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Item 1. Business

2023-03-14 compared with 2022-03-28 · 326 added, 270 removed, 508 unchanged (54% of the section changed)

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

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

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

Our most advanced product candidates, VS-6766 and defactinib, are being investigated in both preclinical and clinical studies for the treatment of various solid tumors, including, low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer, uveal melanoma, and endometrial cancer.

We believe that VS-6766 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.

VS-6766 is an orally available first-in-class unique small molecule RAF/MEK clamp.

In contrast to other MEK inhibitors commercially available and in development, VS-6766 is a dual RAF/MEK clamp that blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK.

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.

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”).

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.

By inhibiting RAF-mediated phosphorylation of MEK, VS-6766 has the advantage of not inducing pMEK.

This unique mechanism of VS-6766 enables more effective inhibition of ERK signaling and may confer enhanced therapeutic activity against ERK-dependent, RAS or BRAF mutant tumors.

VS-6766 has been shown to inhibit signaling and proliferation of tumor cell lines with a variety of mitogen-activated pathway kinase (MAPK) pathway alterations including Kirsten rat sarcoma viral oncogene homolog (KRAS), Harvey rat sarcoma viral oncogene homolog (HRAS), or B-Raf proto-oncogene serine/threonine kinase (BRAF) mutations, among others.

VS-6766 has also been shown to synergize with agents targeting the MAPK pathway including G12C inhibitors in KRAS mutant NSCLC and CRC in preclinical models and enhances the anti-tumor effects of anti-PD-1 in KRAS mutant NSCLC mouse models.

VS-6766 has shown compelling synergy with defactinib in preclinical models.

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

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

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

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

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

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

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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.

The combination of VS-6766 and defactinib has been found to be clinically active in patients with KRAS mutant tumors and received breakthrough designation from the U.S.

Food & Drug Administration (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 an ongoing investigator-initiated Phase 1/2 study (the FRAME study), the combination of VS-6766 and defactinib is being evaluated in patients with recurrent LGSOC, KRAS mutant NSCLC, KRAS-G12V mutant NSCLC, CRC, pancreatic cancer, and KRAS mutant endometrial cancer.

Based on the LGSOC and KRAS-G12V

NSCLC cohorts of the FRAME study, we have initiated our registration directed trials entitled RAF and MEK Program (RAMP) 201 and 202 discussed in further detail below.

Updated data from the FRAME study presented at the European Society of Medicine Congress in September 2021, demonstrated an ORR of 46% (11 of 24) among the evaluable patients with LGSOC (n=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 median progression-free survival 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 fourth quarter of 2020, we commenced registration-directed trials investigating VS-6766 as a monotherapy and in combination with defactinib.

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

RAMP 201 is an adaptive two-part multicenter, parallel cohort, randomized, open label trial to evaluate the efficacy and safety of VS-6766 alone and in combination with defactinib in patients with recurrent LGSOC.

RAMP 202 study is a Phase 2, adaptive two-part multicenter, parallel cohort, randomized, open-label trial to evaluate the efficacy and safety of VS-6766 alone and in combination with defactinib in patients with KRAS G12V mutant NSCLC, following treatment with a platinum-based regimen and immune checkpoint inhibitor.

Additionally, the combination of VS-6766 with defactinib is being evaluated in several exploratory cohorts including KRAS non-G12V and BRAF (V600E and non-V600E) mutant NSCLC.

Based on preclinical rationale, we have added BRAF mutant cohorts (V600E and non-V600E) to the RAMP 202 study in order to efficiently evaluate VS-6766 with defactinib in BRAF-mutant NSCLC.

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.

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

(Amgen) to evaluate the combination of VS-6766 with Amgen’s KRAS-G12C inhibitor LUMAKRAS TM (sotorasib) in a Phase 1/2 trial entitled RAMP 203.

The Phase 1/2 trial will evaluate the safety, tolerability and efficacy of VS-6766 in combination with LUMAKRAS TM in patients with KRAS G12C-mutant 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 therefore investigate the potential benefits of a more complete vertical blockade of the RAS pathway with the combination of VS-6766 with LUMAKRAS TM (G12C inhibition) in KRAS G12C-mutant locally advanced or metastatic NSCLC.

(“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.

