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Item 1. Business

2024-03-14 compared with 2023-03-14 · 313 added, 276 removed, 558 unchanged (51% of the section changed)

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

Our most advanced product candidates, avutometinib (VS-6766) and defactinib, are being investigated in both preclinical and clinical studies for the treatment of various solid tumors, including, but not limited to low-grade serous ovarian cancer (“LGSOC”), non-small cell lung cancer (“NSCLC”), colorectal cancer (“CRC”), pancreatic cancer, and melanoma.

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

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

Avutometinib is an orally available first-in-class unique small molecule RAF/MEK clamp.

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

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

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

MEK-only inhibitors (e.g.

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

This unique mechanism of avutometinib enables it to inhibit ERK signaling more effectively and may confer enhanced therapeutic activity against mitogen-activated pathway kinase (“MAPK”) pathway-driven cancers.

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

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

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

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

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

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

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

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

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

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

FAK is a non-receptor tyrosine kinase encoded by the protein tyrosine kinase-2 (“PTK-2”) gene that is involved in cellular adhesion and, in cancer, metastatic capability.

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

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

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

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

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

Preclinical research by our scientists and collaborators at world-renowned research institutions has described the effect of FAK inhibition as enhancing immune response by decreasing immuno-suppressive cells, increasing cytotoxic T cells and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.

Furthermore, it has been shown that FAK activation in response to MAPK inhibitor therapy may bypass MAPK pathway blockade by driving tumor growth through activation of downstream pathways such as RhoA and YAP, supporting the clinical evaluation of avutometinib in combination with defactinib for treatment of cancers harboring MAPK alterations.

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

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

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

In the fourth quarter of 2020, we commenced two registration-directed trials investigating avutometinib as a monotherapy and in combination with defactinib.

The registration-directed trials are entitled RAMP 201 and RAMP 202.

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

RAMP 202 is 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 KRAS G12V NSCLC, following treatment with a platinum-based regimen and immune checkpoint inhibitor.

Additionally, and based on preclinical rationale, we added additional cohorts to the RAMP 202 study including KRAS non-G12V NSCLC and BRAF mutant (V600E and non-V600E) NSCLC.

Both studies are discussed in greater detail below.

In January 2023, we reported data from a planned interim analysis of Part A of the ongoing RAMP 201 trial among patients with LGSOC treated with avutometinib alone and in combination with defactinib.

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

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

Of the 29 patients evaluable for response by blinded independent central review (“BICR”) in the combination arm, the initial results showed a confirmed objective response rate (“ORR”) of 28% in all patients and 27% vs 29% in KRAS mutant (n=15) and KRAS wild-type (n=14) LGSOC, respectively.

Three additional patients with KRAS mutant LGSOC showed an unconfirmed partial response.

In addition, the vast majority of patients showed tumor regression, as the overall disease control rate (stable disease plus partial response) was 93%.

Most evaluable patients (62%) were still on study treatment on the combination arm at the time of the data cut with a minimum follow-up of five months.

The confirmed ORR for the monotherapy arm by BICR was 7% in evaluable patients (n=30).

The overall disease control rate for the monotherapy arm by BICR was 90%.

Across both the combination and monotherapy arms, there have been no additional safety signals reported with a continued favorable safety and tolerability profile, with 9% discontinuation due to adverse events in the combination arm.

We will continue future enrollment of RAMP 201 in the combination arm only in all patients with recurrent LGSOC, regardless of their KRAS status.

Target enrollment for the combination arm has been achieved.

We are planning a RAMP 201 presentation at a scientific medical conference in 2023.

In the fourth quarter of 2022, a type B meeting with the FDA was held to discuss the results to date of the ongoing RAMP 201 trial, confirm the go-forward treatment regimen selection and discuss the regulatory path forward.

The combination of avutometinib with defactinib has been selected versus monotherapy as the go-forward treatment in all recurrent LGSOC regardless of KRAS status, acknowledging the demonstrated contribution of defactinib.

We intend to include mature data from the RAMP 201 study and the FRAME study to potentially support filing for accelerated approval in patients with recurrent LGSOC .

Both studies are evaluating avutometinib and defactinib in patients with recurrent LGSOC.

We are in ongoing discussions with the FDA on the confirmatory study and plan to provide an update after agreement with the FDA.

Continued enrollment in the combination arm of RAMP 201 is planned to expand the clinical experience in anticipation of initiation of a confirmatory study.

