What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2022-03-28 compared with 2021-03-18 · 260 added, 222 removed, 518 unchanged (48% of the section changed)

We are a development-stage biopharmaceutical company committed to the development and commercialization of new medicines to improve the lives of patients diagnosed with cancer.

Our pipeline is focused on novel small molecule drugs 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 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 these compounds may be beneficial as therapeutics either as single agents or when used together in combination with 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 inhibitor.

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

We are a late stage development biopharmaceutical company, with ongoing registration directed trials, 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.

MEK-only inhibitors (e.g.

2 unchanged sentences

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 KRAS, HRAS, or BRAF mutations.

VS-6766 has also been shown to synergize with 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 trials.

Defactinib, is a targeted inhibitor of FAK.

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.

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.

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 Verastem Oncology 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.

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.

The combination of VS-6766 and defactinib has been found to be clinically active in patients with KRAS mutant tumors.

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 and CRC.

Updated data from this study presented at the 2nd Annual RAS-Targeted Drug Development Summit in September 2020 demonstrated a 56% overall response rate (ORR) and long duration of therapy among patients with KRAS-G12 mutant LGSOC.

In an updated December 2020 data read-out of the FRAME study LGSOC cohort (n=24), the ORR is 52% (11 of 21 response evaluable patients).

Among the 21 response evaluable patients, the data demonstrated 70% ORR (7 of 10 response evaluable patients) in KRAS mutant LGSOC, 44% ORR (4 of 9 response evaluable patients) in KRAS wild type LGSOC and 0% ORR (0 of 2 response evaluable patients) in KRAS status undetermined LGSOC.

Based on an observation of higher response rates seen in NSCLC patients with KRAS-G12V mutations in the study, we are also exploring the role of VS-6766 and defactinib in KRAS-G12V mutant NSCLC.

The FRAME study was expanded in August 2020 to include new cohorts in pancreatic cancer, KRAS mutant endometrial cancer and KRAS-G12V mutant NSCLC.

We have met with regulatory authorities in third quarter of 2020, and have commenced registration-directed trials investigating VS-6766 as a monotherapy and in combination with defactinib in the fourth quarter of 2020.

The registration-directed trials are called RAF and MEK Program (RAMP) 201 and 202 studies.

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

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

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

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.

Both studies are discussed in greater detail below.

In addition, defactinib is currently being investigated in combination with immunotherapeutic and other agents through ISTs.

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

In 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.

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).

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 2020, more than 1.8 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 2021, almost 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.

7 unchanged sentences

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 228,820 new cases of lung cancer, 147,950 new cases of colorectal cancer and 57,600 new cases of pancreatic cancer.

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.

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.

1 unchanged sentence

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

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

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

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

1 unchanged sentence

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 its discovery 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.

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.

1 unchanged sentence

Low Grade Serous Ovarian Cancer (LGSOC)

LGSOC is a slow-growing cancer with a high mortality rate that comprise 5-10% of serous ovarian cancers and 6-8% of all ovarian cancers, and has a significant prevalence of KRAS mutations which occur in approximately one third of patients.

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.

3 unchanged sentences

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

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 an investigator sponsored trial (IST) entitled FRAME.

Non-Small Cell Lung Cancer

According to the NCI, the most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma.

Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked.

As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with small cell lung cancer (SCLC).

Lung cancer is the leading cause of cancer-related mortality in the United States.

The NCI estimates that the number of new incidences of lung cancer was 54.2 per 100,000 men and women per year based on 2013-2017 cases and that the five-year relative survival rate from 2010 to 2016 for patients with lung cancer was approximately 21%.

Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy.

Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but a cure is seen only in a small number of patients.

Patients with locally advanced unresectable disease may achieve long term survival with radiation therapy combined with chemotherapy.

Recently, immunotherapy has emerged as new treatment option for certain types of lung cancer.

While any cancer treatment can cause side effects, immunotherapy is generally well-tolerated.

In addition, the introduction of targeted treatment has emerged as lung cancer treatment.

Unlike chemotherapy drugs, which cannot tell the difference between normal cells and cancer cells, targeted therapies are designed specifically to attack cancer cells by attaching to or blocking targets that appear on the surfaces of those cells .

Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.

The disease becomes resistant to therapy and returns in the majority of patients.

KRAS mutation occurs in approximately 25% of NSCLC adenocarcinoma patients.

Two of the most common sub-types of KRAS mutations are G12V, which are present in approximately 7% of NSCLC and G12C, which occur in approximately 13% of NSCLCs.

