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Item 1. Business

2026-03-04 compared with 2025-03-20 · 405 added, 458 removed, 429 unchanged (67% of the section changed)

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

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 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 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.

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 in October 2023.

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.

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.

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 pancreatic adenocarcinoma.

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

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.

We are a biopharmaceutical company committed to developing and commercializing new medicines to improve the lives of patients diagnosed with challenging RAS/MAPK pathway-driven cancers.

We market AVMAPKI FAKZYNJA CO-PACK (avutometinib capsules;

defactinib tablets) in the United States (“U.S.”), the first treatment specifically FDA-approved for adults with KRAS-mutated recurrent low-grade serous ovarian cancer (“LGSOC”) who have received prior systemic therapy.

AVMAPKI FAKZYNJA CO-PACK received accelerated approval in the U.S.

on May 8, 2025.

We are also conducting RAMP 301, a Phase 3 trial designed to evaluate avutometinib plus defactinib versus Investigator’s Choice of Treatment (“ICT”) in patients with recurrent LGSOC with and without a KRAS mutation.

This trial will serve as a confirmatory study for the initial U.S.

indication and has the potential to expand the indication regardless of KRAS mutation status.

Results of the RAMP 301 trial may also support future regulatory filings outside of the U.S.

Our pipeline includes clinical-stage programs, preclinical research programs and externally partnered early-stage programs.

Our focus is on novel small molecule drugs developed both as monotherapy and in combination, which inhibit critical signaling pathways in cancer that promote cancer cell survival and tumor growth, including targeting RAS directly with KRAS G12D inhibition, targeting the pathway downstream with RAF/MEK inhibition, and targeting the parallel pathway that drives resistance with FAK inhibition.

Our focus is to expeditiously develop and deliver transformative therapies that truly change outcomes for people living with RAS/MAPK pathway-driven cancers.

For our clinical-stage pipeline programs, we are evaluating VS-7375, a potential best-in-class oral KRAS G12D (ON/OFF) inhibitor, for the treatment of patients with KRAS G12D mutated cancers, including pancreatic ductal adenocarcinoma (“PDAC”), non-small cell lung cancer (“NSCLC”), colorectal cancer (“CRC”) and other KRAS G12D mutated cancers.

A summary of our commercial and pipeline products is shown below.

Two undisclosed assets at discovery phase targeting RAS/MAPK pathway-driven cancers as part of the GenFleet Therapeutics collaboration.

The information below summarizes our key achievements in 2025 and the anticipated near-term milestones for our pipeline programs.

AVMAPKI FAKZYNJA CO-PACK

AVMAPKI FAKZYNJA CO-PACK received accelerated approval by the U.S.

Food and Drug Administration (FDA) on May 8, 2025 for the treatment of adults with KRAS-mutated recurrent LGSOC who have received prior systemic therapy, approximately two months in advance of the Prescription Drug User Fee Act (“PDUFA”) action date of June 30, 2025.

The product was commercially available within a week of approval and was subsequently listed as a Category 2A recommendation for KRAS-mutated recurrent LGSOC in the National Comprehensive Cancer Network® (“NCCN®”) Clinical Practice Guidelines in Oncology (“NCCN Guidelines®”).

Potential label and commercial geographic expansion of the combination therapy progressed:

● Additional patient enrollment for RAMP 301 was completed in December 2025 following a pre-planned interim analysis (“IA”) by the Independent Data Monitoring Committee (“IDMC”), which recommended a modest, one-time increase of 29 patients across KRAS mutation status based on the total enrollment achieved in October 2025.

We expect to report a topline readout of the primary endpoint in mid-2027.

● The European Commission granted Orphan Drug Designation in July 2025 for avutometinib plus defactinib for the treatment of ovarian cancer based on a positive opinion from the European Medicines Agency Committee for Orphan Medicinal Products.

● Preliminary safety and efficacy data from the Phase 2 RAMP 201J trial in Japan was presented in November 2025 at the International Gynecologic Cancer Society (“IGCS”) 2025 Annual Meeting and we are continuing enrollment of patients into the RAMP 301 study in Japan.

Avutometinib in combination with defactinib

In May 2025, we reported that we selected the recommended Phase 2 dose (“RP2D”) known as “dose level 1” in our RAMP 205 trial, which is evaluating avutometinib plus defactinib and in combination with standard of care chemotherapy (gemcitabine and Nab-paclitaxel) in front-line metastatic PDAC.

In the study, dose level 1 demonstrated a confirmed overall response rate (“ORR”) of 83% (10/12) patients.

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.

The collaboration builds on the strengths of both companies in oncology small molecule drug development, enabling us to partner our clinical development and regulatory expertise with GenFleet’s accomplished discovery capabilities.

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 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 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.

Notwithstanding years of intensive research and clinical use, these current treatments often fail to cure cancer and often cause side effects.

For example, conventional chemotherapy works by stopping tumor growth by disrupting the cell cycle leading to cell death.

Chemotherapies are effective at killing cancer cells because cancer cells generally grow more rapidly than normal cells.

However, chemotherapies also target fast-growing normal cells of the body, such as blood cells, hair follicles, and the cells lining the mouth, stomach, and intestines.

As a result, they have a range of side effects and although the treatments may succeed at initially decreasing tumor burden, they ultimately fail to kill all the cancer cells and/or to effectively disrupt the tumor microenvironment, potentially resulting in eventual disease progression.

Accordingly, cancer remains one of the world’s most serious health problems and is the second most common cause of death in the United States after heart disease.

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

“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.

We believe that the potential of oral, targeted therapies, along with the rapidly advancing field of immunotherapy, or using the body’s immune system to fight cancer, present the opportunity to develop more effective cancer treatments.

We leverage our expertise in translational research and deep understanding of cancer treatment pathways as well as strategic partnerships to identify, develop and deliver effective options to address unmet needs.

We believe the best way for us to help patients living with cancer is by advancing newly emerging mechanisms of the disease and developing novel therapies that target these mechanisms.

Despite significant advances in the treatment of cancer, unmet needs persist.

KRAS has long been one of the most elusive cancer-causing proteins.

KRAS mutant tumors are present in about 30% of all human cancers, have historically presented a difficult treatment challenge, and are often associated with significantly worse prognosis.

Since the discovery of KRAS almost four decades ago, researchers have persistently tried to develop therapies that effectively block the cancer-promoting effects of KRAS mutation.

Sotorasib (LUMAKRAS) and adagrasib (KRAZATI) are the first agents to directly target KRAS G12C and received FDA approval for patients with KRAS G12C NSCLC in 2021 and 2022, respectively.

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.

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 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.

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 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.

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

Non-Small Cell Lung Cancer (“NSCLC”)

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%-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 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.

Pancreatic cancer typically spreads rapidly and is seldom detected in its early stages, which is a major reason why it is a leading cause of cancer death.

Signs and symptoms may not appear until pancreatic cancer is so advanced that complete surgical removal is not possible.

Pancreatic cancer is one of the few cancers where survival has not improved significantly during the past 40 years.

The NCI estimates that the number of new incidences of pancreatic cancer was 13.5 per 100,000 people per year based on 2017-2021 cases.

Pancreatic cancer has a very high mortality rate with approximately 87% of patients dying within five years of their initial diagnosis based on the five-year relative survival rate from 2014 to 2020.

The median age for diagnosis is 70 with the disease affecting males slightly more than females.

The prognosis for pancreatic cancer is extremely poor as shown by the survival rate, which indicates the need for new treatments.

Chemotherapy or chemotherapy plus radiation is offered to patients whose tumors are unable to be removed surgically.

Immuno-oncology agents have not demonstrated a significant improvement in treatment outcome for patients with pancreatic cancer.

