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Item 1. Business

2025-03-20 compared with 2024-03-14 · 332 added, 316 removed, 555 unchanged (54% of the section changed)

We are a late-stage development biopharmaceutical company, with an ongoing registration directed trial, committed to advancing new medicines for patients battling cancer.

Our pipeline is focused on novel anticancer agents that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, particularly RAF/MEK inhibition and FAK inhibition.

Our most advanced product candidates, avutometinib and defactinib, are being investigated in both preclinical and clinical studies for the treatment of various solid tumors, including, but not limited to low-grade serous ovarian cancer (“LGSOC”), non-small cell lung cancer (“NSCLC”), pancreatic cancer, colorectal cancer (“CRC”), and melanoma.

We believe that avutometinib may be beneficial as a therapeutic, as a single agent or when used together in combination with defactinib, other agents, other pathway inhibitors, or other current and emerging standard of care treatments in cancers that do not adequately respond to currently available therapies.

Avutometinib is an orally available first-in-class unique small molecule RAF/MEK clamp that inhibits the ras sarcoma (“RAS”)/RAF/MEK, ERK mitogen activated pathway kinase (“MAPK”) pathway which is involved in cell proliferation, migration, transformation, and survival of tumor cells.

In contrast to other MEK-only inhibitors, avutometinib is a dual RAF/MEK clamp that blocks MEK kinase activity and induces th e fo rmation of dominant negative RAF-MEK complexes preventing phosphorylation of MEK by A-Raf proto-oncogene, serine/threonine kinase (“ARAF”), B-Raf proto-oncogene serine/threonine kinase (“BRAF”) and C-raf proto-oncogene serine/threonine kinase (“CRAF”).

MEK-only inhibitors (e.g.

trametinib) may have limited efficacy because they induce MEK phosphorylation (“pMEK”) by relieving extracellular-signal-regulated-kinase (“ERK”)-dependent feed back inhibition of RAF.

By inhibiting RAF-mediated phosphorylation of MEK, avutometinib has the advantage of not inducing pMEK.

This unique mechanism of avutometinib enables it to inhibit ERK signaling more effectively and may confer enhanced therapeutic activity against MAPK pathway-driven cancers.

We use the term “RAMP” to refer to our RAF and MEK Program.

Avutometinib has been shown to inhibit MAPK pathway signaling and proliferation of tumor cell lines harboring MAPK pathway alterations including Kirsten rat sarcoma viral oncogene homolog (“KRAS”), neuroblastoma rat sarcoma viral oncogene homolog (“NRAS”), and BRAF mutations, among others.

Avutometinib has demonstrated strong antitumor activity as monotherapy and in combination with (i) agents targeting parallel pathways (e.g.

inhibitors of FAK, CDK4/6 and mTOR), (ii) agents targeting other nodes in the MAPK pathway (e.g.

anti-EGFR, SOS1, KRAS G12C, and KRAS G12D inhibitors), (iii) chemotherapy, and (iv) anti-PD-1.

We are a late-stage development biopharmaceutical company committed to the development and commercialization of new medicines to improve the lives of patients diagnosed with ras sarcoma (“RAS”)/ mitogen activated pathway kinase (“MAPK”) pathway-driven cancers.

Our pipeline is focused on novel small molecule drugs that inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including RAF/MEK inhibition, FAK inhibition and KRAS G12D inhibition.

Our most advanced product candidates, avutometinib and defactinib, are being investigated in both preclinical and clinical studies for the treatment of various solid tumors, including, but not limited to LGSOC, non-small cell lung cancer (“NSCLC”) and pancreatic cancer.

We believe that avutometinib may be beneficial as a therapeutic, both as a single agent or when used together in combination with defactinib, other agents, other pathway inhibitors, or other current and emerging standard of care treatments in cancers that do not adequately respond to currently available therapies.

Avutometinib is an oral RAF/MEK clamp that inhibits MEK1/2 kinase activities and induces inactive complexes of MEK with A-Raf proto-oncogene, serine/threonine kinase (“ARAF”), B-Raf proto-oncogene serine/threonine kinase (“BRAF”) and C-raf proto-oncogene serine/threonine kinase (“CRAF”) , potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition.

In contrast to currently available MEK-only inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK.

We believe that this unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the response achieved with the MEK-only inhibitors.

Defactinib is an oral, selective inhibitor of FAK and proline-rich tyrosine kinase (“PYK2”), the two members of the focal adhesion kinase family of non-receptor protein tyrosine kinases.

FAK and PYK2 integrate signals from integrin and growth factor receptors to regulate cell proliferation, survival, migration, and invasion.

FAK activation has been shown to mediate resistance to multiple anti-cancer agents, including RAF and MEK inhibitors.

The combination of avutometinib and defactinib is clinically active in patients with KRAS mutant (“KRAS mt”) and KRAS wt recurrent LGSOC and has received breakthrough designation from the FDA for the treatment of all patients with recurrent LGSOC, regardless of KRAS status, after one or more prior lines of therapy including platinum-based chemotherapy.

Avutometinib, alone or in combination with defactinib, has received orphan drug designation for the treatment of all patients with LGSOC in the United States.

Defactinib is an oral small molecule inhibitor of FAK and proline-rich tyrosine kinase (“PYK2”) that is currently being evaluated as a potential combination therapy for various solid tumors.

FAK and PYK2 are members of the same family of nonreceptor protein tyrosine kinases that integrate signals from integrin and growth factor receptors to regulate cell proliferation, survival, migration, and invasion.

Defactinib targets malignant cells both directly and through modulation of the tumor microenvironment.

Preclinical research by our scientists and collaborators at world-renowned research institutions has indicated that FAK inhibition delays tumor progression in cancer models, which was associated with reduced stromal density and immunosuppressive cell populations.

Furthermore, it has been shown that activation of FAK is a putative adaptive resistance mechanism to MAPK pathway inhibition, supporting the clinical evaluation of avutometinib in combination with defactinib for treatment of cancers harboring MAPK pathway alterations.

Defactinib has received orphan drug designation in ovarian cancer in the United States, the European Union, and Australia.

The combination of avutometinib and defactinib has been found to be clinically active in patients with KRAS mutant and KRAS wild-type recurrent LGSOC and has received breakthrough designation from the U.S.

Food & Drug Administration (the “FDA”) for the treatment of all patients with recurrent LGSOC, regardless of KRAS status, after one or more prior lines of therapy including platinum-based chemotherapy.

In the fourth quarter of 2020, we commenced a registration-directed trial investigating avutometinib as a monotherapy and in combination with defactinib for the treatment of patients with recurrent LGSOC entitled RAMP 201 study.

The RAMP 201 study is an adaptive two-part multicenter, parallel cohort, randomized, open label trial to evaluate the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent LGSOC.

The combination of avutometinib and defactinib has been declared the go-forward treatment regimen based on a higher rate of confirmed objective responses in a planned interim analysis with prespecified criteria, acknowledging the demonstrated contribution of defactinib.

An abstract highlighting updated interim results from Part A (selection phase) of our RAMP 201 study was presented in a Poster Discussion Session at the American Society of Clinical Oncology (“ASCO”) annual meeting that took place on June 2-6, 2023 in Chicago, Illinois (data cutoff April 6, 2023).

In this data cut from Part A of the RAMP 201 study, 31 patients with recurrent LGSOC were treated with the combination of avutometinib and defactinib, of which 29 were evaluable for efficacy with a minimum follow-up of 12 months and 13 patients remained on study treatment.

Overall, patients were heavily pretreated with a median of 4 prior systemic regimens (up to 11), including prior platinum-based chemotherapy, endocrine therapy and bevacizumab in most patients and prior MEK inhibitor therapy in about 13% of patients.

Confirmed objective response rates (“ORR”) by blinded independent central review of 45% (13/29;

26%-64%) were observed. Tumor shrinkage was observed in the majority of patients, 86% (25/29).

Further, three out of four patients who received prior MEK inhibitors responded to the combination.

Among the patients with KRAS mutant LGSOC, the ORR was 60% (9/15) in the combination arm.

Among the patients with KRAS wild-type LGSOC, the ORR was 29% (4/14) in the combination arm.

The median time to response was 5.5 months (range 1.6-14.7 months).

The median duration of response and median progression free survival have not been reached.

We plan to present full data from Parts A and Part B of the RAMP 201 study at a scientific medical conference in the first half of 2024.

In addition, the FDA granted orphan drug designation to avutometinib, in combination with defactinib, for the treatment of pancreatic cancer.

In the fourth quarter of 2020, we commenced a registration-directed trial investigating avutometinib in combination with defactinib for the treatment of patients with recurrent LGSOC entitled RAMP 201 study.

We use the term “RAMP” to refer to our RAF and MEK Program.

The RAMP 201 study is an adaptive two-part multicenter, parallel cohort, randomized, open label trial evaluating the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent LGSOC.

In October 2024, we announced updated results from the RAMP 201 study with a data cutoff of June 30, 2024, that was presented at the International Gynecologic Cancer Society (“IGCS”) 2024 Annual Meeting.

The primary analysis of the RAMP 201 study showed a confirmed overall response rate (“ORR”) by blinded independent central review of 31% (34/109;

23-41) in all evaluable patients with measurable disease with approximately 12 months of follow up.

Among patients with KRAS mt LGSOC, the confirmed ORR was 44% (25/57;

31-58) and for patients with KRAS wt LGSOC the confirmed ORR was 17% (9/52;

The median duration of response was 31.1 months (95% CI:

14.8-31.1) in all evaluable patients, with 31.1 months (95% CI:

14.8-31.1) in the KRAS mt population and 9.2 months (95% CI:

5.5-NEi) in the KRAS wt population.

The median progression-free survival was 12.9 months (95% CI:

10.9-20.2) in all evaluable patients, with 22 months (95% CI:

11.1-36.6) in the KRAS mt population and 12.8 months (95% CI:

7.4-18.4) in the KRAS wt population.

The disease control rate at six or more months was 61% in the total evaluable population, 70% in KRAS mt population and 50% in KRAS wt population.

The updated data continues to demonstrate avutometinib in combination with defactinib is generally well-tolerated, with a 10% discontinuation rate due to adverse events and no new safety signals were identified.

The most common treatment-related adverse events (all grades, grade ≥3) for the combination were nausea (67.0%, 2.6%), diarrhea (58.3%, 7.8%), and increased blood creatine phosphokinase levels (60.0%, 24.3%).

In December 2023, we announced initiation of a confirmatory Phase 3 trial to evaluate the combination of avutometinib and defactinib for the treatment of patients with recurrent LGSOC entitled RAMP 301.

RAMP 301 is a randomized global confirmatory trial, which will evaluate the efficacy and safety of avutometinib and defactinib versus standard chemotherapy or hormonal therapy in patients with recurrent LGSOC.

RAMP 301 is the confirmatory study required by the FDA for the combination of avutometinib and defactinib to potentially receive full approval for the treatment of recurrent LGSOC.

We intend to submit an accelerated approval new drug application (“NDA”) with the FDA in the first half of 2024 for the combination of avutometinib and defactinib based on mature data from the RAMP 201 study, together with the results of the investigator-initiated Phase 1 FRAME trial.

We also intend to initiate discussions with global regulatory authorities, including those in Europe and Japan with the objective of ultimately seeking approval for the combination in additional regions.

RAMP 301 is a randomized global confirmatory trial, which is evaluating the efficacy and safety of avutometinib and defactinib versus standard of care chemotherapy or hormonal therapy in patients with recurrent LGSOC.

RAMP 301 will serve as the confirmatory study required by the FDA for the combination of avutometinib and defactinib for the initial indication of recurrent KRAS mt LGSOC to potentially receive full approval and has the potential to support an expanded indication regardless of KRAS mutation status.

RAMP 301 is currently open and enrolling patients.

On October 31, 2024, we completed our rolling NDA submission to the FDA for avutometinib and defactinib for treatment of adults with recurrent KRAS mt LGSOC who received at least one prior systemic therapy.

On December 30, 2024, the FDA accepted for review our NDA under the accelerated approval pathway and granted priority review for avutometinib and defactinib for treatment of adult patients with recurrent KRAS mt LGSOC who received at least one prior systemic therapy and designated June 30, 2025 as the Prescription Drug User Fee Act (“PDUFA”) action date.

In addition, at the time the FDA accepted our NDA for review, the FDA stated that it is not planning to hold an advisory committee meeting to discuss the application.

