On November 6, 2024 Tango Therapeutics, Inc. (NASDAQ: TNGX), a clinical-stage biotechnology company committed to discovering and delivering the next generation of precision cancer medicines, reported its financial results for the third quarter ended September 30, 2024, and provided business highlights (Press release, Tango Therapeutics, NOV 6, 2024, View Source [SID1234647867]).

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"We have made great progress with our PRMT5 development program, including positive data from the TNG462 phase 1/2 clinical trial that showcase the best-in-class potential of TNG462 in multiple tumor types, including pancreatic and non-small cell lung cancers (NSCLC). Based on these early data, we are advancing TNG462 into trials with multiple targeted and standard of care combinations, including two RAS(ON) tri-complex inhibitors from Revolution Medicines. Given that nearly all MTAP-deleted pancreatic cancer has a co-occurring RAS mutation, we believe this could be a powerful approach to changing the treatment landscape for this challenging cancer," said Barbara Weber, M.D., President and Chief Executive Officer of Tango Therapeutics. "As part of the expanded capabilities needed to rapidly move TNG462 development forward, Dr. Maeve Waldron-Lynch, M.D. is joining Tango as Senior Vice President, Head of Clinical Development. Dr. Waldron-Lynch has extensive late-stage oncology clinical development and regulatory experience and will be invaluable as we prepare to advance TNG462 to registration."

In a separate press release issued earlier today, Tango Therapeutics provided an update on its ongoing PRMT5 clinical development program:

Data from the ongoing phase 1/2 clinical trial of TNG462, a potentially best-in-class MTA-cooperative PRMT5 inhibitor, demonstrate clinical activity across multiple tumor types, including NSCLC and pancreatic cancer. Of note, this includes an ORR of 43% in cholangiocarcinoma (n=7). Substantive durability and a good safety and tolerability profile also were observed in this ongoing trial. The next clinical update is expected in 2025.
The Company plans to initiate multiple targeted and standard of care combinations with TNG462 including RAS(ON) multi-selective and RAS(ON) G12D-selective inhibitors (Revolution Medicines), osimertinib (AstraZeneca) and pembrolizumab (Merck). These studies are expected to begin enrolling in 1H 2025.
TNG908, an MTA-cooperative brain-penetrant PRMT5 inhibitor, is clinically active and well-tolerated across non-CNS cancers in the phase 1/2 clinical trial. In particular, there were a total of nine evaluable pancreatic cancer patients, two with partial responses (ORR 22%) and five with stable disease as best response to date. The five ongoing pancreatic cancer patients have been on study for an average of 24 weeks, the longest for 72 weeks.
TNG908 did not demonstrate activity in glioblastoma (n=23 at active doses) likely because CNS exposure did not meet the required exposure threshold for clinical efficacy.
TNG908 enrollment is being stopped to allow full resourcing of TNG462 as a potential best-in-class molecule. In particular, the notably longer time on treatment observed – 24 weeks and still increasing for TNG462 versus 16 weeks for TNG908 – the superior target coverage, and the safety and tolerability profile all support selection of TNG462 for further development.
TNG456 is a next-generation brain-penetrant MTA-cooperative PRMT5 inhibitor that is 55X selective for MTAP deletion with 20 nM potency. Preclinical studies suggest TNG456 central nervous system exposure has the potential to be sufficient for meaningful efficacy in glioblastoma and brain metastases.
The Company expects to begin enrolling patients in the planned phase 1/2 trial during 1H 2025.
Business Highlights

Clinical collaboration with Revolution Medicines

In November 2024, the Company entered into a clinical collaboration with Revolution Medicines to evaluate the efficacy and safety of TNG462 in combination with RMC-6236, a RAS(ON) multi-selective inhibitor, and with RMC-9805, a RAS(ON) G12D-selective inhibitor.
The agreement provides that Revolution Medicines will supply RMC-6236 and RMC-9805 to Tango and that Tango will be the sponsor of any combination trials. Each company will retain commercial rights to their respective compounds and the agreement is mutually non-exclusive.
TNG260, a first-in-class, highly selective CoREST complex inhibitor

