On September 24, 2025 FibroGen, Inc. (NASDAQ: FGEN) reported the initiation of the Phase 2 monotherapy, dose-optimization trial of FG-3246, a potential first-in-class antibody-drug conjugate (ADC) targeting CD46-expressing cancer lesions in patients with metastatic castration-resistant prostate cancer (mCRPC) (Press release, FibroGen, SEP 24, 2025, View Source [SID1234656192]). The trial will also assess the diagnostic and predictive performance of FG-3180, a companion PET imaging agent, which shares the same CD46-targeted antibody used in FG-3246. The ability of FG-3180 to identify mCRPC lesions and predict response to FG-3246 will be evaluated.

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"With the transformation of FibroGen to a U.S.-focused organization now complete and a robust cash runway into 2028, we are excited to advance our FG-3246 program and initiate the Phase 2 monotherapy trial with the activation of the University of California San Francisco (UCSF) site," said Thane Wettig, Chief Executive Officer of FibroGen. "FG-3246 demonstrated compelling clinical activity in patients that were heavily pre-treated, with a competitive radiographic progression free survival benefit in the Phase 1 monotherapy study. We are confident that the dosing regimen of FG-3246, use of prophylactic G-CSF, and the enrollment of patients in earlier lines of treatment of mCRPC set us up to further demonstrate the potential of this program. We anticipate results from the interim analysis of our Phase 2 study in the second half of 2026. We also look forward to reporting the results from the ongoing investigator-sponsored study of FG-3246 in combination with enzalutamide in the fourth quarter of this year."

The Phase 2 monotherapy trial (NCT06842498) is a randomized, open label, dose optimization trial designed to evaluate the safety, efficacy, tolerability, and pharmacokinetics (PK) of FG-3246 for the treatment of patients with mCRPC who have progressed following ARSI treatment and who have not received chemotherapy for their mCRPC. The trial is scheduled to enroll 75 patients who will be randomized 1:1:1 to receive either 1.8, 2.4 or 2.7 mg/kg AJBW of FG-3246. The primary endpoint of the trial is the determination of the optimal dose for the Phase 3 trial based on efficacy, safety, and PK parameters. Secondary endpoints include radiographic progression free survival (rPFS), prostate-specific antigen (PSA) 50 response, and PSA90 response. An interim analysis is planned once 12 patients enrolled in each of the three dose arms have completed 12 weeks on study or discontinued and is anticipated in the second half of 2026. An exploratory sub-study will evaluate FG-3180, a companion PET imaging agent, as a diagnostic radiopharmaceutical. All patients deemed eligible for participation in the Phase 2 trial will participate in the sub-study evaluating FG-3180 prior to randomization.

In addition, topline results from the ongoing investigator-sponsored study of FG-3246 in combination with enzalutamide in patients with mCRPC are expected in the fourth quarter of 2025.

About FG-3246
FG-3246 (FOR46) is a potential first-in-class fully human antibody-drug conjugate (ADC), exclusively in-licensed from Fortis Therapeutics, and is being developed by FibroGen for metastatic castration-resistant prostate cancer and potentially other tumor types. FG-3246 binds to an epitope of CD46, a cell receptor target, that induces internalization upon antibody binding, is present at high levels in prostate cancer and other tumor types and demonstrates very limited expression in most normal tissues. FG-3246 is comprised of an anti-CD46 antibody, YS5, linked to the anti-mitotic agent, MMAE, which is a clinically and commercially validated ADC payload. FG-3246 has demonstrated anti-tumor activity in both preclinical and clinical studies.

FG-3246 is currently in an ongoing Phase 1b/2 study being conducted at UCSF as an investigator-sponsored trial to evaluate FG-3246 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). An additional investigator-sponsored radiopharmaceutical marker trial using a zirconium-89 positron emission tomography (PET) tracer for CD46 that utilizes the YS5 antibody is also underway at UCSF. The Phase 2 monotherapy dose optimization trial for FG-3246 in mCRPC was initiated in the third quarter of 2025, with interim results expected in the second half of 2026. FG-3246 is an investigational drug and not approved for marketing by any regulatory authority.

About Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Prostate cancer is the second most common malignancy in men, contributing significantly to male mortality rates. Approximately 13% of men will be diagnosed with prostate cancer at some point during their lifetime. There are about 65,000 drug treatable mCRPC cases in the U.S. annually and 5-year survival in mCRPC is approximately 30%.