The limited impact of chemotherapies and immunotherapies to improve the outcome may be due to the dense stroma that is prevalent in pancreatic tumors and the tumor microenvironment.

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.

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.

Thus, there is a strong scientific rationale for combining avutometinib (to target mutant KRAS) and defactinib (to reduce stromal density and adaptive resistance to avutometinib) to the standard GEMZAR/ABRAXANE regimen with the objective of increasing response rate and survival.

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.

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.

Our goal is to build a leading biopharmaceutical company focused on the development and commercialization of novel drugs that use a multi-faceted approach to improving outcomes for patients with cancer.

Key elements of our strategy to achieve this goal are:

● 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.

We are assessing combinations of avutometinib with (i) agents targeting other nodes in the MAPK pathway (e.g.

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.

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

● 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.

We may pursue the acquisition or in-license of rights to additional agents from third parties that may supplement our internal programs and allow us to initiate clinical development of a diverse pipeline of agents more quickly.

● We may seek third-party collaborators for the eventual commercialization of our product candidates both in the U.S.

and around the world.

OUR PRODUCT CANDIDATES AND PIPELINE

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:

1 FDA breakthrough therapy designation

2 FDA fast track designation

RAMP 301 Study = NCT06072781

RAMP 201 Study = NCT04625270

RAMP 203 Study = NCT05074810

RAMP 205 Study = NCT05669482

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.

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 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.

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 ARAF, BRAF and CRAF.

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.

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 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.

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.

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 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.

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;

We completed enrollment of the expansion cohort of a total of 29 patients at RP2D, and we expect to report an update on the safety and efficacy of this expansion cohort in the first half of 2026.

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

(“Amgen”) to evaluate avutometinib in combination with Amgen’s KRAS G12C inhibitor LUMAKRAS® (sotorasib) with and without defactinib in a Phase1/2 study entitled RAMP 203 in patients naïve to or previously treated with a KRAS G12C inhibitor.

Following evaluation of interim data in December 2025 we announced the discontinuation of RAMP 203 to focus resources on clinical development of VS-7375, reflecting the evolving treatment landscape for KRAS G12C inhibitors and the strategic prioritization of programs with the greatest potential impact for patients living with advanced lung cancer.

In January 2025, we licensed VS-7375 from GenFleet Therapeutics (“GenFleet”) and announced in June 2025 that the first patient had been dosed in the monotherapy portion of VS-7375-101, the U.S.

Phase 1/2 clinical trial evaluating VS-7375 in patients with advanced KRAS G12D mutant solid tumors, including PDAC, NSCLC, and CRC.

In July 2025, the FDA granted Fast Track Designation (“FTD”) to VS-7375, for the first-line (“1L”) treatment of patients with KRAS G12D-mutated locally advanced or metastatic PDAC and for the treatment of patients with

KRAS G12D-mutated locally advanced or metastatic PDAC who have received at least one prior line of standard systemic therapy.

We continue to make progress with the VS-7375-101 trial, which includes both monotherapy and combination dose escalation and dose expansion cohorts, as follows:

● In the monotherapy dose escalation phase, we cleared the 400 mg, 600 mg, and 900 mg daily dose (“QD”) dose levels with no dose-limiting toxicities (“DLTs”) and no major toxicities and dose escalation continues.

In October 2025, we reported promising anti-tumor activity was observed in patients with various solid tumors, including metastatic PDAC.

● In a pharmacokinetics (PK) analysis, doses of VS-7375 at 600 mg QD and above, with feeding and anti-emetic prophylaxis, yielded similar exposures to fasted patients in China.

The clinical exposures observed correspond with the exposures achieved in preclinical models necessary for maximal anti-tumor efficacy.

● As of the January 30, 2026 data cutoff, VS-7375 demonstrated an encouraging safety profile and was generally well-tolerated across all monotherapy dose levels evaluated to date.

Patients (n=23) receiving VS-7375 at either 400 mg QD, 600 mg QD or 900 mg QD with a mean duration of therapy of 1.6 months (0.7-5.6), reported no drug related liver function test abnormalities.

There was no drug-related neutropenia or anemia >Grade 2 and rates of nausea, vomiting and diarrhea remained lower than those reported by our partner in China.

No DLTs have been reported to date, and the maximum tolerated dose has not been reached.

● We initiated the monotherapy dose expansion cohorts with the 600 mg QD dose and are increasing enrollment across three different cohorts:

second line (“2L”) PDAC, second- and third-line (“2L/3L”) NSCLC, and other second line or greater (“2L+”) KRAS G12D mutated solid tumors.

● In our combination cohorts we are enrolling patients into three different cohorts, including 2L+ solid tumors in combination with cetuximab, 1L NSCLC in combination with carboplatin/pemetrexed/pembrolizumab, and 2L PDAC in combination with gemcitabine and Nab-paclitaxel.

● We cleared the 400 mg and 600 mg QD dose of VS-7375 in combination with cetuximab and are evaluating higher doses.

We plan to report an update on early dose-escalation data from the VS-7375-101 trial in first half of 2026.

Following recent feedback from the FDA, we are amending the VS-7375-101 Phase 1/2 protocol and breaking out disease-specific Phase 2 registration-directed trials for KRAS G12D mutated 2L PDAC, 2L/3L NSCLC (monotherapy), and 2L+ CRC in combination with cetuximab.

Our partner, GenFleet, is developing VS-7375 as GFH375 in greater China and to date has generated data in more than 150 patients with PDAC, NSCLC and other solid tumor cancers.

GenFleet reported initial positive safety and anti-tumor activity in 2L PDAC (58.3% ORR in 12 patients) and 2L NSCLC (68.8% ORR in 16 patients).

GenFleet has an ongoing Phase 1/2b trial of GFH375 in combination with cetuximab or chemotherapy in KRAS G12D-mutated solid tumors in China.

The chemotherapy combination will be conducted in 1L PDAC in China.

GenFleet is also conducting a Phase 3 trial in China evaluating GFH375 in patients with pretreated KRAS G12D-mutated metastatic pancreatic cancer.

Preclinical Programs

We continue to progress preclinical research programs across our pipeline assets.

We also have two undisclosed assets at discovery phase targeting RAS/MAPK pathway-driven cancers as part of the GenFleet Agreement.

Our goal is to deliver transformative therapies that meaningfully improve outcomes for patients living with RAS/MAPK pathway-driven cancers.

We are developing small molecule therapeutics targeting this pathway and have already successfully demonstrated clinical-to-commercial success in bringing novel RAS/MAPK pathway-targeted therapies from development through FDA approval to commercialization.

We are well-positioned to deliver continued commercial success and develop a potential best-in-class treatment for long-term growth.

Precision targeting of RAS/MAPK pathway-driven cancers differentiates our science.

Our focus is on novel small molecule drugs developed both as monotherapy and in combination that inhibit critical signaling pathways in cancer promoting cell survival and tumor growth.

This includes targeting RAS directly with KRAS G12D inhibition, targeting the pathway downstream with RAF/MEK inhibition, and targeting the parallel pathway that drives resistance with FAK inhibition.

Our lead FDA-approved combination product, AVMAPKI FAKZYNJA CO-PACK, is indicated for the treatment of patients with KRAS-mutated recurrent LGSOC who have received prior systemic therapy.

We have established a commercial presence in the U.S.

that is scalable to maximize future oncology development programs and launches.

Our innovative pipeline is anchored by VS-7375, a potential best-in-class KRAS G12D (ON/OFF) inhibitor targeting the most prevalent KRAS mutation in human cancers.

We believe VS-7375 addresses a significant opportunity across multiple KRAS G12D-mutated solid tumors with a differentiated profile and best-in-class anti-tumor activity.

We see substantial potential to address a significant unmet medical need and establish leadership in this therapeutic area.