The NDA was based on the positive, mature safety and efficacy data from the RAMP 201 trial as presented at the IGCS 2024 Annual Meeting.

The NDA also includes supportive data from the FRAME Phase 1 trial, the first study conducted with the combination therapy in recurrent LGSOC.

We intend to initiate discussions with other global regulatory authorities, including those in Europe and Japan with the objective of ultimately seeking approval for the combination in additional regions.

We estimate the total annual incident addressable market opportunity in the United States for the combination of avutometinib and defactinib to be approximately $300 million for KRAS mt.

We estimate the total prevalent addressable market opportunity to be approximately $1.7 billion for KRAS mt.

Our estimates of the patient population, pricing and revenue opportunities for our product candidates, including for KRAS mt patients with recurrent LGSOC, are based on several internal and third-party estimates and assumptions, including, without

limitation, internal forecasts, the median duration of treatment from initial interim clinical data and the assumed prices at which we can commercialize our product candidates.

In September 2021, we entered into a clinical collaboration agreement with Amgen, Inc.

(“Amgen”) to evaluate the combination of avutometinib with Amgen’s KRAS G12C inhibitor LUMAKRAS® (sotorasib) in a Phase 1/2 study entitled RAMP 203.

The Phase 1/2 trial will evaluate the safety, tolerability and efficacy of avutometinib in combination with LUMAKRAS in patients with KRAS G12C NSCLC who have not been previously treated with a KRAS G12C inhibitor, as well as in patients who have progressed on a KRAS G12C inhibitor.

The trial will build on preclinical data showing a deeper blockade of MAPK pathway signaling resulting in enhanced anti-tumor efficacy with the combination of LUMAKRAS (KRAS G12C inhibition) and avutometinib (RAF/MEK inhibition) relative to either agent alone.

The RAMP 203 study has progressed to the recommended Phase 2 dose of 4 mg avutometinib in combination with 960 mg of LUMAKRAS and to initiation of Part B dose expansion in patients who are G12C inhibitor treatment naïve and in patients who experienced disease progression on prior G12C monotherapy.

In October 2023, we announced initial safety and pharmacokinetics results, as well as preliminary efficacy results, from the RAMP 203 study which were presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on October 11-15, 2023 in Boston, Massachusetts.

The Phase 1/2 trial began evaluating the safety, tolerability and efficacy of avutometinib in combination with LUMAKRAS in patients with KRAS G12C NSCLC who have not been previously treated with a KRAS G12C inhibitor, as well as in patients who have progressed on a KRAS G12C inhibitor.

The trial built upon initial preclinical data showing enhanced anti-tumor efficacy with the combination of LUMAKRAS (KRAS G12C inhibition) and avutometinib (RAF/MEK inhibition) relative to either agent alone.

These preliminary results showed a confirmed ORR of 25% (3/12) across efficacy-evaluable patients and seen in both KRAS G12C inhibitor resistant (14.3%;

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2/5) patients.

In January 2024, the

FDA granted fast track designation for combination of avutometinib and LUMAKRAS for the treatment of patients with KRAS G12C-mutant metastatic NSCLC who have received at least one prior systemic therapy and have not been previously treated with a KRAS G12C inhibitor.

Based on stronger tumor regressions in KRAS G12C-mutant NSCLC preclinical models when a FAK inhibitor is added along with G12C inhibitor and avutometinib, we plan to add defactinib to the RAMP 203 study.

We plan to provide data updates from the RAMP 203 study in the middle of 2024.

In November 2021, we entered into a clinical collaboration agreement with Mirati Therapeutics, Inc.

(“Mirati”) to evaluate the combination of avutometinib with Mirati’s KRAS G12C inhibitor KRAZATI ® (adagrasib) in a Phase 1/2 trial entitled RAMP 204.

The Phase 1/2 trial will evaluate the safety, tolerability and efficacy of avutometinib in combination with KRAZATI in patients with KRAS G12C NSCLC who have progressed on a KRAS G12C inhibitor.

The trial will build on preclinical data showing a deeper blockade of MAPK pathway signaling resulting in enhanced anti-tumor efficacy with the combination of KRAZATI (KRAS G12C inhibition) and avutometinib (RAF/MEK inhibition) relative to either agent alone.

The RAMP 204 study is open and enrolling.

Dose escalation is ongoing.

We plan to provide data updates from RAMP 204 in the middle of 2024.

In May 2022, we received the first “Therapeutic Accelerator Award” from the Pancreatic Cancer Network (“PanCAN”) for up to $3.8 million.

The grant is expected to support a Phase 1b/2 clinical trial of avutometinib in combination with defactinib entitled RAMP 205.

This Phase 1b/2 trial is evaluating the safety, tolerability and efficacy of avutometinib and defactinib in combination with GEMZAR ® (gemcitabine) and ABRAXANE ® (Nab-paclitaxel) in patients with previously untreated metastatic adenocarcinoma of the pancreas.

The RAMP 205 trial is evaluating whether combining avutometinib (to target mutant KRAS which is mutated in more than 90% of pancreatic adenocarcinomas) and defactinib (to reduce stromal density and adaptive resistance to avutometinib) to the standard GEMZAR/ABRAXANE regimen improves outcomes for patients with this type of pancreatic cancer.

In January 2024, the FDA granted fast track designation for combination of avutometinib and LUMAKRAS for the treatment of patients with KRAS G12C-mutant metastatic NSCLC who have received at least one prior systemic therapy and have not been previously treated with a KRAS G12C inhibitor.

The RAMP 203 study has progressed to the recommended Phase 2 dose of 4 mg avutometinib in combination with 960 mg of LUMAKRAS for the doublet of avutometinib and LUMAKRAS.

RAMP 203 is currently enrolling patients who have experienced disease progression on a KRAS G12C inhibitor in the dose expansion phase (Part B) and is on track to complete by end of quarter 1 of 2025.

Enrollment of patients without prior G12C treatment to the initial doublet dose expansion phase has completed.

Based on emerging data demonstrating improved tumor regressions in KRAS G12C-mutant NSCLC preclinical models when a FAK inhibitor is combined with a G12C inhibitor and avutometinib, defactinib was added to the RAMP 203 study in new triplet cohorts in 2024.

In December 2024, we announced three patients whose cancer previously progressed on a G12C inhibitor have been treated with the triplet combination of sotorasib 960 mg administered daily on a continuous schedule and avutometinib 3.2 mg twice-weekly plus defactinib 200 mg twice-daily.

Avutometinib and defactinib are administered on a three out of four weeks schedule. There were no dose limiting toxicities (“DLTs”) observed in the first triplet combination cohort.

We expect to present an interim update of both the doublet and triplet data at a medical meeting in the second half of 2025.

In May 2022, we received the first “Therapeutic Accelerator Award” from Pancreatic Cancer Network (“PanCAN”) for up to $3.8 million.

The grant is supporting a Phase 1b/2 clinical trial of avutometinib in combination with defactinib entitled RAMP 205.

RAMP 205 is evaluating the safety, tolerability and efficacy of avutometinib and defactinib in combination with GEMZAR ® (gemcitabine) and ABRAXANE ® (Nab-paclitaxel) in patients with previously untreated metastatic adenocarcinoma of the pancreas.

In August 2022, PanCAN agreed to provide us with an additional $0.5 million for the collection and translational analysis of patient samples.

The RAMP 205 trial is open and enrolling.

Dose escalation is ongoing.

We plan to provide initial safety and efficacy results from RAMP 205 in the first half of 2024.

Furthermore, avutometinib and defactinib are currently being investigated in combination with immunotherapeutic and other agents through investigator sponsored trials (“ISTs”) for the treatment of various solid tumors, including, but not limited to, CRC, gynecological cancer with MAPK pathway alterations, breast cancer, thyroid cancer and melanoma .

In August 2023, we entered into a collaboration and option agreement (the “GenFleet Agreement”) with GenFleet pursuant to which GenFleet granted us options to obtain exclusive development and commercialization rights worldwide outside of mainland China, Hong Kong, Macau, and Taiwan (the “GenFleet Territory”) for up to three oncology programs targeting RAS pathway driven cancers (the “GenFleet Options”) .

Combination dose evaluation is ongoing.

As of a data cut of May 14, 2024, we reported patients receiving the combination of avutometinib and defactinib with gemcitabine and Nab-paclitaxel in dose level 1 cohort achieved a confirmed ORR of 83% (5/6), one dose-limiting toxicity was observed in the dose level 1 cohort, and the dose level was subsequently cleared after additional patients were enrolled.

The initial interim results were presented at the American Society of Clinical Oncology (“ASCO”) Annual Meeting in June 2024.

A dose level “0” has been added to the RAMP 205 study protocol that evaluates 3.2 mg of avutometinib twice a week, 200 mg of defactinib twice a day for three weeks out of every four weeks with 800 mg/m 2 of gemcitabine and 100 mg/m 2 of Nab-paclitaxel on a schedule of day 1, day 8, and day 15.

All dose levels have been expanded to 12 patients each, including six additional patients recently enrolled to dose devel 1, where five out of six patients reported an ORR at the ASCO 2024 Annual Meeting.

In dose level 1, of the six additional patients, five remain on therapy and continue to be monitored for response given the initial length of time to response.

59 of 60 patients have been treated and enrollment is on track to be completed in quarter 1 of 2025.

Based on the initial safety

and efficacy data from these cohorts, dose level 1 or 0 is anticipated to be chosen for expansion.

Adverse events across all dose cohorts remained generally consistent with the previously announced safety and tolerability profile, and no new safety signals have emerged.

We expect to present data at a medical meeting in mid-year of 2025 and we expect to choose a recommended Phase 2 dose for trial expansion in first half of 2025.

Furthermore, avutometinib and defactinib are currently being investigated in combination with immunotherapeutic and other agents through investigator sponsored trials (“ISTs”) for the treatment of various solid tumors, including, but not limited to, colorectal cancer (“CRC”), gynecological cancer with MAPK pathway alterations, breast cancer, thyroid cancer and melanoma .

In August 2023, we entered into a collaboration and option agreement (the “GenFleet Agreement”) with GenFleet pursuant to which GenFleet granted us options to obtain exclusive development and commercialization rights worldwide outside of mainland China, Hong Kong, Macau, and Taiwan (the “Verastem Territory”) for up to three oncology programs targeting RAS pathway driven cancers (the “GenFleet Options”) .

We may exercise our GenFleet Options on a program-by-program basis.

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This synergistic collaboration includes our experience and established network of collaborators, including scientific and clinical experts in RAS biology and RAS pathway-driven cancers and GenFleet’s accomplishments with its KRAS G12C inhibitor program.

In December 2023, we announced the selection of an oral KRAS G12D inhibitor with a potential best-in-class profile as the lead program from our collaboration with GenFleet.

The lead oncology discovery program is an orally bioavailable, potent and selective small molecule KRAS G12D inhibitor entitled GFH375/VS-7375.

GenFleet plans to file an investigational new drug application (“IND”) in China in the first half of 2024 and initiate the Phase 1 clinical trial of GFH375/VS-7375 in the second half of 2024.

We are focused on the development and commercialization of anticancer kinase inhibitors for optimized efficacy and safety – primarily as orally available drugs and drug candidates that are designed to treat various forms of cancer.

In December 2023, we announced the selection of an oral and selective KRAS G12D (ON/OFF) inhibitor entitled VS-7375 (known as GFH375 in China) with a potential best-in-class profile as the lead program from our collaboration with GenFleet.

An investigational new drug (“IND”) application by GenFleet in China for VS-7375 was cleared in June 2024.

In July 2024, GenFleet began dosing several patients in a Phase 1/2 trial in China that is evaluating VS-7375 in patients with KRAS G12D-mutated advanced solid tumors.

The Phase 1/2 study is being conducted in approximately 20 hospitals in China.

The Phase 1 study will be used to determine the recommended Phase 2 dose, and the Phase 2 study will further evaluate the efficacy and safety of VS-7375 in patients with advanced solid tumors, such as pancreatic ductal adenocarcinoma, CRC, and NSCLC.

On January 14, 2025, we announced the early exercise of the GenFleet Option with respect to VS-7375.

As previously announced by GenFleet, 26 patients have been treated with VS-7375 in a Phase 1 dose-escalation study being conducted in China.

Both confirmed and unconfirmed partial responses have been observed, including patients with metastatic pancreatic cancer and advanced NSCLC.

In addition, six dose cohorts have been cleared with no DLTs observed.