In October 2022, we reported data from a planned interim analysis of Part A from the RAMP 202 trial among patients with KRAS G12V NSCLC treated with avutometinib or the combination of avutometinib and defactinib.

The results did not meet the pre-defined criteria to continue to the trial expansion phase.

Among patients with KRAS non-G12V NSCLC, no KRAS subtype was identified for further clinical evaluation of avutometinib with defactinib in this trial.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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 trial entitled RAMP 203.

The Phase 1/2 trial will evaluate the safety, tolerability and efficacy of avutometinib in combination with LUMAKRAS in patients with KRAS G12C NSCLC who have not been

previously treated with a KRAS G12C inhibitor, as well as in patients who have progressed on a KRAS-G12C inhibitor.

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

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

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

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

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

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

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

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.

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

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

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

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

The RAMP 204 trial is open and enrolling.

The RAMP 204 study is open and enrolling.

Dose escalation is ongoing.

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

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

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

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

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

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

We received $1.0 million of cash proceeds in July 2022.

We opened the RAMP 205 trial in the fourth quarter of 2022.

Avutometinib and defactinib are currently being investigated in combination with immunotherapeutic and other agents through investigator sponsored trials (“ISTs”).

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

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

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

The RAMP 205 trial is open and enrolling.

Dose escalation is ongoing.

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

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

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

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 KRAS G12D inhibitor with a potential best-in-class profile as the lead program from our collaboration with GenFleet.

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

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

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

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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.

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.

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

“SEER”) reported that in 2022 there were approximately 19,880 new cases of ovarian cancer, 236,740 new cases of lung cancer, 151,030 new cases of colorectal cancer and 62,210 new cases of pancreatic cancer in the United States.

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

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

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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, and failed, to develop therapies that effectively block the cancer-promoting effects of KRAS mutation.

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.

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

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

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

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

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

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

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

Approximately 15% of lung cancers are small cell lung cancer, approximately 55% are adenocarcinomas, approximately 20% are squamous carcinomas, and about 5% are large cell carcinomas with the remainder being mixed or rare histologies.

Approximately 80-85% of lung cancers are NSCLCs, comprising of adenocarcinomas, squamous carcinomas, and large cell carcinomas.

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

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

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

The most frequent molecular alterations are mutations in the KRAS gene (about 25% of adenocarcinomas) of which KRAS G12C is most common (14%) and G12V second most frequent (7%).

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

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

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

Currently, avutometinib is being evaluated (i) in combination with Amgen’s KRAS-G12C inhibitor LUMAKRAS (sotorasib) in a Phase 1/2 trial in patients with KRAS G12C mutant NSCLC entitled RAMP 203, (ii) in combination with Mirati’s KRAZATI (adagrasib) in patients with KRAS G12C mutant NSCLC in a Phase 1/2 trial entitled RAMP 204, and (iii) in combination with everolimus for treatment of patients with NSCLC in an IST.

BRAF mutations, including BRAF class II and class III non-V600E, also occur in NSCLC.

Whereas BRAF inhibitors in combination with MEK inhibitors are currently approved for BRAF V600E NSCLC, no targeted therapies are approved for BRAF non-V600E NSCLC.

Currently, the combination of avutometinib and defactinib is being evaluated for treatment of patients with BRAF mutant NSCLC including a non-V600E cohort in RAMP 202.

Colorectal Cancer (“CRC”)

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

One in 23 men and one in 25 women will be diagnosed with CRC in their lifetime.

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

The NCI estimates that the number of new incidences of CRC was 37.7 per 100,000 men and women per year based on 2015-2019 cases and the five-year relative survival rate from 2012 to 2018 for patients with CRC was approximately 65%.

The individual likelihood of survival depends on how advanced the cancer is, whether or not all the cancer can be removed with surgery, and the person's overall health.

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

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

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

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

Thus, novel therapies are needed for patients with CRC harboring other KRAS mutations including KRAS G12D and KRAS G12V which represent 11% and 9%, respectively.

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

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

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

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

Pancreatic Cancer

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

Colorectal Cancer (“CRC”)

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

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

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

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

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

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

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

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

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

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

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

In patients with melanoma, mutations in the MAPK pathway occur mainly in BRAF (41%), NRAS (27%), NF1 (25%) and RAF1 (CRAF) (2.6%).

Although several selective BRAF inhibitors are FDA-approved alone or in combination with MEK inhibitors for melanomas with BRAF V600E/K, there is still a need for agents to improve response rate, duration of response, and tolerability.

