyzed patients (41 of 42 patients) with a decrease for either MCL-1 or MYC expression and 95.2% (40 of 42 patients) had a decrease in both biomarkers.

The Phase 1 dose-escalating clinical trial in the United States and China for SLS009 was completed in 2023.

The study evaluated both twice-a-week and once-a-week dosing and the indications were r/r AML, chronic lymphocytic leukemia, or CLL, small lymphocytic leukemia, or SLL, and lymphoma.

The primary goal of the trial was to establish the RP2D which was established at 60 mg for AML and 100mg for lymphomas.

Two dosing regimens were tested in incremental SLS009 dose levels from 2.5 mg to 100 mg, either twice a week, or BIW, dosing regimen or once a week, or QW, dosing regimen.

A total of 34 patients were treated in the AML cohort and 52 patients in the r/r lymphoma cohort.

Among the 52 r/r lymphoma patients, 15 were diagnosed with PTCL.

For the cohort of patients with AML and with lymphomas, all key study objectives regarding PK, PD, safety and clinical activity data were met:

• Anti-tumor activity and clinical responses across groups and dose levels were observed, indicating a broad therapeutic index.

Meaningful cell killing activity was defined as ≥50% reduction in blasts in the bone marrow.

◦ AML cohort:

cell killing activity observed at the following dose levels:

50.0% bone marrow blast (BMB) reduction;

53.8% BMB reduction;

57.1% BMB reduction;

61.3% BMB reduction;

77.3% BMB reduction.

◦ Durable complete remission (CR) with no MRD in one patient with AML who had failed prior aza/ven therapy was achieved.

The duration of the CR was eight months.

Historic, best available therapy median OS for patients relapsed after aza/ven is estimated at 2.5 months.

Lymphomas cohort:

• Among 34 evaluable r/r lymphoma patients, five (14.7%) achieved a clinical response with a reduction in tumor burden of up to 62%.

• An additional seven patients (20.6%) achieved stable disease, or SD, resulting in an overall DCR of 35.3%.

• In the subgroup of PTCL patients, four out of 11 (36.4%) evaluable patients achieved a clinical response.

• No dose limiting toxicities and no higher grade non-hematologic toxicities of any kind were observed.

• Some hematologic toxicities were difficult to determine in patients with hematologic cancers but were short in duration and reversible.

Lymphomas cohort:

• There were no drug-related fatalities at any dose level, and the drug was well tolerated.

• In patients treated with BIW dosing regimen, no significant safety events appeared to be dose-dependent.

• In patients receiving the QW dosing regimen, ≥ G3 treatment-related adverse events, or TRAEs, occurred, primarily hematologic events, at higher dose levels.

• Non-hematologic toxicities were rare across all dose levels with five out of 52 patients (9.6%) experiencing higher grade toxicities, including hypokalemia (3/52 patients, 5.8%), upper respiratory tract infection (1/52 patients, 1.9%) and increase in bilirubin (1/52 patients, 1.9%).

• Maximum Tolerated Dose, or MTD, was not reached with only 1/5 patients at the highest dose level studied (100 mg) experiencing a dose-limiting toxicity, or DLT.

• No DLTs were observed at any other dose level, and there were no unexpected toxicities across the study.

• Achieved desired 24 hours > IC90 peripheral blood concentrations after the first infusion, with IC90 concentrations resulting in up to 97% cancer cells killed.

Lymphomas cohort:

• Exposure parameters (maximum concentration, or C max, and area under curve, or AUC) increased in an approximately proportional manner with the dose range of 30 mg~60 mg QW.

The exposure of 100 mg was the highest, and the mean plasma concentration remained above IC 90 for the longest time period (nearly 50 hours).

• Achieved desired levels of MCL1 and MYC suppression in peripheral blood with decrease in MCL1 or MYC observed in 97% (66/68) of analyzed patients.

A trend of proportionally increased maximum inhibition of MCL1 and MYC observed among higher doses (22.5 mg to 60 mg) in both AML and lymphoma patients, which is more prominent in QW cohorts compared to BIW cohorts.

QW regimen was able to induce longer sustained inhibition (at least 6 hours) of MCL1 and MYC than BIW treatment, allowing longer period for CDK9 inhibition to induce cancer cell apoptosis.

Lymphomas cohort:

• Desired levels of suppression in peripheral blood were achieved, leading to a decrease in MCL1 or MYC biomarkers in all (100%) studied patients.

Biomarker suppression was dose-dependent in patients receiving QW dosing.

The biomarkers studied included MYC and MCL1 with SLS009 administration resulted in biomarkers suppression across dose levels in both administration regimens (BIW and QW) and a dose-dependent decrease in QW groups.

100mg QW dose level resulted in the longest sustained inhibition of both MCL1 and MYC.

Phase 2 Development Program

In the second quarter of 2023, following the determination of the recommended Phase 2 dose, we intend to commence a Phase 2a clinical trial of GFH009 in combination with venetoclax and azacitidine in AML patients who failed or did not respond to treatment with venetoclax and azacitidine.

The primary endpoint of the Phase 2a clinical trial will likely be complete remission, or CR, rate and secondary endpoints will likely include progression free survival, OS and proportion of patients proceeding to transplant.

We expect to receive preliminary data from the Phase 2a study by the end of 2023.

Phase 2a clinical trial in AML patients

In the second quarter of 2023, we commenced an open label, single arm, multi-center Phase 2a clinical trial of SLS009 in combination with aza/ven in AML patients who failed or did not respond to treatment with venetoclax-based therapies.

The trial is designed to evaluate safety, tolerability, and efficacy at two dose levels of SLS009, 45 mg QW, and 60 mg QW or 30 mg BIW, in combination with aza/ven.

In addition to safety and tolerability of SLS009 in combination with aza/ven, the primary endpoints are complete response composite rate and duration of response.

Additional endpoints include event free survival, OS, and PK and PD assessments.

The trial includes several sites in the United States, will enroll a minimum of 20 patients and, based on initial results, may be expanded into a registrational trial.

In the fourth quarter of 2023, we completed enrollment in the 45 mg QW dose cohort in the Phase 2a study and reported positive initial topline data.

We also commenced enrollment of the 60 mg dose cohort with patients

randomized to one of two groups, 60 mg fixed dose QW or 30 mg fixed dose BIW.

Each group will enroll approximately five to 10 patients.

In March 2024, we announced positive topline data from the Phase 2a STUDY of SLS009 in combination with aza/ven in r/r AML.

As of March 15, 2024 data cutoff, 21 patients were treated.

All patients were diagnosed with AML refractory to or relapsed after venetoclax containing regimens.

20 out of 21 (95%) enrolled patients had adverse/high-risk cytogenetics and 1 patient (5%) had intermediate cytogenetics.

Median age was 70 and 19/21 (90.5%) of patients were older than 60.

A total of 21 patients were enrolled in the study as of March 15, 2024:

10 in the 45 mg safety cohort and 11 in the 60 mg cohort (2 x 30 mg twice a week or 60 mg once a week).

• 10% response rate in the 45 mg QW safety cohort (dose level below the RP2D).

• 20% response rate in the 60 mg QW cohort.

• 50% response rate in the 60 mg, 2 x 30 mg BIW cohort.

• Observed strong anti-leukemic activity, defined as 50% or more bone marrow blast reduction in 67% of patients across all dose levels.

• Median survival rate has not been reached in any of the dose levels.

• The first patient enrolled in the study who achieved a complete response (CR) continues on the study and remains leukemia-free 9 months after enrollment.

• During the trial, we identified potential biomarkers currently undergoing testing as predictive markers in the most recent portion of the study.

• Patients with the identified biomarkers exhibited significantly higher response rates:

• 100% response rate at the optimal dose level (30 mg BIW).

• 57% response rate across all dose levels.

• Furthermore, we have clarified the proposed biological basis and mechanism of action for SLS009 activity in patients with these biomarkers.

• The relevant biomarkers are present in multiple hematologic and solid cancer indications, with a substantial proportion of patients exhibiting them in additional indications, ranging up to ~50% of patients in some indications.

• SLS009 in combination with aza/ven has been well-tolerated at all tested dose levels.

• No DLTs at any of the studied dose levels and no treatment-related high-grade (≥G3) toxicities were observed.

• Hematologic toxicities profile was consistent with aza/ven standalone treatment.

Patients with AML that fail venetoclax-based therapies have limited treatment options and a poor prognosis with a median OS of approximately 2.5 months.

See Current AML Treatment Therapies for more information on the AML treatment landscape.

We are also planning to potentially commence a Phase 2 clinical trial of GFH009 in certain solid tumors and/or lymphoma in the third quarter of 2023.

Additional data from the 60 mg dose cohort are expected in the second quarter of 2024.

Phase 1b/2 in PTCL

The first patient in a Phase 1b/2 trial evaluating SLS009 in r/r PTCL was dosed in the fourth quarter of 2023.

The open-label, single-arm trial will enroll up to 95 patients to evaluate safety and efficacy and, based on the results,

may serve as a registrational study.

This initial PTCL study is fully funded by GenFleet and is being conducted in China.

We expect to report initial topline data from the study in the second quarter of 2024.

Phase 1b/2 in Combination with Brukinsa ® in Diffuse Large B-Cell Lymphoma (DLBCL)

In March 2024, GenFleet announced that it entered into a collaboration and supply agreement with BeiGene Switzerland GmbH to initiate a combination study of SLS009 and Brukinsa (zanubrutinib), a BTK inhibitor, in r/r DLBCL and the first patient was dosed in the trial.

The open-label, single-arm multi-center trial will be conducted in two parts.

In the Phase 1b portion, 6-18 patients will be enrolled.