In the study, oral dosing of VS-7375 has achieved plasma levels in patients that correlate with efficacious exposures that induced deep tumor regressions across all preclinical KRAS G12D tumor models as presented in collaboration with GenFleet at the American Association for Cancer Research (“AACR”) 2024 annual meeting.

We filed an IND application in the United States for VS-7375 during the first quarter of 2025 and expect to initiate a Phase 1/2a study in middle of 2025 in the United States.

GenFleet expects to share updated preclinical and clinical data from the Phase 1 study of VS-7375 in China at upcoming medical meetings in the first half of 2025.

We are focused on the development and commercialization of new medicines to improve the lives of patients diagnosed with RAS/MAPK pathway-driven cancers.

Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells.

The American Cancer Society estimated that in the United States in 2023, over 1.9 million new cases of cancer were diagnosed and more than 600,000 people died from the disease.

The American Cancer Society estimates that in the United States in 2025, over 2.0 million new cases of cancer will be diagnosed, and more than 618,000 people will die from the disease.

RAS is the most frequently mutated oncogene in human cancers.

Approximately 30% of all human cancers are driven by mutations of the RAS family of genes.

These cancers are typically highly aggressive and recurrent, sending signaling commands through the RAS pathway.

Current treatments for cancer include surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, cell therapy, and targeted therapy.

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For example, the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (“NCI”;

“SEER”) reported that in 2023 there were approximately 19,710 new cases of ovarian cancer, 238,340 new cases of lung cancer, 64,050 new cases of pancreatic cancer, and 153,020 new cases of colorectal cancer in the United States.

“SEER”) reported that in 2024 there were approximately 19,680 new cases of ovarian cancer, 234,580 new cases of lung cancer, and 66,440 new cases of pancreatic cancer in the United States.

With the application of new technologies and key discoveries, we believe that we are now entering an era of cancer research characterized by a more sophisticated understanding of the biology of cancer.

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Challenges associated with identifying new treatment options for these types of cancers include resistance to single agents, identifying tolerable combination regimens with MEK inhibitors, and new KRAS inhibitors in development addressing only a minority of all KRAS mutated cancers.

Our focus is targeting cancer cells both directly and indirectly by way of the tumor microenvironment.

Low Grade Serous Ovarian Cancer (“LGSOC”)

LGSOC is a slow-growing cancer with a high mortality rate.

It is estimated that approximately 70% of LGSOC tumors are driven by mutations in MAPK pathway-associated genes, with approximately 30% of patients harboring KRAS mutations and an additional approximately 40% of patients harboring mutations in other MAPK pathway associated genes.

It is estimated that approximately 70% of LGSOC tumors are driven by mutations in MAPK pathway-associated genes, with approximately 30% of patients harboring KRAS mutations with other mutations including NRAS, BRAF, NF1, and other RAS pathway-associated gene mutations.

There are an estimated 6,000 patients in the United States and 80,000 worldwide living with this disease.

Approximately half of those diagnosed are in their 20s-40s.

LGSOC has a median survival rate of 10 years, with 85% of patients experiencing recurrence and enduring severe pain and complications as the disease progresses.

Despite low response rates, chemotherapy continues to be the standard of care for this disease.

research has focused on high grade serous ovarian cancer (“HGSOC”).

LGSOC can be diagnosed early in adulthood impacting health, fertility, long-term quality of life, and survival.

LGSOC has a median survival rate of 10 years from time of diagnosis, with over 80% of patients experiencing

recurrence and enduring severe pain and complications as the disease progresses.

Recurrent LGSOC that is not amenable to surgical management is currently treated with medicines listed on National Comprehensive Cancer Network or other clinical guidelines because no available therapies are currently FDA approved for the specific indication of recurrent LGSOC.

The current standard of care treatments offers poor to moderate response rates (6%-13%) and patients often cycle through multiple therapies.

Most prior research has focused on high grade serous ovarian cancer (“HGSOC”).

However, LGSOC is clinically, histologically and molecularly unique from HGSOC with limited treatments available.

Currently, avutometinib is being evaluated in combination with defactinib for the treatment of patients with recurrent LGSOC (i) in a Phase 2 registration directed study entitled RAMP 201, (ii) in a Phase 3 confirmatory trial entitled RAMP 301 and (iii) in an IST entitled FRAME.

Currently, avutometinib is being evaluated in combination with defactinib for the treatment of patients with recurrent LGSOC (i) in a global Phase 3 trial entitled RAMP 301 which is the confirmatory trial required by the FDA for the initial indication of recurrent KRAS mt LGSOC to potentially receive full approval and has the potential to support an expanded indication regardless of KRAS mutation status with enrollment open in the United States, Australia, Canada, Europe, United Kingdom, and Korea;

and (ii) in a Phase 2 registration directed trial in Japan entitled RAMP 201J.

Avutometinib is also being investigated in combination with defactinib in ISTs to assess efficacy in other gynecological cancers with MAPK pathway mutations (e.g.

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Non-Small Cell Lung Cancer (“NSCLC”)

Lung cancer is the leading cause of cancer-related death in the United States and worldwide.

Approximately 85% of lung cancers are NSCLC with the remaining 15% of lung cancers being small cell lung cancer.

Adenocarcinoma and squamous cell carcinoma are the most common subtypes of NSCLC, accounting for 50% and 30% of NSCLC cases, respectively, with the remaining NSCLC cases being large cell carcinomas, mixed or rare histologies.

In 2024, the NCI estimated that lung cancer was the leading cause of cancer-related death in the United States.

According to the American Cancer Society, approximately 80% to 85% of lung cancers are NSCLC and 10% to 15% of lung cancers are small cell lung cancer.

Adenocarcinoma is the most common subtype of NSCLC, accounting for approximately 40% of NSCLC cases, with the remaining NSCLC cases being squamous cell carcinoma, large cell carcinomas, mixed or rare histologies.

Adenocarcinomas most frequently have molecular alterations that can be targeted with oral therapies.

The most frequent molecular alterations are mutations in the KRAS gene (approximately 25% of adenocarcinomas) of which KRAS G12C is most common (approximately 13% of adenocarcinomas).

Several tyrosine kinase inhibitors are in development for patients with KRAS G12C NSCLC of which the KRAS G12C inhibitors LUMAKRAS (sotorasib) and KRAZATI (adagrasib) are currently approved.

LUMAKRAS and KRAZATI monotherapy have relatively low response rates and short times to progression and thus, number of agents are being combined with these G12C inhibitors including avutometinib in RAMP 203 and RAMP 204, respectively.

Currently, avutometinib is being evaluated (i) in combination with Amgen’s KRAS-G12C inhibitor LUMAKRAS in a Phase 1/2 study in patients with KRAS G12C mutant NSCLC entitled RAMP 203, and (ii) in combination with Mirati’s KRAZATI in patients with KRAS G12C mutant NSCLC in a Phase 1/2 trial entitled RAMP 204.

The most frequent molecular alterations are mutations in the KRAS gene (approximately 25%-30% of non-squamous NSCLC) of which KRAS G12C is most common (approximately 10-13% of non-squamous NSCLC) Several tyrosine kinase inhibitors are in development for patients with KRAS G12C NSCLC of which the KRAS G12C inhibitors LUMAKRAS (sotorasib) and KRAZATI (adagrasib) are currently FDA approved.

LUMAKRAS and KRAZATI monotherapy have relatively low response rates and short times to progression and thus, number of agents are being combined with these G12C inhibitors including LUMAKRAS in combination with avutometinib + defactinib in RAMP 203 study.

Currently, avutometinib is being evaluated (i) in combination with Amgen’s KRAS-G12C inhibitor LUMAKRAS +/- defactinib in a Phase 1/2 study in patients with KRAS G12C mutant NSCLC entitled RAMP 203, and (ii) in combination with everolimus (mTORi) in patients with KRAS G12C mutant NSCLC in an IST.

Pancreatic Cancer

In 2023, the NCI estimated that pancreatic cancer was the tenth most common cancer diagnosed in the United States and that the disease represented the third leading cause of cancer-related death in the country.

In 2024, the NCI estimated that pancreatic cancer was the tenth most common cancer diagnosed in the United States and that the disease represented the third leading cause of cancer-related death in the United States.

Pancreatic cancer often has a poor prognosis, even when diagnosed early.

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Activating mutations in KRAS represent a key initiating event in pancreatic cancer.

KRAS mutations occur in up to 95% of pancreatic cancer, with KRAS G12D, G12V and G12R occurring in approximately 37%, 28% and 13% of patients, respectively.

KRAS mutations occur in up to 95% of pancreatic cancer, with KRAS G12D, G12V and G12R occurring in approximately

37%, 28% and 13% of patients, respectively.

Furthermore, pancreatic cancer typically presents with high stromal density, comprised of fibroblasts and dense extracellular matrix, which is thought to limit the penetration of cytotoxic drugs and T cells into pancreatic tumors.

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Currently, avutometinib is being evaluated in combination with defactinib + gemcitabine/nab-paclitaxel for the treatment of patients with advanced pancreatic cancer in a Phase 1b/2 clinical trial entitled RAMP 205.

Colorectal Cancer (“CRC”)

CRC, also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine).

According to the American Cancer Society, one in 23 men and one in 26 women will be diagnosed with CRC in their lifetime.

CRC is the second leading cause of cancer death among people in the United States.

The NCI estimates that the number of new incidences of CRC was 36.6 per 100,000 men and women per year based on 2016-2020 cases and the five-year relative survival rate from 2013 to 2019 for patients with CRC was approximately 65%.

The individual likelihood of survival depends on how advanced the cancer is, whether all the cancer can be removed with surgery, and the person's overall health.

Treatments used for colorectal cancer may include some combination of surgery, radiation therapy, chemotherapy and targeted therapy.

Cancers that are confined within the wall of the colon may be curable with surgery, while cancer that has spread widely is usually not curable, with management being directed towards improving quality of life and symptoms.

KRAS mutations are present in approximately 45% of CRC and predict lack of response to anti-EGFR antibodies such as cetuximab.

Although clinical trials of the KRAS G12C inhibitors LUMAKRAS (sotorasib) and KRAZATI (adagrasib) in combination with anti-EGFR antibodies in KRAS G12C CRC have shown promising activity, KRAS G12C only occurs in 3% of CRCs.

Thus, novel therapies are needed for patients with CRC harboring other KRAS mutations including KRAS G12D and KRAS G12V which represent 13% and 9%, respectively.

It has been shown that simultaneous targeting of multiple nodes in the MAPK pathway may be necessary for deep and durable response, supporting the clinical evaluation of avutometinib in combination with anti-EGFR for patients with KRAS mutant CRC.

Currently, avutometinib in combination with the anti-EGFR antibody cetuximab is being evaluated for the treatment of patients with advanced KRAS mutant CRC in an IST.

In 2023, the NCI estimated melanoma cancer was diagnosed in approximately 97,610 patients or 21.0 cases per 100,000 people based on 2016-2020 cases.

The NCI estimates the five year survival rate from 2013-2019 was approximately 94% Melanoma is a type of skin cancer that develops in melanocytes.

Melanocytes are in the deep layer of the epidermis between the layer of basal cells.

Melanocytes make a pigment called melanin.

This gives skin its natural color.

The pigment helps to protect the body from ultraviolet light (UV radiation) from the sun.

Melanoma is most common at body sites that have received intense, intermittent sun/UV exposure.

Melanoma is dangerous and aggressive due to its ability to spread to other organs rapidly if it is not treated at an early stage.

About 30% of melanomas begin in existing moles, but the rest start in normal skin.

The five types of standard treatment for melanoma are surgery, chemotherapy, radiation therapy, immunotherapy and targeted therapy.

In patients with melanoma, mutations in the MAPK pathway occur mainly in BRAF (52%), NRAS (28%), and NF1 (14%) Although several selective BRAF inhibitors are FDA-approved alone or in combination with MEK inhibitors for melanomas with BRAF V600E/K, there is still a need for agents to improve response rate, duration of response, and tolerability.

Furthermore, there are no targeted therapy options for patients with BRAF V600E melanoma following progression on BRAF + MEK inhibitor combination and immune checkpoint inhibitors.

Currently, avutometinib plus defactinib, with or without the BRAF inhibitor encorafenib, is being evaluated for the treatment of patients with brain metastases from cutaneous melanoma in an IST.

With the combination of avutometinib and defactinib, we seek to utilize a multi-faceted approach to treat cancer by directly targeting the cancer cells, enhancing anti-tumor immunity, modulating the local tumor microenvironment, and overcoming mechanisms of adaptive resistance to MAPK pathway inhibition.