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

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

This provides rationale for the planned IST which will evaluate avutometinib in combination with the anti-PD-1 antibody pembrolizumab for patients with BRAF V600E melanoma.

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

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

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.

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:

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● Assessing synergy of avutometinib 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 is necessary for maximal depth and duration of anti-tumor response.

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.

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

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

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

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

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

The combination of avutometinib with defactinib has been selected vs.

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

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

high-grade and mucinous ovarian cancers, endometrial and cervical cancers) with MAPK pathway mutations.

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

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

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

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

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

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

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

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

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

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

Avutometinib is being investigated in combination with the anti-EGFR antibody cetuximab in KRAS mutant CRC and in combination with the anti-PD-1 antibody pembrolizumab in BRAF V600E melanoma through ISTs.

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

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

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

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

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

● 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.

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1 FDA breakthrough therapy designation

2 Registration-directed trial

3 Imminent initiation

* Pre-clinical studies ongoing in multiple KRAS mutant tumors

2 FDA fast track designation

RAMP 301 Study = NCT06072781

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FRAME Study = NCT03875820

IST in MAPK pathway-driven gynecological cancer = NCT05512208

IST in mesonephric gynecologic cancer = NCT05787561

IST in KRAS mutant CRC = NCT05200442

IST in ER+ breast cancer = NCT05608252

IST in MAPK pathway-driven gynecological cancer = NCT05512208

IST in KRAS mutant NSCLC combining avutometinib + everolimus = NCT02407509

IST in thyroid cancer = NCT06007924

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

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Avutometinib and defactinib

Avutometinib is an investigational oral first-in-class unique small molecule RAF/MEK clamp.

In contrast to other MEK inhibitors commercially available and in development, avutometinib is a dual RAF/MEK clamp that blocks MEK kinase activity and induces the formation of dominant negative RAF-MEK complexes preventing phosphorylation of MEK by ARAF, BRAF and CRAF.

MEK-only inhibitors (e.g., PD0325901) paradoxically induce MEK phosphorylation (“pMEK”) by relieving extracellular-signal-regulated-kinase ( ERK)-dependent feedback inhibition of RAF which may limit their efficacy.

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

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

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

This unique mechanism of avutometinib enables more effective inhibition of ERK signaling and may confer enhanced therapeutic activity against MAPK pathway-driven cancers.

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

therapeutic activity against MAPK pathway-driven cancers.

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

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

FAK is a non-receptor tyrosine kinase encoded by PTK-2 gene that is involved in cellular adhesion and, in cancer, metastatic capability.

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

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

Preclinical research by our scientists and collaborators at world-renowned research institutions has described the effect of FAK inhibition to enhance immune response by decreasing immuno-suppressive cells, increasing cytotoxic T cells, and reducing stromal density, which allows tumor-killing immune cells to enter the tumor.

The combination of avutometinib and defactinib 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 and defactinib are clinically active against MAPK pathway-driven cancers.

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

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

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

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

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

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

The primary endpoint is progression free survival by Blinded Independent Central Review.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The safety profile was consistent with previously reported safety data.

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

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

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

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

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

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

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

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

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

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

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

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

The FRAME study is being led by Dr.

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

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

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)

At the September 2021 European Society of Medical Oncology Congress, updated data from the LGSOC cohort of the ongoing, investigatory sponsored Phase 1/2 FRAME study were presented.

The results showed encouraging response rates and progression-free survival (“PFS”).

Among the evaluable patients with LGSOC (n=24), the ORR was 46% (11 of 24).

Among the patients with KRAS mutant LGSOC (n=11), the ORR was 64% (7 of 11).

Among the patients with KRAS wild type LGSOC (n=9), the ORR was 44% (4 of 9).

Of the evaluable patients, 10 (42%) received previous MEK inhibitor therapy.

The estimated median PFS (“mPFS”) across all patients was 23.0 months (95% CI:

10.6- not reached).

As of the April 2021 data cutoff date, 13 of 24 patients (54%) remained on study.

In the FRAME study, the most common Grade 3/4 treatment-related adverse events were creatine kinase elevation (12%), rash (8%), diarrhea (4%), mouth ulcer/mucositis/glossitis (4%), and hyperbilirubinemia (4%), with only one discontinuation due to adverse events as of the data cutoff.

This data suggests that the novel, intermittent dosing schedule used in the FRAME study continues to show encouraging clinical activity in patients with recurrent LGSOC, including in patients previously treated with a MEK inhibitor.