In the Phase 2 portion, approximately 45 patients will be enrolled.

This study is funded by GenFleet and is being conducted in China.

Preclinical Studies

In August 2022, we announced results from preclinical in vitro studies for GFH009 in AML cell lines.

The in vitro studies were conducted at an independent third-party contract research organization, and utilized the following cell lines based on their unique characteristics in combination with GFH009’s mechanism of action:

In August 2022, we announced results from preclinical in vitro studies for SLS009 in AML cell lines.

RH30, a pediatric soft tissue sarcoma cell line that is a model for studying high-risk pediatric rhabdomyosarcoma, NCI-H209, a small cell lung cancer cell line characterized by the loss of function of two major tumor suppressor genes, RB1 and TP53, and which also expresses MCL-1, a major target of CDK9 inhibition, SKOV-3, an ovarian cancer cell line containing the wild type BRCA1 gene and highly expresses CDK9, and OCI-AML-2, an AML cell line that develops resistance to venetoclax.

The data showed that GFH009 demonstrated significant anti-tumor effects in all four selected cell lines.

In three out of the four cell lines, GFH009 inhibited cancer cell growth by 90 to 100 percent.

In August, we announced results from a new preclinical in vitro study for GFH009 in neuroendocrine prostate cancer, or NEPC.

The data shows that GFH009 demonstrated significant anti-tumor effects in the selected cell line at nanomolar concentrations and, in certain samples, complete growth inhibition with no viable cancer cells.

Additionally, in December 2022, we announced results from a preclinical in vivo study for GFH009 that demonstrated robust inhibition of tumor growth in a mouse xenograft model of SCLC.

GFH009 was tested against NCI-H209 SCLC xenografts in athymic nude mice in four treatment groups of eight mice each (n=32) consisting of GFH009 alone, olaparib (a PARP inhibitor) alone, a combined regimen of GFH009 and olaparib, and a vehicle control.

The data showed that SLS009 demonstrated significant anti-tumor effects in all four selected cell lines.

In three out of the four cell lines, SLS009 inhibited cancer cell growth by 90 to 100 percent.

In August, we announced results from a new preclinical in vitro study for SLS009 in neuroendocrine prostate cancer, or NEPC.

The data shows that SLS009 demonstrated significant anti-tumor effects in the selected cell line at nanomolar concentrations and, in certain samples, complete growth inhibition with no viable cancer cells.

Additionally, in December 2022, we announced results from a preclinical in vivo study for SLS009 that demonstrated robust inhibition of tumor growth in a mouse xenograft model of SCLC.

SLS009 was tested against NCI-H209 SCLC xenografts in athymic nude mice in four treatment groups of eight mice each (n=32) consisting of SLS009 alone, olaparib (a PARP inhibitor) alone, a combined regimen of SLS009 and olaparib, and a vehicle control.

Treatments were initiated after tumor xenograft volumes exceeded 120 mm3 in each animal group and mice were subsequently sacrificed after mean tumor volume exceeded 1,500 mm3 in the control group.

GFH009 treated mice exhibited a 40.4% decrease in mean tumor growth compared to the control group in this very aggressive cancer model which had a tenfold increase in average tumor volume over 20 days.

Strongest effects were observed with GFH009 in combination with olaparib, with mean tumor growth decreased by 72.3%.

SLS009 treated mice exhibited a 40.4% decrease in mean tumor growth compared to the control group in this very aggressive cancer model which had a tenfold increase in average tumor volume over 20 days.

Strongest effects were observed with SLS009 in combination with olaparib, with mean tumor growth decreased by 72.3%.

Treatment with olaparib alone resulted in a 30.2% mean decrease in tumor growth.

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PIVOT Program

In December 2022, we announced that GFH009 will be evaluated in pediatric solid tumors and leukemia models through the NCI Pediatric Preclinical in Vivo Testing, or PIVOT, program.

GFH009 testing through the program involves a two-phase research plan for PK and efficacy in pediatric tumors.

In the first phase, PIVOT principal investigators will conduct PK experiments to confirm the appropriate dose and route administration for GFH009.

In the second phase, monotherapy in vivo efficacy testing for GFH009 will be performed by PIVOT investigators.

In December 2022, we announced that SLS009 will be evaluated in pediatric solid tumors and leukemia models through the NCI Pediatric Preclinical in Vivo Testing, or PIVOT, program.

SLS009 testing through the program involves a three-phase research plan for PK, tolerability, and efficacy in pediatric tumors.

In the first phase, PIVOT principal investigators will conduct PK experiments to confirm the appropriate dose and route administration for SLS009.

In the second phase, tolerability of the dose and route of administration selected from the PK phase will be determined.

In the last phase, monotherapy in vivo efficacy testing for SLS009 will be performed by PIVOT investigators.

Studies will be supported through cooperative agreement grants from the NCI to the seven PIVOT research programs performing the testing and a centralized coordinating center.

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Each PIVOT principal investigator has expertise in preclinical testing of childhood cancer in vivo models.

These models utilize patient derived xenografts, many of which are refractory to current standard of care treatments, from high-risk childhood cancers and have undergone comprehensive genomic characterization to demonstrate close resemblance to genetic alterations seen in the respective human cancers.

These models utilize patient derived xenografts, many of which are refractory to current standard of care treatments, from

high-risk childhood cancers and have undergone comprehensive genomic characterization to demonstrate close resemblance to genetic alterations seen in the respective human cancers.

Research strategies are based on a substantial body of data showing that preclinical testing in the appropriate pediatric cancer models, combined with expertise on relative drug exposures tolerated in mice and humans, provides powerful insights into likely clinical utility of investigational agents.

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• Children’s Hospital of Philadelphia for neuroblastoma

The first phase of the program, pharmacokinetics, has been successfully completed and dosing regimens have been developed.

The second phase of the program, tolerability, is currently in progress and is projected to be completed at all sites in the first half of 2024.

The final phase of the program, efficacy, is in progress at certain sites and will have commenced at all sites by the second quarter of 2024.

We expect to report relevant data from the program in the second half of 2024.

Strategic Collaborations and License Agreements

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We raised this amount from the proceeds received from the sale of our Series A Convertible Preferred stock in March 2018 and our underwritten public offering of shares of common stock, pre-funded warrants to purchase shares of common-stock, and warrants to purchase shares of common stock in July 2018.

Under the terms of the agreement, we achieved a clinical development milestone at the end of the fourth quarter of 2018, triggering a $0.5 million payment in the first quarter of 2019.

Under the terms of the agreement, we achieved a clinical

development milestone at the end of the fourth quarter of 2018, triggering a $0.5 million payment in the first quarter of 2019.

Unless terminated earlier in accordance with its terms, the MSK license agreement as amended and restated, will continue on a country-by-country and licensed product-by-licensed product basis, until the later, of:

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Clinical Trial Collaboration and Supply Agreement

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 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.

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 PD-1 inhibitor pembrolizumab in a Phase 1/2 clinical trial enrolling patients in up to five cancer indications, including both hematologic malignancies and solid tumors.

This trial was initiated in December 2018.

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

We plan to present final data from this study at a medical conference in the first half of 2023.

In November 2022, we reported topline clinical and initial immune response data from this study, which showed that treatment with the combination of GPS and pembrolizumab compared favorably to treatment with anti-PD-1 therapy alone in a similar patient population and presented final data from this study at the International Gynecologic Cancer Society 2023 Annual Global Meeting in November 2023.

Exclusive License Agreement with 3D Medicines Inc.

In December 2020, we, together with our wholly-owned subsidiary, SLSG Limited, LLC, entered into an Exclusive License Agreement (the “3DMed License Agreement”) with 3D Medicines pursuant to which we granted 3D Medicines a sublicensable, royalty-bearing license, under certain intellectual property owned or controlled by us, to develop, manufacture and have manufactured, and commercialize GPS and heptavalent GPS, or GPS-Plus, product candidates, or the GPS Licensed Products, for all therapeutic and other diagnostic uses in Greater China, or the 3DMed Territory.

In December 2020, we, together with our wholly-owned subsidiary, SLSG Limited, LLC, entered into an Exclusive License Agreement (the “3D Medicines Agreement”) with 3D Medicines pursuant to which we granted 3D Medicines a sublicensable, royalty-bearing license, under certain intellectual property owned or controlled by us, to develop, manufacture and have manufactured, and commercialize GPS and heptavalent GPS, or GPS-Plus, product candidates, or the GPS Licensed Products, for all therapeutic and other diagnostic uses in Greater China, or the 3DMed Territory.

The license is exclusive, except with respect to certain know-how that has been non-exclusively licensed to us and is sublicensed to 3D Medicines on a non-exclusive basis.

We have retained development, manufacturing and commercialization rights with respect to the GPS Licensed Products in the rest of the world.

In partial consideration for the rights granted by us, 3D Medicines agreed to pay us (i) a one-time upfront cash payment of $7.5 million in order to reimburse us for certain expenses incurred with respect to the development of the GPS Licensed Products prior to execution of the 3DMed License Agreement, and (ii) milestone payments totaling up to $194.5 million in the aggregate upon the achievement of certain technology transfer, development and regulatory milestones, as well as certain net sales thresholds of GPS Licensed Products in the 3DMed Territory in a given calendar year.

In partial consideration for the rights granted by us, 3D Medicines agreed to pay us (i) a one-time upfront cash payment of $7.5 million in order to reimburse us for certain expenses incurred with respect to the development of the GPS Licensed Products prior to execution of the 3D Medicines Agreement, and (ii) milestone payments totaling up to $194.5 million in the aggregate upon the achievement of certain technology transfer, development and regulatory milestones, as well as certain net sales thresholds of GPS Licensed Products in the 3DMed Territory in a given calendar year.