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Key elements of our strategy to achieve this goal are:

● Establishing avutometinib as the backbone of therapy for MAPK pathway-driven tumors.

● Assessing synergy of avutometinib with other agents in preclinical models to prioritize for clinical development.

● Obtain accelerated approval from the FDA for avutometinib plus defactinib in recurrent KRAS mt LGSOC and continue to advance the regulatory pathway in Japan and Europe.

On December 30, 2024, the FDA accepted for review our NDA under the accelerated approval pathway for avutometinib in combination with defactinib for treatment of patients with recurrent KRAS mt LGSOC with a PDUFA action date of June 30, 2025.

● Successfully build a commercial infrastructure in the United States for the potential launch of avutometinib plus defactinib in recurrent KRAS mt LGSOC in the U.S.

To further our position for a potential mid-2025 launch in the United States, we previously announced a strategic collaboration with IQVIA, Inc.

(“IQVIA”) intended to leverage IQVIA’s infrastructure and commercialization solutions to complement our launch strategy in recurrent KRAS mt LGSOC.

● Execute on the confirmatory component of the RAMP 301 trial required by the FDA for the combination of avutometinib and defactinib to potentially receive full approval for treatment of patients with recurrent KRAS mt LGSOC.

In addition, execute on the additional component of the RAMP 301 trial that has the potential to support an expanded indication for avutometinib and defactinib regardless of KRAS mutation status .

● Expanding the indications in which avutometinib may be used alone and in combination with other agents.

We have entered into clinical collaboration agreements with Amgen to evaluate avutometinib + defactinib in patients with KRAS G12C NSCLC in combination with Amgen’s KRAS G12C inhibitor LUMAKRAS (sotorasib) in our RAMP 203 study.

Further, avutometinib is being investigated in combination with defactinib + GEMZAR/ABRAXANE in patients with frontline pancreatic cancer in a trial entitled RAMP 205.

Additionally, ISTs and preclinical studies are in progress to prioritize additional cancer indications and approaches to expand the potential clinical development of our product candidates.

Avutometinib is being investigated in multiple ISTs including, but not limited to, in combination with the anti-EGFR antibody cetuximab in KRAS mutant CRC, in combination with abemacicilib and fulvestrant in breast cancer, in combination with everolimus (mTORi) in KRAS mt NSCLC, and in combination with defactinib to assess efficacy in other gynecological cancers with MAPK pathway mutations (e.g.

high-grade and mucinous ovarian cancers, endometrial and cervical cancers).

● Assessing synergy of avutometinib and defactinib with other agents in preclinical models to prioritize for clinical development.

It is becoming well established that blockade of multiple nodes in the MAPK pathway or co-targeting the MAPK pathway and relevant parallel pathways or resistance pathways may be necessary for maximal depth and duration of anti-tumor response.

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KRAS G12C, KRAS G12D, anti-EGFR and SOS1 inhibitors), (ii) agents targeting parallel pathways that may mediate resistance to MAPK pathway inhibition (e.g.

FAK, mTOR and CDK4/6 inhibitors), (iii) chemotherapy, and (iv) anti-PD-1.

FAK, mTOR and CDK4/6 inhibitors), (iii)

chemotherapy, and (iv) anti-PD-1.

These studies may lead to discussions with other companies and clinical investigators with the objective of assessing high priority combinations in the clinic.

● Continuing to develop and explore avutometinib in combination with defactinib and execute on the registration-directed RAMP 201 study.

The combination of avutometinib with defactinib has been selected vs.

avutometinib monotherapy as the go-forward treatment for patients with recurrent LGSOC regardless of KRAS status, acknowledging the demonstrated contribution of defactinib.

Avutometinib is also being investigated in combination with defactinib in ISTs to assess efficacy in other gynecological cancers with MAPK pathway mutations (e.g.

high-grade and mucinous ovarian cancers, endometrial and cervical cancers).

● Execute on our confirmatory trial RAMP 301 required by the FDA for the combination of avutometinib and defactinib to potentially receive full approval for treatment of patients with recurrent LGSOC.

We intend to submit an Accelerated Approval NDA for the combination of avutometinib and defactinib based on mature data from the RAMP 201 study, together with the results of the investigator-initiated FRAME trial in the first half of 2024.

● Expanding the indications in which avutometinib may be used alone and in combination with other agents.

We have entered into clinical collaboration agreements with both Amgen and Mirati to evaluate avutometinib in patients with KRAS G12C NSCLC in combination with Amgen’s KRAS G12C inhibitor LUMAKRAS (sotorasib) in a study entitled RAMP 203 or in combination with Mirati’s KRAS G12C inhibitor KRAZATI (adagrasib) in a trial entitled RAMP 204.

Avutometinib is also being investigated in combination with defactinib + GEMZAR/ABRAXANE in patients with frontline pancreatic cancer in a trial entitled RAMP 205.

Additionally, ISTs and preclinical studies are in progress to prioritize additional cancer indications and approaches to expand the potential clinical development of our product candidates.

Avutometinib is being investigated in combination with the anti-EGFR antibody cetuximab in KRAS mutant CRC, in combination with abemacicilib and fulvestrant in breast cancer, and in combination with the BRAF inhibitor encorafenib in BRAF V600E melanoma through ISTs.

● Continue to advance three oncology discovery programs targeting RAS/MAPK pathway-driven cancers with GenFleet for which we have three exclusive GenFleet Options that may be exercised on a program-by-program basis.

The lead oncology discovery program is an orally bioavailable, potent and selective small molecule KRAS G12D inhibitor entitled GFH375/VS-7375.

GenFleet plans to file an IND in China in the first half of 2024 and initiate the Phase 1 clinical trial of GFH375/VS-7375 in the second half of 2024.

● Continue to advance three oncology discovery programs targeting RAS/MAPK pathway-driven cancers with GenFleet including VS-7375, its potential best-in-class oral KRAS G12D (ON/OFF) inhibitor, to create multiple opportunities to demonstrate transformative outcomes for people living with RAS/MAPK pathway-driven cancers.

In January 2025, we exercised the option to license from GenFleet VS-7375 in the Verastem Territory.

GenFleet’s IND for VS-7375/GFH375 was approved in China in June 2024, and the first patient was dosed in a Phase 1/2 study in July 2024.

We filed an IND for VS-7375 in the United States in the first quarter of 2025 and plan to initiate a phase 1/2a trial in the United States in mid-2025.

● Consider the acquisition or in-licensing of rights to additional agents.

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OUR PRODUCT CANDIDATES AND PIPELINE

Our pipeline product candidates currently consist of avutometinib as a monotherapy and in combination with defactinib and other agents which continue to be evaluated in the clinic for the treatment of a variety of cancer types.

Our pipeline product candidates currently consist of avutometinib in combination with defactinib and other agents, and VS-7375 which continue to be evaluated in the clinic for the treatment of a variety of cancer types.

The following table represents the status of our pipeline:

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RAMP 205 Study = NCT05669482

FRAME Study = NCT03875820

IST in MAPK pathway-driven gynecological cancer = NCT05512208

IST in mesonephric gynecologic cancer = NCT05787561

IST in KRAS mutant CRC = NCT05200442

IST in ER+ breast cancer = NCT05608252

IST in thyroid cancer = NCT06007924

The status of our development programs in the table above represents the ongoing phase of development and does not correspond to the completion of a particular phase.

Drug development involves a high degree of risk and investment, and the status, timing, and scope of our development programs are subject to change.

Important factors that could adversely affect our drug development efforts are discussed in the “Risk Factors” section of this Annual Report on Form 10-K.

factors that could adversely affect our drug development efforts are discussed in the “Risk Factors” section of this Annual Report on Form 10-K.

Avutometinib and defactinib

Avutometinib is an investigational oral first-in-class unique small molecule RAF/MEK clamp that inhibits the MAPK pathway which is involved in cell proliferation, migration, transformation, and survival of tumor cells.

MEK-only inhibitors (e.g., trametinib) paradoxically induce pMEK by relieving extracellular-signal-regulated-kinase (ERK)-dependent feedback inhibition of RAF which may limit their efficacy.

By inhibiting RAF-mediated phosphorylation of MEK, avutometinib has the advantage of not inducing pMEK.

This unique mechanism of avutometinib enables more effective inhibition of ERK signaling and may confer enhanced

therapeutic activity against MAPK pathway-driven cancers.

Avutometinib, alone or in combination with defactinib, has received orphan drug designation for the treatment of all patients with LGSOC in the United States.

Defactinib is an oral small molecule inhibitor of FAK and PYK2 that is currently being evaluated as a potential combination therapy for various solid tumors.

Avutometinib is an orally available first-in-class, small molecule RAF/MEK clamp that inhibits RAS/RAF/MEK, extracellular-signal-regulated-kinase (“ERK”) MAPK pathway which is involved in cell proliferation, migration, transformation, and survival of tumor cells.

MEK-only inhibitors (e.g.

trametinib) may have limited efficacy because they induce MEK phosphorylation (“pMEK”) by relieving ERK-dependent feed back inhibition of RAF.

By inhibiting RAF-mediated phosphorylation of MEK, avutometinib has the potential advantage of not inducing pMEK.

This unique mechanism of avutometinib enables it to inhibit ERK signaling more effectively and may confer enhanced therapeutic activity against MAPK pathway-driven cancers.

Avutometinib inhibits MAPK pathway signaling and proliferation of tumor cell lines harboring MAPK pathway alterations including KRAS, neuroblastoma rat sarcoma viral oncogene homolog (“NRAS”), and BRAF mutations, among others.

Avutometinib has demonstrated strong antitumor activity as monotherapy and in combination with (i) agents targeting parallel pathways (e.g.

inhibitors of FAK, CDK4/6 and mTOR), (ii) agents targeting other nodes in the MAPK pathway (e.g.

anti-EGFR, SOS1, KRAS G12C, and KRAS G12D inhibitors), (iii) chemotherapy, and (iv) anti-PD-1.

Defactinib is an oral small molecule inhibitor of FAK and proline-rich tyrosine kinase (“PYK2”) that is currently being evaluated as a potential combination therapy for various solid tumors.

Defactinib targets malignant cells both directly and through modulation of the tumor microenvironment.

Defactinib disrupts malignant cells both directly and through modulation of the tumor microenvironment.

Preclinical research by our scientists and collaborators indicates that FAK inhibition delays tumor progression in cancer models, which was associated with reduced stromal density and immunosuppressive cell populations.

Furthermore, activation of FAK is a putative adaptive resistance mechanism to MAPK pathway inhibition, supporting the clinical evaluation of avutometinib in combination with defactinib for treatment of cancers harboring MAPK pathway alterations.

The combination of avutometinib and defactinib is clinically active in patients with KRAS mt and KRAS wt recurrent LGSOC and has received breakthrough designation from the FDA for the treatment of all patients with recurrent LGSOC, regardless of KRAS status, after one or more prior lines of therapy including platinum-based chemotherapy.

Avutometinib, alone or in combination with defactinib, has received orphan drug designation for the treatment of all patients with LGSOC in the United States.

Defactinib has received orphan drug designation in ovarian cancer in the United States, the European Union, and Australia.

The combination of avutometinib and defactinib has received breakthrough designation from the FDA for the treatment of patients with recurrent LGSOC, regardless of KRAS status, after one or more prior lines of therapy, including platinum-based chemotherapy.

In addition, the FDA granted orphan drug designation to avutometinib, in combination with defactinib, for the treatment of pancreatic cancer.

Phase 3 Study (known as RAMP (RAF and MEK Program) 301 Study) Confirmatory Trial of Avutometinib and Defactinib in Recurrent LGSOC

The RAMP 301 study is an international collaboration between The GOG Foundation, Inc.

and the European Network of Gynaecological Oncological Trial groups sponsored by us.

The trial is expected to enroll 270 patients who will be randomized to either the combination of avutometinib and defactinib or investigator’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel, or topotecan) or hormone therapy (letrozole or anastrozole).

and the European Network of Gynaecological Oncological Trial groups.

RAMP 301 is sponsored by Verastem and is the confirmatory study required by the FDA for the combination of avutometinib and defactinib for the initial indication of recurrent KRAS mt LGSOC to potentially receive full approval and has the potential to support an expanded indication regardless of KRAS mutation status .

In July 2023, we announced we finalized the design of the RAMP 301 trial and, in December 2023, we initiated the RAMP 301 trial.