Phase 2 study (known as RAMP (RAF and MEK Program) 201 Study) Registration-Directed Trial of avutometinib and defactinib in Recurrent LGSOC

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

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

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

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

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

Updated Phase 2 RAMP 201 Study Results in Patients with LGSOC (January 2023)

Overall, patients on the combination arm were heavily pretreated with an average of four prior systemic regimens (up to 11), including prior platinum-based chemotherapy, endocrine therapy and bevacizumab in most patients and prior MEK inhibitor therapy in about 20% of patients.

Of the 29 patients evaluable for response by BICR in the combination arm, the initial results showed a confirmed objective response rate (ORR) of 28% in all patients and 27% vs 29% in KRAS mutant (n=15) and KRAS wild-type (n=14) LGSOC, respectively.

Three additional patients with KRAS mutant LGSOC showed an unconfirmed partial response.

In addition, the vast majority of patients showed tumor regression, as the overall disease control rate (stable disease plus partial response) was 93%.

Most evaluable patients (62%) were still on study treatment on the combination arm at the time of the data cut with a minimum follow-up of five months.

The confirmed ORR for the monotherapy arm by BICR was 7% in evaluable patients (n=30).

The overall disease control rate for the monotherapy arm by BICR was 90%.

Across both the combination and monotherapy arms, there have been no additional safety signals reported with a continued favorable safety and tolerability profile.

The most common treatment-related adverse events for the combination in all treated patients were diarrhea, nausea, blood creatine phosphokinase (“CPK”) increased, vision blurred, dermatitis acneiform and rash, fatigue and peripheral edema, most of which were mild to moderate, with 9% discontinuation due to adverse events.

We intend to include mature data from RAMP 201 study and the FRAME study to potentially support filing for accelerated approval.

We will continue future enrollment of RAMP 201 in the combination arm only to expand on the clinical experience in anticipation of a confirmatory study.

Target enrollment for the combination arm has been achieved.

We are in ongoing discussions with the FDA on the confirmatory study and plan to provide an update after agreement with the FDA.

We are planning a RAMP 201 presentation at a scientific medical conference in 2023.

Phase 2 Study (known as RAMP (RAF and MEK Program) 202 Study) Registration-Directed Trial of avutometinib and defactinib in Previously Treated KRAS Mutant NSCLC

The RAMP 202 Study that was initiated in December 2020 is a registration-directed clinical trial of avutometinib and defactinib, in patients with KRAS G12V NSCLC.

A dditionally, and based on preclinical data, we added several exploratory cohorts to the RAMP 202 study including KRAS non-G12V NSCLC and BRAF mutant (V600E and non-V600E) NSCLC.

The RAMP 202 study is 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

KRAS and BRAF mutant NSCLC, following treatment with a platinum-based regimen and immune checkpoint inhibitor.

The first part of the study will determine the optimal regimen of either avutometinib monotherapy or in combination with defactinib in patients with KRAS G12V NSCLC.

The second phase of the study (expansion phase) will examine efficacy and safety parameters of the most effective regimen in patients with KRAS G12V NSCLC.

While active, the results did not meet the pre-defined criteria to continue to the trial expansion phase.

Also among patients with KRAS non G12V NSCLC, no KRAS subtype was identified for further clinical evaluation of avutometinib with defactinib in this trial.

We plan to present the Part A results of RAMP 202 at an upcoming medical congress.

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

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 (sotorasib) in a Phase 1/2 trial entitled RAMP 203.

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

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

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

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

In 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.

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

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

1/7) and naïve (40%;

2/5) patients.

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

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

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

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

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

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

In November 2021, we entered into a clinical collaboration agreement to evaluate the combination of avutometinib with Mirati’s KRAS G12C inhibitor KRAZATI (adagrasib) in a Phase 1/2 trial entitled RAMP 204.

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

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

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

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

The RAMP 204 trial is open and enrolling.

Phase 1/2 Trial (known as RAMP (RAF and MEK Program) 205 Study) of avutometinib + defactinib + gemcitabine/nab-paclitaxel

The RAMP 204 study is open and enrolling.

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

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

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

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

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

We opened the RAMP 205 trial in the fourth quarter of 2022.

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

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

The RAMP 205 study is open and enrolling.

Dose escalation is ongoing.

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

INTELLECTUAL PROPERTY

We strive to protect the proprietary technology that we believe is important to our business, including seeking and maintaining patents intended to cover our product candidates and compositions, their methods of use and processes for their manufacture, and any other aspects of inventions that are commercially important to the

development of our business.