The TNG260 phase 1/2 clinical trial is ongoing, evaluating safety, pharmacokinetics, pharmacodynamics and efficacy of TNG260 in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors with an STK11 loss-of-function mutation. To date, safety, tolerability and pharmacokinetic profiles are favorable.
STK11 mutations occur in approximately 15% of non-small cell lung, 15% of cervical, 10% of carcinoma of unknown primary, 5% of breast and 3% of pancreatic cancers.
Upcoming Milestones

TNG462 clinical data update expected in 2025
TNG462 combination trial enrollment expected to begin 1H 2025
TNG456 phase 1/2 trial enrollment expected to begin 1H 2025
TNG260 clinical data expected in 2025
Additional Business and Pipeline Highlights

Leadership Update

Maeve Waldron-Lynch, M.D. will join Tango as Senior Vice President, Head of Clinical Development later this month. In this role, Dr. Waldron-Lynch will lead clinical development functions under Adam Crystal, M.D., Ph.D., President of Research and Development at Tango. Dr. Waldron-Lynch most recently served as VP and Global Clinical Program Head at MorphoSys, where she oversaw the clinical program for tafasitamab. Prior to MorphoSys, she was a Clinical Development Medical Director at Novartis. Dr. Waldron-Lynch also has served as Senior Clinical Director, Oncology at Roche, and as Associate Director of Medical Science, Oncology at Mundipharma. Dr. Waldron-Lynch graduated from the University College Cork School of Medicine and served as a Specialty Registrar Medical Oncology at the Royal College of Physicians of Ireland, and a Clinical Fellow in Medical Oncology at the Yale University School of Medicine.

Financial Results

As of September 30, 2024, the Company held $293.3 million in cash, cash equivalents and marketable securities, which the Company expects to be sufficient to fund operations into the third quarter of 2026, including for additional planned TNG462 and TNG456 clinical trials.

Collaboration revenue was $11.6 million for the three months ended September 30, 2024, compared to $10.7 million for the same period in 2023, and $25.9 million for the nine months ended September 30, 2024 compared to $26.1 million for the same period in 2023. Collaboration revenue increased due to changes to estimated costs expected to be incurred under the collaboration during the three months ended September 30, 2024.

License revenue was $0 and $12.1 million for the three and nine months ended September 30, 2024, respectively, compared to $0 and $5.0 million for the three and nine months ended September 30, 2023, respectively. The year-to-date increase is primarily due to licensing a drug discovery program to Gilead for $12.0 million during the second quarter of 2024 as compared to Gilead licensing a program for $5.0 million during the second quarter of 2023.

Research and development expenses were $33.3 million for the three months ended September 30, 2024, compared to $27.1 million for the same period in 2023, and $110.0 million for the nine months ended September 30, 2024 compared to $83.9 million for the same period in 2023. The change is due to increased spend related to the advancement of TNG462, preclinical programs and personnel-related costs to support our research and development activities.

General and administrative expenses were $11.2 million for the three months ended September 30, 2024, compared to $9.2 million for the same period in 2023, and $32.7 million for the nine months ended September 30, 2024 compared to $26.4 million for the same period in 2023. The change was primarily due to increases in personnel-related costs.

Net loss for the three months ended September 30, 2024 was $29.2 million, or $0.27 per share, compared to a net loss of $22.3 million, or $0.23 per share, in the same period in 2023. Net loss for the nine months ended September 30, 2024 was $92.6 million, or $0.85 per share, compared to a net loss of $71.0 million, or $0.78 per share, in the same period in 2023.

On November 6, 2024 Charles River Laboratories International, Inc. (NYSE: CRL) reported its results for the third quarter of 2024. For the quarter, revenue was $1.01 billion, a decrease of 1.6% from $1.03 billion in the third quarter of 2023 (Press release, Charles River Laboratories, NOV 6, 2024, View Source [SID1234647807]).

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The impact of foreign currency translation benefited reported revenue by 0.4%, and an acquisition contributed 0.9% to consolidated third-quarter revenue. A divestiture of a small Safety Assessment site reduced reported revenue by 0.2%. Excluding the effect of these items, revenue declined 2.7% on an organic basis. On a segment basis, organic revenue growth in the Manufacturing Solutions (Manufacturing) and Research Models and Services (RMS) segments were more than offset by lower revenue in the Discovery and Safety Assessment (DSA) segment.
In the third quarter of 2024, the GAAP operating margin decreased to 11.6% from 14.8% in the third quarter of 2023. This GAAP decrease was primarily driven by costs associated with the Company’s restructuring initiatives. On a non-GAAP basis, the operating margin improved in all three segments; however, the improvements were more than offset by higher unallocated corporate costs, which resulted in the third-quarter operating margin decreasing to 19.9% from 20.5%.