There are several agents in development for KRAS-G12C mutations, but our study represents the first time that an agent will be studied specifically for KRAS-G12V.

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.

Non-Small Cell Lung Cancer (NSCLC)

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

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

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

Adenocarcinomas most frequently (>50%) have molecular alterations that can be targeted with oral therapies.

The most frequent molecular alterations are mutations in the KRAS gene (about 25% of adenocarcinomas) of which KRAS G12c is most common (14%) and G12V second most frequent (7%).

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

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

Colorectal Cancer

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.

Colorectal Cancer (CRC)

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

One in twenty people will be diagnosed with colorectal cancer and colorectal cancer is the second leading cause of cancer death among men and women combined in the United States.

The NCI estimates that the number of new incidences of CRC was 38.2 per 100,000 men and women per year based on 2013-2017 cases and that the five-year relative survival rate from 2010 to 2016 for patients with CRC was

approximately 65%.

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.

The NCI estimates that the number of new incidences of CRC was 37.8 per 100,000 men and women per year based on 2014-2018 cases and the five-year relative survival rate from 2011 to 2017 for patients with CRC was approximately 65%.

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

1 unchanged sentence

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 an IST entitled FRAME.

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

Pancreatic Cancer

12 unchanged sentences

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 an IST entitled FRAME.

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

5 unchanged sentences

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

According to the American Cancer Society, there are approximately 3,400 new cases of eye cancer (mainly melanoma) in the United States each year and the five year survival rate for eye melanoma is approximately 82%.

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 examples.

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.

5 unchanged sentences

Endometrial Cancer

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

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.

7 unchanged sentences

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 an IST entitled FRAME.

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.

1 unchanged sentence

Key elements of our strategy to achieve this goal are:

● Continuing to develop and explore VS-6766 alone and in combination with defactinib and execute on the registration-directed studies for VS-6766 and defactinib for treatment of LGSOC and KRAS G12V mutant NSCLC.

● Expanding the indications in which VS-6766 and defactinib may be used.

In parallel with clinical studies in NSCLC and LGSOC, signal-finding clinical studies are also in progress to assess safety and efficacy of this combination for patients with pancreatic cancer, KRAS/BRAF mutant endometrioid cancer, and metastatic uveal melanoma.

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

● 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).

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).

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

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

● 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.

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

3 unchanged sentences

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.

The follow table represents the status of our pipeline:

The following table represents the status of our pipeline:

1 Registration-directed trial

* Pre-clinical studies ongoing in multiple KRAS mutant tumors.

1 Investigator-sponsored trial

2 NCT03875820

3 NCT04625270

4 NCT04620330

RAMP 201 Study = NCT04625270

RAMP 202 Study = NCT04620330

FRAME study = NCT03875820

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.

2 unchanged sentences

VS-6766 and defactinib

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

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

MEK-only inhibitors (e.g.

PD0325901) paradoxically induce pMEK by relieving extracellular-signal-regulated-kinase ( ERK)-dependent feedback inhibition of RAF which may limit their efficacy.

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.

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 a targeted inhibitor of FAK.

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

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.

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.

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

Defactinib and VS-6766 have each shown independent clinical activity against RAS mutant cancers.

Phase I 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 wild type), NSCLC and CRC.

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 being led by Dr.

7 unchanged sentences

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

The FRAME study is has expanded to include new cohorts in pancreatic cancer, KRAS mutant endometrial cancer and KRAS-G12V mutant NSCLC.

Initial Results from the FRAME Study Investigating the Combination of VS-6766 and Defactinib in Patients with KRAS Mutant Cancers and Subsequent Analyses

The poster presentation at the American Association for Cancer Research (AACR) 2020 Virtual Meeting held in April 2020 described safety and dose response data from the dose-escalation portion and expansion cohorts from an open-label, investigator-initiated Phase 1 study conducted in the United Kingdom assessing the combination of RAF/MEK and FAK inhibitor therapy in patients with LGSOC and KRAS mutant NSCLC.

The study evaluated the combination of VS-6766 and defactinib.

VS-6766 was administered using a twice-weekly dose escalation schedule and was administered 3 out of every 4 weeks.

Defactinib was administered using a twice-daily dose escalation schedule, also 3 out of every 4 weeks.

Dose levels were assessed in 3 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).

In the patients with LGSOC (n=8), the ORR was 50% (n=4).