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

(Mirati) to evaluate the combination of Mirati’s investigational KRAS-G12C inhibitor adagrasib with VS-6766 in KRAS G12C mutant NSCLC.

The primary objective of this multi-center, single-arm, open-label Phase 1/2 trial entitled RAMP 204 is to determine the maximum tolerated dose and recommended Phase 2 dose for the combination of adagrasib and VS-6766 in patients with KRAS-G12C mutant NSCLC.

The study will also investigate the safety, tolerability and efficacy of the combination in patients who have progressed on a KRAS-G12C inhibitor.

The trial will build on preclinical data showing a deeper blockade of ERK pathway signaling resulting in enhanced anti-tumor efficacy with the combination of adagrasib and VS-6766 relative to either agent alone.

In addition, VS-6766 and defactinib are currently being investigated in combination with immunotherapeutic and other agents through investigator sponsored trials (ISTs).

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

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

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

The RAMP 204 trial is open and enrolling.

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”).

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.

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

The American Cancer Society estimated that in the United States in 2021, almost 1.9 million new cases of cancer were diagnosed and more than 600,000 people died from the disease.

The American Cancer Society estimated that in the United States in 2022, over 1.9 million new cases of cancer were diagnosed and more than 600,000 people died from the disease.

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

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

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

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

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

For example, the U.S.

annual incidence, based on 2021 estimates from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (NCI;

SEER), is that during the year there were approximately, 21,410 new cases of ovarian cancer, 235,760 new cases of lung cancer, 149,500 new cases of colorectal cancer, and 60,430 new cases of pancreatic cancer.

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.

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

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

RAS 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 RAS almost four decades ago, researchers have persistently tried, and failed, to develop therapies that effectively block the cancer-promoting effects of RAS mutation, including KRAS, NRAS, BRAF, and HRAS mutations.

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 RAS inhibitors in development addressing only a minority of all RAS mutated cancers.

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

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

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

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

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

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

Low Grade Serous Ovarian Cancer (“LGSOC”)

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

It is estimated that 70% of LGSOC tumors are driven by mutations in the RAS pathway, including an estimated 30% of those that are KRAS mutant.

The remaining KRAS wild-type patients include those with mutations in NRAS, or BRAF.

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

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

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

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

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”).

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

Currently, VS-6766 is being evaluated (i) in combination with defactinib and as a monotherapy for the treatment of patients with recurrent LGSOC in a Phase 2 registration directed study entitled RAMP 201 and (ii) in combination with defactinib for patients with advanced LGSOC in the FRAME study.

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.

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

Non-Small Cell Lung Cancer (“NSCLC”)

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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%).

Studies suggest that these types of KRAS mutations differ in clinical characteristics and response to traditional treatments such as chemotherapy.

Several tyrosine kinase inhibitors are in development for KRAS G12c mutations of which sotorasib is currently approved.

There are no drugs other than VS-6766 being developed for G12V mutations.

Sotorasib has relatively low response rates and short times to progression so a number of agents are being combined with the G12C inhibitors including VS-6766.

BRAF mutations occur in 2-3 % of lung adenocarcinomas and activate similar downstream pathways including RAF and MEK as KRAS mutations.

Currently, there is a high unmet need in the second-line treatment of KRAS and BRAF mutant NSCLC as evidenced by the low response rates and short survival times.

Currently, VS-6766 is being evaluated (i) in combination with defactinib and as a monotherapy for treatment of patients with recurrent KRAS G12V mutant NSCLC in a registration directed study entitled RAMP 202, (ii) in combination with defactinib for the treatment of patients with a recurrent non-G12V KRAS mutant and BRAF mutant NSCLC in a signal finding cohort of RAMP 202, (iii) in combination with defactinib for the treatment of patients with advanced KRAS mutant NSCLC and advanced KRAS G12V mutant NSCLC in the FRAME study, and (iv) in combination with everolimus for treatment of patients with NSCLC in an IST.

In addition, in September 2021 we entered into a clinical collaboration agreement to evaluate VS-6766 in combination with Amgen’s KRAS-G12C inhibitor LUMAKRAS TM (sotorasib) in a Phase 1/2 trial in patients with KRAS G12C mutant NSCLC entitled RAMP 203 and in November 2021, we entered into a clinical collaboration agreement to evaluate VS-6766 in combination with Mirati’s investigation KRAS G12C inhibitor adagrasib in a Phase 1/2 trial in patients with KRAS G12C mutant NSCLC entitled RAMP 204.