The trial is expected to enroll 270 patients who will be randomized to either the combination of avutometinib and defactinib or investigator’s choice chemotherapy (pegylated liposomal doxorubicin or paclitaxel) or hormone therapy (letrozole or anastrozole).

The primary endpoint is progression free survival by blinded independent central review .

Secondary endpoints include ORR, duration of response, disease control rate, safety and tolerability, patient reported outcomes, and overall survival.

RAMP 301 is a global study with enrollment open in the U.S.

and Australia and enrollment planned in Canada, the United Kingdom, Europe, and Korea.

RAMP 301 is the confirmatory study required by the FDA for the combination of avutometinib and defactinib to potentially receive full approval for the treatment of patients with recurrent LGSOC.

We intend to submit an Accelerated Approval NDA for the combination of avutometinib and defactinib based on mature data from RAMP 201 study, together with the results of the investigator-initiated FRAME trial in the first half of 2024.

In July 2023, we announced we finalized with the FDA the design of RAMP 301 and, in December 2023, we initiated the RAMP 301 study.

RAMP 301 is a global study with enrollment open in the United States, Australia, Canada, Europe United Kingdom , and Korea.

Enrollment is on track, and we are targeting full enrollment by the end of 2025.

Phase 2 Study (known as RAMP (RAF and MEK Program) 201 Study) Registration-Directed Study of Avutometinib and Defactinib in Recurrent LGSOC

The RAMP 201 study that was initiated in November 2020 is a registration-directed clinical study of avutometinib and defactinib in patients with recurrent LGSOC.

The RAMP 201 Study is an international adaptive two-part multicenter, parallel cohort, randomized, open label study to evaluate the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent LGSOC.

The objective of Part A (selection phase) of the RAMP 201 study was to select the go-forward regimen between avutometinib monotherapy or the combination of avutometinib and defactinib being studied in Part B (expansion phase).

In addition, the efficacy was assessed in both KRAS mutant and KRAS wild-type LGSOC.

Part B (expansion phase) of the study is examining efficacy and safety parameters of the regimen selected.

Part A randomized eligible patients to avutometinib monotherapy (n=33) or the combination of avutometinib and defactinib (n=31).

We plan to present full data from Parts A and Part B of the RAMP 201 study at a scientific medical conference in first half of 2024.

Updated Phase 2 RAMP 201 Study Results in Patients with LGSOC Part A (May 2023)

An abstract highlighting updated interim results from Part A of the RAMP 201 study was presented in a Poster Discussion Session at the American Society of Clinical Oncology (ASCO) annual meeting that took place on June 2-6, 2023, in Chicago, Illinois (data cutoff April 6, 2023).

Overall, patients were heavily pretreated with a median of four prior systemic regimens (up to 11), including prior platinum-based chemotherapy, endocrine therapy and bevacizumab in most patients and prior MEK inhibitor therapy in about 13% of patients.

Confirmed ORR by blinded independent central review of 45% (13/29;

26%-64%) were observed. Tumor shrinkage was observed in the majority of patients, 86% (25/29).

Further, three out of four patients who received prior MEK inhibitors responded to the combination.

Among the patients with KRAS mutant LGSOC, the ORR was 60% (9/15) in the combination arm.

Among the patients with KRAS wild-type LGSOC, the ORR was 29% (4/14) in the combination arm.

The median time to response was 5.5 months (range 1.6-14.7 months).

The median duration of response and median progression free survival have not been reached.

The safety profile was consistent with previously reported safety data.

The most common treatment-related adverse events for the combination in all treated patients (n=81) were nausea and vomiting, diarrhea, blood creatine phosphokinase (CPK) increased, peripheral edema, vision blurred, dermatitis acneiform and rash, fatigue, and dry skin, most of which were mild to moderate.

The discontinuation rate, due to adverse events, was 12% in the study overall to date (4.9% due to elevated blood CPK).

Efficacy and Safety Data of Avutometinib and Defactinib in Recurrent LGSOC in Heavily Pretreated Patient Population (November 2023)

The results of a planned subgroup analysis of Part A of the RAMP 201 study were presented in an oral presentation during a plenary session at the Annual Global Meeting of the International Gynecologic Cancer Society (IGCS 2023) from November 5-7, 2023 in Seoul, Korea.

This planned subgroup analysis was performed to assess efficacy (confirmed ORR via blinded independent central review per RECIST v1.1) and safety in prior lines of therapy (“LoT”) (1-3 LoT, ≥4 LoT).

The analysis also evaluated efficacy in the context of best response to most recent prior treatment in the metastatic/recurrent setting.

In the combination arm of the RAMP 201 study, the observed ORRs were consistent across patients who received 1-3 (45.5%, 5/11, 95% CI 17-77) and ≥4 (44.4%, 8/18, 95% CI 22-69) lines of therapy.

Prior to enrollment in the RAMP 201 study, only 2/23 (8.7%) patients responded to their last prior treatment in the metastatic/recurrent setting, whereas the combination of avutometinib and defactinib yielded an ORR of 43.5% (10/23) in this subgroup.

The safety profiles of avutometinib and defactinib were similar in the less and more heavily pretreated subgroups and both analyses were consistent with previously reported safety data.

The majority of treatment-emergent adverse events were mild to moderate.

RAMP 201 is an adaptive, three-part multicenter, parallel cohort, randomized, open-label trial to evaluate the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent LGSOC.

The first part of the study (Part A) determined the selection of the go forward regimen, which was the combination of avutometinib and defactinib versus avutometinib alone, based on overall response rates.

The expansion phases of the trial (Parts B and C) are evaluating the safety and efficacy of the go forward regimen of avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily.

The Part D portion of the trial is evaluating a low dose of avutometinib in combination with defactinib.

In October 2024, the Japanese Gynecologic Oncology Group dosed the first patient in a Phase 2 trial called RAMP 201J, evaluating the safety and efficacy of avutometinib in combination with defactinib in recurrent LGSOC in Japan.

We expect to report initial data from RAMP 201J in the second half of 2025.

Updated Phase 2 RAMP 201 Study Results in Patients with LGSOC (October 2024)

In October 2024, we announced updated results from the RAMP 201 study with a data cutoff of June 30, 2024 which were presented at the IGCS 2024 Annual Meeting in October 2024.

The primary analysis of RAMP 201 study showed a confirmed ORR by blinded independent central review of 31% (34/109;

23-41) in all evaluable patients with measurable disease with approximately 12 months of follow up.

Among patients with KRAS mt LGSOC, the confirmed ORR was 44% (25/57;

31-58) and for patients with KRAS wt LGSOC the confirmed ORR was 17% (9/52;

The median duration of response was 31.1 months (95% CI:

14.8-31.1) in all evaluable patients, with 31.1 months (95% CI:

14.8-31.1) in the KRAS mt population and 9.2 months (95% CI:

5.5-NEi) in the KRAS wt population.

The median progression-free survival was 12.9 months (95% CI:

10.9-20.2) in all evaluable patients, with 22 months (95% CI:

11.1-36.6) in the KRAS mt population and 12.8 months (95% CI:

7.4-18.4) in the KRAS wt population.

The disease control rate at six or more months was 61% in the total evaluable population, 70% in KRAS mt population and 50% in KRAS wt population.

Phase 1/2 Study (FRAME) Investigating the Combination of Avutometinib and Defactinib in Patients with KRAS Mutant Cancers and Subsequent Analyses

The FRAME study is an open-label, investigator-initiated study that is designed to assess safety, dose response and preliminary efficacy of the combination of avutometinib and defactinib in patients with KRAS mutant solid tumors, including LGSOC (including KRAS mutant and KRAS wild-type), KRAS mutant NSCLC, KRAS

G12V NSCLC, KRAS mutant CRC, pancreatic cancer, and RAS/RAF mutant endometrial cancer.

The FRAME study is being led by Dr.

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Updated Phase 1/2 FRAME Study Results in Patients with LGSOC (September 2023)

In September 2023 we presented updated FRAME study efficacy data at the 5th Annual RAS-Target Development Summit in Boston Massachusetts (data cutoff July 2023) showing an ORR of 42% (11 of 26) in evaluable patients with LGSOC.

In September 2023 we presented updated FRAME study efficacy data was presented at the 5th Annual RAS-Target Development Summit in Boston Massachusetts (data cutoff July 2023) showing an ORR of 42% (11 of 26) in evaluable patients with LGSOC.

Among patients with KRAS mutant LGSOC (n=12), the ORR was 58% (7 of 12), compared to patients with KRAS wild-type LGSOC (n=12), the ORR was 33% (4 of 12).

Across all LGSOC patients, the median duration of response was 26.9 months (95% CI:

Across all LGSOC

patients, the median duration of response was 26.9 months (95% CI:

8.5-47.3) while median progression free survival was 20.0 months (95% CI:

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Phase 1/2 Trial (known as RAMP (RAF and MEK Program) 203 Study) of Avutometinib in Combination with Amgen’s LUMAKRAS (sotorasib) in Patients with KRAS G12C NSCLC

In September 2021, we entered into a clinical collaboration agreement with Amgen to evaluate the combination of avutometinib with Amgen’s KRAS G12C inhibitor LUMAKRAS (sotorasib) in a Phase 1/2 study entitled RAMP 203.

The Phase 1/2 trial will evaluate the safety, tolerability and efficacy of avutometinib in combination with LUMAKRAS in patients with KRAS G12C NSCLC who have not been previously treated with a KRAS G12C inhibitor as well as in patients who have progressed on a KRAS G12C inhibitor.

The study is investigating the potential benefits of a more complete vertical blockade of the MAPK pathway with the combination of avutometinib (RAF/MEK inhibition) with LUMAKRAS (KRAS G12C inhibition) in KRAS G12C locally advanced or metastatic NSCLC.

The RAMP 203 study has advanced to cohort 2 of 4 mg avutometinib in combination with 960 mg of LUMAKRAS.

In October 2023 we presented the initial safety, pharmacokinetics, and recommended Phase 2 dose at the AACR-NCI-EORTC Internal Conference on Molecular Targets and Cancer Therapeutics on October 11-15, 2023 in Boston, Massachusetts (data cutoff September 2023).

The confirmed ORR was 25% (3/12) across efficacy-evaluable patients and seen in both KRAS G12C inhibitor resistant (14.3%;

In September 2021, we entered into a clinical collaboration agreement with Amgen to evaluate the combination of avutometinib with Amgen’s KRAS G12C inhibitor LUMAKRAS in a Phase 1/2 study entitled RAMP 203.

These preliminary results showed a confirmed ORR of 25% (3/12) across efficacy-evaluable patients and seen in both KRAS G12C inhibitor resistant (14.3%;

1/7) and naïve (40%;

2/5) patients.

The pharmacokinetic profile of avutometinib in combination with sotorasib was similar to results in monotherapy studies.

No drug-drug interactions were observed between avutometinib and sotorasib.

Avutometinib 4.0 mg orally twice per week 21/28 days + sotorasib 960 mg orally once per day 28/28 days was selected as recommended phase 2 dose based on dose limiting toxicity assessment.

Enrollment of patients with KRAS G12C-mutant NSCLC who are either naïve to or previously treated with a KRAS G12C inhibitor is ongoing in the expansion phase of the RAMP 203 study.

We plan to provide data updates from the RAMP 203 study in the middle of 2024.

Phase 1/2 Trial (known as RAMP (RAF and MEK Program) 204 Study) of Avutometinib in Combination with Mirati’s KRAZATI (adagrasib) in Patients with KRAS G12C NSCLC

In November 2021, we entered into a clinical collaboration agreement with Mirati to evaluate the combination of avutometinib with Mirati’s KRAS G12C inhibitor KRAZATI (adagrasib) in a Phase 1/2 trial entitled

The Phase 1/2 trial is evaluating the safety, tolerability and efficacy of avutometinib in combination with KRAZATI in patients who have progressed on a KRAS G12C inhibitor.

The trial will build on preclinical data showing deeper blockade of MAPK pathway signaling resulting in enhanced anti-tumor efficacy with the combination of KRAZATI (KRAS G12C inhibition) and avutometinib (RAF/MEK inhibition) relative to either agent alone.

The RAMP 204 study is open and enrolling.

We plan to provide data updates from RAMP 204 in the middle of 2024.

The RAMP 203 study has progressed to the recommended Phase 2 dose of 4 mg avutometinib in combination with 960 mg of LUMAKRAS for the doublet of avutometinib and LUMAKRAS.