Among the patients with KRAS mutant LGSOC (n=6), the ORR was 67% (n=4).

Of the 4 patients who have responded, 3 had a prior MEK inhibitor and as of November 2019 had been on study for a median of 20.5 months (range 7-23 months).

In the patients with NSCLC (n=10), all of which had KRAS mutations, 1 patient achieved a partial response and 1 patient with a 22% tumor reduction still on treatment as of November 2019.

Median time on treatment for this cohort was approximately 18 weeks.

Based on an observation of higher response rates seen in patients with KRAS G12V mutations in the investigator-initiated Phase 1 combination study, we conducted a combined analysis with data from the combination study and the prior single-agent study that utilized a twice-weekly dosing schedule of VS-6766 to get a more complete picture of activity in KRAS G12V mutations.

The subsequent, combined analysis (VS-6766 monotherapy and defactinib combination) showed a 57% ORR (4/7 patients);

as a single agent (2/5 patients) and in combination with defactinib (2/2 patients) in KRAS G12V mutant NSCLC.

Similarly, the combined analysis showed a 60% ORR (3/5 patients);

as a single agent (1/2 patients) and in combination with defactinib (2/3 patients) in KRAS G12V mutant gynecologic cancers.

All KRAS G12V responses were confirmed responses per RECIST criteria.

These additional analyses were conducted to understand the impact that various KRAS variants may have had on response to identify potential signals to pursue in future prospective studies.

This additional analysis was not part of the AACR 2020 poster presentation.

The most common side effects seen in the Phase 1 study were rash, creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea, most being NCI CTC Grade 1/2 and all were reversible.

The recommended Phase 2 dose was determined to be cohort 1 (VS-6766 3.2mg, defactinib 200mg).

The preliminary data reported in the study suggest that a novel intermittent dosing schedule of RAF/MEK and FAK inhibitor combination therapy has promising clinical activity in patients with KRAS mutant LGSOC and KRAS G12V mutant NSCLC, including patients previously treated with a MEK inhibitor.

Expansion cohorts remain ongoing.

Updated Phase 1/2 FRAME Study Results in Patients with LGSOC

On September 16, 2020, updated Phase 1/2 FRAME study results in patients with LGSOC were presented.

Among the patients with LGSOC (n=17), the ORR was 41% (7 of 17 patients), all partial responses (PRs).

Among the patients with KRAS-G12 mutant LGSOC (n=9), the ORR was 56% (5 of 9 patients).

Among the nine patients who had received one or more prior MEK inhibitors, five had responded.

In patients with KRAS mutant LGSOC receiving the recommended Phase 2 dosing (RP2D) regimen, the ORR was 50% (3 of 6 patients).

The LGSOC cohort of the FRAME study remains ongoing, with 53% (9 of 17 patients) still on study as of the data cutoff date of August 17, 2020, with three patients on treatment for two years or more.

The most common Grade ≥3 treatment-related adverse events (TEAEs) observed for the recommended Phase 2 dosing regimen were rash (4%) and elevated creatine kinase (4%).

No patients discontinued from the FRAME study due to TEAEs.

In an updated December 2020 read-out of the FRAME study LGSOC cohort (n=24), the overall response rate (ORR) is 52% (11 of 21 response evaluable patients), with KRAS mutant ORR at 70% (7 of 10 response evaluable patients), KRAS wild-type ORR at 44% (4 of 9 response evaluable patients) and KRAS status undetermined ORR at 0% (0 of 2 response evaluable patients).

As reported previously, the most common side effects seen in the study were rash, creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea, most being NCI CTC Grade 1/2 and all were reversible.

The data from the LGSOC cohort are anticipated to be presented at a major medical meeting during the second half of 2021.

The novel, intermittent, combination dosing schedule used in the FRAME study continues to show encouraging clinical activity in patients with KRAS mutant and KRAS wild type LGSOC, including in patients who had previously progressed following treatment 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 Low-Grade Serous Ovarian Cancer (LGSOC)

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.

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

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

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

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

10.6- not reached).

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

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.

1 unchanged sentence

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.

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

Trial enrollment is underway in the United States with European sites to follow.

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 2020 Study that was initiated in December 2020 is a registration-directed clinical trial of VS-6766 and defactinib, in patients with KRAS 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 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 mutant NSCLC randomized 1:1 in each treatment arm.

An exploratory arm of the initial phase of the study will evaluate other KRAS mutations.

The determination of which regimen to take forward into the expansion phase of the trial will be made based on data from KRAS-G12V mutant patients.