On a GAAP basis, third-quarter net income attributable to common shareholders was $68.7 million, a decrease of 21.4% from $87.4 million for the same period in 2023. Third-quarter diluted earnings per share on a GAAP basis were $1.33, a decrease of 21.3% from $1.69 for the third quarter of 2023. The GAAP net income and earnings per share decreases were driven primarily by lower revenue and operating income, which included higher costs associated with the Company’s restructuring initiatives. On a non-GAAP basis, net income was $133.7 million for the third quarter of 2024, a decrease of 4.8% from $140.5 million for the same period in 2023. Third-quarter diluted earnings per share on a non-GAAP basis were $2.59, a decrease of 4.8% from $2.72 per share for the third quarter of 2023. The decreases in non-GAAP net income and earnings per share were driven primarily by lower revenue and operating income.

James C. Foster, Chair, President and Chief Executive Officer, said, "Forward-looking demand indicators were relatively stable in the third quarter, contributing to third-quarter financial performance which exceeded our prior outlook. We are continuing to navigate through a challenging period as global biopharmaceutical clients reduce spending in conjunction with major restructuring and pipeline reprioritization activities, but overall demand trends do not appear to have deteriorated further. In addition, biotech funding has improved in 2024, and demand appears to be demonstrating early signs of stabilization. These factors resulted in a slight, sequential improvement in net book-to-bill and the cancellation rate in the Safety Assessment business."

"We remain laser focused during this period on our strategy, which includes aggressively managing our cost structure, enhancing our clients’ experiences to gain additional share, and protecting shareholder value. We will continue to distinguish ourselves through our exceptional science and preclinical focus, in order to extend our leading position as our clients’ preferred, global, non-clinical drug development partner. We expect to emerge from this period as a stronger, leaner, and more profitable company, and an even more responsive partner for our clients," Mr. Foster concluded.
Third-Quarter Segment Results

Research Models and Services (RMS)

Revenue for the RMS segment was $197.8 million in the third quarter of 2024, an increase of 5.9% from $186.8 million in the third quarter of 2023. The Noveprim acquisition in November 2023 contributed 4.9% to third-quarter RMS reported revenue, and the impact of foreign currency translation increased revenue by 0.4%. Organic revenue increased by 0.6%, due primarily to higher sales of small research models in all geographic regions, principally driven by higher pricing. This was largely offset by a revenue decline for research model services, particularly in the Insourcing Solutions business.

In the third quarter of 2024, the RMS segment’s GAAP operating margin decreased to 13.9% from 15.2% in the third quarter of 2023. The GAAP operating margin decline was driven primarily by higher amortization expense related to the Noveprim acquisition coupled with higher costs associated with the Company’s restructuring initiatives, including severance and site consolidation costs. On a non-GAAP basis, the operating margin increased to 21.0% from 18.9%. The non-GAAP operating margin increase was primarily driven by higher pricing for small research models, a favorable revenue mix related to the Noveprim acquisition, and the benefit of cost savings associated with the Company’s restructuring initiatives.

Discovery and Safety Assessment (DSA)

Revenue for the DSA segment was $615.1 million in the third quarter of 2024, a decrease of 7.4% from $664.0 million in the third quarter of 2023. The divestiture of a small Safety Assessment site reduced reported revenue by 0.3% and the impact of foreign currency translation increased DSA revenue by 0.3%. Organic revenue decreased by 7.4%, driven primarily by lower sales volume in both the Discovery Services and Safety Assessment businesses.