On September 24, 2025 Pi Health, a global health technology and clinical research company, reported it will provide fully outsourced clinical research services in a GSK clinical trial with the aim of significantly improving the time and efficiency of the clinical trial process (Press release, GlaxoSmithKline, SEP 24, 2025, View Source [SID1234656210]). Pi Health and GSK have executed a Master Clinical Services Outsourcing Agreement for the collaboration and have begun initial activities for a global Phase 2 oncology clinical trial.

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Pi Health will manage all aspects of this GSK clinical trial through a technology-driven service model, including site selection and activation, patient enrollment, study conduct, real-time monitoring and regulatory submissions.

Pi Health will leverage its Front-end Interoperable Capture System (FICS) platform — integrated with an international network of clinical trial sites across the globe — for the clinical trial. FICS is an end-to-end clinical trial software platform with artificial intelligence capabilities that enriches current systems by using a unified solution that connects sites and sponsors to accelerate trials, enhances compliance, streamlines data flow and automates manual processes.

The FICS platform can make study conduct 50% faster while maintaining audit-ready data quality. Pi Health’s technology and operational workflows are built to achieve regulatory-grade data capture throughout the lifecycle of trials, enabling perpetual, real-time readiness for regulatory reviews and eliminating the need for manual reconciliation and expensive third-party processing.

"By applying Pi Health’s technology and international reach to GSK’s global scale and expertise, we believe we can accelerate the development of vital treatments for patients in need of new therapies by making clinical trials faster and more efficient," said Pi Health CEO and co-founder Geoffrey Kim, M.D., former Deputy Director of the Oncology Center of Excellence at the Food and Drug Administration (FDA). "This collaboration validates our commitment to fundamentally reimagining how trials should be run. Our technology provides the transparency and efficiency that senior leadership demands while delivering the data quality that regulators require."

"We are thrilled about what this agreement represents for global drug development," said Bobby Reddy, M.D., Chief Operating Officer and co-founder of Pi Health. "We are optimistic about collaborating with GSK to support its efforts in streamlining clinical trial delivery, with our shared goal of developing medicines more efficiently for patients."

"Pi Health’s integrated approach to clinical trial management, and its team’s strong background in drug development and regulation, made them a natural choice," said Zeshaan Rasheed, M.D., Ph.D., Senior Vice President, Head of Oncology Clinical Development at GSK. "By removing inefficiencies that can slow progress in clinical trials, Pi Health is well positioned to help us focus on our main priority: getting innovative medicines to people with cancer as quickly and as safely as possible."

Pi Health was founded by physicians and has assembled a multidisciplinary team that includes highly experienced clinicians, principal investigators, former industry leaders with deep experience in pharma and biotech clinical development and operations, and former FDA leaders with extensive approval track records (>100 NDAs, BLAs, PMAs reviewed; >1000 INDs reviewed) — giving the company a unique window into the challenges and solutions needed in clinical research.

On September 24, 2025 FORE Biotherapeutics, a registration stage biotherapeutics company dedicated to developing targeted therapies to treat patients with cancer, reported that following a pre-specified interim efficacy analysis for the Phase 2 FORTE basket study evaluating plixorafenib as a monotherapy in patients with recurrent or progressive BRAF V600-mutated primary central nervous system (CNS) tumors, the Independent Data Monitoring Committee (IDMC) has recommended that the study should continue as planned (Press release, Fore Biotherapeutics, SEP 24, 2025, View Source [SID1234656194]).

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The interim efficacy analysis was conducted by the IDMC and was pre-specified to evaluate plixorafenib at a defined efficacy threshold after the first 25 participants treated in this basket had sufficient data for response assessment, in addition to the IDMC’s ongoing oversight for safety.

"We are very pleased that the BRAF V600 primary CNS basket of the FORTE study has passed the protocol-specified interim analysis supporting that tumor regressions in patients treated with plixorafenib continue to be observed," said Stacie Peacock Shepherd, M.D., Ph.D., Chief Medical Officer of Fore. "We believe this is an encouraging development for the study, and more importantly, for patients in need of novel treatment options for recurrent primary CNS tumors. The data with this novel BRAF inhibitor, known as a paradox breaker, builds on the recent momentum for the potential of plixorafenib to benefit patients across BRAF-altered solid tumors, including the recent presentation of encouraging data in patients with BRAF-altered thyroid cancers, which has generated significant enthusiasm in the field. This significant milestone builds upon the validated approach of targeting BRAF, while avoiding the limitations of the earlier generation compounds that led to rapid recurrence of disease and the need for combination with a MEK inhibitor, and brings us one step closer to our objective of accelerating access to adults and children diagnosed with recurrent BRAF-altered brain or spinal cord tumors. We look forward to completing enrollment and reporting topline results from this registrational CNS basket in the second half of 2026."