Enrollment of patients without prior G12C treatment to the initial doublet dose expansion phase has completed.

In December 2024, we announced the dose escalation cohort of three patients completed the DLT evaluation period receiving the triplet combination of sotorasib 960 mg administered daily on a continuous schedule and avutometinib 3.2 mg twice-weekly plus defactinib 200 mg twice-daily without experiencing any DLTs.

Avutometinib and defactinib are administered on a three out of four weeks schedule. We expect to present an interim update of both the doublet and triplet data at a medical meeting in the second half of 2025.

Phase 1/2 Trial (known as RAMP (RAF and MEK Program) 205 Study) of Avutometinib Plus Defactinib in Combination with Gemcitabine/Nab-Paclitaxel

In May 2022, we received the first “Therapeutic Accelerator Award” from PanCAN for up to $3.8 million.

The grant is expected to support a Phase 1b/2 clinical trial of avutometinib in combination with defactinib entitled RAMP 205.

This Phase 1b/2 trial is evaluating the safety, tolerability and efficacy of GEMZAR (gemcitabine) and ABRAXANE (Nab-paclitaxel) in combination with avutometinib and defactinib in patients with previously untreated metastatic adenocarcinoma of the pancreas.

The RAMP 205 study is evaluating whether combining avutometinib (to target mutant KRAS which is mutated in more than 90% of pancreatic tumors) and defactinib (to reduce stromal density and adaptive resistance to avutometinib) to the standard GEMZAR/ABRAXANE regimen improves outcomes for patients with pancreatic cancer.

The RAMP 205 study is open and enrolling.

Dose escalation is ongoing.

We plan to provide initial safety and efficacy results from the RAMP 205 study in the first half of 2024.

The grant is supporting a Phase 1b/2 clinical trial of avutometinib in combination with defactinib entitled RAMP 205.

In August 2022, PanCAN agreed to provide us with an additional $0.5 million for the collection and translational analysis of patient samples.

The RAMP 205 trial is open and enrolling.

Combination dose evaluation is ongoing.

The initial interim results were presented at the American Society of Clinical Oncology (“ASCO”) Annual Meeting in June 2024.

In dose level 1, of the six additional patients, five remain on therapy and continue to be monitored for response given the initial length of time to response.

59 of 60 patients have been treated and enrollment is on track to be completed in quarter 1 of 2025.

Based on the initial safety and efficacy data from these cohorts, dose level 1 or 0 is anticipated to be chosen for expansion.

Adverse events across all dose cohorts remained generally consistent with the previously announced safety and tolerability profile, and no new safety signals have emerged.

We expect to present data at a medical meeting in mid-year of 2025 and we expect to choose a recommended Phase 2 dose for trial expansion in first half of 2025.

INTELLECTUAL PROPERTY

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Patent and Trademark Office to determine priority of invention.

Our patent portfolio includes issued and pending applications worldwide.

These patent applications fall into two categories:

(1) RAF/MEK inhibition program;

and (2) FAK inhibition program.

RAF/MEK inhibition program

We have exclusively licensed a portfolio of four patent families owned by Chugai Pharmaceutical Co., Ltd.

The first patent family has claims directed to the composition of matter of avutometinib, and includes granted patents in the United States, Australia, Brazil, Canada, China, Europe, Japan, Korea, Israel, and New Zealand that are expected to expire in February of 2027.

The second patent family has claims directed to methods of making avutometinib and includes granted patents in Europe, Japan, and the United States that are expected to expire in September of 2032.

The third patent family has claims directed to a dosing protocol of avutometinib, and includes a granted patent in the United States that is expected to expire in November of 2038, granted patents in Russia and Taiwan, and pending patent applications in the United States, Australia, Brazil, Canada, China, Europe, Hong Kong, Japan, Korea, Mexico, and Singapore.

Patents that issue in this family will have a statutory expiration date in May of 2038.

The fourth patent family covers a method of using avutometinib in combination with a FAK inhibitor, such as defactinib, for treating a patient, and includes a granted patent in the United States that is expected to expire in September of 2040 and pending patent applications in Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, Indonesia, Japan, Korea, Mexico, Malaysia, New Zealand, Singapore, the United States, and Taiwan.

In addition to the issued and pending patent applications exclusively licensed from Chugai, we own one patent family covering solid forms of avutometinib, which includes one granted patent in the United States that is expected to expire in December of 2042 and a pending patent application in the United States and an international application.

We also own ten patent families covering methods of using a dual RAF/MEK inhibitor for treating a patient.

The first, second, and third patent families cover methods of using a dual RAF/MEK inhibitor in combination with another therapeutic agent such as a KRAS G12C inhibitor or an immunotherapeutic agent for treating a patient, and are pending in the United States and worldwide.

The fourth patent family covers a method of using a dual RAF/MEK inhibitor to treat a patient with certain mutations, and is pending in the United States and worldwide.

We also have six patent families covering methods of using a dual RAF/MEK inhibitor in combination with another therapeutic agent for treating a patient, which are pending as international applications.

One of the six patent families is co-owned with Francis Crick Institute;

and another of the six patent families is co-owned with the University of North Carolina at Chapel Hill.

patents that will issue in the ten families will have a statutory expiration date ranging from January of 2041 to May of 2043.

FAK inhibition program

We have exclusively licensed a portfolio of patent applications owned by Pfizer, Inc.

As of December 31, 2024, our patent portfolio includes issued and pending patent applications worldwide.

These patents and patent applications fall into three categories:

(1) the RAF/MEK inhibition program;

(2) the FAK inhibition program and (3) KRAS inhibition program.

RAF/MEK inhibition program (avutometinib)

We have exclusively licensed a patent portfolio of four patent families that are owned or exclusively licensed by Chugai or Chugai and therefore we have an exclusive option to exclusively license.

The first patent family has claims directed to the composition of matter of avutometinib, and includes granted patents in various jurisdictions, such as the United States, Australia, Brazil, Canada, China, Europe (validated in several countries),

Japan, Korea, Israel, and New Zealand that are expected to expire in February of 2027, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

The second patent family has claims directed to methods of making avutometinib and includes granted patents in Europe, Japan, and the United States that are expected to expire in September of 2032, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

The third patent family has claims directed to a dosing protocol of avutometinib, and includes a granted patent in the United States, that is expected to expire in November of 2038, granted patents in Europe, Korea, and Taiwan, and pending patent applications in various jurisdictions, such as the United States, Australia, Brazil, Canada, China, Europe, Hong Kong, Japan, Mexico, and Singapore.

Patents that issue in this family will have a statutory expiration date in May of 2038, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

The fourth patent family covers a method of using avutometinib in combination with a FAK inhibitor, such as defactinib, for treating a patient, and includes granted patents in the United States and Taiwan that are expected to expire in September of 2040, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, and pending patent applications in Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, Indonesia, Japan, Korea, Mexico, Malaysia, New Zealand, Singapore, and the United States.

In addition to the issued and pending patent applications that are either exclusively licensed from Chugai or which Chugai has an exclusive option to exclusively license, we own one patent family covering solid forms of avutometinib, which includes one granted patent in the United States that is expected to expire in December of 2042 and a pending patent application in the United States, and pending foreign patent applications in various jurisdictions, such as Australia, Canada, China, Europe, Japen, Korea, and Singapore, that if issued are expected to expire in May of 2043, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

We also own eight patent families and co-own three patent families covering various methods of using a dual RAF/MEK inhibitor for treating a patient.

Our eight patent families have claims directed to using a dual RAF/MEK inhibitor in combination with various therapeutic agents, such as a KRAS G12C inhibitors, KRAS G12D inhibitors, and immunotherapeutic agents for treating a patient, and have patent applications pending in various jurisdictions, such as Australia, Canda, China, Europe, and the United States, that if issued would expire between 2041 and 2043, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

Our three co-owned patent families have claims directed to using a dual RAF/MEK inhibitor in combination with other therapeutics and including a pending US provisional application and patent applications pending in various jurisdictions, such as Australia, Canada, China, Europe, and the United States, that if issued are expected to expire in 2042 to 2045, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

FAK inhibition program (defactinib)

We have exclusively licensed a portfolio of patents owned by Pfizer, Inc.

(“Pfizer”), which are directed to FAK inhibitor compounds and methods of their use, for example in cancer.

One patent family is related generally to defactinib.

This patent family includes issued patents having claims covering defactinib generically and specifically.

One patent family has claims directed to the composition of matter of defactinib and has patents granted in various jurisdictions, such as Australia, Canada, China, Europe (validated in various countries), Israel, Japan, Korea, Singapore, and the United States, that are expected to expire in April of 2028, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

For example, US 7,928,109 covers the composition of matter of defactinib specifically, and US 8,247,411 covers the composition of matter of defactinib generically.

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For example, US 8,440,822 and US 10,450,297 cover methods of making defactinib.

patents that have issued or will issue in this family will have a statutory expiration date in April of 2028.

Related cases have been granted worldwide, including Australia, Europe, Brazil, Mexico, India, Hong Kong, Canada, China, Korea, Israel, New Zealand, South Africa, Singapore, Taiwan, Thailand, and Japan.

In addition to the issued and pending patent applications exclusively licensed from Pfizer, we own three patent families covering defactinib.

One family is directed to compositions (e.g., oral dosage forms) of defactinib and certain methods of use.

patents that will issue in this family will have a statutory expiration date in January of 2035.

Patent applications in this family are pending worldwide, including in the United States, Thailand, and China, and have been granted in Australia, Brazil, Canada, Europe, Hong Kong, Israel, Mexico, Japan, Korea, New Zealand, Singapore, and South Africa.

The second family is directed to methods of using a FAK inhibitor, such as defactinib, in combination with a MEK inhibitor for treating a patient.

patents that will issue in this family will have a statutory expiration date in February of 2035.

Patent applications in this family have been granted

worldwide, including the United States, Japan, Hong Kong, and Europe.

The third family is directed to methods of using a FAK inhibitor, such as defactinib, in combination with an immunotherapeutic agent.

patents that have issued or will issue in this family will have a statutory expiration date in June of 2036.

Patent applications in this family are pending worldwide, including for example in Europe, New Zealand, Brazil, Korea, Israel, Canada, Japan, and Hong Kong, and have been granted in the United States, Australia, China, Eurasia, Mexico, Singapore, and South Africa.

Our licensed portfolio of patent applications from Pfizer also includes four families of patent applications directed to VS-6062 and related methods of use.

The patent families include issued and pending patent applications having claims directed to VS-6062, methods of manufacture, and pharmaceutical salts.

Patents have issued in these families in the United States that will expire in December of 2023, April of 2025, and November of 2028, respectively.

Related cases have been granted worldwide, including in Australia, Canada, China, Japan, and Europe.

Stanford University has an option to certain United States rights in VS-6062.

In addition to the issued patents exclusively licensed from Pfizer, we own or co-own three patent families with claims directed to defactinib.

One patent family is co-owned with Pfizer and has claims directed to compositions (e.g., oral dosage forms) of defactinib and certain methods of use.

This family contains granted patents in various jurisdictions, such as Europe, Australia, Brazil, Hong Kong, Israel, Japan, Korea, Mexico, New Zealand,

and South Africa and pending patent applications in the United States, Brazil, China, Europe, Israel, and Japan.

The patents and pending patent applications, if issued, are expected to expire in January of 2035, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

We own a second patent family with claims directed to methods of using a FAK inhibitor, such as defactinib, in combination with a MEK inhibitor for treating a patient.

Patents in this family have been granted in the United States, Japan, Hong Kong, and Europe, and are expected to expire in February 2035, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

We own a third patent family with claims directed to methods of using a FAK inhibitor, such as defactinib, in combination with an immunotherapeutic agent.

Patent applications in this family have been granted in the United States, Europe, Canada, China, Israel, and Mexico, and are expected to expire in June 2036, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

Patent applications in this family are also pending the United States, Australia, Canada, China, Europe, Japan, and Singapore.

KRAS inhibition program (VS-7375)

We in-license a patent portfolio of KRAS inhibitors from GenFleet, which includes four patent families directed to KRAS inhibitors.

In regard to VS-7375, two patent families have claims directed to the composition of matter of VS-7375.

One patent family includes patent applications pending in various jurisdictions, such as the United States, China, Europe, and Japan, that if issued would expire in March of 2042, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

The other patent family includes a pending Patient Cooperation Treaty (“PCT”) patent application, and patent applications claiming the benefit of this PCT application, if issued, are expected to expire in September of 2043.