In the third quarter of 2024, the DSA segment’s GAAP operating margin decreased to 20.6% from 22.1% in the third quarter of 2023 primarily driven by lower revenue and higher severance costs related to restructuring initiatives. On a non-GAAP basis, the operating margin increased to 27.4% from 27.2% in the third quarter of 2023. The non-GAAP operating margin increase was primarily driven by the benefit of cost savings associated with restructuring initiatives.
Manufacturing Solutions (Manufacturing)
Revenue for the Manufacturing segment was $196.9 million in the third quarter of 2024, an increase of 12.0% from $175.7 million in the third quarter of 2023. The impact of foreign currency translation increased Manufacturing revenue by 0.2%. Organic revenue growth of 11.8% reflected higher revenue across each of the segment’s businesses.
In the third quarter of 2024, the Manufacturing segment’s GAAP operating margin increased to 20.4% from 15.0% in the third quarter of 2023, and on a non-GAAP basis, the operating margin increased to 28.7%, from 24.5% in the third quarter of 2023. The GAAP and non-GAAP operating margin increases were driven primarily by improved operating leverage from higher revenue in each of segment’s businesses, as well as the benefit of cost savings associated with restructuring initiatives.
Stock Repurchase Update
On August 2, 2024, the Company’s Board of Directors approved a new stock repurchase authorization of $1.0 billion. Following the new authorization, the Company repurchased 500,000 shares during the third quarter of 2024 for a total of $100.7 million. As of September 28, 2024, the Company has $899.3 million remaining on its $1.0 billion stock repurchase authorization.
Updates 2024 Guidance
The Company is updating its financial guidance for 2024, which was previously revised on August 7, 2024. Revenue and non-GAAP earnings per share guidance have been narrowed and slightly raised from the midpoint of the previous ranges to principally reflect the third-quarter financial performance, which exceeded the Company’s prior outlook. In addition, GAAP earnings per share guidance has been reduced due primarily to increased charges related to the Company’s additional restructuring actions.

On November 6, 2024 Oxford Vacmedix (OVM), the UK-based biopharma company developing vaccines to treat cancer reported the lead investment in its Series B fund of $3.0m from existing investors, Dx&Vx of Seoul, South Korea and Mr. Jin of Jia He Hui Investment of Beijing, China (Press release, Oxford Vacmedix, NOV 6, 2024, View Source;utm_medium=rss&utm_campaign=oxford-vacmedix-announces-lead-investment-for-series-b-fund [SID1234647823]). Dx&Vx is OVM’s largest shareholder, and Jia He Hui Investment is the second largest shareholder. The most recent investment has been made at the valuation for OVM of $54.0m, which reflects the substantial progress the company has made in developing the novel Recombinant Overlapping Peptide (ROP) technology. Funds will be used to accelerate the development of the lead cancer vaccine OVM-200 and support further research in the Professor Shisong Jiang’s labs in the Department of Oncology at the University of Oxford.

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OVM-200 targets survivin, a protein overexpressed by cancer cells that allow unregulated growth, and stimulates an immune response. The OVM-200 vaccine is in a Phase 1 clinical trial in the UK, which is focused on safety and on establishing an immune response in advanced cancer patients in three cancer indications: non-small cell lung cancer (NSCLC), prostate cancer and ovarian cancer. Initial results from the Phase 1a dose escalation study indicated good safety and a strong immune response. The ROP technology is unique in being suitable for all HLAs (human leucocyte antigen) and has potential to be used with mRNA technology. ROPs hold the promise of minimally invasive, cost effective and efficacious therapy that can also extend and enhance the effect of immunotherapy.

William Finch, CEO of OVM said:

We are delighted to have this support from our largest shareholders. It shows their confidence in OVM’s ROP technology and in the initial results with OVM-200. This funding will allow the completion of Phase 1 and preparation for Phase 2 trials of OVM-200 alone and in combination, to help patients with advanced cancer. We look forward to interest from other investors to complete Series B.

Kevin Kwon, CEO of Dx&Vx added:

We are very pleased to be supporting OVM through this investment. We look forward to completing licensing discussions for OVM-200 for S. Korea, China, and India. We plan to proceed with Phase 1b/ Phase 2 clinical trials and will try to launch OVM-200 through an accelerated approval that will allow patients to benefit early from these effective vaccines.

On November 6, 2024 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with cancer, reported business updates and announced financial results for the third quarter ended September 30, 2024 (Press release, Verastem, NOV 6, 2024, View Source [SID1234647852]).