Our key priorities are as follows:

● Maximize and sustain commercial momentum leveraging our established engagement with the healthcare provider community and building upon the strong foundation achieved in our initial launch

● Advance VS-7375 through development to produce topline clinical data readouts and drive toward registration-directed studies across KRAS G12D mutated solid tumors, including PDAC, NSCLC, and CRC

● Rigorously follow patients to achieve data maturity in our Phase 3 confirmatory trial, RAMP 301, which may support label expansion in the U.S.

and regulatory submissions outside of the U.S.

● Maintain prudent capital management through key inflection points

● Continue to support our people and culture through this next phase of growth

AVMAPKI FAKZYNJA CO-PACK FDA Approved for KRAS-mutated recurrent LGSOC

AVMAPKI FAKZYNJA CO-PACK received accelerated approval by the FDA on May 8, 2025, approximately two months in advance of the PDUFA action date of June 30, 2025, for the treatment of adult patients with KRAS-mutated recurrent LGSOC who have received prior systemic therapy.

The product was commercially available within a week of approval and was subsequently listed as a Category 2A recommendation in the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®).

Prior to this approval, there were no FDA-approved treatments specifically for KRAS-mutated recurrent LGSOC.

LGSOC is a rare ovarian cancer that is persistent and starts in the thin layer of tissue around the ovaries (also known as the epithelium).

Low-grade means the cancer cells look a lot like normal cells, and serous means the cancer started in the serous membrane, which is part of the epithelium.

There are approximately 6,000 to 8,000 women with LGSOC living in the U.S., and 1,000 to 2,000 cases are diagnosed each year.

LGSOC is most commonly diagnosed in women between the ages of 20 to 30 and 50 to 60.

More than 80% of patients experience a recurrence.

The RAS/MAPK pathway is a primary driver of tumor growth and genetic mutations that activate this pathway are found in many cancers.

In LGSOC, 70% of patients have a RAS/MAPK pathway-associated mutation.

One of these mutations, known as KRAS , is present in approximately 30% of patients with LGSOC.

Cancer is highly dependent on the RAS/MAPK signaling pathway for its growth, and blocking any single node in this pathway is generally insufficient for deep and durable anti-cancer activity as the cancer will compensate by activating other signaling proteins within the RAS pathway or in parallel pathways.

AVMAPKI (avutometinib) inhibits MEK kinase activity while also blocking the compensatory reactivation of MEK by upstream RAF.

RAF and MEK proteins are regulators of the RAS/RAF/MEK/ERK (MAPK) pathway.

Blocking RAF and/or MEK activates FAK, a key mediator of drug resistance.

FAKZYNJA (defactinib) is a FAK inhibitor.

The avutometinib and defactinib combination was designed to provide a more complete blockade of the signaling that drives the growth and drug resistance of RAS/MAPK pathway-dependent tumors.

Commercial Launch

AVMAPKI plus FAKZYNJA is only commercially available in the U.S.

as an oral combination co-pack with the two prescription products, known as “AVMAPKI FAKZYNJA CO-PACK.” The product was available at our designated specialty pharmacies within five days of approval.

Our first full seven months of commercial launch in 2025 resulted in the recognition of $30.9 million in net product revenue.

Over the past few years, as part of our pre-launch efforts and educational work with our medical science liaisons, and now with the addition of our field sales team, we have generated strong awareness and built a highly experienced and motivated team.

We believe our initial launch success has been driven by consistent adoption among both academic centers and community oncologists.

We defined three key strategic launch imperatives to drive our launch:

1) effectively reach healthcare providers, keeping in consideration that the top 100 commercial healthcare organizations in the U.S.

comprise approximately 50% of the sales opportunity;

2) engage and support patients throughout their journey since, as patients progress through other therapies, many will be ready for a new treatment option;

and 3) ensure seamless access to support patients and ensure any barriers to reimbursement are removed.

Our approach is highly targeted, and we are utilizing a deliberate mix of one-on-one meetings, group discussions, and conference engagements to maximize the impact of every interaction in this rare disease market.

We have received a favorable mix of orders between the two specialty pharmacies onboarded in the second quarter of 2025 and the four specialty distributors we added in the third quarter of 2025.

We believe we are well-positioned for continued growth as we aim to achieve our goal that every KRAS-mutated LGSOC patient should not only receive this treatment but should do so at their first recurrence.

Accelerated Approval

Verastem initiated a rolling New Drug Application (“NDA”) in May 2024 and aligned with the FDA on plans to complete the NDA submission in October 2024 for adult patients with KRAS-mutated recurrent LGSOC, who received at least one prior systemic therapy.

The NDA included safety and efficacy results from 57 patients with KRAS-mutated recurrent LGSOC enrolled in our Phase 2 RAMP 201 clinical trial.

In the study, AVMAPKI and FAKZYNJA, in combination, showed a confirmed ORR by blinded independent central review (“BICR”) of 44% (25/57;

95% Confidence Interval (“CI”):

31-58) in patients with a KRAS mutation.

The DOR ranged from 3.3 to 31.1 months in the KRAS mutant population.

The safety of AVMAPKI and FAKZYNJA, in combination, was evaluated in 57 patients with KRAS - mutated recurrent LGSOC.

Possible serious side effects with AVMAPKI FAKZYNJA CO-PACK include ocular disorders, skin toxicities (“rash”), hepatotoxicity, rhabdomyolysis, and fetal harm when administered during pregnancy.

The most common side effects, including laboratory changes, of AVMAPKI FAKZYNJA CO-PACK include increased levels of an enzyme in the blood (“CPK”), nausea, fatigue, abnormal liver test (“AST”), and rash.

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

We completed our submission in October 2024, and the FDA accepted the NDA under the accelerated approval pathway in December 2024.

The NDA was granted Priority Review with a PDUFA action date of June 30, 2025.

Prior to NDA acceptance, the FDA granted Breakthrough Therapy Designation (“BTD”) for the combination therapy for patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy, in May 2021.

BTD allows for the expedited development and review of drugs for serious or life-threatening conditions.

Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC, which recognized this rare cancer as distinct from high-grade serous ovarian cancer (“HGSOC”).

These designations, combined with the early approval, underscored the urgency and importance of addressing the unmet treatment needs of women living with LGSOC.

RAMP 201 Clinical Trial

RAMP 201 (ENGOTov60/GOG3052) was a Phase 2 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 low-grade serous ovarian cancer.

The first part of the study 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 evaluated the safety and efficacy of the go forward regimen of avutometinib 3.2 mg twice weekly and defactinib 200 mg twice daily.

In October 2024, we announced the primary analysis of the RAMP 201 study with a data cutoff of June 30, 2024, that was presented at the IGCS 2025 Annual Meeting.

The study showed a confirmed ORR by BICR 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:

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

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

The median duration of response (“mDOR”) 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.

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

5.5-NEi) in the KRAS wild-type 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.

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

7.4-18.4) in the KRAS wild-type population.

The disease control rate (“DCR”) at six or more months was 61% in the total evaluable population, 70% in KRAS mutant population and 50% in KRAS wild-type population.

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

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.

Udai Banerji and is being conducted in the United Kingdom.

In this study, avutometinib was administered using a twice-weekly dose escalation schedule and was administered three out of every four weeks.

Defactinib was administered using a twice-daily dose escalation schedule, also three out of every four weeks.

Dose levels were assessed in three cohorts:

cohort 1 (avutometinib 3.2 mg, defactinib 200 mg);

cohort 2a (avutometinib 4 mg, defactinib 200 mg);

and cohort 2b (avutometinib 3.2 mg, defactinib 400 mg).

The recommended Phase 2 dose was determined to be avutometinib 3.2 mg plus defactinib 200 mg.