3D Medicines also agreed to pay tiered royalties based upon a percentage of annual net sales of GPS Licensed Products in the 3DMed Territory ranging from the high single digits to the low double digits.

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3D Medicines is responsible for all costs related to developing, obtaining regulatory approval of and commercializing the GPS Licensed Products in the 3DMed Territory.

3D Medicines is required to use commercially reasonable best efforts to develop and obtain regulatory approval for, and upon receipt of regulatory approval, commercialize the GPS Licensed Products in the 3DMed Territory.

3D Medicines is required to use commercially reasonable best efforts to develop and obtain regulatory approval for, and upon receipt of regulatory approval, commercialize the

GPS Licensed Products in the 3DMed Territory.

A joint development committee has been established between 3D Medicines and us to coordinate and review the development, manufacturing and commercialization plans with respect to the GPS Licensed Products in the 3DMed Territory.

We and 3D Medicines 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 3D Medicines with all quantities of the GPS Licensed Product necessary for 3D Medicines to develop and commercialize the GPS Licensed Products in the 3DMed Territory until 3D Medicines has received all approvals required for 3D Medicines or its designated contract manufacturing organization to manufacture the GPS Licensed Products in the 3DMed Territory.

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

Upon expiration of the 3DMed License Agreement, the license granted to 3D Medicines will become fully paid-up, perpetual and irrevocable.

Either party may terminate the 3DMed License Agreement for the other party’s material breach following a cure period or upon certain insolvency events.

We may terminate the 3DMed License Agreement if 3D Medicines or its affiliates or sublicensees challenge the validity or enforceability of the licensed patents.

following the two-year anniversary of the effective date, 3D Medicines has the right to terminate the 3DMed License Agreement for convenience, subject to certain requirements.

3D Medicines may terminate the 3DMed License Agreement upon prior notice to us if the grant of the license to 3D Medicines is prohibited or delayed for a period of time due to a change of U.S.

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

Upon expiration of the 3D Medicines Agreement, the license granted to 3D Medicines will become fully paid-up, perpetual and irrevocable.

Either party may terminate the 3D Medicines Agreement for the other party’s material breach following a cure period or upon certain insolvency events.

We may terminate the 3D Medicines Agreement if 3D Medicines or its affiliates or sublicensees challenge the validity or enforceability of the licensed patents.

At any time following the two-year anniversary of the effective date, 3D Medicines has the right to terminate the 3D Medicines Agreement for convenience, subject to certain requirements.

3D Medicines may terminate the 3D Medicines Agreement upon prior notice to us if the grant of the license to 3D Medicines is prohibited or delayed for a period of time due to a change of U.S.

export laws and regulations.

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 and upon approval by the NMPA in March 2022 of an IND for a Phase 1 study, which triggered a $1.0 million milestone payment to us.

A total of $191.5 million in potential future development, regulatory and sales milestones, not including future royalties, remains under the 3DMed License Agreement.

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

Under the 3D Medicines Agreement, we achieved regulatory milestones relating to agreement upon and completion of a technology transfer plan in March 2021 and June 2021, respectively, for $1.0 million each and upon approval by the NMPA in March 2022 of an IND for a Phase 1 study, which triggered a $1.0 million milestone payment to us.

A total of $191.5 million in potential future development, regulatory and sales milestones, not including future royalties, remains under the 3D Medicines Agreement.

We entered into a Side Letter Agreement with 3D Medicines, dated December 5, 2022, or Side Letter, arising from our agreement with 3D Medicines for 3D Medicines to participate in the REGAL study through the inclusion of approximately 20 patients from mainland China.

The Side Letter, together with the 3D Medicines Agreement, details the terms and conditions of 3D Medicines' participation in the REGAL study.

In December 2023, we announced that we had commenced a binding arbitration proceeding against 3D Medicines regarding, among other things, the trigger and payment of relevant milestone payments due to us as well as 3D Medicines' failure to use commercially reasonable best efforts to develop GPS in accordance with the terms of the agreement.

Legal Proceedings .

Exclusive License Agreement with GenFleet Therapeutics (Shanghai), Inc.

On March 31, 2022, or the GenFleet Agreement Effective Date, we entered into a License Agreement, or the GenFleet License Agreement, with GenFleet pursuant to which GenFleet granted to us a sublicensable, royalty-bearing license, under certain of its intellectual property, to develop, manufacture and have manufactured, and commercialize a small molecule CDK9 inhibitor, or the CDK9 Licensed Product, for the treatment, diagnosis or prevention of disease in humans and animals in all territories other than Greater China, or the GFH009 Territory.

The CDK9 inhibitor, known as GFH009, is currently in a Phase 1 clinical trial in the United States and China.

In consideration for these rights, we agreed to pay to GenFleet (i) an initial payment of $10.0 million as an upfront license fee and for a technology transfer, $4.5 million of which was paid within 30 days of the GenFleet Agreement Effective Date and $5.5 million of which is due upon the first day of the 15th calendar month following the GenFleet Agreement Effective Date, (ii) development and regulatory milestone payments for up to three indications totaling up to $48.0 million in the aggregate, and (iii) milestone payments totaling up to $92.0 million in the aggregate upon the achievement of certain net sales thresholds of CDK9 Licensed Products in the GFH009 Territory in a given calendar year.

We also agreed to pay GenFleet tiered royalties based upon a percentage of annual net sales of CDK9 Licensed Products in the GFH009 Territory ranging from the low to high single digits.

On March 31, 2022, or the GenFleet Agreement Effective Date, we entered into a License Agreement, or the GenFleet Agreement, with GenFleet pursuant to which GenFleet granted to us a sublicensable, royalty-bearing license, under certain of its intellectual property, to develop, manufacture and have manufactured, and commercialize a small molecule CDK9 inhibitor, or the CDK9 Licensed Product, for the treatment, diagnosis or prevention of disease in humans and animals in all territories other than Greater China, or the SLS009 Territory.

The CDK9 inhibitor, known as SLS009, is currently in a Phase 1 clinical trial in the United States and China.

We also agreed to pay GenFleet tiered royalties based upon a percentage of annual net sales of CDK9 Licensed Products in the SLS009 Territory ranging from the low to high single digits.

The royalties are payable on a CDK9 Licensed Product-by-CDK9 Licensed Product and region-by-region basis commencing on the first commercial sale of a CDK9 Licensed Product in a region and continuing until the later of (i) the date that is 10 years following the date of first commercial sale for such CDK9 Licensed Product in such region and (ii) the date of the expiration of the last valid claim of a licensed patent covering or claiming such CDK9 Licensed Product in such region.

The royalty rate is subject to reduction under certain circumstances, including when generic competition for a CDK9 Licensed Product exists in a particular region.

We are responsible for all costs related to developing, obtaining regulatory approval of and commercializing the CDK9 Licensed Products in the GFH009 Territory and we are required to use commercially reasonable efforts to develop and obtain regulatory approval for, and upon receipt of regulatory approval, commercialize the CDK9 Licensed Products in the GFH009 Territory.

We and GenFleet have established a joint steering committee to coordinate and review the development, manufacturing and commercialization plans with respect to the CDK9 Licensed Products in the GFH009 Territory.

We and GenFleet also have entered into a supply agreement and related quality agreement pursuant to which GenFleet is manufacturing, or having manufactured, and supplying us with all quantities of the CDK9 Licensed Product necessary for us to develop and commercialize the CDK9 Licensed Products in the GFH009 Territory.

The GenFleet License Agreement will expire on a CDK9 Licensed Product-by-CDK9 Licensed Product and region-by-region basis on the date of the expiration of all of our payment obligations to GenFleet.

Upon expiration of the GenFleet License Agreement, the license granted to us will become fully paid-up, perpetual and irrevocable.

Either party may terminate the GenFleet License Agreement for the other party’s material breach following a cure period or upon certain insolvency events.

During the period from the first anniversary of the GenFleet Agreement Effective Date until the first regulatory approval of a CDK9 Licensed Product in any country within the GFH009 Territory, we

will have the right to terminate the GenFleet License Agreement upon 180 days’ prior written notice to GenFleet if a clinical failure, as described in the GenFleet License Agreement, occurs.

If we terminate the GenFleet License Agreement before the first day of the 15th calendar month following the GenFleet Agreement Effective Date, then we will be required to pay to GenFleet the remainder of the $10 million initial payment upon the first day of the 15th calendar month following the GenFleet Agreement Effective Date.

Upon receipt of the first regulatory approval of a CDK9 Licensed Product and continuing throughout the term of the GenFleet License Agreement, we will have the right to terminate the GenFleet License Agreement upon one year’s prior written notice to GenFleet.

In addition, we may terminate the GenFleet License Agreement upon 90 days’ notice to GenFleet upon the occurrence of certain safety events described in the GenFleet License Agreement.

GenFleet may terminate the GenFleet License Agreement upon notice to us if we become in arrears in any payments due pursuant to the GenFleet License Agreement and we fail to make the required payment within 60 days after the delivery of written notice from GenFleet.

In addition, if we fail to meet the deadline for a diligence milestone event (as described in the GenFleet License Agreement), GenFleet may treat such failure as a material breach which has not been cured and GenFleet will be entitled to terminate the GenFleet License Agreement if such material breach is not cured within 90 days of receiving notice of such material breach.

At GenFleet’s request within 30 days of termination of the GenFleet License Agreement, other than termination by us for GenFleet’s material breach following a cure period, we will grant GenFleet an option to enter into negotiations with us with respect to a license agreement pursuant to which we would grant GenFleet a non-exclusive, royalty-bearing, worldwide license for certain of our intellectual property that is necessary and used to develop, commercialize and manufacture the terminated products.