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"In the third quarter of 2024, we made advancements in our recurrent low-grade serous ovarian cancer program, including sharing updated Phase 2 RAMP 201 data demonstrating robust and durable response rates, tumor reductions across a majority of patients regardless of their KRAS mutation status, and low discontinuation rates due to adverse events. We also completed our rolling NDA submission for recurrent KRAS mutant low-grade serous ovarian cancer and strengthened our balance sheet," said Dan Paterson, president and chief executive officer of Verastem Oncology. "Looking ahead to the fourth quarter of 2024, we anticipate an FDA decision on the acceptance of our NDA, plan to submit our updated RAMP 201 trial data for publication and expect to prepare a U.S. IND application for VS-7375, an oral KRAS G12D (ON/OFF) inhibitor."

Third Quarter 2024 and Recent Updates

Avutometinib and Defactinib Combination in Low-Grade Serous Ovarian Cancer (LGSOC)

Completed the rolling New Drug Application (NDA) submission for the combination of avutometinib and defactinib for adult patients with recurrent KRAS mutant LGSOC, who received at least one prior systemic therapy, in October 2024. The Company submitted the NDA under the U.S. Food and Drug Administration (FDA) Accelerated Approval pathway and requested Priority Review based on the combination’s potential to address significant unmet medical need among patients with recurrent LGSOC.
RAMP 301, which is currently enrolling patients with recurrent LGSOC regardless of KRAS mutation status across the U.S., UK, EU, Canada, and Australia, will serve as a confirmatory study for the initial indication and has potential to expand the indication regardless of KRAS mutation status. The Company plans to complete enrollment in RAMP 301 by the end of 2025. The Company plans to map out a path forward with the FDA for the KRAS wild-type indication, including the ability to leverage data from the ongoing RAMP 301 Phase 3 trial.
Announced mature data from the RAMP 201 trial that continued to show robust and durable response rates with low discontinuation rates due to adverse events in patients with recurrent KRAS mutant or KRAS wild-type LGSOC who had a minimum follow-up of 12 months, at the International Gynecologic Cancer Society (IGCS) 2024 Annual Meeting on October 17, 2024. The primary analysis of the RAMP 201 trial, with a data cutoff of June 30, 2024, showed a confirmed overall response rate (ORR) by blinded independent central review (BICR) of 31% (34/109; 95% CI: 23-41), 44% (25/57; 95% CI: 31-58) in KRAS mutant LGSOC, and 17% (9/52; 95% CI: 8-30) in KRAS wild-type LGSOC. The majority (82%) of all patients had a reduction in their tumors, regardless of KRAS status. The updated data continue to demonstrate avutometinib in combination with defactinib is generally well-tolerated, with a 10% discontinuation rate due to adverse events (AEs) and no new safety signals.
The Company continued its commercial preparation activities for a potential U.S. launch in mid-2025.
The Japanese Gynecologic Oncology Group (JGOG) dosed the first patient in a Phase 2 Verastem sponsored clinical trial, called RAMP201J, evaluating the safety and efficacy of avutometinib in combination with defactinib for recurrent LGSOC in Japan in October 2024.
Avutometinib in Combination with KRAS G12C Inhibitors in Non-Small Cell Lung Cancer (NSCLC)

Following a thorough evaluation of the Company’s lung cancer clinical development program, Verastem has decided to discontinue the Phase 1/2 RAMP 204 clinical trial evaluating the combination of avutometinib and adagrasib in patients with KRAS G12C-mutant NSCLC. There are no safety concerns with the RAMP 204 trial. The Company is prioritizing the Phase 1/2 RAMP 203 clinical trial, which is evaluating the doublet of avutometinib and sotorasib and the triplet combination of avutometinib and sotorasib plus defactinib in similar patient populations.