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

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:

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

As of the July 2023 data cutoff date, 19% of patients (5 of 26) were still on study treatment with a minimum follow-up of 17 months.

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 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 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 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.

The primary analysis of the RAMP 201 study was published in the Journal of Clinical Oncology in July 2025.

The FRAME study was published in Nature in June 2025.

RAMP 301 Phase 3 Confirmatory Clinical Trial

AVMAPKI FAKZYNJA CO-PACK is approved under accelerated approval based on the tumor response rate and duration of response.

The FDA requires that we confirm the benefit in a confirmatory trial.

In December of 2023, we initiated a global, randomized, confirmatory Phase 3 trial known as RAMP 301 in an international collaboration between The GOG Foundation, Inc.

and the European Network of Gynaecological Oncological Trial groups.

RAMP 301 is evaluating the combination of avutometinib and defactinib versus standard of care chemotherapy or hormonal therapy for the treatment of patients with recurrent LGSOC with and without a KRAS mutation.

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

The primary endpoint is progression-free survival by BICR .

Secondary endpoints include ORR, DOR, DCR, safety and tolerability, patient-reported outcomes, and overall survival (“OS”).

RAMP 301 has enrolled patients in the United States, Australia, Canada, Europe, United Kingdom , and Korea.

The planned enrollment for RAMP 301 of the targeted 270 patients was completed in October 2025, a full quarter earlier than anticipated.

Additional patient enrollment was also completed ahead of schedule in December 2025, following a pre-planned IA by the IDMC, which recommended a modest, one-time increase of 29 patients across KRAS mutation status based on the total enrollment achieved in October 2025.

We expect to report a topline readout of the primary endpoint in mid-2027.

Post-marketing Accelerated Approval Requirement and Commitments

As a condition of receiving accelerated approval for the AVMAPKI FAKZYNJA CO-PACK, we are required to conduct additional studies to verify the clinical benefit of AVMAPKI FAKZYNJA CO-PACK and address post-marketing commitments as agreed upon with the FDA.

We need to complete the ongoing Phase 3 RAMP 301 trial and provide the progression-free survival (“PFS”) and the final overall survival analyses, intended to describe and verify the clinical benefit of avutometinib and defactinib combination in adult patients with recurrent KRAS-mutated LGSOC with central KRAS testing results for all patients.

We are also required to complete a pediatric study of avutometinib and defactinib to evaluate preliminary efficacy, and characterize dose, pharmacokinetics (“PK”) pharmacodynamics (“PD”) and preliminary safety in pediatric patients ages 2 to <17 years of age with relapsed or refractory unresectable or metastatic RAS/MAPK pathway-driven pediatric cancers.

In addition, we are also required to:

● assess drug-drug interaction risks when defactinib is taken with CYP3A4 inhibitors through a trial evaluating the effect of a moderate CYP3A4 inhibitor on defactinib PK and identify the appropriate dosing

● evaluate the potential risk of cardiomyopathy in adult patients with recurrent LGSOC receiving the combination of avutometinib and defactinib

● enroll at least 15 evaluable patients with moderate hepatic impairment to evaluate the potential risk of increased serious adverse reactions with avutometinib in combination with defactinib

● assess the effect of severe hepatic impairment on defactinib and its active metabolite to evaluate the potential serious risk of increased serious adverse reactions in patients with severe hepatic impairment

● assess the effect of severe hepatic impairment on avutometinib to evaluate the potential serious risk of increased serious adverse reactions in patients with severe hepatic impairment

● assess the severe renal impairment on avutometinib to evaluate the potential serious risk of increased serious adverse reactions in patients with severe renal impairment

● complete study VS-6063-108, assessing drug interactions between defactinib and BCRP inhibitor, a P-gp Inhibitor, and a moderate CYP2C9 inhibitor

● assess effects of multiple doses of defactinib on single dose pharmacokinetics of substrates of CYP3A4, CYP2C9, P-gp, BCPR, OATP1B1, and OATP1B3 to evaluate the potential serious risks of

increased serious adverse reactions from elevated levels of CYP3A4, CYP2C9, P-gp, BCPR, OATP1B1, and OATP1B3 substrates, respectively, when they are used concomitantly with defactinib

● assess the effect of defactinib on MATE2-K substrates drugs interaction risks

● conduct an in vitro study to assess whether additional drug interaction studies are needed for defactinib metabolite M4

● conduct an appropriate analytical and clinical validation study to support the development of a diagnostic device that is essential to the safe and effective use of the combination of avutometinib and defactinib in KRAS-mutated, recurrent low-grade serous ovarian cancer

LGSOC Geographic Commercial Expansion

We continue to make progress on potential geographic commercial expansion of the AVMAPKI and FAKZYNJA combination therapy.

The European Commission granted Orphan Drug Designation in July 2025 for avutometinib plus defactinib for the treatment of ovarian cancer based on a positive opinion from the European Medicines Agency Committee for Orphan Medicinal Products.

Preliminary safety and efficacy data from the Phase 2 RAMP 201J trial in Japan was presented at the IGCS 2025 Annual Meeting in November 2025 and we are continuing enrollment of patients into the RAMP 301 study in Japan.

Plans to engage regulatory authorities in these regions are ongoing.

Product Pipeline

Avutometinib in Combination with Defactinib in First-line Advanced Pancreatic Cancer

In 2025, the National Cancer Institute (“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 U.S.

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

Early detection remains a challenge, and survival rates have not improved significantly during the past 40 years.

According to the NCI, the five-year survival rate for pancreatic cancer is 13% (2015-2021) and only 3% for those with advanced disease.

In 2025, the NCI estimated that more than 67,000 people in the U.S.

would be diagnosed with pancreatic cancer and more than 50,000 were estimated to die from this disease.

The treatment options for pancreatic cancer remain primarily limited to combinations of chemotherapy or chemotherapy plus radiation.

Immuno-oncology agents have not demonstrated a significant improvement in treatment outcomes for patients with pancreatic cancer.

KRAS mutations occur in up to 95% of pancreatic cancer.

KRAS mutations confer constitutive activation of the KRAS protein, which activates RAF and MEK downstream supporting proliferation and survival of tumor cells.

This provides the rationale for use of avutometinib to block both RAF and MEK to inhibit KRAS signaling in pancreatic cancer.

Additionally, it has been previously reported that inhibition of the MAPK pathway with targeted therapies activates FAK as an adaptive resistance mechanism.

Furthermore, FAK has been shown to be hyperactivated in human PDAC, and FAK activation has been correlated with high levels of fibroblasts, poor T cell infiltration and poor overall survival in these patients.

Thus, there is a strong scientific rationale for combining avutometinib (to inhibit RAF and MEK to block the MAPK pathway) and defactinib (to inhibit FAK to reduce stromal density and adaptive resistance to avutometinib) to the standard of care gemcitabine/Nab-paclitaxel regimen with the objective of increasing response rate and survival.

In preclinical models of pancreatic cancer, this combination of avutometinib and FAK inhibition with gemcitabine and paclitaxel has been shown to induce strong tumor regression.

Avutometinib and defactinib in combination with standard of care chemotherapy (gemcitabine and Nab-paclitaxel) are being evaluated in patients with previously untreated advanced PDAC in the RAMP 205 clinical trial.

RAMP 205 is a multicenter, open-label, single-arm Phase 1b/2a study designed to evaluate the safety, tolerability and efficacy of the combination at different doses and schedules to determine the recommended RP2D.

We received the first “Therapeutic Accelerator Award” from Pancreatic Cancer Network (“PanCAN”) for up to $3.8 million to support the RAMP 205 study.

In May of 2025, we announced an update on the RAMP 205 trial and that we selected our RP2D as DL1.

In the update, DL1 demonstrated a confirmed ORR of 83% (10/12) in patients.