The second phase of the study will examine efficacy and safety parameters of the most effective regimen.

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.

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

4 unchanged sentences

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

COPIKTRA (duvelisib)

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

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

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

A detailed description of the terms and conditions of the Secura APA is contained below under the heading Licenses and Commercial Agreements .

With the transition of the duvelisib program to Secura, we are focusing our efforts on our lead product candidates, VS-6766 and defactinib.

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.

INTELLECTUAL PROPERTY

9 unchanged sentences

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

often lags behind actual discoveries, we cannot be certain of the priority of inventions covered by pending patent applications.

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

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

11 unchanged sentences

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 Japan and Taiwan and as an international application.

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 three patent families covering methods of using a MEK inhibitor for treating a patient.

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.

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

We have two families covering a method of using a MEK inhibitor to treat a patient with certain mutations and a method 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 two families will have a statutory expiration date in April of 2041 and July of 2041.

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.

FAK inhibition program

7 unchanged sentences

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

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

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

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

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

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

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

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

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

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

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

1 unchanged sentence

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

patents that have issued or will issue in

this family will have a statutory expiration date in June of 2036.

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

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.

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

1 unchanged sentence

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

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

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

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

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 a provisional patent application.

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.

11 unchanged sentences

LICENSES AND COMMERCIAL AGREEMENTS

On August 10, 2020, we and Secura signed the Secura APA and on September 30, 2020, the transaction closed.

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

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

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

7 unchanged sentences

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 will provide certain support functions at Secura’s directions for a term of less than one year from the date of execution, unless earlier terminated or extended according to the terms of the Secura TSA.

Services performed are paid at a mutually agreed upon rate.

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.

Chugai Pharmaceutical Co., Ltd.

3 unchanged sentences

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 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-6766as the sole active pharmaceutical ingredient.

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.

5 unchanged sentences

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

containing certain of Pfizer’s inhibitors of FAK, including defactinib, for all therapeutic, diagnostic and prophylactic uses in humans.

On July 11, 2012, we entered into a license agreement (the Pfizer Agreement) with Pfizer under which Pfizer granted us worldwide, exclusive rights to research, develop, manufacture and commercialize products containing certain of Pfizer’s inhibitors of FAK, including defactinib, for all therapeutic, diagnostic and prophylactic uses in humans.

We have the right to grant sublicenses under the foregoing licensed rights, subject to certain restrictions.

7 unchanged sentences

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.

11 unchanged sentences

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

There are many generic products currently on the market for the indications that we are pursuing, and additional

products are expected to become available on a generic basis over the coming years.

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

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

8 unchanged sentences

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.

2 unchanged sentences

Such companies include:

● Novartis AG, which has received FDA approval for dabrafenib (Taflinar), a RAF inhibitor, in combination with trametinib (Mekinist), 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 encorafenib (Braftovi), a RAF inhibitor, in combination with binimetinib (Mektovi), 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 encorafenib (Braftovi) in combination with cetuximab (Erbitux), an anti-EGFR antibody for treatment of adult patients with metastatic CRC with a BRAF V600E mutation;

● 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;

● Genentech, Inc.

a member of the Roche Company, which has received FDA approval for vemurafenib, a RAF inhibitor, in combination with 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 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;

● AstraZeneca and Merck & Co., Inc.

has received FDA approval for 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 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.

FAK inhibition program

2 unchanged sentences

RAS Pathway Inhibitors

There are other companies working to develop therapies to target the RAS pathway.

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

● Amgen Inc., which we believe is conducting Phase 2 and Phase 3 clinical trials of sotorasib, formerly called AMG 510;

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.

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;

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

● Fochon Pharmaceutical Ltd.

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

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

● Binjang Pharma, Inc.

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

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

● Mapkure, LLC, together with BeiGene Ltd.

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

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

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

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

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

● 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;

● Boehringer Ingelheim, which we believe is conducting a Phase 1 clinical trial of BI 1701963;

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

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

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

3 unchanged sentences

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/labelling.

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 /labelling.

We have development agreements in place with these CMOs and we obtain drug substance, drug product and packaging/labelling 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/labelling for later-stage clinical trials, commercialization or for risk management.