We are responsible for all costs related to developing, obtaining regulatory approval of and commercializing the CDK9 Licensed Products in the SLS009 Territory and we are required to use commercially reasonable efforts to develop and obtain regulatory approval for, and upon receipt of regulatory approval, commercialize the CDK9 Licensed Products in the SLS009 Territory.

The GenFleet Agreement will expire on a CDK9 Licensed Product-by-CDK9 Licensed Product and region-by-region basis on the date of the expiration of all of our payment obligations to GenFleet.

Upon expiration of the GenFleet Agreement, the license granted to us will become fully paid-up, perpetual and irrevocable.

Either party may terminate the GenFleet Agreement for the other party’s material breach following a cure period or upon certain insolvency events.

During the period from the first anniversary of the GenFleet Agreement Effective Date until the first regulatory approval of a CDK9 Licensed Product in any country within the SLS009 Territory, we will have the right to terminate the GenFleet Agreement upon 180 days’ prior written notice to GenFleet if a clinical failure, as described in the GenFleet Agreement, occurs.

If we terminate the GenFleet Agreement before the first day of the 15th calendar month following the GenFleet Agreement Effective Date, then we will be required to pay to GenFleet the remainder of the $10 million initial payment upon the first day of the 15th calendar month following the GenFleet Agreement Effective Date.

Upon receipt of the first regulatory approval of a CDK9 Licensed Product and continuing throughout the term of the GenFleet Agreement, we will have the right to terminate the GenFleet Agreement upon one year’s prior written notice to GenFleet.

In addition, we may terminate the GenFleet Agreement upon 90 days’ notice to GenFleet upon the occurrence of certain safety events described in the GenFleet Agreement.

GenFleet may terminate the GenFleet Agreement upon notice to us if we become in arrears in any payments due pursuant to the GenFleet Agreement and we fail to make the required payment within 60 days after the delivery of written notice from GenFleet.

In addition, if we fail to meet the deadline for a diligence milestone event (as described in the GenFleet Agreement), GenFleet may treat such failure as a material breach which has not been cured and GenFleet will be entitled to terminate the GenFleet Agreement if such material breach is not cured within 90 days of receiving notice of such material breach.

At GenFleet’s request within 30 days of termination of the GenFleet Agreement, other than termination by us for GenFleet’s material breach following a cure period, we will grant GenFleet an option to enter into negotiations with us with respect to a license agreement pursuant to which we would grant GenFleet a non-exclusive, royalty-bearing, worldwide license for certain of our intellectual property that is necessary and used to develop, commercialize and manufacture the terminated products.

Manufacturing

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We currently employ internal resources and third-party consultants to manage our manufacturing contractors.

Our sole CMO for GPS drug substance peptides is Polypeptide Group.

Our sole CMO for GPS drug product is Lyophilization Services of New England, Inc., or LSNE.

In 2022, process improvements were introduced into the LSNE manufactured drug product batches.

The new manufacturing batch met all the release criteria and, to date, has shown favorable stability of at least 42 months on already known long-term conditions (-20°C) as well at least 12 months at accelerated conditions (5°C and 25°C).

Both long-term and accelerated stability 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), which would be more optimal for supply chain logistics.

The GPS drug substance is manufactured at PolyPeptide Group.

In October 2022, we entered into a Clinical Supply Agreement with GenFleet pursuant to which GenFleet will manufacture and/or have manufactured through third parties (with which GenFleet entered into agreements and to which we have access, as necessary), and supply GFH009 and any back-up molecule or intermediary related to GFH009 (including all methods, forms, presentations, dosage strengths, dosage forms, and formulations), for our use in all research and development activities necessary to obtain, maintain or expand regulatory approval worldwide, except Greater China.

Our CMOs comply with cGMP requirements and manufacture product batches used in ongoing clinical trials.

We anticipate the same CMOs to manufacture commercial batches.

All batches for clinical trials meet release criteria and are monitored for long-term and accelerated stability.

We have significantly advanced the chemistry, manufacturing, and controls, or CMC, objectives in support of the GPS clinical development program and for licensure, including:

• Manufacturing lyophilized clinical GMP batches;

• Qualifying processes;

• Validating analytical methods;

• Monitoring the stability program.

In the third quarter of 2023, based upon this work, we concluded a Type C meeting with the FDA regarding the CMC sections in a potential BLA for GPS.

We had submitted a briefing package to FDA which provided an up-to-date overview of the extensive work we have completed for the GPS CMC program, including commercial manufacturing and regulatory plans.

Following review of the package and accompanying questions to FDA, the FDA responded with positive guidance, including agreement on our proposed potency assay and manufacturing processes validation and our stability data generation plan for the commercial presentation of GPS.

The current storage condition of GPS drug product is -20°C and we are collecting stability data to allow GPS to be stored in 2-8°C (36° – 46°F), which would be more optimal for supply chain logistics and would make it more accessible for end-users.

In October 2022, we entered into a Clinical Supply Agreement with GenFleet pursuant to which GenFleet will manufacture and/or have manufactured through third parties (with which GenFleet entered into agreements and to which we have access, as necessary), and supply SLS009 and any back-up molecule or intermediary related to SLS009 (including all methods, forms, presentations, dosage strengths, dosage forms, and formulations), for our use in all research and development activities necessary to obtain, maintain or expand regulatory approval worldwide, except Greater China.

Sales and Marketing

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As GPS and our other product candidates may initially be developed for orphan indications with a relatively small number of treating physicians, we anticipate that a reduced infrastructure, including a small, targeted sales force, will be sufficient to support our sales and marketing objectives.

In 2022, we hired a Chief Commercial Officer, who will build the infrastructure for our commercial operations.

We continue to assess the infrastructure and resources needed to establish our commercial operations and support other relevant commercial matters, such as pricing and market access.

We may elect in the future to utilize strategic partners, distributors, or contract sales forces and clinical nurse educators to assist in the commercialization of our products.

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 Greater China.

In December 2020, we entered into the 3D Medicines Agreement 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 Greater China.

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

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Our commercial success depends in part on our ability to avoid infringing the proprietary rights of third parties, our ability to obtain and maintain proprietary protection for our product candidates, technologies and know-how, and our ability to prevent others from infringing our proprietary rights.

We seek to protect our proprietary position by, among other methods, evaluating relevant patents, establishing defensive positions, monitoring European Union oppositions and pending intellectual property rights, preparing litigation strategies in view of the U.S.

We seek to protect our proprietary position by, among other methods, evaluating relevant patents, establishing defensive positions, monitoring European Union, or EU, oppositions and pending intellectual property rights, preparing litigation strategies in view of the U.S.

legislative framework, filing U.S.

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The length of the patent term extension is related to the length of time the drug is under regulatory review.

Patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, and only one patent applicable to an

approved drug may be extended.

Similar provisions are available in the European Union and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug.

Patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, and only one patent applicable to an approved drug may be extended.

Similar provisions are available in the EU and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug.

In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those products, depending upon the length of the clinical trials for each drug and other factors.

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• Patent application co-owned by us and MSK:

• Applications in the United States, Australia, Canada, China, Europe, Hong Kong, 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.

◦ Patent applications 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 pending in the United States, Australia, Canada, China, Europe, Hong Kong, India, Israel, Japan, South Korea, Mexico and Russia, which, if granted, are expected to expire in 2040.

• Patents and patent applications in-licensed from MSK:

• 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, Australia, China, several countries in the European Union and Japan, and which are expected to expire in 2037(United States) and 2036 (Australia, China, European Union and Japan);

• 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, and which if granted, are expected to expire in 2036.

• 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 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;

patent covering peptide conjugates of the WT1-427 long peptide or WT1-331 long peptide, which is expected to expire in 2027;

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;

• 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, and 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, 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 patents covering certain WT1-targeting peptides and methods of use in the United States, which are expected to expire in 2034;

and a composition-of-matter patent covering

additional WT1-targeting peptides and methods of use in the United States, which is expected to expire in 2035;

◦ Composition-of-matter patents covering certain WT1-targeting peptides and methods of use in Australia, China, Hong Kong, several countries of the EU and Japan, which are expected to expire in 2034;

◦ Patent applications covering certain WT1-targeting peptides and methods of use pending in the United States, Australia, EU, Canada, China, Hong Kong, and Japan, 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, Australia, China, Hong Kong, several countries in the EU and Japan, which are expected to expire in 2037 (United States) and 2036 (Australia, China, Hong Kong, EU and Japan);

◦ 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 pending in the United States, Australia, Canada, China, Hong Kong, EU, South Korea, and Japan, which, if granted, are expected to expire in 2036;

◦ Composition-of-matter patents covering the WT1-A1 peptide of GPS in the United States, Canada, Australia, and several countries of the EU, 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;

a patent covering peptide conjugates of the WT1-427 long peptide or WT1-331 long peptide in the United States, which is expected to expire in 2027;

and a patent application covering peptide conjugates of the WT1-427 long peptide or WT1-331 long peptide pending in the United States, 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, in Australia and several countries of the EU, which are expected to expire in 2026;

composition-of-matter patent covering the WT1-427 long peptide of GPS and method of use in Canada, which is expected to expire in 2026;

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

◦ Composition-of-matter patent covering a WT1-specific peptide 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;

patent covering the WT1-122A1 long peptide of GPS and methods of use in the United States, which is expected to expire in 2029;

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 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, Hong Kong and Canada, and which if granted, are expected to expire in 2027;

Patents and patent applications covering GFH009:

and patent application covering the WT1-122A1 long peptide of GPS and methods of use pending 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 EU, 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 EU, Hong Kong and Canada, which, if granted, are expected to expire in 2027.