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 completed enrollment of 29 patients in an expansion cohort at the RP2D in 2025, and we expect to report an update on the safety and efficacy of this cohort in the first half of 2026.

VS-7375, an Oral KRAS G12D (ON/OFF) Inhibitor

VS-7375 is a potential best-in-class, potent, and selective oral KRAS G12D dual ON/OFF inhibitor.

VS-7375 has a differentiated profile compared to other RAS inhibitors.

Based on preclinical data, VS-7375 offers dual, potent inhibition of both ON and OFF states of KRAS G12D.

We believe this correlates with better in vivo efficacy and durability versus ON-only RAS inhibitors.

VS-7375 has demonstrated a high affinity for KRAS G12D with long residence time (18-24 hours) in preclinical models.

We believe this correlates with a more rapid and durable suppression of pERK signaling (which controls growth and cell survival) when compared to other ON-only KRAS G12D inhibitors in tumor cell lines.

The selective inhibition of VS-7375 to KRAS G12D has shown, in preclinical models, to spare T cell proliferation to maintain a normal healthy immune response, versus a RAS-multi-inhibitor which impairs T cell proliferation at increasing concentrations of drug.

The once daily oral dosing of VS-7375 achieves exposures corresponding to maximal tumor regressions across preclinical models for pancreatic, lung and colorectal cancers.

VS-7375 Licensing

VS-7375 is the lead program from the discovery and development collaboration with GenFleet.

We exercised the GenFleet Option (defined herein) in January 2025, announced that our IND application for VS-7375 had been approved by the FDA in April 2025, and initiated a Phase 1/2a clinical trial in June 2025.

GenFleet is developing VS-7375 as GFH375 in greater China.

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

To date, GenFleet has generated data in more than 150 patients with PDAC, NSCLC, and other solid tumor cancers, and reported initial positive safety and anti-tumor activity in 2L PDAC (58.3% ORR in 12 patients) and 2L NSCLC (68.8% ORR in 16 patients).

GenFleet also has an ongoing Phase 1/2b trial of GFH375 in combination with cetuximab or chemotherapy in KRAS G12D-mutated solid tumors in China.

The chemotherapy combination will be conducted in 1L PDAC.

GenFleet is also conducting a Phase 3 trial in China evaluating GFH375 in patients with pretreated KRAS G12D-mutated metastatic pancreatic cancer.

VS-7375-101 Phase 1/2 Clinical Trial KRAS G12D Solid Tumors

In June 2025, we dosed the first patient in the monotherapy portion of VS-7375-101, the U.S.

Phase 1/2 clinical trial evaluating VS-7375 in patients with advanced KRAS G12D mutant solid tumors, including PDAC, NSCLC, CRC and other KRAS G12D mutated solid tumors.

We continue to make progress with the VS-7375-101 trial, which includes both monotherapy and combination dose escalation and dose expansion cohorts.

VS-7375-101 Phase 1/2b Monotherapy Dose Escalation and Dose Expansion Phases

In the monotherapy dose escalation phase, we cleared the 400 mg, 600 mg, and 900 mg daily dose levels with no DLTs and no major toxicities.

We reported early safety data that showed limited nausea and vomiting through feeding patients and using standard prophylaxis treatments.

We also addressed diarrhea quickly with standard oral agents.

Promising anti-tumor activity was observed in patients with various solid tumors, including metastatic PDAC.

We initiated dose expansion cohorts with the 600 mg QD dose and are increasing enrollment across three different cohorts:

2L PDAC, 2L/3L NSCLC, and other 2L+ KRAS G12D mutated solid tumors.

We plan to report early data from the VS-7375-101 trial in the first half of 2026.

VS-7375-101 Phase 1/2b Combination Dose Escalation and Dose Expansion Phases

In our combination cohorts, we are enrolling patients into three different dose escalation cohorts, including 2L+ solid tumors in combination with cetuximab, 1L NSCLC in combination with carboplatin/pemetrexed /pembrolizumab, and 2L PDAC in combination with gemcitabine and Nab-paclitaxel.

We cleared the 400 mg QD dose and 600 mg QD dose of VS-7375 in combination with cetuximab and higher doses are now being evaluated.

In our dose expansion cohorts, we plan to continue to evaluate VS-7375 alone and in combination with cetuximab in 2L+ CRC.

We also plan to continue to evaluate VS-7375 with chemotherapy or immunotherapy in 1L NSCLC and move into the 1L PDAC setting in combination with chemotherapy.

VS-7375 Regulatory Pathway

In July 2025, the FDA granted FTD to VS-7375, for 1L treatment of patients with KRAS G12D-mutated locally advanced or metastatic PDAC and for the treatment of patients with KRAS G12D-mutated locally advanced or metastatic PDAC who have received at least one prior line of standard systemic therapy.

Based on recent FDA feedback, we plan to amend the VS-7375-101 Phase 1/2 protocol to breakout disease specific Phase 2 registration-directed trials for KRAS G12D mutated 2L PDAC, 2L/3L NSCLC and 2L+ CRC.

Our development focus is on the highest unmet need populations, and we plan to expedite regulatory submissions as quickly as possible.

Market Opportunity in U.S.

for PDAC, NSCLC, CRC KRAS G12D Tumors

KRAS G12D represents 26% of all KRAS mutations, making it the most prevalent KRAS mutation in human cancers.

The KRAS G12D mutation occurs most commonly in pancreatic (40%), colorectal (15%), non-small cell lung (5%) and other cancers such as endometrial (5%), biliary tract cancer (7-15%) and small bowel cancer (16%).

Across the various KRAS G12D-mutated cancers, the KRAS G12D mutation often correlates with worse outcomes.

In pancreatic cancer, it is associated with shorter survival and a higher risk of progression.

In lung cancer, the KRAS G12D mutation is a significant driver of the disease, especially among non-smokers and is linked to poor responses to standard of care.

In colorectal cancer, which is impacting younger populations, the KRAS G12D mutation is often linked to aggressive tumors.

Overall, the KRAS G12D mutation appears across many types of cancer and remains an unmet medical need.

According to external sources, market research, and internal analyses and calculations, we estimate the potential addressable market in KRAS G12D-mutated cancers at launch in the U.S.

represents a multi-billion dollar opportunity with the ability to treat approximately 40,000 patients annually across either 1L or 2L treatment (with or without combination treatments) in PDAC, NSCLC, CRC and other solid tumors.

Currently, no therapies are approved in the U.S., Europe or Japan, specifically targeting KRAS G12D mutations in cancer.

INTELLECTUAL PROPERTY

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We plan to continue to expand our intellectual property estate by filing patent applications directed to compositions, methods of treatment, and patient selection created or identified from our ongoing development of our product candidates.

Our success will depend on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business, defend and enforce our patents, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and proprietary rights of third parties.

Our success will depend on our ability to obtain and maintain patent and other proprietary protection for

commercially important technology, inventions and know-how related to our business, defend and enforce our patents, preserve the confidentiality of our trade secrets, and operate without infringing the valid and enforceable patents and proprietary rights of third parties.

We also rely on know-how, continuing technological innovation, and in-licensing opportunities to develop and maintain our proprietary position.

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We cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient protection from competitors.

Because patent applications in the United States and certain other jurisdictions are maintained in secrecy for 18 months or potentially even longer, and since publication of discoveries in the scientific or patent literature often lags behind actual discoveries, we cannot be certain of the priority of inventions covered by pending patent applications.

Because patent applications in the U.S.

and certain other jurisdictions are maintained in secrecy for 18 months or potentially even longer, and because publication of discoveries in the scientific or patent literature often lags behind actual discoveries, we cannot be certain of the priority of inventions covered by pending patent applications.

Moreover, we may have to participate in interference proceedings or derivation proceedings declared by the U.S.

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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.