We also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

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

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

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

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

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

In addition to the issued and pending patent applications exclusively licensed from Chugai, we own eleven patent families covering methods of using a dual RAF/MEK inhibitor for treating a patient.

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

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

The fourth patent family covers solid forms of avutometinib, and is pending in the United States as a nonprovisional patent application.

We also have six patent families covering methods of using a dual RAF/MEK inhibitor in combination with another therapeutic agent for treating a patient,

which are pending as international applications.

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

We also have one patent family covering methods of using a MEK inhibitor to treat certain populations of patients, which is pending as a provisional patent application in the United States.

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

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

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

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

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

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

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

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

FAK inhibition program

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

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

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

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

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

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

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

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

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

Patent applications in this family are pending worldwide, including for example in Japan, and granted in the United States, Hong Kong, and Europe.

Patent applications in this family have been granted

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

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

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

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

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

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

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The extended patent term cannot exceed the shorter of five years beyond the non-extended expiration of the patent or 14 years from the date of the FDA approval of the drug.

jurisdictions, including Europe and Japan, have analogous patent term extension provisions, which allow for extension of the term of a patent that covers a drug approved by the applicable foreign regulatory agency.

Some foreign jurisdictions, including Europe and Japan, have analogous patent term extension provisions, which allow for extension of the term of a patent that covers a drug approved by the applicable foreign regulatory agency.

LICENSES AND COMMERCIAL AGREEMENTS

On August 10, 2020, we and Secura Bio, Inc.

(“Secura”) signed an Asset Purchase Agreement (“Secura APA”) and on September 30, 2020, the transaction closed.

GenFleet Therapeutics Inc.

On August 24, 2023, we entered into the GenFleet Agreement, pursuant to which GenFleet granted us 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 an orally bioavailable, potent and selective small molecule KRAS G12D inhibitor entitled GFH375/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 development and commercial milestones, and upon us exercising all three GenFleet Options, GenFleet will be entitled to receive payments of up to $622.0 million.

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

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

Either party may terminate the GenFleet Agreement in its entirety or on a program-by-program and country-by-country basis, with 60 days’ written notice for the other party’s material breach if such party fails to cure the breach.

Either party may also terminate the GenFleet Agreement in its entirety upon certain insolvency events involving the other party.

Secura Bio, Inc.

On August 10, 2020, we and Secura signed an Asset Purchase Agreement (the “Secura APA”) and on September 30, 2020, the transaction closed.

Pursuant to the Secura APA, we sold to Secura our exclusive worldwide license for the research, development, commercialization, and manufacture in oncology indications of products containing duvelisib.

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We are further obligated to pay Chugai double-digit royalties on net sales of products containing avutometinib, subject to reduction in certain circumstances.

Chugai also obtained opt back rights to develop and commercialize avutometinib (a) in the European Union, which option may be exercised through the date we submit a New Drug Application (“NDA”) to the FDA for a product which contains avutometinib as the sole active pharmaceutical ingredient and (b) in Japan and Taiwan, which option may be exercised through the date we receive marketing authorization from the FDA for a product which contains avutometinib as the sole active pharmaceutical ingredient.

As consideration for executing either option, Chugai would have to make a payment to us calculated on our development costs to date.

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

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

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

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

Unless earlier terminated, the Chugai Agreement will expire upon the fulfillment of our royalty obligations to Chugai for the sale of any products containing the avutometinib , which royalty obligations expire on a product-by-product and country-by-country basis, upon the last to occur, in each specific country, of (a) expiration of valid patent claims covering such product or (b) 12 years from the first commercial sale of such product in such country.

Unless earlier terminated, the Chugai Agreement will expire upon the fulfillment of our royalty obligations to Chugai for the sale of any products containing the avutometinib , which royalty obligations expire on a product-by-product and country-by-country basis, upon the last to occur, in each specific country, of (a) expiration of valid licensed patent claims covering such product or (b) 12 years from the first commercial sale of such product in such country.

We may terminate the Chugai Agreement upon 180 days’ written notice.

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FAK inhibition program

There is a company, InxMed, developing a FAK small molecule inhibitor 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.

MAPK Pathway Inhibitors

There are two companies with an approved drug with FDA approval targeting the MAPK pathway in the market and companies working to develop therapies to target the MAPK pathway.

