On January 13, 2025 Rappta Therapeutics ("Rappta"), focused on developing first-in-class anti-cancer drugs activating protein phosphatase 2A (PP2A), reported an exclusive global license agreement with SpringWorks Therapeutics ("SpringWorks") for RPT04402, a first-in-class molecular glue of specific Protein Phosphatase 2A (PP2A) complexes (Press release, Rappta Therapeutics, JAN 13, 2025, View Source [SID1234649683]).

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Rappta’s PP2A-reactivating technologies developed using its proprietary high resolution structural data have the potential to create a new class of anti-cancer drugs for treating a broad range of human cancers. PP2A is a critical enzyme in regulating protein de-phosphorylation and its reactivation is fundamental for tumor suppression, but it has been historically hard to target.

PP2A mutations are oncogenic drivers in molecularly defined subsets of uterine cancer and represent a targetable subset of patients with a high unmet clinical need. In pre-clinical models of PP2A mutant uterine cancer, RPT0402 achieved rapid, deep and durable tumor regressions at as monotherapy.

Under the exclusive license agreement, SpringWorks Therapeutics will be responsible for global development and commercialization of RPT04402. SpringWorks has paid Rappta $13 million upfront, and Rappta is also eligible to receive further clinical, regulatory and commercial milestone payments, and tiered single-digit royalties on net sales. SpringWorks expects to file an Investigational New Drug (IND) application for RPT04402 by the end of 2025.

Sunjeet Sawhney, Chief Executive Officer of Rappta Therapeutics, commented: "Rappta is the only company to have successfully targeted PP2A, a notoriously difficult and undruggable target. Data we generated demonstrated the potential of RPT04402 for treating large, underserved patient populations. SpringWorks, a leader in the targeted oncology space, has the expertise and knowledge to accelerate the further development of our first in class asset. I would like to thank our team and investors who have supported our journey and we look forward to following the progress made in this area"

Goutham Narla, Chief Scientific Officer of Rappta Therapeutics and Professor of Internal Medicine and Human Genetics at the University of Michigan, said: "Our team at Rappta Therapeutics has been able to leverage our proprietary structural data to develop a first-in-class series of molecular glues to the previously undruggable tumor suppressor PP2A. We are excited to be able to work with SpringWorks to potentially translate this approach to the clinic with the hope that this approach will have broad applications for the treatment of human cancers."

Rappta was founded by Goutham Narla & Mikko Mannerkoski, back in 2019 with funding from Novartis Venture Fund ("NVF"), Novo Holdings, Advent Life Sciences and a family office in Series A financing alongside other non-dilutive funding from Business Finland.

On January 13, 2025 Simcere Zaiming, a subsidiary of Simcere Pharmaceutical Group Ltd (HKEX: 2096) and AbbVie Inc. (NYSE: ABBV) reported an option to license agreement to develop SIM0500, an investigational new drug candidate (Press release, Jiangsu Simcere Pharmaceutical Company, JAN 13, 2025, View Source [SID1234649682]). SIM0500 is currently in Phase 1 clinical trials in patients with relapsed or refractory multiple myeloma (MM), in both China and the U.S.

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SIM0500 is a humanized trispecific antibody that targets GPRC5D, BCMA, and CD3, developed independently by Simcere Zaiming using their T-cell engager polyspecific antibody technology platform. This molecule features a low affinity/high target-activating CD3 engaging arm and binding sites for the two tumor antigens: G-Protein-coupled receptor class 5 member D (GPRC5D) and B-cell maturation antigen (BCMA). SIM0500 has shown strong T cell cytotoxicity against multiple myeloma (MM) cells by leveraging a combination of various antitumor effects.

"As a leader in hematologic malignancies, AbbVie is committed to advancing innovative treatments for complex cancers like multiple myeloma through our relentless R&D efforts and collaborations," said Mariana Cota Stirner, M.D., Ph.D., vice president, therapeutic area head for hematology, AbbVie. "We look forward to partnering with Simcere Zaiming, to advance this novel trispecific antibody, which has the potential to help address significant unmet medical needs for people living with multiple myeloma"

"SIM0500 is developed via Simcere Zaiming’s proprietary T-cell engager platform," said Renhong Tang, PhD, CEO of Simcere Zaiming. "We are excited to partner with AbbVie on this novel drug candidate and look forward to working together to advance the clinical development of SIM0500. "

Simcere Zaiming will receive an upfront payment from AbbVie and is eligible to receive option fees and milestone payments of up to $1.055B, as well as tiered royalties on net sales outside of the Greater China territory. AbbVie is eligible to receive tiered royalties on net sales in the Greater China territory

On January 13, 2025 Rise Therapeutics, a biotechnology company engaged in developing novel oral Immunotherapeutics, reported that the U.S. Food and Drug Administration (FDA) has accepted its investigational new drug (IND) application to proceed with a cancer Phase 1 clinical trial for its program candidate, R-5780 (Press release, Rise Therapeutics, JAN 13, 2025, View Source [SID1234649681]). This is Rise Therapeutics’ fourth clinical program to enter patient clinical testing. For separate products, other clinical studies are ongoing for the treatment of ulcerative colitis, rheumatoid arthritis, and type 1 diabetes.