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

The first patent family has claims directed to the composition of matter of avutometinib, and includes granted patents in various jurisdictions, such as the U.S., 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 U.S.

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 two granted patents in the United States, that are expected to expire in November of 2038, granted patents in Australia, Europe, Korea, and Taiwan, and pending patent applications in various jurisdictions, such as 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.

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 two granted patents in the U.S.

and granted patents in Japan, Hong Kong, Macau, Singapore, 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 U.S.

In addition, we own one patent family covering solid forms of avutometinib, which includes two granted patents in the U.S.

that are expected to expire in December of 2042, a pending patent application in the U.S., 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.

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, Canada, China, Europe, and the U.S., 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 U.S., 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 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.

We have exclusively licensed a portfolio of patents owned by Pfizer, which are directed to FAK inhibitor compounds and methods of their use, for example in cancer.

One patent family has claims directed to the composition of matter of defactinib, has a patent application pending in the United States, and 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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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.

This family contains granted patents in various jurisdictions, such as Europe (validated in various countries), 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.

Patents in this family have been granted in the U.S., 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.

Patent applications in this family have been granted in the U.S., 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 U.S., 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.

We in-licensed a patent portfolio 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.

One patent family includes patent applications pending in various jurisdictions, such as the United States, Europe, and Japan, that if issued would expire in August 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 patent applications pending in various jurisdictions, such as Australia, Brazil, Canada, Europe, Japan, Korea, Mexico, and the U.S., that if issued, are expected to expire in September 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.

The other two patent families are directed to other KRAS inhibitors.

One family includes patent applications in the U.S.

and Europe, that if issued are expected to expire in April 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 remaining family includes patent applications in various jurisdictions such as the U.S., Australia, Brazil, Canada, Europe, Japan, and Korea, that if issued are expected to 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 base term of a U.S.

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patent is shortened by terminal disclaimer that reduces its term to that of an earlier-expiring patent.

The term of a United States patent may be eligible for patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Act, to account for at least some of the time the drug is under development and regulatory review after the patent is granted.

The term of a U.S.

patent may be eligible for patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, referred to as the Hatch-Waxman Act, to account for at least some of the time the drug is under development and regulatory review after the patent is granted.

With regard to a drug for which FDA approval is the first permitted marketing of the active ingredient, the Hatch-Waxman Act allows for extension of the term of one United States patent that includes at least one claim covering the composition of matter of an FDA-approved drug, an FDA-approved method of treatment using the drug, and/or a method of manufacturing the FDA-approved drug.

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GenFleet Therapeutics Inc.

On August 24, 2023, we entered into the GenFleet Agreement, pursuant to which GenFleet granted us the GenFleet Options.

On August 24, 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.

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 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.

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 VS-7375.

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 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.

In addition, pursuant to the GenFleet Agreement, upon achievement of certain milestones, and upon us 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.

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On June 30, 2022, the FDA issued a drug safety communication warning that resulted from a clinical trial showing a possible increased risk of death with COPIKTRA compared to another medicine to treat chronic blood cancer called leukemia and lymphoma.

The clinical trial also found that COPIKTRA was associated with a higher risk of serious side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood.

The clinical trial also found that COPIKTRA was associated with a higher risk of serious

side effects, including infections, diarrhea, inflammation of the intestines and lungs, skin reactions, and high liver enzyme levels in the blood.

In September 2022, the FDA’s Oncologic Drug Advisory Committee (“ODAC”) voted eight to four against COPIKTRA’s use in patients with relapsed or refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma after at least two prior therapies citing an unfavorable risk/benefit profile.

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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 16,001 shares of our common stock, adjusted for our Reverse Stock Split (defined herein).

Upon entering into the Pfizer Agreement, we made a onetime 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).

In April 2025, we entered into an amendment to the Pfizer Agreement such that a $7.5 million milestone became payable upon FDA approval of AVMAPKI FAKZYNJA CO-PACK on May 8, 2025 (the “First Pfizer Milestone”), and $8.0 million milestone (the “Second Pfizer Milestone”) is payable upon the one-year anniversary of the FDA approval of AVMAPKI FAKZYNJA CO-PACK.

We made the First Pfizer Milestone payment in 2025 and expect to make the Second Pfizer Milestone payment in 2026.

Pfizer is also eligible to receive up to $2.0 million in developmental milestones and up to an additional $110.0 million based on the successful attainment of regulatory and commercial sales milestones.

Pfizer is also eligible to receive high single to mid-double-digit royalties on future net sales of the products.

Our royalty obligations with respect to each product in each country begin on the date of first commercial sale of the product in that country, and end on the later of 10 years after the date of first commercial sale of the product in that country or the date of expiration or abandonment of the last claim contained in any issued patent or patent application licensed by Pfizer to us that covers the product in that country.

product in that country or the date of expiration or abandonment of the last claim contained in any issued patent or patent application licensed by Pfizer to us that covers the product in that country.

The Pfizer Agreement will remain in effect until the expiration of all our royalty obligations to Pfizer, determined on a product by product and country by country basis.

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In addition, our ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic products.

There are many generic products currently on the market for the indications that we are pursuing, and additional products are expected to become available on a generic basis over the coming years.

There are many generic products currently on the market for the indications that we are pursuing, and additional generic products are expected to become available over the coming years.

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

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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.

In general, although there has been considerable progress over the past few decades in the treatment of cancer and the currently marketed therapies provide benefits to many patients, these therapies all are limited to some extent in their efficacy and frequency of adverse events, and none of them are successful in treating all patients.

efficacy and frequency of adverse events, and none of them are successful in treating all patients.

As a result, the level of morbidity and mortality from cancer remains high.

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As a result, they may provide significant competition for any of our product candidates for which we obtain market approval.

RAF/MEK inhibition program

There are other companies with approved RAF and/or MEK inhibitors with FDA approval in the market and companies working to develop RAF and/or MEK inhibitor.

We believe the following companies have an approved RAF and/or MEK inhibitor:

● Novartis AG, which has received FDA approval for Taflinar ® (dabrafenib), a RAF inhibitor, in combination with Mekinist ® (trametinib), a MEK inhibitor, for treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, adjuvant treatment for melanoma with BRAF V600E or V600K mutations and involvement of lymph nodes following complete resection, metastatic NSCLC with BRAF V600E or V600K mutations and locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation;

● Pfizer, through its acquisition of Array BioPharma, Inc, has received FDA approval for Braftovi ® (encorafenib), a RAF inhibitor, in combination with Mektovi ® (binimetinib), a MEK inhibitor, for treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

In addition, the FDA has granted approval for Braftovi ® (encorafenib) in combination with Erbitux ® (cetuximab), an anti-EGFR antibody for treatment of adult patients with metastatic CRC with a BRAF V600E mutation;

● Genentech, Inc.

a member of the Roche Company, which has received FDA approval for Zelboraf ® (vemurafenib), a RAF inhibitor, in combination with Cotellic ® (cobimetinib), a MEK inhibitor, to treat patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation;

● AstraZeneca and Merck & Co., Inc.

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

We understand that InxMed, a clinical-stage biotech company, is developing a FAK small molecule inhibitor program.

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

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.

For example, we understand that AbbVie Inc.

has received FDA approval for Elahere for treatment of adult patients with folate receptor alpha positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens.

Our competition also includes hundreds of private and publicly traded companies that operate in the area of oncology but have therapeutics with different mechanisms of action.

The oncology market in general is highly competitive, with over 1,000 molecules currently in clinical development.

Several FDA-approved RAF and/or MEK inhibitors are commercially available;

however, we are not aware of any products that are specifically approved for KRAS-mutated recurrent LGSOC.