Since the last update of RAMP 203 in October of 2023, enrollment to the doublet of avutometinib plus sotorasib for the KRAS G12C inhibitor naïve Stage I Part B cohort has recently completed, and per protocol patients are being followed to determine if the efficacy supports further expanded enrollment into Stage II. The KRAS G12C inhibitor prior-treated Stage I Part B cohort enrollment is nearly complete.
Earlier this year, RAMP 203 was modified to include the triplet combination of avutometinib and sotorasib plus defactinib and the first safety cohort of this triplet has been fully enrolled. Preclinical data provide strong evidence that addition of a FAK inhibitor to the sotorasib and avutometinib doublet has the potential to deepen anti-tumor response and significantly delay tumor progression.
Expect to report updated interim data from the doublet combination of avutometinib plus sotorasib and provide initial safety data and a status of enrollment for the triplet combination of avutometinib, sotorasib and defactinib in the RAMP 203 trial by the end of 2024.
Avutometinib and Defactinib Combination in First-Line Metastatic Pancreatic Cancer

Preclinical data outlining the scientific rationale for the combination of avutometinib plus defactinib with standard of care chemotherapy was published in the October 23, 2024 edition of Science Translational Medicine.
Presented initial interim safety and efficacy results from the ongoing RAMP 205 trial of avutometinib and defactinib in combination with current standard of care gemcitabine and nab-paclitaxel in first-line metastatic pancreatic cancer on June 1, 2024, at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.
Expect to report updated data from the ongoing RAMP 205 trial in Q1 2025.
VS-7375/GFH375: Oral KRAS G12D (ON/OFF) Inhibitor

GenFleet began dosing several patients in the Phase 1/2 trial in China evaluating VS-7375/GFH375 in patients with KRAS G12D-mutated advanced solid tumors in July 2024.
After evaluating initial dose escalation data from the Phase 1 study of VS-7375/GFH375 in China, Verastem anticipates filing a U.S. investigational new drug (IND) application by Q1 2025​.
Discovery/lead optimization continues for the second and third programs in the GenFleet collaboration.
Third Quarter 2024 Financial Results

Verastem Oncology ended the third quarter of 2024 with cash, cash equivalents and short-term investments of $113.2 million which provides an expected cash runway through the potential approval of avutometinib and defactinib for recurrent LGSOC in mid-2025.

Total operating expenses for the three months ended September 30, 2024 (the "2024 Quarter") were $37.0 million, compared to $21.3 million for the three months ended September 30, 2023 (the "2023 Quarter").

Research & development expenses for the 2024 Quarter were $24.8 million, compared to $13.9 million for the 2023 Quarter. The increase of $10.9 million, or 78.4%, was primarily related to contract research organization costs, consulting costs, investigator fees associated with ensuring continued rapid start-up of RAMP 301, and a clinical milestone expense that was reached in the GenFleet G12D program.

Selling, general & administrative expenses for the 2024 Quarter were $12.3 million, compared to $7.4 million for the 2023 Quarter. The increase of $4.9 million, or 66.2%, was primarily related to a one-time cost associated with July 2024 financing activities, personnel costs, including non-cash stock compensation and additional costs in anticipation of a potential launch of avutometinib and defactinib in LGSOC.

Net loss for the 2024 Quarter was $24.0 million, or $0.60 per share (basic and diluted), compared to $20.0 million, or $0.75 per share (basic and diluted) for the 2023 Quarter.

For the 2024 Quarter, non-GAAP adjusted net loss was $35.3 million, or $0.88 per share (diluted) compared to non-GAAP adjusted net loss of $19.0 million, or $0.71 per share (diluted) for the 2023 Quarter. Please refer to the GAAP to non-GAAP Reconciliation attached to this press release.

Use of Non-GAAP Financial Measures

To supplement Verastem Oncology’s condensed consolidated financial statements, which are prepared and presented in accordance with generally accepted accounting principles in the United States (GAAP), the Company uses the following non-GAAP financial measures in this press release: non-GAAP adjusted net loss and non-GAAP net loss per share. These non-GAAP financial measures exclude certain amounts or expenses from the corresponding financial measures determined in accordance with GAAP. Management believes this non-GAAP information is useful for investors, taken in conjunction with the Company’s GAAP financial statements, because it provides greater transparency and period-over- period comparability with respect to the Company’s operating performance and can enhance investors’ ability to identify operating trends in the Company’s business. Management uses these measures, among other factors, to assess and analyze operational results and trends and to make financial and operational decisions. Non-GAAP information is not prepared under a comprehensive set of accounting rules and should only be used to supplement an understanding of the Company’s operating results as reported under GAAP, not in isolation or as a substitute for, or superior to, financial information prepared and presented in accordance with GAAP. In addition, these non-GAAP financial measures are unlikely to be comparable with non-GAAP information provided by other companies. The determination of the amounts that are excluded from non-GAAP financial measures is a matter of management judgment and depends upon, among other factors, the nature of the underlying expense or income amounts. Reconciliations between these non-GAAP financial measures and the most comparable GAAP financial measures for the three and nine months ended September 30, 2024 and 2023 are included in the tables accompanying this press release after the unaudited condensed consolidated financial statements.