Macarena de la Fuente, M.D., Chief of Neuro-Oncology at the University of Miami Sylvester Comprehensive Cancer Center and lead CNS Investigator for both the Phase 1/2a and FORTE Phase 2 plixorafenib clinical studies, commented, "Primary CNS tumors can lead to significant disease and treatment-related morbidity, including neurocognitive deterioration and seizures, and premature death. The unique mechanism and tolerable safety profile seen in early clinical trials set plixorafenib apart from current limited treatments, including lower side effects of rash or fever and less risk of intratumoral bleeding, cardiac, ocular, or growth effects. The data that have been previously presented are very promising with durable clinical activity and favorable tolerability and we look forward to the full readout of data at the completion of this trial. We anticipate plixorafenib, with its unique mechanism of action, has the potential to transform the treatment paradigm for people with BRAF-altered recurrent or refractory primary CNS tumors."

The primary endpoint of overall response rate (ORR), supported by duration of response, in the FORTE CNS basket is being evaluated in up to 50 patients with BRAF V600 primary recurrent CNS tumors.

About the Global Phase 2 FORTE Basket Study

The registration-intended FORTE Master Protocol is a global Phase 2 clinical trial which includes four sub-protocol baskets evaluating plixorafenib in distinct patient populations. The three monotherapy indications currently under evaluation are recurrent or progressive BRAF V600 primary CNS tumors, solid tumors with BRAF fusions and rare BRAF V600 mutated solid tumors. As part of the design of the trial, interim efficacy analyses will be conducted in the other two baskets of FORTE – the advanced solid tumors with BRAF fusions basket and the rare BRAF V600 solid tumors basket – after sufficient scans from approximately 25 patients in each basket are evaluated by the IDMC.

About BRAF Altered Recurrent Primary CNS Tumors

BRAF altered recurrent primary CNS tumors represent a high unmet medical need and a large market opportunity for plixorafenib. In the advanced treatment setting, patients are offered currently approved therapies, but those therapies have significant limitations in efficacy, tolerability, and safety.

About Plixorafenib

Plixorafenib is a novel BRAF inhibitor, with a unique mechanism of action that functions both as a dimer and paradox breaker, and that has demonstrated a differentiated and compelling monotherapy profile in clinical studies. In a previously conducted Phase 1/2 study, in patients with MAPK inhibitor naïve BRAF V600 primary recurrent CNS tumors (n=9), plixorafenib monotherapy demonstrated an ORR of 67% and a clinical benefit rate of greater than 75%. Plixorafenib also demonstrated a favorable safety and tolerability profile across tumor types, including relative to existing standard of care treatments for various BRAF altered tumors, with a discontinuation rate due to drug-related adverse events of less than 2%. Fore Bio believes plixorafenib has the potential to overcome the limitations of currently available BRAF inhibitors through its unique mechanism of action targeting BRAF, while avoiding the limitations of the earlier generation BRAF inhibitors that led to rapid recurrence of disease and the need for combination with a MEK inhibitor.

On September 24, 2025 Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit," "we," or the "Company") reported that data from the Phase III HARMONi-6 trial, conducted in China and sponsored by our partner, Akeso, Inc. (HKEX Code: 9926.HK), featuring the novel, potential first-in-class investigational bispecific antibody, ivonescimab, will be featured as part of the Presidential Symposium at the European Society for Medical Oncology 2025 Congress (ESMO 2025) which takes place from October 17–21, 2025, in Berlin, Germany (Press release, Summit Therapeutics, SEP 24, 2025, View Source [SID1234656211]). The presentation will take place on Sunday, October 19 during the Presidential Symposium from 4:30pm – 6:30pm CET (10:30am – 12:30pm EDT).

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HARMONi-6 is evaluating ivonescimab in combination with platinum-based chemotherapy compared with tislelizumab, a PD-1 inhibitor, in combination with platinum-based chemotherapy in patients with locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) irrespective of PD-L1 expression. HARMONi-6 is a single region, multi-center, Phase III study conducted in China sponsored by Akeso with all relevant data exclusively generated, managed, and analyzed by Akeso.