We believe the following companies, among others, have an approved drug, developed or in the clinical stage of development of compounds targeting the MAPK pathway:

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

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

In addition, we believe Amgen, Inc.

is conducting Phase 1, Phase 2 and Phase 3 clinical trials of LUMAKRAS (sotorasib) as monotherapy or in combination with other agents;

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

In addition, we believe Mirati is conducting Phase 2 and Phase 3 clinical trials of KRAZTI (adagrasib) as monotherapy or in combination with other agents;

● Revolution Medicines, Inc., which we believe is conducting Phase 2 clinical trial of RMC-4630 in collaboration with Sanofi and Phase 1 clinical trials of RMC-5552, RMC-6236, and RMC-6291;

● SpringWorks Therapeutics, Inc., which we believe is conducting Phase 1 and Phase 2 clinical trials of mirdametinib;

● Recursion Pharmaceuticals, Inc., which we believe is conducting Phase 2 and Phase 1 clinical trials of REC-4881;

● Fochon Pharmaceutical Ltd.

which we believe is conducting Phase 2 and Phase 1 clinical trials of FCN-159;

● Eisai Co., Ltd., which we believe is conducting Phase 1 clinical trials of E-6201;

● Binjang Pharma, Inc.

which we believe is conducting Phase 2 and Phase 1 clinical trials of HL-085;

● Jiangsu Hengrui Medicine Co., Ltd., which we believe is conducting Phase 1 clinical trials of SHR-7390;

● Mapkure, LLC, together with BeiGene Ltd.

and SpringWorks Therapeutics, Inc., which we believe is conducting a Phase 2 clinical trial of BGB-3245;

● BeiGene Ltd., which we believe is conducting Phase 2 clinical trials of lifrafenib;

● Fore Biotherapeutics, Inc., which we believe is conducting a Phase 2 clinical trial of FORE-8394 (previously PLX-8394);

● Day One Biopharmaceuticals, Inc., which we believe is conducting Phase 2 and Phase 1 clinical trials of DAY-101 (tovorafenib);

● Erasca, Inc.

which we believe is conducting Phase 1 and Phase 2 clinical trials of naporafenib (ERAS-254) and ERAS-007, and Phase 1 clinical trials of ERAS-601;

● Genentech Inc., which we believe is conducting a Phase 1 clinical trial of belvarafenib;

● Relay Therapeutics, Inc., which we believe is conducting Phase 1 clinical trials of RLY-1971;

● Kinnate Biopharma, Inc., which we believe is conducting Phase 1 clinical trials of exarafenib (KIN-2787);

● Boehringer Ingelheim, which we believe is conducting Phase 1 clinical trials of BI 1701963 and BI 3011441;

● Moderna, Inc., which we believe is conducting a Phase 1 clinical trial of mRNA-5671.

In addition to companies that have inhibitors addressing our targets of interest, 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.

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

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

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

and Kinnate Biopharma, Inc.

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.

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

We have development agreements in place with these CMOs and we obtain drug

substance, drug product and packaging/labeling services from these CMOs on a purchase order basis.

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

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

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

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

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

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

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

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● satisfactory completion of an FDA advisory committee review, if applicable;

(“cGMP”) requirements and to assure that the facilities, methods, and controls are adequate to preserve the drug’s identity, strength, quality and purity;

● satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with current good manufacturing practices (“cGMP”) requirements and to assure that the facilities, methods, and controls are adequate to preserve the drug’s identity, strength, quality and purity;

● FDA review and approval of the NDA.

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Post-approval trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing approval.

These trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication and are commonly intended to generate additional safety data regarding use of the product in a

clinical setting.

In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of a NDA or, in certain circumstances, post-approval.

In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of a NDA or, in certain circumstances, post-approval, such as in the case of drugs approved under the accelerated approval pathway.

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

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

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

completed successfully within any specified period, or at all.

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

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

Data obtained from clinical activities are not always conclusive and may be

susceptible to varying interpretations, which could delay, limit or prevent regulatory approval.

Data obtained from clinical activities are not always conclusive and may be susceptible to varying interpretations, which could delay, limit or prevent regulatory approval.

The FDA may not grant approval on a timely basis, or at all.

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The breakthrough therapy designation provides all the benefits of the fast track program, including the eligibility for rolling review.

sponsor regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team and taking other steps to aid sponsors in designing the clinical trials.

The FDA may take certain administrative actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process, providing timely advice to the product sponsor regarding development and approval, involving more senior staff in the review process, assigning a cross-disciplinary project lead for the review team and taking other steps to aid sponsors in designing the clinical trials.