About the Avutometinib and Defactinib Combination

Avutometinib is a RAF/MEK clamp that induces inactive complexes of MEK with ARAF, BRAF and CRAF potentially creating a more complete and durable anti-tumor response through maximal RAS/MAPK pathway inhibition. In contrast to currently available MEK-only inhibitors, avutometinib blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. This unique mechanism allows avutometinib to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of other MEK-only inhibitors.

Verastem Oncology is currently conducting clinical trials with avutometinib in RAS/MAPK driven tumors as part of its Raf And Mek Program or RAMP. Verastem is currently enrolling patients and activating sites for RAMP 301 (NCT06072781) an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib, a selective FAK inhibitor, versus standard chemotherapy or hormonal therapy for the treatment of recurrent low-grade serous ovarian cancer (LGSOC). RAMP 201 (NCT04625270) is a Phase 2 registration-directed trial of avutometinib in combination with defactinib in patients with recurrent LGSOC and enrollment has been completed for the RAMP 201 trial.

Verastem has completed its submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the investigational combination of avutometinib and defactinib in adults with recurrent KRAS mutant LGSOC who received at least one prior systemic therapy in October 2024, with a potential FDA decision mid-2025. The FDA granted Breakthrough Therapy Designation of the investigational combination of avutometinib and defactinib for the treatment of patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy. Avutometinib alone or in combination with defactinib was also granted Orphan Drug Designation by the FDA for the treatment of LGSOC.

Verastem Oncology has established a clinical collaboration with Amgen to evaluate LUMAKRAS (sotorasib) in combination with avutometinib and defactinib in both treatment naive and in patients who progressed on a G12C inhibitor as part of the RAMP 203 trial (NCT05074810). Verastem has received Fast Track Designation from the FDA for the triplet combination in April 2024. RAMP 205 (NCT05669482), a Phase 1b/2 clinical trial evaluating avutometinib and defactinib with gemcitabine/nab-paclitaxel in patients with front-line metastatic pancreatic cancer, is supported by the PanCAN Therapeutic Accelerator Award. FDA granted Orphan Drug Designation to avutometinib and defactinib combination for the treatment of pancreatic cancer.

About VS-7375/GFH375

VS-7375/GFH375 is a potential best-in-class, potent and selective oral KRAS G12D (ON/OFF) inhibitor, identified as the lead discovery program from the Verastem Oncology discovery and development collaboration with GenFleet Therapeutics. GenFleet’s IND for VS-7375/GFH375 was approved in China in June 2024 and the Phase 1/2 trial in KRAS G12D-mutant solid tumors was subsequently initiated and the first patient was dosed in July 2024. The collaboration includes three discovery programs, the first being the KRAS G12D inhibitor, and provides Verastem Oncology with exclusive options to license three compounds selected for collaboration after successful completion of pre-determined milestones in Phase 1 trials. The licenses would give Verastem Oncology development and commercialization rights outside of the GenFleet territories of mainland China, Hong Kong, Macau, and Taiwan.

On November 6, 2024 BostonGene, a leading provider of AI-driven molecular and immune profiling solutions, reported the Company will present six posters at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 39th Annual Meeting taking place November 6-10, 2024 at the George R. Brown Convention Center in Houston, Texas (Press release, BostonGene, NOV 6, 2024, View Source [SID1234647868]). The research, conducted in collaboration with leading cancer centers, showcases the impact of BostonGene’s technology in advancing cancer treatment strategies, from deep molecular insights to predictive biomarkers. BostonGene will also exhibit at booth 514.

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BostonGene session details are below:

Abstract number: 135
Title: Multiplex immunofluorescence of whole slide images for enhanced tumor microenvironment immune cell characterization in multiple cancer types
Date & time: Friday, November 8 | 9:00 AM to 7:00 PM CST
Presenter: Vladimir Kushnarev, MD, PhD, BostonGene

This study used BostonGene’s MxIF pipeline that combines cell segmentation and spatial analysis to identify the immune cell types in various tumor microenvironment (TME) subtypes across multiple cancer types. The findings revealed the diverse nature of TME landscapes across cancers and the necessity for tailored immunotherapeutic approaches.