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R-5780 is an orally delivered immune oncology drug candidate being developed for the treatment of cancer. R-5780 has demonstrated a pronounced ability to engage immune pathways that enhance the effectiveness immune checkpoint inhibitor therapy. This drug candidate builds upon the growing understanding of how certain gut-regulated immune pathways can help promote efficacy of immune oncology drugs. R-5780 is a precision-directed synthetic biology medicine that engages selective immune pathways that can support a robust anti-tumor T cell response. This revolutionary immune oncology drug candidate is one of the first of its kind in the context of mechanism of action and potential for success in the context of cancer treatment.

"The FDA’s clearance for R-5780 is a testament to the innovation and dedication of our team at Rise Therapeutics driving novel immunotherapies forward into human proof-of-concept" states Christian Furlan Freguia, Senior Vice President of Research at Rise Therapeutics. "R-5780 represents a pioneering approach that leverages the power of gut-regulated immune pathways to enhance the effectiveness of immune checkpoint inhibitors… We believe R-5780 has the potential to expand responses in patients that become refractory to immune checkpoint inhibitors and increase responsiveness in tumors initially unresponsive to these medications".

The Phase I clinical trial (NCT06398418) will be a multi-dose clinical trial assessing the safety, drug exposure, and clinical activity of R-5780 in patients with cancer. The study will enroll up to 33 participants.

On January 13, 2025 AstraZeneca and Daiichi Sankyo reported that its Biologics License Application (BLA) for datopotamab deruxtecan (Dato-DXd) has been accepted and granted Priority Review in the US for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) who have received prior systemic therapies, including an EGFR-directed therapy (Press release, AstraZeneca, JAN 13, 2025, View Source [SID1234649680]).

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The Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance.1 The Prescription Drug User Fee Act date, the FDA action date for its regulatory decision, is anticipated during the third quarter of 2025. Datopotamab deruxtecan was previously granted Breakthrough Therapy Designation (BTD) by the FDA for this patient population.

The BLA and BTD are based on data from the TROPION-Lung05 Phase II trial and supported by data from the TROPION-Lung01 Phase III trial. In addition, the BLA is supported by data from the TROPION-PanTumor01 Phase I trial.

In a pooled analysis of patients with previously treated advanced or metastatic EGFRm NSCLC in the TROPION-Lung05 and TROPION-Lung01 trials presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia 2024 Congress, datopotamab deruxtecan demonstrated a confirmed objective response rate (ORR) of 42.7% (95% confidence interval [CI] 33.6-52.2) as assessed by blinded independent central review (BICR) and a median duration of response (DoR) of 7.0 months (95% CI 4.2-9.8). The safety profile of datopotamab deruxtecan was consistent with previous reports from the TROPION-Lung05 and TROPION-Lung01 trials, with no new safety concerns identified.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Acquired resistance to front-line therapies and, ultimately, disease progression are unfortunate realities for most patients with advanced EGFR-mutated non-small cell lung cancer. This Priority Review, and the previously granted Breakthrough Therapy Designation, recognise the potential for datopotamab deruxtecan to provide a much-needed option to patients whose disease has become resistant to current treatments."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "Treating advanced EGFR-mutated non-small cell lung cancer presents a significant challenge due to the limited efficacy of available treatments once the disease has progressed following front-line therapies, including the use of an EGFR-tyrosine kinase inhibitor. If approved, datopotamab deruxtecan could become the first TROP2-directed antibody drug conjugate for lung cancer, providing a promising option for patients."

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by AstraZeneca and Daiichi Sankyo.

AstraZeneca and Daiichi Sankyo are evaluating datopotamab deruxtecan alone and in novel combinations as treatment for patients with NSCLC in seven Phase III trials including the TROPION-Lung14 and TROPION-Lung15 trials of datopotamab deruxtecan alone and with Tagrisso (osimertinib) as treatment for patients with advanced or metastatic EGFRm nonsquamous NSCLC.