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

10 unchanged sentences

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

● completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice (GLP) regulations;

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

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

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

● performance of adequate and well-controlled human clinical trials in accordance with good clinical practices (GCP) to establish the safety and efficacy of the proposed drug for each indication;

● submission to the FDA of an NDA;

● performance of adequate and well-controlled human clinical trials in accordance with good clinical practices (GCP) and other clinical-trial related regulations to establish the safety and efficacy of the proposed drug for each indication;

● submission to the FDA of an NDA and payment of user fees for FDA review of NDA;

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

● satisfactory completion of an FDA 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;

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

● FDA review and approval of the NDA.

Preclinical studies

Before testing any product candidate in humans, the product candidate must undergo rigorous preclinical testing.

Preclinical studies include laboratory evaluation of product chemistry and formulation, as well as in vitro and animal studies to assess the potential for adverse events and in some cases to establish a rationale for therapeutic use.

2 unchanged sentences

Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity, may continue after the IND is submitted.

An IND automatically becomes effective 30 days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on clinical hold.

An IND automatically becomes effective thirty days after receipt by the FDA, unless before that time the FDA raises concerns or questions related to one or more proposed clinical trials and places the trial on clinical hold.

In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.

1 unchanged sentence

Clinical trials

requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial.

Clinical trials involve the administration of the investigational new drug to human subjects under the supervision of qualified investigators in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial.

Clinical trials are conducted under written study protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.

8 unchanged sentences

The drug is administered to an expanded patient population in adequate and well-controlled clinical trials to generate sufficient data to statistically confirm the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product and to provide adequate information for the labeling of the product.

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

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

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

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

4 unchanged sentences

Assuming successful completion of the required clinical testing, the results of the preclinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.

Under federal law, the submission of most NDAs is additionally subject to a substantial application user fee, currently scheduled to exceed $2.9 million, and the sponsor of an approved NDA is also subject to annual program fees, based on the number of approved products.

Under federal law, the submission of most NDAs is additionally subject to a substantial application user fee, scheduled in 2022 to exceed $3.1 million, and the sponsor of an approved NDA is also subject to annual program fees, based on the number of approved products.

These fees are typically adjusted annually.

8 unchanged sentences

The FDA has agreed to specified performance goals in the review of NDAs.

Under these goals, the FDA has committed to review most such applications for non-priority products within 10 months after accepting the application for filing, and most applications for priority review products, that is, drugs that the FDA determines represent a

significant improvement over existing therapy, within six months after accepting the application for filing.

The review process may be extended by the FDA for three additional months to consider certain information or clarification regarding information already provided in the submission.

1 unchanged sentence

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Under the Pediatric Research Equity Act of 2003, as amended and reauthorized by the Food and Drug Administration Amendments Act of 2007 (FDAAA), an NDA or supplement to an NDA must contain data that are adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan drug designation.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured.

4 unchanged sentences

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.

1 unchanged sentence

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

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

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

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

3 unchanged sentences

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

Expedited Development and Review Programs

The FDA has various programs, including fast track designation, breakthrough therapy designation, priority review and accelerated approval, which are designed to expedite or facilitate the process for the development and FDA review of drugs and biologics that are intended for the treatment of serious or life threatening diseases or conditions and demonstrate the potential to address unmet medical needs.

The purpose of these programs is to provide important new drugs and biologics to patients earlier than under standard FDA review procedures.

Fast Track Designation.

The FDA is required to facilitate the development and expedite the review of drugs that are intended for the treatment of a serious or life- threatening condition for which there is no effective treatment, and which demonstrate the potential to address unmet medical needs for the condition.

To be eligible for a fast track designation, the FDA must determine, based on the request of a sponsor, that the product is intended for the treatment of a serious or life-threatening condition for which there is no effective treatment, and demonstrates the potential to address unmet medical needs for the condition.

Under the fast track program, the sponsor of a new drug candidate may request the FDA to designate the product for a specific indication as a fast track product concurrent with or after the filing of the IND for the product candidate.

3 unchanged sentences

However, the FDA’s time period goal for reviewing a fast track application does not begin until the last section of the NDA is submitted.

addition, the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

In addition, the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.

Breakthrough Designation .

A drug may be designated as a breakthrough therapy if the drug is intended to treat a serious or life-threatening disease and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

A drug may be designated as a breakthrough therapy if the drug is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

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

3 unchanged sentences

Priority Review.

Under FDA policies, a product candidate may be eligible for priority review, or review within a six- month time frame from the time a complete application is accepted for filing.

Under FDA policies, a product candidate may be eligible for priority review, or review within a six-month time frame, compared to the ten-month time frame for a standard review, from the time a complete application is accepted for filing.