On April 23, 2025, Akeso announced, via a press release, topline results from HARMONi-6. At a prespecified interim analysis conducted by an Independent Data Monitoring Committee, ivonescimab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS by blinded independent central radiology review committee (BICR) compared to tislelizumab plus chemotherapy. The PFS benefit was demonstrated in patients with either PD-L1-positive or PD-L1-negative tumors. Akeso noted that no new safety signals were identified in this Phase III study. Prior to HARMONi-6, there were no known Phase III clinical trials in NSCLC which have shown a statistically significant improvement compared to PD-(L)1 inhibitor therapy in combination with chemotherapy in a head-to-head setting.

The trial results will be presented by Dr. Shun Lu, MD, PhD, Chief of Shanghai Lung Cancer Center at Shanghai Chest Hospital, Professor of Medicine at Shanghai Jiaotong University, and associate editor for Journal of Thoracic Oncology, Lung Cancer, and editor for The Oncologist.

Summit is currently enrolling patients in the HARMONi-3 study. HARMONi-3 is a multiregional Phase III clinical trial sponsored by Summit which is intended to evaluate ivonescimab combined with chemotherapy compared to pembrolizumab, an anti-PD-1 antibody, combined with chemotherapy in patients with first-line metastatic, squamous and non-squamous NSCLC. HARMONi-3 is currently enrolling patients globally and is conducted with registrational intent for the United States and other regions within Summit’s license territories.

About the ESMO (Free ESMO Whitepaper) 2025 Presidential Symposium Presentation

Presidential Symposium Presentation
Presentation Title: Phase III Study of Ivonescimab plus chemotherapy versus Tislelizumab plus chemotherapy as First-line Treatment for advanced squamous non-small cell lung cancer (HARMONi-6)
Presenter: Dr. Shun Lu, MD, PhD, Chief of Shanghai Lung Cancer Center at Shanghai Chest Hospital
ESMO Presentation No.: Presidential Symposium 2, #3035
Session Date & Time: Sunday, October 19, 2025, 4:30pm – 6:30pm CET (10:30am – 12:30pm ET)

About Ivonescimab

Ivonescimab, known as SMT112 in Summit’s license territories, North America, South America, Europe, the Middle East, Africa, and Japan, and as AK112 in China and Australia, is a novel, potential first-in-class investigational bispecific antibody combining the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking VEGF into a single molecule. Ivonescimab displays unique cooperative binding to each of its intended targets with multifold higher affinity to PD-1 when in the presence of VEGF.

This could differentiate ivonescimab as there is potentially higher expression (presence) of both PD-1 and VEGF in tumor tissue and the tumor microenvironment (TME) as compared to normal tissue in the body. Ivonescimab’s tetravalent structure (four binding sites) enables higher avidity (accumulated strength of multiple binding interactions) in the TME (Zhong, et al, SITC (Free SITC Whitepaper), 2023). This tetravalent structure, the intentional novel design of the molecule, and bringing these two targets into a single bispecific antibody with cooperative binding qualities have the potential to direct ivonescimab to the tumor tissue versus healthy tissue. The intent of this design, together with a half-life of 6 to 7 days after the first dose (Zhong, et al, SITC (Free SITC Whitepaper), 2023), is to improve upon previously established efficacy thresholds, in addition to side effects and safety profiles associated with these targets.

Ivonescimab was engineered by Akeso Inc. (HKEX Code: 9926.HK) and is currently engaged in multiple Phase III clinical trials. Over 2,800 patients have been treated with ivonescimab in clinical studies globally.

Summit began its clinical development of ivonescimab in non-small cell lung cancer (NSCLC), commencing enrollment in 2023 in two multiregional Phase III clinical trials, HARMONi and HARMONi-3. Additionally, in early 2025, the Company began enrolling patients in the United States for HARMONi-7.

HARMONi is a Phase III clinical trial which intends to evaluate ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a 3rd generation EGFR TKI (e.g., osimertinib).

HARMONi-3 is a Phase III clinical trial which is intended to evaluate ivonescimab combined with chemotherapy compared to pembrolizumab combined with chemotherapy in patients with first-line metastatic, squamous or non-squamous NSCLC, irrespective of PD-L1 expression.

HARMONi-7 is a Phase III clinical trial which is intended to evaluate ivonescimab monotherapy compared to pembrolizumab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression.