We also co-own with GenFleet a priority patent application with claims directed to a combination of a KRAS inhibitor and another therapeutic agent for treating a subject.

Patent applications claiming the benefit of this priority patent application, if issued, are expected to expire in November of 2046, without giving effect to any potential patent term extensions and patent term adjustments and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees.

The base term of a U.S.

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We may exercise our GenFleet Options on a program-by-program basis.

In December 2023, we announced the lead oncology discovery program is an orally bioavailable, potent and selective small molecule KRAS G12D inhibitor entitled GFH375/VS-7375.

In December 2023, we

announced the lead oncology discovery program is VS-7375, a potential best-in-class oral and selective KRAS G12D (ON/OFF) inhibitor.

In January 2025, we exercised our GenFleet Option with respect to VS-7375 and made a $6.0 million payment to GenFleet.

In January 2025, we entered into a supply agreement with GenFleet pursuant to which GenFleet agreed to provide us with compound and licensed product for development use for programs we have exercised our GenFleet Option.

We made an upfront payment of $2.0 million to GenFleet in September 2023 and will provide $1.5 million of research support over the first three years of the GenFleet Agreement.

In addition, pursuant to the GenFleet Agreement, upon achievement of certain development and commercial milestones, and upon us exercising all three GenFleet Options, GenFleet will be entitled to receive payments of up to $622.0 million.

We have also agreed to pay GenFleet royalties on net sales of licensed products in the GenFleet Territory ranging from the mid to high single digits.

In addition, pursuant to the GenFleet Agreement, upon achievement of certain milestones, and upon the Company exercising its GenFleet Options, GenFleet will be entitled to receive payments of up to $622.0 million, inclusive of (i) up to $154.0 million upon achievement of certain development and commercialization milestones, (ii) up to $450.0 million upon achievement of certain sales milestones, and (iii) up to $18.0 million upon exercise of all three GenFleet Options.

We paid GenFleet a $3.0 million milestone payment in the year ended December 31, 2024, upon GenFleet achieving a development milestone.

We have also agreed to pay GenFleet royalties on net sales of licensed products in the Verastem Territory ranging from the mid to high single digits.

We may terminate the GenFleet Agreement in its entirety or on a program-by-program basis by providing 90 days written notice to GenFleet.

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(“Infinity”).

Pursuant to the terms of the Secura APA, Secura has paid us an up-front payment of $70.0 million, and has agreed to pay us (i) regulatory milestone payments up to $45.0 million, consisting of a payment of $35.0 million upon receipt of regulatory approval of COPIKTRA in the United States for the treatment of peripheral T-cell lymphoma (“PTCL”) and a payment of $10.0 million upon receipt of the first regulatory approval for the commercial sale of COPIKTRA in the European Union for the treatment of PTCL, (ii) sales milestone payments of up to $50.0 million, consisting of $10.0 million when total worldwide net sales of COPIKTRA exceed $100.0 million, $15.0 million when total worldwide net sales of COPIKTRA exceed $200.0 million and $25.0 million when total worldwide net sales of COPIKTRA exceed $300.0 million, (iii) low double-digit royalties on the annual aggregate net sales above $100.0 million in the United States, European Union, and the United Kingdom of Great Britain and Northern Ireland and (iv) 50% of all royalty, milestone and sublicense revenue payments payable to Secura under our existing license agreements with Sanofi, Yakult, and CSPC, and 50% of all royalty, and royalty payments payable to Secura under any license or sublicense agreement entered into by Secura in certain jurisdictions.

Pursuant to the terms of the Secura APA, Secura paid us an up-front payment of $70.0 million, and has agreed to pay us (i) regulatory milestone payments up to $45.0 million, consisting of a payment of $35.0 million upon receipt of regulatory approval of COPIKTRA in the United States for the treatment of peripheral T-cell lymphoma (“PTCL”) and a payment of $10.0 million upon receipt of the first regulatory approval for the commercial sale of COPIKTRA in the European Union for the treatment of PTCL, (ii) sales milestone payments of up to $50.0 million, consisting of $10.0 million when total worldwide net sales of COPIKTRA exceed $100.0 million, $15.0 million when total worldwide net sales of COPIKTRA exceed $200.0 million and $25.0 million when total worldwide net sales of COPIKTRA exceed $300.0 million, (iii) low double-digit royalties on the annual aggregate net sales above $100.0 million in the United States, European Union, and the United Kingdom of Great Britain and Northern Ireland and (iv) 50% of all royalty, milestone and sublicense revenue payments payable to Secura under our existing license agreements with Sanofi, Yakult, and CSPC, and 50% of all royalty, and royalty payments payable to Secura under any license or sublicense agreement entered into by Secura in certain jurisdictions.

In the year ended December 31, 2024, Secura achieved $100.0 million of total worldwide net sales of COPIKTRA which triggered a $10.0 million milestone payment to us, which we received in July 2024.

Secura’s royalty obligations remain in effect on a country-by-country basis upon the last to occur (a) 10 years from the first commercial sale of product containing duvelisib in such country or (b) the expiration of all valid patent claims covering products containing duvelisib in such country.

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Chugai also obtained opt back rights to develop and commercialize avutometinib (a) in the European Union, and (b) in Japan and Taiwan.

communicated their intention not to exercise their opt back rights for Japan, Taiwan, or the European Union.

Chugai has communicated their intention not to exercise their opt back rights for Japan, Taiwan, or the European Union.

Chugai and we have made customary representations and warranties and have agreed to certain customary covenants, including confidentiality and indemnification.

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Pfizer provided us with an initial quantity of clinical supplies of one of the products for an agreed upon price.

Upon entering into the Pfizer Agreement, we made a one-time cash payment to Pfizer in the amount of $1.5 million and issued 192,012 shares of our common stock.

Upon entering into the Pfizer Agreement, we made a one-time cash payment to Pfizer in the amount of $1.5 million and issued 16,001 shares of our common stock, adjusted for our Reverse Stock Split (defined herein).

Pfizer is also eligible to receive up to $2.0 million in developmental milestones and up to an additional $125.0 million based on the successful attainment of regulatory and commercial sales milestones.

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To the extent our product candidates are ultimately used in combination with or as an adjunct to existing drug or other therapies, our product candidates will not be competitive with them.

Some of the currently approved drug therapies are branded and subject to patent protection, and others are available on a generic basis.

Some of the currently approved

drug therapies are branded and subject to patent protection, and others are available on a generic basis.

Many of these approved drugs are well established therapies and are widely accepted by physicians, patients and third-party payors.

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has received FDA approval for Koselugo ® (selumetinib), a MEK inhibitor, for the treatment of pediatric patients two years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic inoperable plexiform neurofibromas;

● Bristol Myers Squibb Company (“BMS”) through its acquisition of Mirati Therapeutics, Inc.

has received FDA approval for Ojemda TM (tovorafenib), a RAF kinase inhibitor, for patients six months of age and older with relapsed or refractory pediatric low-grade glioma harboring a BRAF fusion or rearrangement, or a BRAF V600 mutation.

FAK inhibition program

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We believe InxMed is conducting Phase 1 and Phase 2 clinical trials of their product candidate IN10018.

MAPK Pathway Inhibitors

We understand that there are currently two companies with FDA approval targeting the MAPK pathway in the market.

Amgen has received FDA approval for LUMAKRAS (sotorasib) for the treatment of adult patients with KRAS G12C locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy.

Mirati has received FDA approval for KRAZATI (adagrasib) for treatment of adult patients with KRAS G12C locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy.

We are also aware of other companies in clinical trials developing compounds targeting the MAPK pathway.

Such companies include but are not limited to Amgen, Mirati, Revolution Medicines, Inc., SpringWorks Therapeutics, Inc., BeiGene Ltd., Immuneering Corporation, Mapkure, LLC, Erasca, Inc., Relay Therapeutics, Inc.

and Kinnate Biopharma, Inc.

KRAS Inhibitors

We understand that there are currently two companies with KRAS inhibitors with FDA approval in the market.

Amgen has received FDA approval for LUMAKRAS (sotorasib) for the treatment of adult patients with

KRAS G12C locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy and in combination with panitumumab for adult patients with KRAS G12C-mutated metastatic colorectal cancer (mCRC), as determined by an FDA-approved test, who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

BMS has received FDA approval for KRAZATI (adagrasib) for treatment of adult patients with KRAS G12C locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy and in combination with cetuximab for adults with KRAS G12C-mutated locally advanced or metastatic colorectal cancer, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

We are also aware of other companies in clinical trials developing compounds targeting KRAS inhibition.

Such companies include but are not limited to Amgen, BMS, Revolution Medicines, Inc., Quanta Therapeutics, Inc.

BeiGene Ltd., Erasca, Inc.

and Eli Lilly and Company.

In addition, we are aware of companies that have inhibitors addressing our targets of interest some of which have received FDA approval.

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MANUFACTURING

We contract with third parties for the manufacture of our product candidates for preclinical studies and clinical trials, and we intend to continue to do so in the future.

We contract with third parties for the manufacture of our product candidates for preclinical studies and clinical trials, and commercial requirements we intend to continue to do so in the future.

We currently work with one contract manufacturing organization (“CMO”) for the manufacture of avutometinib drug product, one CMO for the production of avutometinib drug substance, and one CMO for avutometinib drug packaging/labeling.

For defactinib, we currently have one CMO for the manufacture of drug product, one CMO for the production of drug substance, and one CMO for drug packaging /labeling.

We have development agreements in place with these CMOs and we obtain drug substance, drug product and packaging/labeling services from these CMOs on a purchase order basis.

We have supply agreements in place with these CMOs and we obtain drug substance, drug product and packaging/labeling services from these CMOs on a purchase order basis.

We may elect to pursue relationships with other CMOs for manufacturing of drug product, drug substance, and packaging/labeling for later-stage clinical trials, commercialization or for risk management.

We do not own or operate, and currently

have no plans to establish, any manufacturing facilities.

We are party to a supply agreement with GenFleet pursuant to which we expect to obtain VS-7375 finished product from GenFleet.

We do not own or operate, and currently have no plans to establish, any manufacturing facilities.

We have personnel with pharmaceutical development and manufacturing experience who are responsible for the relationships with our CMOs.

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In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act (“FDCA”) and implementing regulations.

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

financial resources.

Failure to comply with the applicable United States requirements at any time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal penalties.

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● completion of preclinical laboratory tests, animal studies, and formulation studies in compliance with the FDA’s good laboratory practice regulations and applicable requirements for the humane use of laboratory animals or other applicable requirements;

● submission to the FDA of an investigational new drug (“IND”) application, which must become effective before human clinical trials may begin;

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

● approval by an independent institutional review board (“IRB”) at each clinical site before each trial may be initiated;

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● FDA review and approval of the NDA.

Supreme Court’s June 28, 2024 decision in Loper Bright Enterprises v.

Raimondo overturned the longstanding Chevron doctrine under which administrative agencies, including the FDA, were entitled to deference in the interpretation of “ambiguous” federal statutes.

The full impact of the Loper decision is not yet known, but it could lead to significant changes in FDA regulation of our business and the pharmaceutical industry.

Preclinical studies

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Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

Phase 1, Phase 2 and Phase 3 clinical trials may not be

completed successfully within any specified period, or at all.

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

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

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User fee statutory authority expires every five years.

The Prescription Drug User Fee Act was re-authorized for an additional five years in 2022 until 2027.

The Prescription Drug User Fee Act was re-authorized for an

additional five years in 2022 until 2027.

Fee waivers are available in certain circumstances, including a waiver of the application fee for an orphan drug application.

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Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval and refuse to approve the NDA.

Even if the FDA approves a product, it may limit the approved indications for use for the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, which can materially affect the potential market and profitability of the product.

distribution restrictions or other risk management mechanisms, which can materially affect the potential market and profitability of the product.

The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs.

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

Failure to conduct required post-approval studies or confirm a clinical benefit during post-marketing studies, would allow the FDA to withdraw the drug from the market on an expedited basis.

Failure to conduct required post-approval studies or confirm a

clinical benefit during post-marketing studies, would allow the FDA to withdraw the drug from the market on an expedited basis.

The Food and Drug Omnibus Reform Act of 2022 (“FDORA”) signed by President Biden on December 29, 2022 as part of the Consolidated Appropriations Act, 2023 (H.R.

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In seeking approval for a drug through an NDA, applicants are required to list with the FDA each patent with claims that cover the applicant’s product or a method of using the product.