Competitors that are currently developing RAF and/or MEK inhibitors are Abbvie, AstraZeneca, Bristol Myers Squibb Company, Erasca, Genentech, Novartis AG, and Pfizer.

Other competitors developing KRAS G12D inhibitors and pan-KRAS inhibitors are Astellas Pharma Inc., AstraZeneca, Bayer, BeOne, Boehringer Ingelheim, Chugai, D3 Bio, Eli Lilly, GenFleet, Genentech, Incyte Corporation, Jacobio, Jiangsu Hengrui Pharmaceuticals Company Ltd, Quanta Therapeutics, Ranok Therapeutics, Revolution Medicine, and Tyligand Bioscience;

however, we are not aware of any FDA-approved treatments for the KRAS G12D mutation.

MANUFACTURING

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

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

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

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

We are in the process of completing tech transfers with a two domestic CMO to onshore the manufacture of both drug substance and drug product of VS-7375 to the US.

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

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 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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APPLICABLE LAWS AND GOVERNMENT REGULATION

Government authorities in the United States, at the federal, state and local level, and in other countries extensively regulate, among other things, the research, development, testing, manufacture, including any manufacturing changes, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, import and export of pharmaceutical products, such as those we are developing.

United States drug approval process

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.

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.

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

Government authorities in the U.S., at the federal, state and local level, and in other countries extensively regulate, among other things, the research, development, testing, manufacture, including any manufacturing changes, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, import and export of pharmaceutical products, such as those we are developing.

Drug Approval Process

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

Failure to comply with the applicable U.S.

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.

The process required by the FDA before a drug may be marketed in the U.S.

generally involves the following:

● 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;

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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.

Raimondo (“ Loper ”) 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.

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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 PDUFA was re-authorized for an additional five years in 2022

until 2027, and negotiations are underway to re-authorize PDUFA for fiscal years 2028 through 2032.

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

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A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application.

If the FDA issues a complete response letter, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter.

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

If the FDA issues a complete response letter, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application.

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

The FDA has committed to reviewing such resubmissions in two to six months depending on the type of information included.

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.

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

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.

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.

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.

2617) includes numerous reforms to the accelerated approval process for drugs and biologics and enables FDA to require, as appropriate, that a post-approval study be underway prior to granting accelerated approval.

FDORA also expands the expedited withdrawal procedures available to FDA to allow the agency to use expedited procedures if a sponsor fails to conduct any required post-approval study of the product with due diligence.” FDORA also adds the failure of a sponsor of a product approved under accelerated approval to conduct with due diligence any required post-approval study with respect to such product or to submit timely reports with respect to such product to the list of prohibited acts in the Food, Drug, and Cosmetic Act.

2617) includes numerous reforms to the accelerated approval process for drugs and biologics and enables the FDA to require, as appropriate, that a post-approval study be underway prior to granting accelerated approval.

FDORA also expands the expedited withdrawal procedures available to the FDA to allow the agency to use expedited procedures if a sponsor fails to conduct any required post-approval study of the product with due diligence.

FDORA also adds the failure of a sponsor of a product approved under accelerated approval to conduct with due diligence any required post-approval study with respect to such product or to submit timely reports with respect to such product to the list of prohibited acts in the FDCA.

All promotional materials for drug candidates approved under accelerated regulations are subject to prior review by the FDA.

Under the Orphan Drug Act, the FDA may grant orphan drug designation to drugs intended to treat a rare disease or condition, which is generally defined as a disease or condition that affects fewer than 200,000 individuals in the United States.

Orphan drug designation must be requested before submitting an NDA.

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

The first NDA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDA orphan drug designation is entitled to a seven-year exclusive marketing period in the United States for that product, for that indication.

for that product, for that indication.

During the seven-year exclusivity period, the FDA may not approve any other applications to market the same drug for the same orphan indication, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity in that it is shown to be safer, more effective or makes a major contribution to patient care.

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Combination therapy is a treatment modality that involves the use of two or more drugs to be used in combination to treat a disease or condition.

If those drugs are combined in one dosage form, such as one pill, that is known as a fixed dose combination product and it is reviewed pursuant to the FDA’s Combination Rule at 21 CFR 300.50.

If those drugs are combined in one dosage form, such as one pill, that is known as a fixed dose combination product, and it is reviewed pursuant to the FDA’s Combination Rule at 21 CFR 300.50 (“the Rule”).

The Rule provides that two or more drugs may be combined in a single dosage form when each component contributes to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.

But not all combination therapy falls under the category of a fixed dose combination.

Not all combination therapy falls under the category of a fixed dose combination.

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.

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In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements.

Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented.

Changes to the manufacturing process are strictly regulated and often require prior FDA approval before implementation.

FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon us and any third-party manufacturers that we may decide to use.

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The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability.

The current administration announced in September 2025 that it intends to prioritize enforcement of pharmaceutical advertising requirements.

Additional Provisions

Physician drug samples

As part of the sales and marketing process, pharmaceutical companies frequently provide samples of approved drugs to physicians.

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Other Healthcare Laws

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

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

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

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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.

and protect the privacy of individual information.

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

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Attorney offices within the Department of Justice, the U.S.

Department of Health and Human Services, or HHS, HHS’ various divisions, including but not limited to, the Centers for Medicare & Medicaid Services, or CMS, and the Office of Inspector General, and state boards of pharmacy.

Department of Health and Human Services (“HHS”), HHS’ various divisions, including but not limited to, the Centers for Medicare & Medicaid Services (“CMS”), and the Office of Inspector General, and state boards of pharmacy.

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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Foreign Regulation

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.

In order to market any product outside of the U.S., 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.

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One third-party payor’s decision to cover a particular drug product or service does not ensure that other payors will also provide coverage for the drug product or will provide coverage at an adequate reimbursement rate.

Within the United States, FDA-approved drugs could potentially be covered by various government health benefit programs as well as purchased by government agencies.

Within the U.S., FDA-approved drugs could potentially be covered by various government health benefit programs as well as purchased by government agencies.

The participation in such programs or the sale of products to such agencies is subject to regulation.

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The amount of the rebate for each product is set by law and may be subject to an additional discount if certain pricing increases more than inflation.

Medicare is a federal program that is administered by the federal government that covers individuals aged 65 and over as well as those with certain disabilities.

Oral drugs may be covered under Medicare Part D.

State Medicaid programs and Medicaid managed care plans can seek additional “supplemental” rebates from manufacturers.

Medicare is a federal program that is administered by the federal government that covers individuals aged 65 and over, disabled individuals and certain other eligible individuals.

Medicare Part D provides coverage to enrolled Medicare patients for self-administered drugs (i.e., drugs that do not need to be injected or otherwise administered by a physician).

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government and each drug plan establishes its own Medicare Part D formulary for prescription drug coverage and pricing, which the drug plan may modify from time-to-time.

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 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.

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

Manufacturers with marketed brand name drugs may be asked to provide discounts on brand name prescription drugs utilized by Medicare Part D beneficiaries in order for a given prescription drug plan to cover the manufacturer’s drug.

Under a new manufacturer discount drug program that became 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 ($2,100) and then 20% of the allowed cost of the drug.

Additionally, as the result of recent changes under the Inflation Reduction Act of 2022 (“IRA”), drug utilization under Medicare Part B and Part D may be subject to an additional Medicare discount if the pricing increases more than inflation.

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

FSS participation is required for a drug product to be covered and reimbursed by certain federal agencies and for coverage under Medicaid, Medicare Part B and the Public Health Service (“PHS”) pharmaceutical pricing program.

FSS participation is required for a drug product to be covered and reimbursed by certain federal agencies and for coverage under the Medicaid Drug Rebate Program and Medicare Part B.

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.

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.

FSS pricing is subject to statutory reporting requirements and is negotiated periodically with the Department of Veterans Affairs, including by reference to a manufacturer’s comparable non-federal customer pricing.