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”)

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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 men and women combined in the United States.

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%.

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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.

Currently, VS-6766 is being evaluated in combination with defactinib for the treatment of patients with advanced CRC in the FRAME study.

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.

Pancreatic Cancer

In 2021, the NCI estimated that pancreatic cancer was the eleventh most common cancer diagnosed in the United States and that the disease represented the third leading cause of cancer-related death in the country.

In 2022, the NCI estimated that pancreatic cancer was the tenth most common cancer diagnosed in the United States and that the disease represented the third leading cause of cancer-related death in the country.

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

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

The NCI estimates that the number of new incidences of pancreatic cancer was 13.2 per 100,000 men and women per year based on 2014-2018 cases.

The NCI estimates that the number of new incidences of pancreatic cancer was 13.3 per 100,000 people per year based on 2015-2019 cases.

Pancreatic cancer has a very high mortality rate with approximately 88% of patients dying within five years of their initial diagnosis based on the five-year relative survival rate from 2012 to 2018.

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

KRAS mutant pancreatic cancer represents approximately 98% of pancreatic cancer diagnoses.

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

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

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

Currently, VS-6766 is being evaluated in combination with defactinib for the treatment of patients with advanced pancreatic cancer in the FRAME study.

Uveal Melanoma

Uveal melanoma, also known as ocular melanoma, is the most common primary cancer of the eye in adults.

It is a disease in which cancer (malignant) cells are found in part of the eye called the uvea.

The uvea includes the iris, the ciliary body, and the choroid layer.

The iris opens and closes to change the amount of light entering the eye.

The ciliary body changes the shape of the lens inside the eye to allow the eye to focus.

The choroid layer is next to the retina, the part of the eye that makes a picture.

According to the American Cancer Society, in 2021, there were an estimated 3,320 new cases of eye cancer (mainly melanoma) in the United States and the five year survival rate for eye melanoma is approximately 81% based on patients diagnosed between 2010 and 2016.

Uveal melanoma has a peak rate of diagnosis around 70 years old.

Uveal melanoma may have no early signs or symptoms, and it is sometimes found during eye exams.

As the tumor grows symptoms may include blurred vision, spots that drift in field of vision or flashes of lights, dark spot on the iris, change in the size or change or pupil or a change in position of the eyeball in eye socket.

Uveal melanoma has a high risk of migrating from the eye to other sites in the body, and, therefore, treatment is aggressive to try to prevent its spread.

Oncologists may initially try watchful waiting if the tumor shows no sign of growing or if the cancer is in the only eye with useful treatment.

When treatment is required, surgery is the most common approach for uveal melanoma.

Other treatments include radiation therapy, photocoagulation, also known as light coagulation, and thermotherapy.

Currently, VS-6766 is being evaluated in combination with defactinib for the treatment of patients with metastatic uveal melanoma in an IST.

Endometrial Cancer

Endometrial cancer, also known as uterine cancer, is a cancer of the endometrium, which is the lining of the uterus.

The uterus is a hollow, pear-shaped organ in a woman’s pelvis in which a fetus grows after conception.

It is the most common type of cancer that affects the female reproductive organs.

Endometrial cancer mainly affects women after menopause, with a median age of diagnosis of 63.

The NCI estimates that the number of new incidences of uterine cancer was 28.1 per 100,000 women per year based on 2014-2018 cases and that the five-year relative survival rate from 2011 to 2017 for patients with endometrial cancer was approximately 81%.

KRAS mutant endometrial cancer represents approximately 21% of endometrial cancer diagnoses.

The current treatment of endometrial cancer depends on the stage and the specific pathology type of the disease at the time of diagnosis.

Surgery is generally considered for this disease.

In early stages, minimal invasive surgery may be the only treatment required.

In later stages, more involved and extensive surgeries to remove the disease outside the uterus and cervix may be required, in combination with chemotherapy and radiation therapy.

Currently VS-6766 is being evaluated in combination with defactinib for the treatment of patients with KRAS mutant endometrial cancer in the FRAME study.

With VS-6766 and defactinib, we seek to utilize a multi-faceted approach to treat cancer by directly targeting the cancer cells, enhancing anti-tumor immunity, and modulating the local tumor microenvironment.