Upon approval of a drug, each of the patents listed in the application for the drug is then published in the FDA’s Approved Drug Products with

Therapeutic Equivalence Evaluations, commonly known as the Orange Book.

Upon approval of a drug, each of the patents listed in the application for the drug is then published in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book.

Drugs listed in the Orange Book can, in turn, be cited by potential competitors in support of approval of an abbreviated New Drug Application (“ANDA”).

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For example, the FDA recognizes that two drugs in separate dosage forms and in separate packaging, that otherwise might be administered as monotherapy for an indication, also may be used in combination for the same indication.

In 2013, the FDA issued guidance to assist sponsors that were developing the range of combination therapies that fall outside the category of fixed dose combinations.

In 2013, the FDA issued

guidance to assist sponsors that were developing the range of combination therapies that fall outside the category of fixed dose combinations.

That guidance provides recommendations and advice on such topics as:

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The FDA may impose a number of post-approval requirements as a condition of approval of an NDA.

For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further

assess and monitor the product’s safety and effectiveness after commercialization.

For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

Regulatory approval of oncology products often requires that patients in clinical trials be followed for long periods to determine the overall survival benefit of the drug.

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In the United States, pharmaceutical manufacturers are subject to numerous other federal, state and local laws designed to, for example, prevent fraud and abuse;

promote transparency in interactions with others in the

healthcare industry;

regulate pricing of drugs and protect the privacy of individual information, some of which may apply only if and when we have marketed products.

prevent the causing of false claims to be submitted to government healthcare programs;

promote transparency in interactions with others in the healthcare industry;

regulate pricing of drugs;

require reporting of drug prices and payment of rebates or offering of discounts to certain government programs and public and private payors;

and protect the privacy of individual information, some of which may apply only if and when we have marketed products.

These laws are enforced by various federal and state enforcement authorities, including but not limited to, the U.S.

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We may be subject to various federal and state laws pertaining to health care “fraud and abuse,” including anti-kickback laws and false claims laws, for activities related to past and future sales of any products reimbursable by third party payors such as federal health care programs (including Medicare and Medicaid) or, in some cases, commercial health plans.

Anti-kickback laws generally prohibit a pharmaceutical manufacturer from soliciting, offering, receiving, or paying anything of value to generate business, including the purchase, prescription or use of a particular drug.

Anti-kickback laws generally prohibit a pharmaceutical manufacturer from soliciting,

offering, receiving, or paying anything of value to generate business, including the purchase, prescription or use of a particular drug.

False claims laws generally prohibit anyone from knowingly and willingly presenting, or causing to be presented, any claims for payment for reimbursed drugs or services to third-party payors that are false or fraudulent.

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In order to market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of our products.

Regardless of our current FDA approval or any future FDA approvals we may obtain for a product, we would need to obtain the necessary

approvals by the comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of the product in those countries.

Regardless of our current FDA approval or any future FDA approvals we may obtain for a product, we would need to obtain the necessary approvals by the comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of the product in those countries.

The approval process varies from country to country and can involve additional product testing and additional administrative review periods.

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The prescription drug plans negotiate pricing with manufacturers and may condition formulary placement on the availability of manufacturer discounts.

Manufacturers with marketed brand name drugs are required to provide discounts on brand name prescription drugs utilized by Medicare Part D beneficiaries, which discounts have changed over time.

Manufacturers with marketed brand name drugs have been required to provide discounts on brand name prescription drugs utilized by Medicare Part D beneficiaries.

Under a new manufacturer discount drug program effective January 1, 2025, manufacturers pay 10% of the allowed cost of the drug after a Medicare beneficiary has met the standard deductible until the beneficiary reaches the annual out-of-pocket cap ($2,000) and then 20% of the allowed cost of the drug.

Drug products are subject to discounted pricing when purchased by federal agencies via the Federal Supply Schedule (“FSS”).

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FSS pricing is negotiated periodically with the Department of Veterans Affairs.

FSS pricing is

intended not to exceed the price that a manufacturer charges its most-favored non-federal customer for its product.

In addition, prices for drugs purchased by the Veterans Administration, Department of Defense (including drugs purchased by military personnel and dependents through the TRICARE retail pharmacy program), Coast Guard, and PHS are subject to a cap on pricing (known as the “federal ceiling price”) and may be subject to an additional discount if pricing increases more than the rate of inflation.

FSS pricing is intended not to exceed the price that a manufacturer charges its most-favored non-federal customer for its product.

PHS are subject to a cap on pricing (known as the “federal ceiling price”) and may be subject to an additional discount if pricing increases more than the rate of inflation.

To maintain coverage of drugs under the Medicaid Drug Rebate Program, manufacturers are required to extend discounts to certain purchasers under the PHS pharmaceutical pricing program.

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From time to time, legislation is drafted, introduced and passed in the United States Congress that could significantly change the statutory provisions governing the testing, approval, manufacturing and marketing of pharmaceutical products.

For example, in December 2016, Congress enacted and President Obama signed into law the 21 st Century Cures Act that amends a number of sections of the FDCA.

For example, in 2016, Congress enacted and President Obama signed into law the 21 st Century Cures Act that amends a number of sections of the FDCA.

Additionally, in December 2022, President Biden signed into law the Consolidated Appropriations Act, 2023 (H.R.

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It is impossible to predict whether further legislative changes will be enacted or whether FDA regulations, guidance, policies or interpretations changed or what the effect of such changes, if any, may be.

Additionally, in the United States, federal and state governments continue to propose and pass legislation designed to reform delivery of, or payment for, healthcare, which include initiatives to reduce the cost of healthcare generally and drugs specifically.

generally and drugs specifically.

For example, in March 2010, the United States Congress enacted the Patient Protection and Affordable Care Act (“ACA”) and the Healthcare and Education Reconciliation Act, or the Healthcare Reform Act, which expanded healthcare coverage through Medicaid expansion and the implementation of the individual mandate for health insurance coverage and which included changes to the coverage and reimbursement of drug products under government healthcare programs as well as the imposition of annual fees on manufacturers of branded pharmaceuticals.

Beyond the ACA, there are ongoing and widespread healthcare reform efforts, a number of which have focused on regulation of prices or payment for drug products.

Drug pricing and payment reform has been a focus of the Biden Administration.

For example, federal legislation enacted in 2021 eliminates a statutory cap on Medicaid drug rebate program rebates effective January 1, 2024.

As another example, the Inflation Reduction Act ("IRA") of 2022 includes a number of changes intended to address rising prescription drug prices in Medicare Parts B and D, with varying implementation dates.

These changes include caps on Medicare Part D out-of-pocket costs, Medicare Part B and Part D drug price inflation rebates, a new Medicare Part D manufacturer discount drug program (replacing the ACA Medicare Part D coverage gap discount program) and a drug price negotiation program for certain high spend Medicare Part B and D drugs (with the first list of drugs announced in 2023).

Subsequent to the enactment of the IRA, in 2022, the Biden administration released an executive order directing the Department of Health and Human Services (“HHS”) to report on how the Center for Medicare and Medicaid Innovation (“CMMI”) could be leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.

The report was issued in 2023 and proposed various models that CMMI is currently developing which seek to lower the cost of drugs, promote accessibility, and improve quality of care, models are currently still in development.

Drug pricing and payment reform has been an ongoing focus.

For example, federal legislation eliminated a statutory cap on Medicaid drug rebate program rebates effective January 1, 2024.

As another example, the Inflation Reduction Act ("IRA") of 2022 includes several changes intended to address rising prescription drug prices in Medicare Parts B and D, with varying implementation dates.

The IRA is anticipated to have a significant impact on the pharmaceutical industry.

Subsequent to the enactment of the IRA, in 2024, the Biden Administration announced its commitment to expanding certain IRA reforms.

There have been significant and wide-ranging reforms to federal policy and the federal government under the new Trump Administration.

The focus on drug pricing and payment reform is likely to continue.

Other potential healthcare reform efforts under the Trump Administration could affect access to healthcare coverage or the funding of health care benefits.

There is significant uncertainty regarding the nature or impact of any such reform implemented by the Trump Administration through executive action or by Congress.

Healthcare reform efforts have been and may continue to be subject to scrutiny and legal challenge.

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Recently, there has been considerable public and government scrutiny of pharmaceutical pricing and proposals to address the perceived high cost of pharmaceuticals.

There have also been efforts at the federal level to implement measures to regulate drug pricing or payment for pharmaceutical products, including legislation on drug importation.

There have also been recent state legislative efforts to address drug costs, which generally have focused on increasing transparency around drug costs or limiting drug prices.

Individual states in the United States have also become increasingly active in passing legislation and implementing regulations designed to control pharmaceutical product pricing, including price constraints, restrictions on copayment assistance by pharmaceutical manufacturers, marketing cost disclosure and transparency measures, and, in some cases, measures designed to encourage importation from other countries and bulk purchasing.

We expect continued scrutiny on drug pricing and government price reporting from Congress, agencies, and other bodies.

Adoption of new legislation at the federal or state level could affect demand for, or pricing of, our product candidates if approved for sale.

We cannot predict the ultimate content, timing or effect of any changes to the Healthcare Reform Act or other federal and state reform efforts.

We cannot predict the ultimate content, timing or effect of any changes to the ACA or other federal and state reform efforts.

There is no assurance that federal or state healthcare reform will not adversely affect our future business and financial results.

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Accordingly, we focus significant attention on attracting and retaining talented individuals.

their career goals, offer competitive wages and benefits, and enhance our culture through efforts aimed at making the workplace more satisfying, engaging and inclusive.

To support these objectives, our human resources programs reflect our commitment to our core values (Purposeful, Unwavering, Influential, Insightful and Symbiotic) and are designed to prioritize our employees’ well-being, support their career goals, offer competitive wages and benefits, and enhance our culture through efforts aimed at making the workplace more satisfying, engaging and inclusive.

In order to attract qualified applicants to Verastem and retain such employees, we offer a total rewards package consisting of base salary and cash target bonus, a comprehensive benefit package and equity compensation for every employee.

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As of December 31, 2024, we had 78 full-time equivalent employees, including a total of 15 employees with M.D.

degrees, and four part-time employees.

Of the full-time equivalent employees, 38 employees are engaged in research and development activities.

degrees, and two part-time employees.

Of the full-time equivalent employees, 42 employees were engaged in research and development activities.

We consider the intellectual capital of our employees to be an essential driver of our business and key to our success.

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Executive Officers:

Daniel Paterson

President, Chief Executive Officer

Chief Operating Officer

Daniel Calkins

Chief Financial Officer

Daniel Paterson , age 62, has served as our Chief Executive Officer since August and as our President since June 2019, in addition to serving as our Chief Operating Officer from December 2014 to July 2023, our Chief Business Officer from July 2013 to December 2014 and as our Vice President, Head of Corporate Development and Diagnostics from March 2012 until July 2013.

Paterson , age 63, has served as our Chief Executive Officer since August 2023 and as our President since June 2019, in addition to serving as our Chief Operating Officer from December 2014 to July 2023, our Chief Business Officer from July 2013 to December 2014 and as our Vice President, Head of Corporate Development and Diagnostics from March 2012 until July 2013.

Prior to joining us in March 2012, Mr.

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in Biology from Boston University and attended the Northeastern University Graduate Pharmacology program.

Ros , age 58, has served as our Chief Operating Officer since January 2025.

Ros has more than 35 years of experience in global pharmaceutical and early-stage biotechnology companies.

Ros served as the Chief Executive Officer and board member at FORE Biotherapeutics, a privately held clinical-stage precision oncology company, from April 2022 to August 2023.

Prior to this, Mr.

Ros served at Epizyme, Inc., a publicly traded biopharmaceutical company, as Chief Operating Officer between May 2016 and November 2018 and then as Executive Vice President, Chief Strategy and Business Officer from October 2018 to November 2021.

Ros has served as a board member at Cogent Biosciences, Inc.

He received a B.S.

from the State University of New York, College at Plattsburgh and completed the Executive Education Program in Finance and Accounting for the Non-Financial Manager at Wharton School of the University of Pennsylvania.

Daniel Calkins, age 37, has served as our Chief Financial Officer since October 2023, prior to which Mr.

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Prior to joining us in December 2018, Mr.

Calkins held various positions of increasing responsibility at CFGI from May 2013 to December 2018.

Calkins held various positions of increasing responsibility at CFGI from May 2013 to

December 2018.

Prior to CFGI, Mr.

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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