Patents and patent applications covering SLS009:

• Patents and patent applications in-licensed from GenFleet:

• Composition-of-matter patents covering GFH009 and use thereof in the treatment or amelioration of cancer, which have issued in the United States, Australia, Canada, Japan, Russia, South Korea, the United Kingdom, and several countries of the European Union, and which are expected to expire in 2038;

and a patent application covering GFH009 and use thereof in the treatment or amelioration of cancer, which is pending in Brazil and which, if granted, is expected to expire in 2038;

• Patent applications covering maleate or fumarate salt forms and polymorphs of GFH009, syntheses thereof, and use thereof in prevention or treatment of CDK9-related diseases, including cancer, pending in the United States, Australia, Brazil, Canada, Japan, Russia, South Korea, the United Kingdom and the European Union (via the European Patent Office), and several former Soviet block countries (via the Eurasian Patent Office), and which, if granted, are expected to expire in 2040.

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

While we believe that our scientific knowledge, assets, development experience and our ability to attract experienced commercial professionals provide us with competitive advantages, we face potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, which either alone or together with their collaborative partners, have substantially greater resources than we have.

Generally, our competitors in the cancer immunotherapy market comprise both companies with currently approved cancer immunotherapy products and companies currently engaged in clinical development of such products.

The large and medium-size competitors who have successfully obtained approval for cancer immunotherapy products include Bristol-Myers Squib Company, or BMS, Merck & Co., Inc., Genentech, Inc.

(a subsidiary of Roche Holding AG), AstraZeneca PLC, Johnson & Johnson/Janssen Pharmaceuticals, Amgen, Novartis, Gilead Sciences, Inc.

and Pfizer, Inc.

◦ Composition-of-matter patents covering SLS009 and use thereof in the treatment or amelioration of cancer in the United States, Australia, Canada, Japan, Russia, South Korea, the United Kingdom, and several countries of the EU, which are expected to expire in 2038;

and a patent application covering SLS009 and use thereof in the treatment or amelioration of cancer pending in Brazil, which, if granted, is expected to expire in 2038;

◦ Patents covering maleate and fumarate crystal salts and polymorphs of SLS009, syntheses thereof, and use thereof in prevention or treatment of CDK9-related diseases, including cancer, in Australia and Japan, which are expected to expire in 2040;

patent applications covering maleate and fumarate salt forms and polymorphs of SLS009, syntheses thereof, and use thereof in prevention or treatment of CDK9-related diseases, including cancer, pending in the United States, Brazil, Canada, South Korea, the United Kingdom and the EU (via the European Patent Office), and several former Soviet bloc countries, including Russia (via the Eurasian Patent Office), which, if granted, are expected to expire in 2040.

Oncology in general, and specifically, cancer immunotherapy, is a significant growth area for the biopharmaceutical industry, attracting large pharmaceutical companies as well as small niche players.

While we believe that our scientific knowledge, assets, development experience and ability to attract experienced commercial professionals provide us with competitive advantages, we face potential competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, which either alone or together with their collaborative partners, have substantially greater resources than we have.

Generally, our competitors in the oncology therapeutic market are large and mid-sized companies with approved oncology therapeutic products and companies currently engaged in clinical development of such products.

Any product candidates that we successfully develop and commercialize may compete with these existing therapies and new therapies that may become available in the future.

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 companies with currently marketed therapies to treat AML and are approved in the United States, such as AbbVie/Genentech (VENCLEXTA), Servier (TIBSOVO), Novartis AG (RYDAPT), Astellas Pharmaceuticals (XOSPATA), BMS (ONUREG/VIDAZA), among others.

While there are many companies developing therapies to treat AML that are in early-stage trials, the following companies have advanced to their later-stage:

GlycoMimetics (uproleselan);

Actinium Pharmaceuticals (Iomab-B);

Delta-Fly Pharma (radgocitabine);

Gilead (magrolimab);

Daiichi Sankyo

(VANFLYTA/quizartinib);

and AROG Pharmaceuticals (crenolanib).

Companies currently engaged in the clinical development of WT1-targeting therapies to treat AML are Astellas (ASP7517), BMS (JTCR016), NexImmune (NEXI-001), Roche (RG63441/RO7283420), and Cue Biopharma (CUE-102).

With respect to GFH009, we anticipate competition with companies who are currently engaged in the clinical development of selective CKD9-targeting therapies including Vincerx, Inc.

(VIP152), AstraZeneca (AZD4573), Kronos Bio (KB-0742), Sumitomo Dainippon Pharma Co., Ltd.

(TP-1287), MEI Pharma, Inc.

(voruciclib) and Prelude Therapeutics, Inc.

(PRT2527), among others.

These companies and others, some with collaborative agreements with larger companies, may compete in the same potential indications as GFH009.

Several companies are developing other CDK inhibitors (e.g., CDK1, CDK2, CDK5, CDK7), such as Cyclacel Pharmaceuticals (CYC065), Merck (SCH-727965), and Biotheryx, Inc., among others, possibly in the same indications as GFH009.

Both with regard to GPS and GFH009, many of our competitors, either alone or with their strategic partners, have substantially greater resources and expertise in research and development, manufacturing, preclinical testing, obtaining regulatory approvals, and marketing approved products than we have.

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

Principal competitors for AML broadly include companies with currently marketed products, such as AbbVie/Genentech (Venclexta), Pfizer (Mylotarg), Daiichi-Sankyo (Vanflyta), Rigel Pharmaceuticals (Rezlidhia) and Bristol Myers Squibb (Vidaza), among others.

There are also companies developing therapies to treat AML in the r/r setting, which are in earlier stages of clinical development, including emavusertib, which is in a Phase 1/2 trial in AML and being developed by Curis, and later-stage clinical development candidates which may enter the market before our potential products, such as GlycoMimetics (uproleselan), Delta-Fly Pharma (DFP-10917), and AROG Pharmaceuticals (crenolanib).

Actinium Pharmaceuticals, which announced in late 2022 / early 2023 positive results in its Phase 3 trial of Iomab-B in adults aged 55 and above with r/r AML, may be a key competitor.

With respect to WT1-targeting therapies, we do not believe GPS has direct competition in AML in the maintenance setting after CR2 at this time.

While there are companies engaged in the clinical development of WT-1 targeting therapies including Astellas (ASP7517) and Cue Biopharma (CUE-102), they are not currently focused on AML.

With respect to SLS009, we anticipate competition from companies who are currently engaged in the clinical development of selective CKD9-targeting therapies.

MEI Pharma is in Phase 1 clinical development for voruciclib alone and in combination with venetoclax for adults with r/r AML.

Vincerx Pharma may also be a potential competitor in our other indication, PTCL, with enitociclib, its CDK9 inhibitor, as a monotherapy and in combination with venetoclax.

There are other companies which are in early development stages for their CDK9 inhibitors and targeting other hematologic malignancies or solid tumors, including Kronos Bio (KB-0742), Sumitomo Dainippon Pharma (TP-1287), Adastra Pharmaceuticals (zotiraciclib) and Prelude Therapeutics (PRT2527).

With regard to both GPS and SLS009, many of our competitors, either alone or with their strategic partners, have substantially greater resources and expertise in research and development, manufacturing, preclinical testing, obtaining regulatory approvals, and marketing approved products than we have.

Mergers and acquisitions in the biotechnology, pharmaceutical and diagnostics industries may result in even more resources being concentrated among a smaller number of our competitors.

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If our therapeutic product candidates are approved, we believe that they would be priced at a premium over competitive generic products.

Human Capital/Employees

Employees and Human Capital

We have assembled a management team of biopharmaceutical experts with extensive experience in building and operating organizations that develop and deliver innovative medicines to patients with cancer.

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We also invest in our employees and are able to recruit talented individuals through our competitive benefits, compensation packages and health and wellness initiatives, which are based on peer company benchmarks.

In addition, the health and safety of our employees is a top priority.

In response to the COVID-19 pandemic, we implemented additional safety protocols and procedures to reduce the risk of exposure for our employees.

Many of these protocols remain in place.

Government Regulation

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

A company can make only those claims relating to safety and efficacy, purity and potency that are approved by the FDA and in accordance with the provisions of the approved label.

A company can make

only those claims relating to safety and efficacy, purity and potency that are approved by the FDA and in accordance with the provisions of the approved label.

A biologic candidate is licensed by the FDA through approval of a biologics license application, or BLA.

Assuming we receive positive data from our REGAL clinical trial for GPS, we will file a BLA.

Assuming we receive positive data from our REGAL clinical trial of GPS for monotherapy in patients with AML, we will submit a BLA to the FDA.

A drug candidate must be approved by the FDA through a new drug application, or NDA.

For GFH009, we will seek marketing approval through the filing of an NDA.

For SLS009, we will seek marketing approval through the submission of an NDA to the FDA.

The process required by the FDA before drug or biological product candidates may be marketed in the United States generally involves the following:

• completion of extensive nonclinical laboratory tests and animal studies performed in accordance with the FDA’s current good laboratory practice, or GLP, regulations or other applicable regulations;

• completion of extensive nonclinical laboratory tests and animal studies performed in accordance with the FDA’s current good laboratory practice, or GLP, regulations and other applicable regulations;

• 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 IRB or ethics committee at each clinical site before the trial is initiated at such sites;

• approval by an institutional review board, or IRB, or ethics committee at each clinical site before the trial is initiated at such sites;

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

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Nonclinical studies during the preclinical development stage include laboratory evaluation of product chemistry and formulation and typically include in vitro and animal studies to assess the potential for adverse events and in some cases to establish a rationale for therapeutic use.