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.

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

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

KRAS mutations occur in up to 98% of pancreatic cancer, with KRAS G12D, G12V and G12R occurring in approximately 28%, 19% and 14% of patients, respectively.

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

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

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

In 2022, the NCI estimated melanoma cancer was diagnosed in approximately 99,780 patients or 21.5 cases per 100,000 people based on 2015-2019 cases.

The NCI estimates the five year survival rate from 2012-2018 was approximately 94% Melanoma is a type of skin cancer that develops in melanocytes.

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

Melanocytes make a pigment called melanin.

This gives skin its natural color.

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

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

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

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

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

In patients with melanoma, mutations in the MAPK pathway occur mainly in BRAF (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.

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.

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

Our goal is to

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

Key elements of our strategy to achieve this goal are:

● Establishing VS-6766 as the backbone therapy for RAS pathway-driven tumors.

● Assessing synergy of VS-6766 with other agents in preclinical models to prioritize for clinical development.

It is becoming well established that blockade of multiple nodes in the ERK pathway is necessary for maximal depth and duration of anti-tumor response.

We are assessing combinations of VS-6766 with other key agents targeting both the vertical RAS pathway (e.g., KRAS G12C and SHP2 inhibitors), as well as agents targeting parallel pathways (e.g., mTOR inhibitors).

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

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

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.

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.

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 VS-6766 alone and in combination with defactinib and execute on the registration-directed studies RAMP 201 and RAMP 202.

RAMP 201 is investigating VS-6766 as monotherapy and in combination with defactinib for treatment of patients with LGSOC and RAMP 202 is investigating VS-6766 as a monotherapy and in combination with defactinib for treatment of patients with KRAS and BRAF mutant NSCLC.

VS-6766 is also being investigated in combination with defactinib in an IST entitled FRAME in patients with rec urrent LGSOC, KRAS mutant NSCLC, KRAS-G12V mutant NSCLC, CRC, pancreatic cancer, and KRAS mutant endometrial cancer.

Furthermore, VS-6766 is being investigated in combination with defactinib for patients with metastatic uveal melanoma.

● Expanding the indications in which VS-6766 may be used alone and in combination with other agents.

We have entered into clinical collaboration agreements with both Amgen and Mirati to evaluate VS-6766 in combination with Amgen’s G12C inhibitor LUMAKRAS (sotorasib) in a trial entitled RAMP 203 and Mirati’s G12C inhibitor adagrasib in patients with KRAS G12C NSCLC in a trial entitled RAMP 204.

Furthermore, VS-6766 is being investigated in combination with everolimus for patients with KRAS mutant NSCLC in an IST.

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

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

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.

● 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.

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.

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

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

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

and around the world.

OUR PRODUCT CANDIDATES AND PIPELINE

Our pipeline product candidates currently consist of VS-6766 as a monotherapy and in combination with defactinib and other agents which continue to be evaluated in the clinic for the treatment of a variety of cancer types.

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

The following table represents the status of our pipeline:

1 FDA breakthrough therapy designation

2 Registration-directed trial

3 Imminent initiation

* Pre-clinical studies ongoing in multiple KRAS mutant tumors

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RAMP 202 Study = NCT04620330

RAMP 203 Study = NCT05074810

RAMP 204 Study = NCT05375994

RAMP 205 Study = NCT05669482

FRAME Study = NCT03875820

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

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

VS-6766 and defactinib

VS-6766 is an investigational oral first-in-class unique small molecule RAF/MEK clamp.

In contrast to other MEK inhibitors commercially available and in development, VS-6766 is a dual RAF/MEK clamp that blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK.

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.

By inhibiting RAF-mediated phosphorylation of MEK, VS-6766 has the advantage of not inducing pMEK.

This unique mechanism of VS-6766 enables more effective inhibition of ERK signaling and may confer enhanced therapeutic activity against ERK-dependent, RAS, or BRAF mutant tumors.

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.

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.

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 VS-6766 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.

VS-6766 and defactinib are clinically active against RAS mutant cancers.

Phase 1/2 Study (FRAME ) investigating the Combination of VS-6766 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 VS-6766/defactinib combination in patients with KRAS mutant solid tumors, including LGSOC (including KRAS wild type), KRAS mutant NSCLC, KRAS G12V mutant NSCLC, CRC, pancreatic cancer, and KRAS mutant endometrial cancer.