Abstract number: 161
Title: The predictive role of comprehensive genomic profiling in angiosarcoma immunotherapy
Date & time: Friday, November 8 | 9:00 AM to 7:00 PM CST
Presenter: Nikita Kotlov, BostonGene

Comprehensive genomic profiling (CGP) of angiosarcomas, a rare and aggressive form of cancer, revealed genetic changes critical for targeted therapy selection. Transcriptomic analysis also uncovered possible associations between tumor microenvironment (TME) subtypes and immunotherapy response, highlighting the importance of CGP in aiding treatment selection and expanding treatment options for angiosarcomas.

Research conducted in collaboration with The University of Texas MD Anderson Cancer Center

Abstract number: 183
Title: Comprehensive molecular profiling in the management of patients with diverse sarcoma subtypes
Date & time: Friday, November 8 | 9:00 AM to 7:00 PM CST
Presenter: Francesca Paradiso, PhD, BostonGene

Comprehensive molecular profiling (CGP) of sarcomas, which are highly heterogeneous, uncovered over 1,000 genetic alterations across 47 histological subtypes among 356 patients. Whole exome sequencing revealed approximately 400 actionable findings that are associated with approved therapy or inclusion criteria in clinical trials, and RNA-seq-based analysis identified diagnostic fusions and unique compositional features of various TME subtypes. These findings underscore a potential role of CGP in guiding treatment options for rare sarcomas.

Research conducted in collaboration with Massachusetts General Hospital Cancer Center and Sarcoma Oncology Center

Abstract number: 46
Title: Comprehensive machine learning-driven platform infers key tumor characteristics from blood-derived cfRNA
Date & time: Saturday, November 9 | 9:00 AM to 8:30 PM CST
Presenter: Andrey Shubin, PhD, BostonGene

A comprehensive machine learning platform was constructed to analyze the transcriptomic data from blood-derived cell-free RNA (cfRNA) of healthy donors and cancer patients to infer clinically important features and biomarkers of malignancies. Coupled with robust cell-free DNA (cfDNA) harvesting protocols, this universal platform offers unprecedented insights into tumor biology and can potentially characterize any tumor-associated transcriptomic changes reflected in the cfRNA.

Abstract number: 144
Title: Identifying a composite signature for predicting immune-related adverse events in advanced melanoma patients treated with immune checkpoint blockade
Date & time: Saturday, November 9 | 9:00 AM to 8:30 PM CST
Presenter: Michael Goldberg, PhD, BostonGene

Using flow cytometry and bulk RNA-seq to analyze blood cells of advanced melanoma patients collected before immune checkpoint blockade (ICB) treatment, we examined if the occurrence of immune-related adverse events (irAEs), severe and potentially fatal side effects of ICB, can be predicted. irAE signatures were constructed and used to detect distinct cellular and gene expression patterns among patients who developed severe irAEs post-ICB treatment. These signatures can potentially identify patients likely to develop irAEs, enabling timely mitigation to improve patient outcomes.

Abstract number: 170
Title: Identifying novel targets for antibody-drug conjugates in sarcomas using RNA sequencing
Date & time: Saturday, November 9 | 9:00 AM to 8:30 PM CST
Presenter: Vladimir Kushnarev, MD, PhD, BostonGene

RNA sequencing uncovered the expression landscape of potential antibody-drug conjugate (ADC) targets in sarcomas, particularly those lowly expressed in normal tissues. The combined expression of ADC targets with tertiary lymphoid structure and immune checkpoint gene signatures also depicts the immune landscape of sarcomas and can guide the development of immunotherapy approaches. Our findings revealed many genes that are precluded from existing clinical trials, underscoring the need to advance clinical trials and precision oncology in sarcoma therapies that prioritize safety and efficacy.

Research conducted in collaboration with The University of Texas MD Anderson Cancer Center, Massachusetts General Hospital Cancer Center, Memorial Sloan Kettering Cancer Center and Sarcoma Oncology Center