The Consolidated Appropriations Act for 2023, signed into law on December 29, 2022, (P.L.

117-328) amended the FDCA and the Public Health Service Act to specify that nonclinical testing for drugs and biologics may, but is not required to, include in vivo animal testing.

Consolidated Appropriations Act for 2023, signed into law on December 29, 2022, (P.L.

117-328) amended the Food, Drug, and Cosmetic Act, or the FDCA, and the Public Health Service Act to specify that nonclinical testing for drugs and biologics may, but is not required to, include in vivo animal testing.

According to the amended language, a sponsor may fulfill nonclinical testing requirements by completing various in vitro assays (e.g., cell-based assays, organ chips, or microphysiological systems), in silico studies (i.e., computer modeling), other human or nonhuman biology-based tests (e.g., bioprinting), or in vivo animal tests.

The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for safety/toxicology studies.

Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after an IND for an investigational drug candidate is submitted to the FDA and human clinical trials have been initiated.

Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after an IND for an investigational drug or biologic candidate is submitted to the FDA and human clinical trials have been initiated.

Prior to beginning the first clinical trial with a product candidate, we must submit an IND to the FDA.

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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 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.

Some studies also include oversight by an independent data safety monitoring board, or DSMB, organized by the clinical trial sponsor, which at designated check points based on access to certain data from the clinical trial may recommend the sponsor to halt the trial if the DSMB 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.

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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.

Final Rule on ClinicalTrials.gov registration and reporting requirements became effective in 2017, and both NIH and FDA have brought enforcement actions against non-compliant clinical trial sponsors.

Failure to timely register a covered clinical trial 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 brought enforcement actions against non-compliant clinical trial sponsors.

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

• Phase 1 -The investigational product is initially introduced into healthy human subjects or patients with the target disease or condition.

These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

These studies are designed to test the safety, dosage tolerance, absorption,

metabolism, distribution, and excretion of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

• Phase 2 -The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.

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• Phase 4 -In some cases, the FDA may require, or companies may voluntarily pursue, additional clinical trials after a product is approved to gain additional information and experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow up.

These so-called Phase 4 studies may be made a condition to approval of the BLA.

These so-called Phase 4 studies may be made a condition to approval of the BLA or NDA.

In the Consolidated Appropriations Act for 2023, Congress amended the FDCA to require sponsors of a Phase 3 clinical trial, or other “pivotal study” of a new drug to support marketing authorization, to submit a diversity action plan for such clinical trial.

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The FDA may grant a waiver for some or all of the requirements for a diversity action plan.

To grant a waiver, FDA must determine that the prevalence or incidence of the disease or condition being studied makes it impracticable to conduct a clinical trial in accordance with a diversity action plan, or that a waiver is necessary to protect public health during a public health emergency.

Our Phase 3 REGAL trial of GPS for AML patients who have achieved CR2 was initiated before this requirement became effective, but for any future Phase 3 trials we plan to conduct, we must submit a diversity action plan to the FDA by the time we submit plans for such Phase 3, or pivotal study, protocol to the agency for review as part of an IND, unless we are able to obtain a waiver for some or all of the requirements for a diversity action plan.

It is unknown at this time how the diversity action plan may affect Phase 3 trial planning and timing or what specific information FDA will expect in such plans, but if FDA objects to a sponsor’s diversity action plan and requires the sponsor to amend the plan or take other actions, it may delay trial initiation.

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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).

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

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

The FDA must make a decision on accepting an NDA or 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.

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

Additionally, before approving an NDA or 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 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.

Additionally, before approving an NDA or BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP and integrity of the clinical data.

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.

Under the Pediatric Research Equity Act, or PREA, amendments to the FDCA, an NDA or BLA or supplement to such applications 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.

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The testing and approval process requires substantial time, effort and financial resources, and each may take several years to complete.

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 an NDA or 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.

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After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.

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.

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, and Breakthrough Therapy Designations

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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 NDA or 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.

We have obtained Fast Track designation for GPS in AML, MPM and MM, and for SLS009 in r/r AML and r/r PTCL.

Priority review is granted when there is evidence that the proposed product would be a significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of a serious condition.

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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.

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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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.

Orphan Drug Product Designation must be requested before submitting a BLA.

Orphan Drug Product Designation must be requested before submitting an NDA or BLA.

After the FDA grants Orphan Drug Product Designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

If a drug or biologic product that has Orphan Drug Product Designation subsequently receives the first FDA approval for a particular active ingredient for the disease for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full NDA or BLA, to market the same drug or biologic for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan product exclusivity or if FDA finds that the holder of the orphan product exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan product to meet the needs of patients with the disease or condition for which the drug or biologic was designated.

quantities of the orphan product to meet the needs of patients with the disease or condition for which the drug or biologic was designated.

Orphan product exclusivity does not prevent the FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition.

the other benefits of Orphan Drug Product Designation are tax credits for certain research and a waiver of the BLA application user fee.

Among the other benefits of Orphan Drug Product Designation are tax credits for certain research and a waiver of the BLA application user fee.

A drug or biologic with Orphan Drug Product Designation may not receive orphan product exclusivity if it is approved for a use that is broader than the indication for which it received Orphan Drug Product Designation.

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however, at this time the agency continues to apply its long-standing interpretation of the governing regulations and has stated that it does not plan to change any orphan drug implementing regulations.

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

We have obtained Orphan Drug Product Designation in the United States for GPS in AML, MPM and MM and for SLS009 for AML and PTCL.

Pediatric exclusivity

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In 1984, with passage of the Drug Price Competition and Patent Term Restoration Act, or Hatch-Waxman Act, which established an abbreviated regulatory scheme authorizing the FDA to approve generic drugs based on an innovator or “reference” product, Congress also enacted Section 505(b)(2) of the FDCA, which provides a hybrid pathway combining features of a traditional NDA and a generic drug application.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application, or ANDA, to the agency.

In support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference-listed drug, or RLD.

To obtain approval of a generic

drug, an applicant must submit an abbreviated new drug application, or ANDA, to the agency.

ANDAs are “abbreviated” because they do not include preclinical and clinical data to demonstrate safety and effectiveness.

Instead, in support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference-listed drug, or RLD.

Specifically, in order for an ANDA to be approved, the FDA must find that the generic version is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, and the strength of the drug.

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A Section 505(b)(2) applicant may eliminate the need to conduct certain preclinical or clinical studies, if it can establish that reliance on studies conducted for a previously approved product is scientifically appropriate.

Unlike the ANDA pathway used by developers of bioequivalent versions of innovator drugs, the 505(b)(2) regulatory pathway does not preclude the possibility that a follow-on applicant would need to conduct additional clinical trials or nonclinical studies;

for example, they may be seeking approval to market a previously approved drug for new indications or for a new patient population that would require new clinical data to demonstrate safety or effectiveness.

In addition, under the Hatch-Waxman Act, the FDA might not approve an ANDA or 505(b)(2) NDA until any applicable period of non-patent exclusivity for the RLD has expired.

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An active moiety is the molecule or ion responsible for the physiological or pharmacological action of the drug substance.

In cases where such NCE exclusivity has been granted, an ANDA or 505(b)(2) NDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the applicant may submit its application four years following the original product approval.

In cases where such NCE exclusivity has been granted, an ANDA or 505(b)(2) NDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification (described below), in which case the applicant may submit its application four years following the original product approval.

The FDCA also provides for a period of three years of exclusivity for an NDA, 505(b)(2) NDA or supplement thereto if one or more new clinical investigations, other than bioavailability or bioequivalence studies, that were conducted by or for the applicant are deemed by the FDA to be essential to the approval of the application.

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Upon approval of an NDA or a supplement thereto, NDA sponsors are required to list with the FDA each patent with claims that cover the applicant’s product or an approved method of using the product.

Each of the patents listed by the NDA sponsor is published in the Orange Book.

Each of the patents listed by

the NDA sponsor is published in the Orange Book.

When an ANDA applicant files its application with the FDA, the applicant is required to certify to the FDA concerning any patents listed for the reference product in the Orange Book, except for patents covering methods of use for which the ANDA applicant is not seeking approval.

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Reference a product exclusivity for biological products

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.

The Biologics Price Competition and Innovation Act of 2009, or 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 mechanism of action for the 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.

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 for the follow-on biological product 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.

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Under the BPCIA, a reference biological product is granted 12 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.

The first approved interchangeable biological product will be granted an exclusivity period of up to one year after it is first commercially marketed, and as part of the Consolidated Appropriations Act for 2023, Congress amended the PHSA in order to permit multiple interchangeable products approved on the same day to receive and benefit from this one-year exclusivity period.

The first approved interchangeable

biological product will be granted an exclusivity period of up to one year after it is first commercially marketed, and as part of the Consolidated Appropriations Act for 2023, Congress amended the PHSA in order to permit multiple interchangeable products approved on the same day to receive and benefit from this one-year exclusivity period.

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.

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

Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a supplement for the reference product for a subsequent application filed by the same sponsor or manufacturer of the reference product (or licensor, predecessor in interest or other related entity) for a change (not including a modification to the structure of the biological product) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device or strength or for a modification to the structure of the biological product that does

not result in a change in safety, purity or potency.

Therefore, one must determine whether a new product includes a modification to the structure of a previously licensed product that results in a change in safety, purity or potency to assess whether the licensure of the new product is a first licensure that triggers its own period of exclusivity.