Products regulated by the FDA’s Center for Drug Evaluation and Research (CDER) are eligible for priority review if they provide a significant improvement compared to marketed products in the treatment, diagnosis or prevention of a disease.

14 unchanged sentences

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

Pediatric information

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan drug designation.

The Hatch-Waxman Act

25 unchanged sentences

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

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

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

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

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

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

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.

That guidance provides recommendations and advice on such topics as:

3 unchanged sentences

and (4) post-marketing safety monitoring and reporting obligations.

Given the wide range of potential combination therapy variations, FDA indicated it intends to assess each potential combination on a case-by case basis and encouraged sponsors to engage in early and regular consultation with the relevant review division at the agency throughout the development process for its proposed combination.

Given the wide range of potential combination therapy variations, the FDA indicated it intends to assess each potential combination on a case-by case basis and encouraged sponsors to engage in early and regular consultation with the relevant review division at the agency throughout the development process for its proposed combination.

Combination products

24 unchanged sentences

● product seizure or detention, or refusal to permit the import or export of products;

● consent decrees, injunctions or the imposition of civil or criminal penalties.

● consent decrees, corporate integrity agreements, injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market.

14 unchanged sentences

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.

13 unchanged sentences

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

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

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

Oral drugs may be covered under Medicare Part D.

3 unchanged sentences

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

Since 2011, under the Medicare Coverage Gap Discount Program, manufacturers with marketed brand name drugs have been required to provide a 50% 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, and, beginning in 2019, that discount increased to 70%.

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.

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

6 unchanged sentences

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.

22 unchanged sentences

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.

Under the Trump administration, there have been ongoing efforts to modify or repeal all or certain provisions of the Healthcare Reform Act.

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

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

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

In December 2018, a federal district court, in a challenge brought by a number of state attorneys general, found the Healthcare Reform Act unconstitutional in its entirety because, once Congress repealed the individual mandate provision, there was no longer a basis to rely on Congressional taxing authority to support enactment of the law.

Pending resolution of the litigation, which could take some time, the Healthcare Reform Act is still operational in all respects.

In December 2019, a federal appeals court agreed that the individual mandate provision was unconstitutional but remanded the case back to the district court to assess more carefully whether any provisions of the Healthcare Reform Act were severable and could survive.

In March 2020, the Supreme Court agreed to hear the case.

There have also been efforts by government officials or legislators to implement measures to regulate drug pricing or payment for pharmaceutical products, including legislation on drug importation.

On June 17, 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.

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

Other reform efforts affect pricing or payment for drug products.

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.

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

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

Pursuant to court order, the removal was delayed and recent legislation imposed a moratorium on implementation of the rule until January 1, 2026.

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

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

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

Specifically, at the federal level, for example, in May 2018, President Trump and the Secretary of the Department of Health and Human Services released a “blueprint” to lower prescription drug prices and out-of-pocket costs.

Certain proposals in the blueprint, and related drug pricing measures proposed since the blueprint, could cause significant operational and reimbursement changes for the pharmaceutical industry.

As another example, legislation passed in 2019 revised how certain prices reported by manufacturers under the Medicaid Drug Rebate Program are calculated, a revision that is reported to potentially increase rebates paid by manufacturers by approximately $3 billion over the next ten years.

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

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

3 unchanged sentences

HUMAN CAPITAL RESOURCES

We believe our employees are among the most important assets to our company and are key to achieving our goals and expectations.

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

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

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

Bonus opportunity and equity compensation increase as a percentage of total compensation based on level of responsibility.

Actual bonus payout is based on our achievement of corporate goals and individual performance.

In addition, many of our employees are stockholders of the Company through participation in our Employee Stock Purchase Plan, which aligns the interests of our employees with our stockholders by providing stock ownership on a tax-deferred basis.

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 1 part-time employee.

degrees, and 3 part-time employees.

Of the full-time equivalent employees, 30 employees are engaged in research and development activities.

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

Biopharmaceutical companies both large and small compete for a limited number of qualified applicants to fill specialized positions and retain such employees.

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

Bonus opportunity and equity compensation increase as a percentage of total compensation based on level of responsibility.

Actual bonus payout is based on our achievement of corporate goals and individual performance.

None of our employees are represented by a labor union or covered by a collective bargaining agreement.

30 unchanged sentences

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.

Gagnon holds an M.B.A.

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

OUR CORPORATE INFORMATION

3 unchanged sentences

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.

1 unchanged sentence

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