In addition, Akeso has recently had positive read-outs in three single-region (China), randomized Phase III clinical trials for ivonescimab in NSCLC: HARMONi-A, HARMONi-2, and HARMONi-6.

HARMONi-A was a Phase III clinical trial which evaluated ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with an EGFR TKI.

HARMONi-2 is a Phase III clinical trial evaluating monotherapy ivonescimab against monotherapy pembrolizumab in patients with locally advanced or metastatic NSCLC whose tumors have positive PD-L1 expression.

HARMONi-6 is a Phase III clinical trial evaluating ivonescimab in combination with platinum-based chemotherapy compared with tislelizumab, an anti-PD-1 antibody, in combination with platinum-based chemotherapy in patients with locally advanced or metastatic squamous NSCLC, irrespective of PD-L1 expression.

Akeso is actively conducting multiple Phase III clinical studies in settings outside of NSCLC, including biliary tract cancer, colorectal cancer, breast cancer, pancreatic cancer, small cell lung cancer, and head and neck cancer.

Ivonescimab is an investigational therapy that is not approved by any regulatory authority in Summit’s license territories, including the United States and Europe. Ivonescimab was initially approved for marketing authorization in China in May 2024. Ivonescimab was granted Fast Track designation by the US Food & Drug Administration (FDA) for the HARMONi clinical trial setting.

On September 24, 2025 Akari Therapeutics, Plc (Nasdaq: AKTX), an oncology biotechnology company developing novel payload antibody drug conjugates (ADCs), reported key preclinical data demonstrating the potential of its novel antibody drug conjugate (ADC) spliceosome modulating payload, PH1, for the treatment of tumors fueled by alternative splicing-drivers, such as the Androgen Receptor splice variant 7 (AR-V7) in prostate cancer (Press release, Akari Therapeutics, SEP 24, 2025, View Source [SID1234656230]).

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AR-V7 is a key driver for progression of metastatic castration resistant prostate cancer (mCRPC). During progression of hormone-sensitive prostate cancer, many patients fail to respond to current first-line therapies known as Androgen Receptor Pathway Inhibitors (ARPIs), which include enzalutamide (Xtandi, $6B/annual sales), apalutamide (Erleada, $3B/annual sales) and darolutamide (Nubeqa, $1.6B/annual sales). Importantly, as patients lose ARPI response, their tumors transform and significantly increase in AR-V7 expression. As a result, there is an increasing and significant unmet need for targeted therapy options in ARPI-resistant hormone refractory patients, where there are currently limited options such as traditional chemotherapy like taxanes.

As referenced in the Company’s recent patent filing, preclinical data demonstrated that Akari’s ADC payloadPH1 is able to suppress the expression levels of the AR-V7 receptor in a hormone-refractory mCRPC model called 22Rv1. As a control, ARPIs had no effect on AR-V7 receptor expression in these experiments, which was expected given the refractory nature of these prostate cancer cell lines.

Surprisingly, in a different model, of hormone-sensitive LnCAP cells that express high levels of normal Androgen Receptor (i.e. ARPI sensitive) and lack AR-V7, PH1 demonstrated a benefit as a single agent, and additive effect when combined with either Xtandi or Erleada. The Company believes this combined efficacy data may potentially lead to the development of robust first-line combination regimens of Xtandi or Erleada with a PH1 payload conjugated ADC (PH1 ADC) to target prostate cancer that is sensitive to ARPIs. As progression is often linked to AR-V7 expression, and PH1 reduces AR-V7 expression, it is hypothesized that the combination of ARPI plus PH1 ADCs may slow the development of resistance and AR-V7-driven tumor progression which typically occurs after patients progress on Xtandi or Erleada. Akari has plans to test this hypothesis using PH1 ADCs against different prostate cancer targets in future research.

Abizer Gaslightwala, President and Chief Executive Officer of Akari Therapeutics commented, "We believe these compelling preclinical data support the rationale for Akari to develop a novel ADC with our PH1 spliceosome-modulating payload targeting prostate cancer either alone or in partnership with potential partners. Our goal is to develop the first ADC therapeutic in prostate cancer, either as a first-line combination therapy with ARPIs or a second-line therapy post ARPI failures in tumors driven by AR-V7. We are excited to continue to advance this novel spliceosome modulating payload to drive robust anti-cancer biological mechanisms to treat difficult alternative splicing-driven tumors, for which there are currently no effective treatment options today."

The Company plans to present the preclinical data at an upcoming scientific conference.