Verastem (NASDAQ:VSTM) Poised for Breakthrough in Oncology Pipeline

Published on September 24, 2024 | Ticker: VSTM

Verastem, Inc. (NASDAQ:VSTM) is a late-stage development biopharmaceutical company committed to advancing new medicines for people diagnosed with cancer. The company's pipeline is focused on RAS/MAPK driven cancers, with a particular emphasis on novel drug candidates that inhibit signaling pathways critical to cancer cell survival and tumor growth.

Business Overview

Verastem's most advanced product candidates, avutometinib 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), pancreatic cancer, colorectal cancer, and thyroid cancer. The company believes that avutometinib may be beneficial as a therapeutic as a single agent or when used in combination with defactinib, other pathway inhibitors, or other current and emerging standard of care treatments in cancers that do not adequately respond to currently available therapies.

RAMP 201 Study

In the fourth quarter of 2020, Verastem commenced a registration-directed trial, known as the RAMP 201 study, investigating avutometinib as a monotherapy and in combination with defactinib for the treatment of patients with recurrent LGSOC. The RAMP 201 study is an adaptive two-part multicenter, parallel cohort, randomized, open label trial to evaluate the efficacy and safety of avutometinib alone and in combination with defactinib in patients with recurrent LGSOC. The combination of avutometinib and defactinib has been declared the go-forward treatment regimen based on a higher rate of confirmed objective responses in a planned interim analysis with prespecified criteria, acknowledging the demonstrated contribution of defactinib.

Verastem intends to submit a new drug application (NDA) for accelerated approval with the FDA in the first half of 2024 for the combination of avutometinib and defactinib for treatment of patients with LGSOC based on mature data from the RAMP 201 study, supported by the results of the investigator-initiated Phase 1 FRAME trial. The company also intends to initiate discussions with global regulatory authorities, including those in Europe and Japan, to determine the regulatory path with the objective of ultimately seeking approval for the combination in additional regions.

RAMP 301 Study

In December 2023, Verastem announced the initiation of a Phase 3 trial, known as the RAMP 301 study, to evaluate the combination of avutometinib and defactinib for the treatment of patients with recurrent LGSOC. The RAMP 301 study is a randomized global trial, evaluating the efficacy and safety of avutometinib and defactinib versus standard chemotherapy or hormonal therapy in patients with recurrent LGSOC. RAMP 301 is intended to serve as the confirmatory study required by the FDA to potentially convert an accelerated approval for the combination of avutometinib and defactinib for the treatment of LGSOC to full approval.

Recent Developments

Collaborations

In September 2021, Verastem entered into a clinical collaboration agreement with Amgen, Inc. to evaluate the combination of avutometinib with Amgen's KRAS G12C inhibitor LUMAKRAS® (sotorasib) in a Phase 1/2 study entitled RAMP 203. The Phase 1/2 trial is evaluating the safety, tolerability and efficacy of avutometinib in combination with LUMAKRAS in patients with KRAS G12C NSCLC who have not been previously treated with a KRAS G12C inhibitor, as well as in patients who have progressed on a KRAS G12C inhibitor. The trial is building on preclinical data showing a deeper blockade of MAPK pathway signaling and enhanced anti-tumor efficacy with the combination of LUMAKRAS and avutometinib relative to either agent alone.

In November 2021, Verastem entered into a clinical collaboration agreement with Mirati Therapeutics, Inc. to evaluate the combination of avutometinib with Mirati's KRAS G12C inhibitor KRAZATI® (adagrasib) in a Phase 1/2 trial entitled RAMP 204. The Phase 1/2 trial will evaluate the safety, tolerability and efficacy of avutometinib in combination with KRAZATI in patients with KRAS G12C NSCLC who have progressed on a KRAS G12C inhibitor.

In May 2022, Verastem received the first "Therapeutic Accelerator Award" from the Pancreatic Cancer Action Network (PanCAN) for up to $3.8 million. The grant is supporting a Phase 1b/2 clinical trial of avutometinib in combination with defactinib entitled RAMP 205. RAMP 205 is evaluating the safety, tolerability and efficacy of avutometinib and defactinib in combination with GEMZAR® (gemcitabine) and ABRAXANE® (Nab-paclitaxel) in patients with previously untreated metastatic adenocarcinoma of the pancreas.

In August 2023, Verastem entered into a collaboration and option agreement with GenFleet Therapeutics, pursuant to which GenFleet granted Verastem options to obtain exclusive development and commercialization rights worldwide outside of mainland China, Hong Kong, Macau, and Taiwan for up to three oncology programs targeting RAS pathway driven cancers. This synergistic collaboration includes Verastem's experience and established network of collaborators, including scientific and clinical experts in RAS biology and RAS pathway-driven cancers and GenFleet's accomplishments with its KRAS G12C inhibitor program.

In December 2023, Verastem announced the selection of an oral KRAS G12D inhibitor with a potential best-in-class profile as the lead program from its collaboration with GenFleet. The lead oncology discovery program is an orally bioavailable, potent and selective small molecule KRAS G12D inhibitor entitled GFH375/VS-7375. GenFleet has submitted an investigational new drug application for GFH375/VS-7375 in China which has been accepted for review, and the company expects to initiate a Phase 1 trial in the second half of 2024, subject to application approval.

Financials

For the fiscal year ended December 31, 2023, Verastem reported an annual net loss of $87.4 million, with no revenue generated. The company's annual operating cash flow was -$86.5 million, and its annual free cash flow was -$86.5 million. As of March 31, 2024, Verastem had cash, cash equivalents, and investments of $110.1 million.

In the first quarter of 2024, Verastem reported a net loss of $33.9 million, with no revenue generated. The company's operating cash flow for the quarter was -$28.3 million, and its free cash flow was -$28.3 million.

Liquidity

Verastem's liquidity position remains a concern, as the company anticipates operating losses may continue for the foreseeable future since it does not yet have regulatory approval to sell any of its product candidates. The company expects to finance its operations with its existing cash, cash equivalents and investments, through potential future milestones and royalties received pursuant to the Secura APA, through the Loan Agreement with Oxford, or through other strategic financing opportunities. However, there is substantial doubt about Verastem's ability to continue as a going concern for the next 12 months.

Outlook

Despite the challenges, Verastem's pipeline of oncology candidates, particularly the combination of avutometinib and defactinib for the treatment of LGSOC, holds significant promise. The company's collaboration with GenFleet and the advancement of the KRAS G12D inhibitor program further diversify its portfolio and provide additional opportunities for growth. Investors will closely monitor Verastem's progress in the coming quarters as the company navigates the regulatory landscape and seeks to unlock the full potential of its oncology pipeline.

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