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.

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 being led by Dr.

Udai Banerji and is being conducted in the United Kingdom.

In this study, VS-6766 was administered using a twice-weekly dose escalation schedule and was administered three out of every four weeks.

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

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

Dose levels were assessed in three cohorts:

cohort 1 (VS-6766 3.2mg, defactinib 200mg);

cohort 2a (VS-6766 4mg, defactinib 200mg);

and cohort 2b (VS-6766 3.2mg, defactinib 400mg).

The recommended Phase 2 dose was determined to be VS-6766 3.2mg, defactinib 200mg.

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

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

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

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

Updated Phase 1/2 FRAME Study Results in Patients with LGSOC (September 2021)

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

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 overall response rate (ORR) was 46% (11 of 24).

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).

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

For context, for other therapies studied in recurrent LGSOC, response rates have been between 6% and 26% and mPFS was between 7.2 and 13.0 months.

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.

These updated data suggest 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 II study (known as RAMP (RAF and MEK Program) 201 Study) Registration-Directed Trial of VS-6766 and Defactinib in Recurrent LGSOC

The RAMP 201 Study that was initiated in November 2020 is a registration-directed clinical trial of VS-6766 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 VS-6766 alone and in combination with defactinib in patients with recurrent LGSOC.

The first part of the study will determine the optimal regimen of either VS-6766 monotherapy or in combination with defactinib in patients with recurrent KRAS mutated and KRAS wild type LGSOC randomized 1:1 in each treatment arm.

The determination of which regimen to take forward into the expansion phase of the trial, which will enroll both KRAS mutated and KRAS wild type LGSOC, will be made based on objective response rate data, safety data and duration of response.

The expansion phase of the study will examine efficacy and safety parameters of the regimen selected.

Trial enrollment is underway in the United States and Europe.

In January 2022, it was reported that target enrollment in the selection phase was completed and enrollment continues in the expansion phase for both treatment arms, KRAS mutated and KRAS wild type LGSOC (including both for VS-6766 alone and in combination with defactinib).

Phase II Study (known as RAMP (RAF and MEK Program) 202 Study) Registration-Directed Trial of VS-6766 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 VS-6766 and defactinib, in patients with KRAS G12V mutant NSCLC.

Additionally, the combination of VS-6766 with defactinib is being evaluated in several exploratory cohorts including KRAS non-G12V and BRAF (V600E and non-V600E) mutant NSCLC.

Based on preclinical rationale, we have added BRAF mutant cohorts (V600E and non-V600E) to the RAMP 202 study in order to efficiently evaluate VS-6766 with defactinib in BRAF-mutant 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 VS-6766 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 VS-6766 monotherapy or in combination with defactinib in patients with KRAS G12V NSCLC.

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.

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 to be 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 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.

Phase II Study of VS-6766 Combined with Defactinib in Patients with Metastatic Uveal Melanoma

The Phase 2 IST was initiated in January 2021 and is an open-label, single arm, investigator-initiated study that is designed to assess potential efficacy, survival benefit and safety profile of the VS-6766/defactinib combination in patients with metastatic uveal melanoma.

The Phase 2 study is being led by Dr.

Takami Sato and is a single-institution study being conducted at Thomas Jefferson University Hospital.

In this study, VS-6766 is being administered at 3.2 mg twice-weekly with defactinib at 200 mg twice daily administered three out of every four weeks.

This recommended Phase 2 dose for the combination is based on the FRAME study.

Phase 1/2 Trial (known as RAMP (RAF and MEK Program) 203 Study) of VS-6766 in combination with Amgen’s LUMAKRAS ™ (sotorasib) in patients with KRAS G12C mutant NSCLC

In September 2021, we entered into a clinical collaboration agreement with Amgen to evaluate the combination of VS-6766 with Amgen’s KRAS G12C inhibitor LUMAKRAS TM (sotorasib) in a Phase 1/2 trial entitled RAMP 203.

The Phase 1/2 trial will evaluate the safety, tolerability and efficacy of VS-6766 in combination with LUMAKRAS TM in patients with KRAS G12C-mutant 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.