Notes

Advanced non-small cell lung cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.2 Lung cancer is broadly split into small or non-small cell lung cancer, the latter accounting for about 80% of cases.3 Approximately 10 to 15% of patients with NSCLC in the US and Europe, and 30 to 40% of patients in Asia have an EGFR mutation.4,5 The majority of EGFR mutations occur in tumours of nonsquamous histology.6

For patients with tumours that have an EGFR mutation, the established 1st-line treatment in the metastatic setting is an EGFR-TKI.7 While EGFR-TKIs have improved outcomes in the 1st-line setting, most patients eventually experience disease progression and receive subsequent therapies, such as chemotherapy.8-11

TROP2 is a protein broadly expressed in the majority of NSCLC tumours.12 There is currently no TROP2-directed ADC approved for the treatment of lung cancer.7,13

TROPION-Lung05
TROPION-Lung05 is a global, multicentre, single-arm, open-label Phase II trial evaluating the efficacy and safety of datopotamab deruxtecan in patients with locally advanced or metastatic NSCLC with actionable genomic alterations who have progressed on at least one TKI (with or without other systemic therapies) and on or after one regimen of platinum-based chemotherapy. Patients receiving up to four prior lines of treatment with tumours with one or more genomic alterations including EGFR, ALK, ROS1, NTRK, BRAF, RET or MET were eligible for the trial.

The primary endpoint of TROPION-Lung05 is ORR as assessed by BICR. Secondary efficacy endpoints include DoR, disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), time to response (TTR), overall survival (OS) and safety. TROPION-Lung05 enrolled 137 patients globally in Asia, Europe and North America. For more information visit ClinicalTrials.gov.

Primary results from TROPION-Lung05 were published in the Journal of Clinical Oncology in January 2025.

TROPION-Lung01
TROPION-Lung01 is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan versus docetaxel in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. Patients with actionable genomic alterations were previously treated with an approved targeted therapy and platinum-based chemotherapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The dual primary endpoints of TROPION-Lung01 are PFS as assessed by BICR and OS. Key secondary endpoints include investigator-assessed PFS, ORR, DoR, TTR, and DCR as assessed by both BICR and investigator, and safety. TROPION-Lung01 enrolled approximately 600 patients in Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov.

Primary results from TROPION-Lung01, as presented at the ESMO (Free ESMO Whitepaper) 2023 Congress, showed datopotamab deruxtecan demonstrated a statistically significant improvement in PFS over docetaxel. OS results were presented at the IASLC 2024 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer and simultaneously published in the Journal of Clinical Oncology in September 2024.

TROPION-PanTumor01
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicentre Phase I trial evaluating the safety and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumours that have relapsed or are refractory to standard treatment or for which no standard treatment is available. The dose escalation portion of the trial enrolled patients with NSCLC to assess the safety and tolerability of datopotamab deruxtecan to determine the recommended dose for expansion (6mg/kg). The dose expansion part of TROPION-PanTumor01 enrolled several different cohorts including patients with NSCLC, triple-negative breast cancer (TNBC), hormone receptor (HR)-positive, HER2-negative breast cancer, small cell lung cancer, urothelial, gastric, pancreatic, castration resistant prostate and esophageal cancer.

Safety endpoints include dose-limiting toxicities and serious adverse events. Efficacy endpoints include ORR, DoR, TTR, PFS and OS. Pharmacokinetic, biomarker and immunogenicity endpoints are also being evaluated. TROPION-PanTumor01 enrolled approximately 900 patients in Asia and North America. For more information visit ClinicalTrials.gov.

Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programmes in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanised anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

Datopotamab deruxtecan is approved in Japan under the brand name Datroway for the treatment of adult patients with unresectable or recurrent HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer after prior chemotherapy based on the results of the TROPION-Breast01 trial. Datopotamab deruxtecan is an investigational medicine in all countries outside of Japan.

Datopotamab deruxtecan clinical development programme
A comprehensive global clinical development programme is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, TNBC and HR-positive, HER2-negative breast cancer. The programme includes seven Phase III trials in lung cancer and five Phase III trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.

On January 13, 2025 Verastem Oncology (Nasdaq: VSTM), a biopharmaceutical company committed to advancing new medicines for patients with RAS/MAPK pathway-driven cancers, reported a new credit facility for up to $150 million along with an equity investment of $7.5 million with Oberland Capital Management LLC (Oberland Capital) (Press release, Verastem, JAN 13, 2025, View Source [SID1234649679]). In addition, the Company announced a strategic collaboration with IQVIA Inc. (IQVIA) to leverage IQVIA’s world-class infrastructure and established commercialization solutions to complement its launch strategy for the investigational combination of avutometinib plus defactinib for the treatment of recurrent KRAS mutant low-grade serous ovarian cancer (LGSOC) planned for mid-2025.