Although breakthrough designation does not affect the regulatory standards for approval, the frequent interactions with the FDA may facilitate a more efficient development program.

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

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

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

Therapeutic Equivalence Evaluations, commonly known as the Orange Book.

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

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Under the Best Pharmaceuticals for Children Act, federal law also provides that periods of patent and non-patent marketing exclusivity listed in the Orange Book for a drug may be extended by six months if the NDA sponsor conducts pediatric studies identified by the FDA in a written request.

For written requests issued

by the FDA after September 27, 2007, the date of enactment of the FDAAA, the FDA must grant pediatric exclusivity no later than nine months prior to the date of expiration of patent or non-patent exclusivity in order for the six-month pediatric extension to apply to that exclusivity period.

For written requests issued by the FDA after September 27, 2007, the date of enactment of the FDAAA, the FDA must grant pediatric exclusivity no later than nine months prior to the date of expiration of patent or non-patent exclusivity in order for the six-month pediatric extension to apply to that exclusivity period.

Combination Therapy

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Other regulatory requirements

Any drug manufactured or distributed by us pursuant to FDA approvals would be subject to extensive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with

After approval, most changes to the approved product, such as adding new indications or other labeling claims are subject to prior FDA review and approval.

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

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

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

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

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

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In addition, the PDMA sets forth civil and criminal penalties for violations.

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;

promote transparency in interactions with others in the

healthcare industry;

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

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

Department of Justice, and individual U.S.

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.

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.

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.

Laws and regulations have also been enacted by the federal government and various states to regulate the sales and marketing practices of pharmaceutical manufacturers with marketed products.

The laws and regulations generally limit financial interactions between manufacturers and health care providers;

require manufacturers to adopt certain compliance standards;

require disclosure to the government and public of financial interactions;

require disclosure of marketing expenditures or pricing information, regulate drug pricing and/or require the registration of pharmaceutical sales representatives.

Many of these laws and regulations contain ambiguous requirements or require administrative guidance for implementation.

Given the lack of clarity in laws and their implementation, any future activities (if we obtain approval and/or reimbursement from federal healthcare programs for our product candidates) could be subject to challenge.

The distribution of drugs and biological products is subject to additional requirements and regulations, including extensive record-keeping, licensing, storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.

Federal and state consumer protection and unfair competition laws and regulations broadly regulate marketplace activities and that potentially harm consumers and could apply to the activities of pharmaceutical manufacturers.

We may be subject to data privacy and security laws in the various jurisdictions in which we operate, obtain or store personally identifiable information.

Numerous U.S.

federal and state laws govern the collection, use, disclosure and storage of personal information.

Various foreign countries also have, or are developing, laws governing the collection, use, disclosure and storage of personal information.

Globally, there has been an increasing focus on privacy and data protection issues that may affect our business.

Efforts to ensure that our activities comply with applicable healthcare laws and regulations will involve substantial costs.

Given the breadth of the laws and regulations, limited guidance for certain laws and regulations and evolving government interpretations of the laws and regulations, governmental authorities may possibly conclude that our business practices may not comply with such laws.

If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, exclusion from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations.

Further, defending against any such actions can be costly, time-consuming and may require significant personnel resources.

Therefore, even if we are successful in defending against any such actions that may be brought against us, our business may be impaired.

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.

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

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

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

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

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Significant uncertainty exists as to the coverage and reimbursement status of new drug products.

Sales of product candidates, if approved, will depend, in part, on the extent to which the costs of the products will be covered by third-party payors, including government health programs such as Medicare and Medicaid, commercial health insurers and managed care organizations.

Sales of our product candidates, if approved, will depend, in part, on the extent to which the costs of the products will be covered by third-party payors, including government health programs such as Medicare and Medicaid, commercial health insurers and managed care organizations.

The process for determining whether a payor will provide coverage for a drug product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the drug product once coverage is approved.

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Our product candidates may not be considered medically necessary or cost- effective.

Even if covered, third party payors may seek to control utilization of our products through various managed care mechanisms (e.g., requiring a prescriber to obtain prior authorization from a health plan before the product will be covered by the health plan or establishing patient copays and deductibles that encourage use of other products over our products).

Even if covered, third party payors may seek to control utilization of our products through various mechanisms (e.g., requiring a prescriber to obtain prior authorization from a health plan before the product will be covered by the health plan or establishing patient copays and deductibles that encourage use of other products over our products).