Phase 1/2 Trial (known as RAMP (RAF and MEK Program) 204 Study) of VS-6766 in combination with Mirati’s adagrasib in patients with KRAS G12C mutant NSCLC

In November 2021, we entered into a clinical collaboration agreement to evaluate the combination of Mirati’s investigation KRAS G12C inhibitor adagrasib with VS-6766 in patients with KRAS G12C mutant NSCLC.

The primary objective of this multi-center, single-arm, open-label Phase 1/2 trial entitled RAMP 204 is to determine

the maximum tolerated dose and recommended Phase 2 dose for the combination of adagrasib and VS-6766 in patients with KRAS G12C-mutant NSCLC.

The study will also investigate the safety, tolerability and efficacy of the combination in patients who have progressed on a KRAS-G12C inhibitor.

The trial will build on preclinical data showing deeper blockade of ERK pathway signaling resulting in enhanced anti-tumor efficacy with the combination of adagrasib and VS-6766 relative to either agent alone.

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.

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.

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.

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

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.

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.

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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Our patent portfolio includes issued and pending applications worldwide.

These patent applications fall into three categories:

These patent applications fall into two categories:

(1) RAF/MEK inhibition program;

(2) FAK inhibition program;

and (3) other programs.

and (2) FAK inhibition program.

RAF/MEK inhibition program

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

The first patent family has claims directed to the composition of matter of VS-6766, and includes granted patents in the United States, Australia, Brazil, Canada, China, Europe, Japan, Korea, Israel, and New Zealand that are expected to expire in February of 2027.

The second patent family has claims directed to methods of making VS-6766 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 VS-6766, and includes pending patent applications in the United States, Australia, Brazil, Canada, China, Europe, Japan, Korea, India, Mexico, Singapore, Taiwan, and Russia.

Patent applications in this family, if issued, would be expected to expire in May of 2038.

The fourth patent family covers a method of using VS-6766 in combination with a FAK inhibitor, such as defactinib, for

treating a patient, and is pending in the United States, Japan, and Taiwan and as an international application.

patents that will issue in this family will have a statutory expiration date in September of 2040.

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

The first patent family covers a method of using a MEK inhibitor in combination with a G12C inhibitor for treating a patient, and is pending as an international application.

The second patent family covers a method of using a MEK inhibitor to treat a patient with certain mutations, and is pending as an international application.

The third and fourth patent families cover methods of using a MEK inhibitor in combination with another therapeutic agent for treating a patient, which are pending as international applications.

patents that will issue in the four families will have a statutory expiration date ranging from January of 2041 to February of 2042.

We also have six patent families covering methods of using a MEK inhibitor to treat certain populations of patients and methods of using a MEK inhibitor in combination with another therapeutic agent for treating a patient, which are pending as provisional patent applications.

patents that will issue in the six families will have a statutory expiration date ranging from May of 2042 to December of 2042.

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

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

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

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.

FAK inhibition program

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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, New Zealand, Brazil, Korea, Israel, Hong Kong, Canada, and China, and granted in Australia, Europe, Mexico, Japan, Singapore, and South Africa.

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.

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.

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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, South Africa, New Zealand, Brazil, Eurasia, Korea, Singapore, Israel, Canada, Mexico, Japan, and Hong Kong, and granted in the United States, Australia, and China.

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.

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

Other programs

We also own one patent family covering a method of treating a patient having a cytokine release syndrome using a PI3K inhibitor, which is pending as an international application.

patents that will issue in this family will have a statutory expiration date in April 2041.

The base term of a U.S.

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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.

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.

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

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Additionally, Secura assumed all royalty payment obligations due under the amended and restated license agreement with Infinity Pharmaceuticals, Inc.

(“Infinity”).

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

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

In connection with the Secura APA, we and Secura entered into a transition services agreement (Secura TSA).

Under the terms of the Secura TSA, we provided certain support functions at Secura’s direction for a term of less than one year from the date of execution.

Services performed were paid at a mutually agreed upon rate.

In December 2021, Secura announced it had voluntarily withdrawn COPIKTRA (duvelisib) from the U.S.

for treatment of patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies.

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

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

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

In September 2022, Secura’s sublicensee, Yakult, announced it had withdrawn its NDA for duvelisib in Japan.

Chugai Pharmaceutical Co., Ltd.

On January 7, 2020, we entered into a license agreement with Chugai (the Chugai Agreement) whereby Chugai granted us an exclusive worldwide license for the development, commercialization, and manufacture of products containing VS-6766.