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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 prescheduled or 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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In addition, the discovery of conditions that violate these rules, including failure to conform to cGMP, could result in enforcement actions, and the discovery of problems with a product after approval may result in restrictions on a product, manufacturer or holder of an approved BLA, including voluntary recall and regulatory sanctions as described below.

Once an approval or clearance of a drug is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

Once an approval of a drug or biologic is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in mandatory revisions to the approved labeling to add new safety information;

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Both the PDMA and state laws limit the distribution of prescription pharmaceutical product samples and impose requirements to ensure accountability in distribution.

Most recently, the Drug Supply Chain Security Act, or DSCSA, was enacted with the aim of building an electronic system to identify and trace certain prescription drugs distributed in the United States, including most biological products.

The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers over a ten-year period that is expected to culminate in November 2023.

Furthermore, the Drug Supply Chain Security Act, or DSCSA, was enacted with the aim of building an electronic system to identify and trace certain prescription drugs distributed in the United States, including most biological products.

The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers over a ten-year period, which culminated in November 2023.

Most recently, the FDA announced a one-year stabilization period to November 2024, giving entities subject to the DSCSA additional time to finalize interoperable tracking systems and to ensure supply chain continuity.

From time to time, new legislation and regulations may be implemented that could significantly change the statutory provisions governing the approval, manufacturing and marketing of products regulated by the FDA.

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Other Health Care Laws and Compliance Requirements

Our sales, promotion, medical education and other activities following product approval will be subject to regulation by numerous regulatory and law enforcement authorities in the United States in addition to FDA, including potentially the Federal Trade Commission, or FTC, the Department of Justice, or DOJ, the Centers for Medicare and Medicaid Services, or CMS, other divisions of the Department of Health and Human Services and state and local governments.

Our promotional and scientific/educational programs must comply with the federal Anti-Kickback Statute, the Foreign Corrupt Practices Act, the False Claims Act, or FCA, the Veterans Health Care Act, physician payment transparency laws, privacy laws, security laws, and additional state laws similar to the foregoing.

The federal Anti-Kickback Statute prohibits, among other things, the offer, receipt, or payment of remuneration in exchange for or to induce the referral of patients or the use of products or services that would be paid for in whole or part by Medicare, Medicaid or other federal health care programs.

Our promotional and scientific/educational programs must comply with the federal

Anti-Kickback Statute, the Foreign Corrupt Practices Act, the False Claims Act, or FCA, the Veterans Health Care Act, physician payment transparency laws, privacy laws, security laws, and additional state laws similar to the foregoing.

The federal Anti-Kickback Statute prohibits, among other things, persons from knowingly and willfully soliciting, offering, receiving, or paying remuneration, directly or indirectly, in cash or in kind, in exchange for or to induce or reward either the referral of patients for, or the purchase, order or recommendation of, any good or service that may be paid for in whole or part by Medicare, Medicaid or other federal health care programs.

Remuneration has been broadly defined to include anything of value, including cash, improper discounts, and free or reduced-price items and services.

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Further, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it to have committed a violation.

In addition, the government may assert that a claim including items or services resulting from a violation of the federal

Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA.

In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the FCA.

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

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.

The FCA imposes liability on persons who, among other things, (i) knowingly present or cause to be presented false or fraudulent claims for payment or approval by a federal health care program, (ii) knowingly make, use, or cause to be made or used a false record or statement material to a false or fraudulent claim to the federal government, or (iii) avoid, decrease, or conceal an obligation to pay money to the federal government.

The FCA has been used to prosecute persons submitting claims for payment that are inaccurate or fraudulent, that are for services not provided as claimed, or for services that are not medically necessary.

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The government has obtained multi-million and multi-billion dollar settlements under the FCA in addition to individual criminal convictions under applicable criminal statutes.

Conviction or civil judgment for violating the FCA may result in exclusion from federal health care programs, and suspension and debarment from government contracts, and refusal of orders under existing government contracts.

In addition, companies have been forced to implement extensive corrective action plans and have often become subject to consent decrees or corporate integrity agreements, restricting the manner in which they conduct their business.

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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 health care providers.

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), certain non-physician health care practitioners 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, or the ACA, requires manufacturers of FDA-approved drugs, devices, biologics and medical supplies covered by Medicare, Medicaid or the Children’s Health Insurance Program to report, on an annual basis, to CMS 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), certain advanced non-physician health care practitioners 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 .

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The federal criminal statutes enacted under HIPAA impose criminal liability for knowingly and willfully executing, or attempting to execute, a scheme to defraud any health care 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 health care benefit program;

knowingly and willfully embezzling or stealing from a health care benefit program;

knowingly and willfully embezzling or

stealing from a health care benefit program;

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

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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.

HIPAA, as amended by the Health Information Technology and Clinical Health Act, or HITECH, and their respective implementing regulations, imposes specified requirements relating to the privacy, security and transmission of individually identifiable health information.

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to “business associates,” defined as independent contractors or agents of covered entities that create, receive, maintain or transmit protected health information in connection with providing a service for or on behalf of a covered entity.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or HITECH, and their respective implementing regulations impose specific requirements on covered entities relating to the privacy, security and transmission of individually identifiable health information, known as protected health information.

HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.

state laws govern the privacy and security of health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect.

We are not a covered entity or a business associate under HIPAA;

however, we are indirectly affected by HIPAA because the protected health information held by investigators conducting our clinical trials is subject to HIPAA and can only be used for our clinical research consistent with HIPAA requirements imposed on those investigators.

In addition, state laws, such as the California Consumer Privacy Act, or the CCPA, govern the privacy and security of the personal information of individuals residing in such states, and may in certain circumstances, apply to health information.

In addition to California, other states have implemented laws protecting identifiable health and personal information, and many of these laws differ from each other in significant ways and may not be preempted by HIPAA, thus complicating compliance efforts.

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 health care items or services reimbursed by non-governmental third-party payors, including private insurers, and may be broader in scope than their federal equivalents.

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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 collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the EU, including personal health data, is subject to the EU’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 EU, 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.

The Company must comply with the GDPR in the performance of its clinical trials in the EU 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.

In July 2023, the European Commission adopted an adequacy decision for a new mechanism for transferring personal data from the EU to the United States – the EU-U.S.

Data Privacy Framework, which provides EU individuals with several new rights, including the right to obtain access to their data, or obtain correction or deletion of incorrect or unlawfully handled data.

In addition, the EU-U.S.

Data Privacy Framework offers additional redress avenues for violations, including free of charge independent dispute resolution mechanisms and an arbitration panel.

The adequacy decision followed the U.S.' signing of an executive order introducing new binding safeguards to address the points raised by the Court of Justice of the EU in its decision on a case known as Schrems II , which invalidated the previous EU-U.S.

Privacy Shield.

Notably, the new obligations were geared to ensure that data can be accessed by U.S.

intelligence agencies only to the extent necessary and proportionate and to establish an independent and impartial redress mechanism to handle complaints from Europeans concerning the collection of their data for national security purposes.

The European Commission will continually review developments in the United States along with its adequacy decision.

Adequacy decisions can be adapted or even withdrawn in the event of developments affecting the level of protection in the applicable jurisdiction.

Future actions of EU data protection authorities are difficult to predict.

Some customers or other service providers may respond to these evolving laws and regulations by asking us to make certain privacy or data-related contractual commitments that we are unable or unwilling to make.

This could lead to the loss of current or prospective customers or other business relationships.

Coverage and Reimbursement

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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.

Our drug or biological candidates may or may not be considered medically necessary or cost-effective or pay require prior authorizations before use.

Our drug or biological candidates may or may not be considered medically necessary or cost-effective or may require prior authorizations before use.

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

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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 the reimbursement for a product may be separate from the process of seeking approval for or setting the price of the product.

The process for determining whether a payor will cover and provide reimbursement for a product may be separate from the process of seeking approval for or 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.

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Adoption of general controls and measures, coupled with the tightening of restrictive policies in jurisdictions with existing controls and measures, could limit payments for drugs and biologics.

The Medicaid Drug Rebate Program requires biopharmaceutical manufacturers to enter into and have in effect a national rebate agreement with the Secretary of the Department of Health and Human Services as a condition for states to receive federal matching funds for the manufacturer’s outpatient therapeutic products furnished to Medicaid patients.

The Medicaid Drug Rebate Program requires biopharmaceutical manufacturers to enter into and have in effect a national rebate agreement with the Secretary of the DHHS as a condition for states to receive federal matching funds for the manufacturer’s outpatient therapeutic products furnished to Medicaid patients.

The ACA made several changes to the Medicaid Drug Rebate Program, including increasing biopharmaceutical manufacturers’ rebate liability by raising the minimum basic Medicaid rebate on most branded prescription drugs from 15.1% of average manufacturer price, or AMP, to 23.1% of AMP and adding a new rebate calculation for “line extensions” (i.e., new formulations, such as extended release formulations) of solid oral dosage forms of branded products, as well as potentially impacting their rebate liability by modifying the statutory definition of AMP.

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As another example, the 2021 Consolidated Appropriations Act, signed into law on December 27, 2020, incorporated extensive health care 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, or 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.

However, following several years of litigation in the federal courts, in June 2021, the U.S.

Supreme Court upheld the ACA when it dismissed a legal challenge to the ACA’s brought constitutionality.

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 was extended by the Consolidated Appropriations Act for 2023, and will remain in effect through 2032 unless additional Congressional action is.

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.

Under Part D, Medicare beneficiaries may enroll in prescription drug plans offered by private entities that provide coverage of outpatient prescription drugs.

Unlike Medicare Part A and B, Part D coverage is not standardized.

While all Medicare drug plans must give at least a standard level of coverage set by Medicare, Part D prescription drug plan sponsors are not required to pay for all covered Part D drugs, and each drug plan can develop its own drug formulary that identifies which drugs it will cover and at what tier or level.