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"The Oberland Capital transaction, coupled with our strategic partnership with IQVIA, enables us to launch avutometinib plus defactinib for recurrent LGSOC from a position of financial strength and with commercialization solutions to accelerate our launch. The additional capital will help us create a commercial revenue stream to support our pipeline with new approaches for patients needing treatments for complex and rare cancers," said Dan Paterson, president and chief executive officer of Verastem Oncology.

Verastem’s commercialization efforts are in anticipation of potential U.S. Food and Drug Administration (FDA) approval of avutometinib plus defactinib in recurrent KRAS mutant LGSOC. The Company announced on December 30, 2024, that the FDA set a Prescription Drug User Fee Act (PDUFA) action date for its NDA submission of June 30, 2025.

Under the terms of the note purchase agreement with Oberland Capital, Verastem will issue an initial $75 million of notes at closing, which is expected to occur on January 13, 2025. The Company then has the ability to access up to an additional $75 million in notes upon achievement of certain pre-determined milestones related to the potential regulatory approval and commercialization of avutometinib plus defactinib for the treatment of LGSOC. The notes carry an interest-only period of six years and will bear interest at a floating rate, which is subject to both a floor and a cap. The note purchase agreement also provides for revenue participation pursuant to which Oberland Capital will initially be entitled to 1.0% of the first $100 million of net sales in each calendar year of certain of the Company’s products, subject to pro-rata increase upon potential future draw downs.

In addition, the Company has entered into a stock purchase agreement with affiliates of Oberland Capital for the private placement of 1,416,939 shares of the Company’s common stock issued at closing, representing $7.5 million of gross proceeds based on the trailing 30-trading days volume-weighted average price or VWAP of $5.2931 per share. Additionally, Oberland has the option to participate in certain future equity offerings that may be consummated by the Company within the three years from closing, for up to $2.5 million at the same price per share in such offering. Closing of the stock purchase agreement is expected to occur concurrently with the closing of the note purchase agreement on January 13, 2025. A portion of the proceeds from the notes and equity investment will be used to fully repay amounts owed under the Company’s existing loan with Oxford Finance ($42.7 million), which has been terminated.

The Company had a preliminary unaudited cash, cash equivalents, and short term investment balance of $88.8 million as of December 31, 2024. Taking into account the initial $75.0 million of notes and $7.5 million of equity to be purchased by Oberland Capital at closing, and the repayment of amounts owed under the Company’s existing loan with Oxford Finance, the Company would have had pro-forma cash, cash equivalents, and short-term investment balance of $128.6 million as of December 31, 2024. Both the actual and pro forma December 31, 2024 balances stated herein are preliminary, unaudited estimates and subject to revision upon completion of the Company’s closing and audit processes and do not present all information necessary for an understanding of the Company’s financial condition as of, and its results of operations for the fiscal year ended December 31, 2024. Additional details regarding this financing will be available in a Current Report on Form 8-K to be filed by the Company with the Securities and Exchange Commission.

The agreement between Verastem and IQVIA allows Verastem to tap into IQVIA’s industry-leading expertise and resources while maintaining strategic oversight through the commercialization process and launch. IQVIA will help accelerate key launch capabilities resulting in significant savings while delivering a world-class product launch.

About the Avutometinib and Defactinib Combination

Avutometinib is an oral RAF/MEK clamp that potentially inhibits MEK1/2 kinase activities and 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 the MEK-only inhibitors. 

Defactinib is an oral, selective inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2), the two members of the focal adhesion kinase family of non-receptor protein tyrosine kinases. FAK and Pyk2 integrate signals from integrin and growth factor receptors to regulate cell proliferation, survival, migration, and invasion. FAK activation has been shown to mediate resistance to multiple anti-cancer agents, including RAF and MEK inhibitors. 

Verastem Oncology is currently conducting clinical trials with avutometinib with and without defactinib 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 (GOG-3097/ENGOT-ov81/NCRI) (NCT06072781), an international Phase 3 confirmatory trial evaluating the combination of avutometinib and defactinib versus standard chemotherapy or hormonal therapy for the treatment of recurrent low-grade serous ovarian cancer (LGSOC). 

Verastem was granted Priority Review and a Prescription Drug User Fee Act (PDUFA) date of June 30, 2025, for its 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. Verastem initiated a rolling NDA in May 2024 to the FDA and completed its NDA submission in October 2024. The FDA granted Breakthrough Therapy Designation for the treatment of patients with recurrent LGSOC after one or more prior lines of therapy, including platinum-based chemotherapy, in May 2021. 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-naïve patients and in patients whose KRAS G12C mutant non-small cell lung cancer 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 the avutometinib and defactinib combination for the treatment of pancreatic cancer.