Under the terms of the Chugai Agreement, we received an exclusive right to develop and commercialize products containing VS-6766 at our own cost and expense.

On January 7, 2020, we entered into a license agreement with Chugai (the “Chugai Agreement”) whereby Chugai granted us an exclusive worldwide license for the development, commercialization, and manufacture of products containing avutometinib.

Under the terms of the Chugai Agreement, we received an exclusive right to develop and commercialize products containing avutometinib at our own cost and expense.

In February 2020, we paid Chugai a non-refundable payment of $3.0 million.

We are further obligated to pay Chugai double-digit royalties on net sales of products containing VS-6766, subject to reduction in certain circumstances.

Chugai also obtained opt back rights to develop and commercialize VS-6766 (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 VS-6766 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 VS-6766 as the sole active pharmaceutical ingredient.

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

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 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 VS-6766, 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 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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The Pfizer Agreement will remain in effect until the expiration of all our royalty obligations to Pfizer, determined on a product-by-product and country-by-country basis.

So long as we are not in breach of the Pfizer

Agreement, we have the right to terminate the license agreement at will on a product-by-product and country-by-country basis, or in its entirety, upon 90 days written notice to Pfizer.

So long as we are not in breach of the Pfizer Agreement, we have the right to terminate the license agreement at will on a product-by-product and country-by-country basis, or in its entirety, upon 90 days written notice to Pfizer.

Either party has the right to terminate the Pfizer Agreement in connection with an insolvency event involving the other party or a material breach of the Pfizer Agreement by the other party that remains uncured for a specified period of time.

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In addition to currently marketed therapies, there are also a number of products in late stage clinical development to treat cancer.

These products in development may provide efficacy, safety, convenience, and other

benefits that are not provided by currently marketed therapies.

These products in development may provide efficacy, safety, convenience, and other benefits that are not provided by currently marketed therapies.

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

RAF/MEK inhibition program

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

Such companies include:

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

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

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

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

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

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

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

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

● Genentech, Inc.

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

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

● AstraZeneca and Merck & Co., Inc.

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

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

FAK inhibition program

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

We believe InxMed is conducting phase 1 clinical trials of their product candidate IN10018.

RAS Pathway Inhibitors

There is one company with an approved drug with FDA approval targeting the RAS pathway in the market and companies working to develop therapies to target the RAS pathway.

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

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

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:

● 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 TM (sotorasib).

● Mirati Therapeutics, Inc., which we believe is conducting Phase 2 and Phase 3 clinical trials of adagrasib (MTRX-849);

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

● SpringWorks Therapeutics, Inc., which we believe is conducting phase 2 clinical trial of mirdametinib;

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;

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

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

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

● Binjang Pharma, Inc.

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

● Novartis AG, which we believe is conducting phase 1 clinical trials of naporafenib (LXH-254);

● 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 a phase 1 clinical trial of RLY-1971;

● Kinnate Biopharma, Inc., which we believe is conducting phase 1 clinical trials of KIN-2787;

● 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;

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

We currently work with one contract manufacturing organization (CMO) for the manufacture of VS-6766 drug product, one CMO for the production of VS-6766 drug substance, and one CMO for VS-6766 drug packaging/labeling.

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

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

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

We 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 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.

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

● 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;

(“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.

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.

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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.

We may encounter difficulties or unanticipated costs in our efforts to

develop our product candidates and secure necessary governmental approvals, which could delay or preclude us from marketing our products.

We may encounter difficulties or unanticipated costs in our efforts to develop our product candidates and secure necessary governmental approvals, which could delay or preclude us from marketing our products.

After the FDA’s evaluation of the NDA and inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter.

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

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.

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

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

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

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

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

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

The FDA has historically taken the position that the scope of orphan exclusivity aligns with the approved indication or use of a product, rather than the disease or condition for which the product received orphan designation.

However, on September 30, 2021, the U.S.

Court of Appeals for the 11 th Circuit issued a decision in Catalyst Pharms., Inc.

Becerra holding that the scope of orphan drug exclusivity must align with the disease or condition for which the product received orphan designation, even if the product’s approval was for a narrower use or indication.

It remains to be seen how this decision affects orphan drug exclusivity going forward.

Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the NDA application user fee.