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

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

Under the Medicare Coverage Gap Discount Program, manufacturers with marketed brand

name drugs are currently required to provide a 70% discount on the negotiated price for brand name prescription drugs utilized by Medicare Part D beneficiaries when those beneficiaries reach the coverage gap in their drug benefits.

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

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

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

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

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.

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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.

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

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

2617) that contains important reforms relevant to the FDA, including the Food and Drug Omnibus Reform Act of 2022 (“FDORA”) and the Prepare for and Respond to Existing Viruses, Emerging New Threats, and Pandemics Act (the “PREVENT Pandemics Act”).

2617) that contains important reforms relevant to the FDA, including the FDORA and the Prepare for and Respond to Existing Viruses, Emerging New Threats, and Pandemics Act.

In addition to new legislation, FDA regulations and policies are often revised or interpreted by the agency in ways that may significantly affect our business and our products.

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.

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 and the Health Care 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.

There have been ongoing efforts to modify or repeal all or certain provisions of the Healthcare Reform Act.

For example, tax reform legislation was enacted at the end of 2017 that eliminated the tax penalty for individuals who do not maintain mandated health insurance coverage beginning in 2019.

The Healthcare Reform Act has also been subject to judicial challenge.

In 2021, the U.S.

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

Beyond the Healthcare Reform Act, there have been ongoing health care reform efforts.

Some recent healthcare reform efforts have sought to address certain issues related to the COVID-19 pandemic, including an expansion of telehealth coverage under Medicare and accelerated or advanced Medicare payments to healthcare providers.

Other reform efforts affect pricing or payment for drug products.

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

For example, in 2022, the Inflation Reduction Act (IRA) of 2022 contains numerous drug pricing and payment reforms.

Among other provisions, the IRA imposes a yearly cap ($2,000 in 2025) on out-of-pocket prescription drug costs in Medicare Part D, implements a new Medicare Part D manufacturer discount drug program in 2025;

requires manufacturers to pay a rebate to the federal government if prices for single-source drugs and biologicals covered under Medicare Part B and nearly all covered drugs under Part D increase faster than the rate of inflation and, starting in 2026, creates a drug price negotiation program under which the prices for certain high Medicare spend drugs and biologicals without generic or biosimilar competition will be limited by a cap that is defined by reference to, among other things, a specified non-federal average manufacturer price.

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.

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

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

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

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

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

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

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

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

For 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.

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.

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

As another example, legislation passed in 2019 revised how certain prices reported by manufacturers under the Medicaid Drug Rebate Program are calculated and legislation enacted in 2021 eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

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 Health

Care Reform Act or other federal and state reform efforts.

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

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

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

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

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

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

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We also provide for employer matching contributions equal to 100% of employee deferral contributions up to a deferral rate of 6% of eligible compensation to our Section 401(k) retirement savings plan.

As of December 31, 2022, we had 57 full-time equivalent employees, including a total of nine employees with M.D.

As of December 31, 2023, we had 73 full-time equivalent employees, including a total of 13 employees with M.D.

degrees, and four part-time employees.

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Executive Officers:

Brian Stuglik

Chief Executive Officer

Daniel Paterson

President, Chief Operating Officer

Significant Employees:

President, Chief Executive Officer

Daniel Calkins

Vice President, Finance

Brian Stuglik , age 63, has served as our Chief Executive Officer since July 2019 and as a member of our Board of Directors since September 2017.

Stuglik founded Proventus Health Solutions in January 2016 and has over three decades of experience in U.S.

and international pharmaceutical development, product strategy, and commercialization.

Prior to founding Proventus Health Solutions, Mr.

Stuglik served as the Vice President and Chief Marketing Officer for the oncology division of Eli Lilly and Company, from 2009 to December 2015.

Stuglik received a Bachelor of Science in Pharmacy from Purdue University and holds memberships in the American Society of Clinical Oncology, the American Association of Cancer Research, and the International Association for the Study of Lung Cancer.

Daniel Paterson , age 61, has served as our President since June 2019 in addition to serving as our Chief Operating Officer since December 2014, 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.

Chief Financial Officer

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

Prior to joining us in March 2012, Mr.

Paterson was a consultant in 2011.

5 unchanged sentences

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

Daniel Calkins, age 35, has served as our Vice President, Finance since September 2022 in addition to serving as our Corporate Controller since March 2020, our Assistant Controller from May 2019 to March 2020, and our Associate Director, SEC Reporting and Technical Accounting from December 2018 to May 2019.

Daniel Calkins, age 36, 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.

Prior to joining us in December 2018, Mr.

14 unchanged sentences

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