However, Part D prescription drug formularies must include drugs within each therapeutic category and class of covered Part D drugs, though not necessarily all the drugs in each category or class.

Any formulary used by a Part D prescription drug plan must be developed and reviewed by a pharmacy and therapeutic committee.

Government payment for some of the costs of prescription drugs may increase demand for products for which we receive marketing approval.

However, any negotiated prices for our products covered by a Part D prescription drug plan likely will be lower than the prices we might otherwise obtain.

Moreover, while the MMA applies only to drug benefits for Medicare beneficiaries, private payors often follow Medicare coverage policy and payment limitations in setting their own payment rates.

Any reduction in payment that results from the MMA may result in a similar reduction in payments from non-governmental payors.

Under currently applicable U.S.

law, certain products that are not self-administered by the patient (including injectable drugs) may be eligible for coverage under Medicare through Medicare Part B.

Medicare Part B is administered by Medicare Administrative Contractors, which generally have the responsibility of making coverage decisions.

Subject to certain payment adjustments and limits, Medicare generally pays for a Part B-covered drug or biologic based on a percentage of manufacturer-reported Average Sales Price, which is regularly updated.

For a drug or biological product to receive federal reimbursement under the Medicaid or Medicare Part B programs or to be sold directly to U.S.

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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.

For example, the 2021 Consolidated Appropriations Act signed into law on December 27, 2020 incorporated extensive health care 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 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.

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 the DHHS, the Department of Labor and the Department of the Treasury.

More recently, in August 2022, President Biden signed into the law the Inflation Reduction Act of 2022, or the IRA.

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If a drug product is selected by CMS for negotiation, it is expected that the revenue generated from such drug will decrease.

CMS has begun to implement these new authorities and entered into the first set of agreements with pharmaceutical manufacturers to conduct price negotiations in October 2023.

However, the IRA’s impact on the pharmaceutical industry in the United States remains uncertain, in part because multiple large pharmaceutical companies and other stakeholders (e.g., the U.S.

Chamber of Commerce) have initiated federal lawsuits against CMS arguing the program is unconstitutional for a variety of reasons, among other complaints.

Those lawsuits are currently ongoing.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control drug and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

For example, in recent years, several states have formed prescription drug affordability boards, or PDABs.

Much like the IRA’s drug price negotiation program, these PDABs have attempted to implement upper payment limits, or UPLs, on drugs sold in their respective states in both public and commercial health plans.

For example, in August 2023, Colorado’s PDAB announced a list of five prescription drugs that would undergo an affordability review.

The effects of these efforts remain uncertain pending the outcomes of several federal lawsuits challenging state authority to regulate prescription drug payment limits.

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.

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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.

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.

For example, the EU 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.

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.

Other member states allow companies to fix their own drug prices but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions.

There can be no assurance that any country that has price controls or reimbursement limitations for drug and biological 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 be priced significantly lower.

Historically, products launched in the EU 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.

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.

In Europe, for example, a clinical trial application, or CTA, must be submitted to the competent national health authority and to independent ethics committees in each country in which a company plans to conduct clinical trials.

Once the CTA is approved in accordance with a country’s requirements, clinical trials may proceed in that country.

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.

Similar to the United States, the various phases of non-clinical and clinical research that takes place in other countries are subject to significant regulatory controls.

For example, the EU’s Clinical Trials Regulation, which took effect in January 2022, was enacted to simplify and streamline the approval of clinical trials in the region.

The main characteristics of the regulation include:

a streamlined application procedure via a single entry point, the “EU portal” or Clinical Trial Information System;

a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;

and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts.

Part I, which contains scientific and medicinal product documentation, is assessed by the competent authorities of all EU member states in which an application for authorization of a clinical trial has been submitted.

Part II, which contains the national and patient-level documentation, will be assessed individually by each such 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.

Medicines used in clinical trials must be manufactured in accordance with applicable cGMP requirements.

Other national and EU-wide regulatory requirements may also apply.

Currently, the extent to which clinical trials will be

governed by the Clinical Trials Regulation will depend on when the clinical trial is initiated or on the duration of an ongoing trial.

Currently, the extent to which clinical trials will be governed by the Clinical Trials Regulation will depend on when the clinical trial is initiated or on the duration of an ongoing trial.

As of January 2023, all new clinical trials must comply with the Clinical Trials Regulation.

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The way in which a medicinal product can be approved in the EU depends on the nature of the medicinal product.

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.

The centralized procedure is compulsory for human drugs that are:

(i) derived from biotechnology processes, such as genetic engineering, (ii) contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative diseases, autoimmune and other immune dysfunctions and viral diseases, (iii) officially designated as “orphan drugs” and (iv) advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines.

The centralized procedure may at the request of the applicant also be used for human drugs which do not fall within the above mentioned categories if (a) the human drug contains a new active substance which was not authorized in the European Community before May 20, 2004;

or (b) the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation or that the granting of authorization in the centralized procedure is in the interests of patients or animal health at the European Community level.

Under the centralized procedure in the European Union, the maximum timeframe for the evaluation of a marketing authorization application by the EMA is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the Committee for Medicinal Products for Human Use, or CHMP), with adoption of the actual marketing authorization by the European Commission thereafter.

The centralized procedure results in a single marketing authorization granted by the European Commission that is valid across the EU, as well as in Iceland, Liechtenstein and Norway, or the European Economic Area.

The centralized procedure is compulsory for human medicines that are:

(i) derived from biotechnology processes, such as genetic engineering, (ii) contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative diseases, autoimmune and other immune dysfunctions and viral diseases, (iii) officially designated as orphan medicinal product and (iv) advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines.

The centralized procedure may at the request of the applicant also be used for human medicines which do not fall within the above mentioned categories if the medicinal product contains a new active substance which has not been previously authorized in the European Economic

Area, or the EEA, the product constitutes a significant therapeutic, scientific or technical innovation, or where the granting of authorization in the centralized procedure is in the interests of public health in the EEA.

Under the centralized procedure in the EU, the maximum timeframe for the evaluation of a marketing authorization application by the EMA is 210 days (excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the Committee for Medicinal Products for Human Use, or CHMP, with adoption of the actual marketing authorization by the European Commission thereafter.

Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest from the point of view of therapeutic innovation, defined by three cumulative criteria:

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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 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.

Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one EU country of a medicinal product that has not yet been authorized in any EU country and that does 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 EU member state which is used as reference in order to obtain marketing authorizations in other EU member states.

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.

In the MRP process, 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 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.

In such case, the reference member state shall update its existing assessment report about the drug in 90 days.

After the assessment is completed, copies of the report are sent to all member states, together with the approved summary of product characteristics, labeling and package leaflet.

After the reference state completes its medicinal product assessment, copies of the report are sent to all member states, together with the approved summary of product characteristics, labeling and package leaflet.

The concerned member states then have 90 days to recognize the decision of the reference member state and the summary of product characteristics, labeling and package leaflet.

National marketing authorizations shall be granted within 30 days after acknowledgement of the agreement.

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.

Should any EU 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.

Within a timeframe of 60 days, member states shall, within the coordination group, make all efforts to reach a consensus.

If this fails, the procedure is submitted to an EMA scientific committee for arbitration.

The opinion of this EMA Committee is then forwarded to the Commission, for the start of the decision-making process.

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.

The opinion of this EMA Committee is then forwarded to the European Commission, for the start of the decision-making process.

As in the centralized procedure, this process entails consulting various European Commission Directorates General and the EU member states Standing Committee on Human Medicinal Products.

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 10-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.

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 EU are similar in principle to those in the United States.

Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as orphan if (1) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;

(2) either (a) such condition affects no more than five in 10,000 persons in the European Union when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the European Union to justify investment;

and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the European Union, or if such a method exists, the product will be of significant benefit to those affected by the condition, as defined in Regulation (EC) 847/2000.

(2) either (a) such condition affects no more than five in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify investment;

and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product will be of significant benefit to those

affected by the condition, as defined in Regulation (EC) 847/2000.

Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing authorization, entitled to ten years of market exclusivity for the approved therapeutic indication.

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Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The 10-year market exclusivity for orphan products in the European Union may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.

The 10-year market exclusivity for orphan products in the EU may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.

Additionally, marketing authorization may be granted to a similar product for the same indication at any time if:

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We have obtained Orphan Medicinal Product Designations from the EMA for GPS in AML, MPM and MM.

For other countries outside of the United States and the European Union, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

For other countries outside of the United States and the EU, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

In all cases, again, the clinical trials are conducted in accordance with GCP and the other applicable regulatory requirements.

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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 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 Act.

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 Act.

In addition to the IRA’s drug price negotiation provisions summarized above, President Biden’s Executive Order 14087, issued in October 2022, called for the CMS Innovation Center to prepare and submit a report to the White House on potential payment and delivery modes that would complement the IRA, lower drug costs, and promote access to innovative drugs.

In February 2023, CMS published its report which described three potential models focusing on affordability, accessibility and feasibility of implementation for further testing by the CMS Innovation Center.

As of January 2024 , the CMS Innovation Center continues to test the proposed models and develop implementation plans.

In the EU, many member states have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage health care expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the EU.

The downward pressure on health care costs in general, particularly prescription products, has become intense.

As a result, increasingly high barriers are being erected to the entry of new medicinal products.

Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained.

Reference pricing used by various EU member states, and parallel trade, i.e., arbitrage between low-priced and high-priced member states, can further reduce prices.

There can be no assurance that any country that has price controls or reimbursement limitations for medicinal products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries.

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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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business