In addition, prices for drugs purchased by the Veterans Administration (“VA”), Department of Defense (including drugs purchased by military personnel and dependents through the TRICARE retail pharmacy program), Coast Guard, and Public Health Service (“PHS”) through the FSS 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 and Medicare Part B, manufacturers are required to participate in and extend discounts to certain purchasers under the PHS pharmaceutical pricing program.

Purchasers eligible for discounts include hospitals that serve a disproportionate share of financially needy patients, community health clinics and other entities that receive health services grants from the PHS.

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

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

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

If these third-party payors do not consider our products to be cost effective compared to other available therapies, they may not cover our products after approval as a benefit under their plans or, if they do, the level of payment may not be sufficient to allow us to sell our products at a profit.

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

Federal and state governments in the U.S.

as well as foreign governments have shown significant interest in implementing cost containment programs to limit the growth of government paid healthcare costs, including price controls, restrictions on reimbursement and requirements for substitution of generic products for branded prescription drugs.

Adoption of such controls and measures, and tightening of existing controls and measures, could limit payments for pharmaceuticals such as the drug candidates that we are developing and could adversely affect our net revenue and results.

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New Legislation and Regulations

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.

From time to time, legislation is drafted, introduced and passed in the U.S.

Congress that could significantly change the statutory provisions governing the testing, approval, manufacturing and marketing of pharmaceutical products.

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.

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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.

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.

Additionally, in the U.S., 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.

For example, in 2010, Congress enacted the Patient Protection and Affordable Care Act and the Healthcare and Education Reconciliation Act (collectively, “ACA”), which expanded healthcare coverage through Medicaid expansion and the implementation of the individual mandate for health insurance coverage, and 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 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.

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.

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.

For example, with respect to the ACA, tax reform legislation was enacted that eliminated the tax penalty established for individuals who do not maintain mandated health insurance coverage beginning in 2019 and, in 2021, the U.S.

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

As another example, revisions to regulations under the federal anti-kickback statute would remove protection for traditional Medicare Part D discounts offered by pharmaceutical manufacturers to pharmacy benefit managers and health plans.

Pursuant to court order, the removal was delayed, and recent legislation imposed a moratorium on implementation of the rule until January 1, 2032.

As further example, the IRA drug price negotiation program has been challenged in litigation filed by various pharmaceutical manufacturers and industry groups.

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

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 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.

For 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.

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 prior 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 set of negotiated Medicare maximum fair prices going into effect in 2026).

The IRA has had a significant impact on the pharmaceutical industry and that impact is anticipated to continue.

Beyond the IRA, changes to Medicaid effective in 2024 eliminated the Medicaid rebate cap and changes to certain Medicare price reporting requirements for drugs beginning in 2026 will likely increase the administrative and compliance burden for manufacturers.

In addition, recent legislation expanded the orphan drug exclusion in the IRA Medicare drug price negotiation program.

Under the current presidential administration, there has been significant reform activity focused on drug pricing and reimbursement.

For example, President Trump issued an Executive Order in April 2025 with multiple directives aimed at lowering drug prices, including refining the Medicare drug price negotiation program established by the IRA, accelerating competition for high-cost prescription drugs by accelerating approval of generics and biosimilars and facilitating the process for re-classifying prescription drugs as over-the-counter drugs, and increasing drug importation.

In May 2025, President Trump issued another Executive Order that directed government agencies and officials to identify most-favored nation pricing targets for prescription drugs (and looked to pharmaceutical manufacturers to make significant progress towards delivering target prices to patients), prevent foreign countries from disproportionately shifting the cost of global pharmaceutical research and development to the U.S., and facilitate direct-to-consumer purchasing programs for pharmaceutical manufacturers to sell their products to patients at the most-favored-nation price.

In the wake of the Executive Orders and related executive initiatives, a number of pharmaceutical manufacturers have announced direct-to-consumer offerings with discounted prices and/or reached agreement with the federal government regarding pricing for drugs, including prices for Medicaid drugs and newly launched products.

A future website sponsored by the federal government that is anticipated to offer pharmaceutical direct-to-consumer channels has also been announced.

Federal agencies are developing new drug pricing pilot programs, such as a Medicaid model that would authorize the federal government to negotiate Medicaid supplemental rebates with participating manufacturers on behalf of state Medicaid programs, in exchange for standardized coverage criteria for participating manufacturer drugs, and proposed Medicare Part B and Part D pilot models that, if finalized as proposed, would replace existing inflation-based Medicare rebates with rebates determined on the basis of international prices, for drugs and patients subject to the model.

Other healthcare reform efforts or actions may affect access to healthcare coverage or the funding of health care benefits, although the full impact of such efforts or actions cannot be predicted.

For example, the Congressional Budget Office has estimated that Medicaid provisions in the 2025 budget reconciliation legislation, including restrictions in eligibility and funding for Medicaid, as well as changes to the healthcare marketplace such as the elimination of certain subsidies, will increase the number of uninsured patients.

Individual states in the U.S.

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

Healthcare reform efforts have been and may continue to be subject to scrutiny, legal challenge and subsequent amendment, creating further uncertainty.

Other government actions could have an adverse effect upon, and could prevent, our products’ commercial success.

For example, the Trump Administration’s announced tariff on branded or patented drugs may increase the cost of drug products that are imported from abroad or manufactured using products or materials imported from abroad.

The timeline for implementation of this tariff has not yet been finalized.

As another example, the Budget Control Act of 2011, as amended, resulted in the imposition of reductions in Medicare (but not Medicaid) payments to providers in

2013 and remains in effect through 2032 unless additional Congressional action is taken.

Any significant spending reductions affecting Medicare, Medicaid or other publicly funded or subsidized health programs that may be implemented and/or any significant taxes or fees that may be imposed on us could have an adverse impact on our results of operations.

Healthcare reform initiatives 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 such reform.

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

HUMAN CAPITAL RESOURCES

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President, Chief Executive Officer

Chief Operating Officer

Michael Kauffman

President of Development

Daniel Calkins

Chief Financial Officer

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.

Paterson , 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, as 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.

Calkins served as our Vice President, Finance from September 2022 to October 2023, our Corporate Controller from March 2020 to September 2022, our Assistant Controller from May 2019 to March 2020, and our Associate Director, SEC Reporting and Technical Accounting from December 2018 to May 2019.

Michael Kauffman M.D., Ph.D.

, has served as our President of Development since December 2025 after serving as lead director of our board of directors since June 2016.

Michael has been a member of our board of directors since November 2012 and continues to serve on our board of directors.

Prior to his role as President of Development, he was the Chief Executive Officer, president and board member of Nereid Therapeutics Inc from November 2023 to November 2025.

Prior to this, Dr.

Kauffman was the cofounding Chief Executive Officer and acting Chief Medical Officer of Karyopharm Therapeutics Inc., a publicly traded commercial stage biotechnology company, from January 2011 to April 2021 and senior clinical advisor from May 2021 to May 2022.

Prior to this, Dr.

Kauffman was the Chief Medical Officer of Onyx Pharmaceuticals, Inc., a publicly traded biotechnology company, from November 2009 until December 2010.

Kauffman received an M.D.

in molecular biology and biochemistry from Johns Hopkins University and holds a B.A.

in biochemistry from Amherst College.

Kauffman trained in Internal Medicine at Beth Israel Deaconess and rheumatology at Massachusetts General Hospitals, and is board certified in internal medicine.

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

Calkins served as our Vice President, Finance from September 2022 to October 2023, as our Corporate Controller from March 2020 to September 2022, as our Assistant Controller from May 2019 to March 2020, and as our Associate Director, SEC Reporting and Technical Accounting from December 2018 to May 2019.

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