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

In 2013, the FDA issued

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

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

That guidance provides recommendations and advice on such topics as:

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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 the product.

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.

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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 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).

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

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.

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

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

Third-party payors are increasingly challenging the prices

charged for medical products and services and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy.

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

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

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

The marketability of products for which we may receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement.

In addition, there is an increasing emphasis on managed care in the United States and we expect will continue to increase the pressure on drug pricing.

Coverage policies, third-party reimbursement rates and drug pricing regulation may change at any time.

The marketability of products for which we may receive regulatory approval for commercial sale may suffer if the government and private third-party payors fail to provide adequate coverage and reimbursement, seek to control utilization, or create pressure to provide price concessions, coverage policies, third-party reimbursement rates and drug pricing regulation may change at any time.

Even if favorable coverage and reimbursement status is attained for a product, less favorable coverage policies and reimbursement rates may be implemented in the future.

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.

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”).

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.

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.

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

On June 17, 2021, the U.S.

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.

Prior to the Supreme Court’s decision,

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

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Other reform efforts affect pricing or payment for drug products.

For example, the Medicaid Drug Rebate Program has been subject to statutory and regulatory changes and the discount that manufacturers of Medicare Part D brand name drugs must provide to Medicare Part D beneficiaries during the coverage gap increased from 50% to 70%.

Additional reform efforts are likely.

The Biden administration has focused on reforms that would address the high cost of drugs.

In response to an Executive Order from President Biden, the Secretary of the Department of Health and Human Services issued a comprehensive plan for addressing high drug prices that describes a number of legislative approaches and identifies administrative tools to address the high cost of drugs.

In addition, Democrats included drug pricing reform provisions reflecting elements of the plan in a broader proposed spending package in late 2021 - such as capping Medicare Part D patients out-of-pocket costs;

establishing penalties for drug prices that increase faster than inflation in Medicare;

and authorizing the federal government to negotiate prices on certain, select high cost drugs under Medicare Parts B and D.

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.

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

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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 Health

Care 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.

Drug development is a complex endeavor which requires deep expertise and experience across a broad array of disciplines.

HUMAN CAPITAL RESOURCES

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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, 2021, we had 48 full-time equivalent employees, including a total of 9 employees with M.D.

degrees, and 3 part-time employees.

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

degrees, and four part-time employees.

Of the full-time equivalent employees, 31 employees are engaged in research and development activities.

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The following table sets forth the name, age and position of each of our executive officers as of February 28, 2023.

Executive Officers:

Brian Stuglik

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President, Chief Operating Officer

Robert Gagnon

Chief Business and Financial Officer

Significant Employees:

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.

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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.

Prior to joining

us in March 2012, Mr.

Paterson was a consultant in 2011.

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

Robert Gagnon , age 47, joined Verastem as Chief Financial Officer in August 2018.

Prior to joining us, Mr.

Gagnon served as the Chief Financial Officer for Harvard Bioscience, Inc.

from November 2013 to August 2018.

From 2012 through 2013, Mr.

Gagnon served as the Executive Vice President, Chief Financial Officer and Treasurer at Clean Harbors, Inc.

Gagnon’s prior experience includes serving as Chief Accounting Officer and Controller at Biogen Idec, Inc., as well as a variety of senior positions at Deloitte & Touche, LLP, and PriceWaterhouseCoopers, LLP.

Gagnon holds an M.B.A.

from the MIT Sloan School of Management and a Bachelor of Arts degree in accounting from Bentley College.

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.

Prior to joining us in December 2018, Mr.

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

Prior to CFGI, Mr.

Calkins began his career at PwC LLP in the assurance practice.

Calkins holds a B.S.

in Accounting from Bryant University and M.S.

in Accounting from Northeastern University.

OUR CORPORATE INFORMATION

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We maintain a website at www.verastem.com.

We make available, free of charge on our website, our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and all amendments to

those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (the Exchange Act) as soon as reasonably practicable after we electronically file those reports with, or furnish them to, the SEC.

We make available, free of charge on our website, our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and all amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (the Exchange Act) as soon as reasonably practicable after we electronically file those reports with, or furnish them to, the SEC.

We also make available, free of charge on our website, the reports filed with the SEC by our executive officers, directors and 10% stockholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those filings are provided to us by those persons.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business