On March 8, 2023 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported that data from the Phase 3 DeFi trial of nirogacestat, an investigational oral gamma secretase inhibitor, in adult patients with progressing desmoid tumors, were published in the New England Journal of Medicine (NEJM) (Press release, SpringWorks Therapeutics, MAR 8, 2023, View Source [SID1234628341]). Results from this study were previously presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in September 2022.

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"Desmoid tumors are aggressive soft tissue tumors that can lead to substantial negative impacts on patients’ lives," said Mrinal M. Gounder, M.D., sarcoma medical oncologist at Memorial Sloan Kettering Cancer Center (MSK) in New York City, an investigator in the DeFi trial and first author of the NEJM publication. "In the Phase 3 DeFi trial, nirogacestat demonstrated significant clinical efficacy and substantially improved pain, symptom burden, physical and role functioning, and health-related quality of life in desmoid tumor patients. Importantly, nirogacestat exhibited a manageable safety profile. These results represent a noteworthy therapeutic advance for patients."

As reported in the NEJM publication and previously presented at ESMO (Free ESMO Whitepaper), the DeFi trial met its primary endpoint of improving progression-free survival (PFS), demonstrating a statistically significant improvement for nirogacestat over placebo, with a 71% reduction in the risk of disease progression (hazard ratio (HR) = 0.29 (95% CI: 0.15, 0.55); p< 0.001). Median PFS was not reached in the nirogacestat arm and was 15.1 months in the placebo arm. Nirogacestat improved PFS across pre-specified subgroups, including sex, tumor location, focality, prior treatment status (including treatment-naïve or previous treatment with chemotherapy or tyrosine kinase inhibitors), prior surgery, mutation status, and history of familial adenomatous polyposis. Confirmed objective response rate (complete response + partial response) based on RECIST v1.1 was 41% with nirogacestat versus 8% with placebo (p<0.001); the complete response rate was 7% in the nirogacestat arm and 0% in the placebo arm. Nirogacestat also demonstrated statistically significant and clinically meaningful improvements in patient-reported outcomes (PROs), which were key secondary endpoints of the study. Specifically, at Cycle 10 nirogacestat significantly reduced pain (p<0.001) and other desmoid tumor-specific symptoms (p<0.001) and also significantly improved physical/role functioning (p<0.001) and overall health-related quality ofi life (p≤0.01).1 Improvements in most PROs occurred early (at Cycle 2, the first post-treatment timepoint evaluated) and were sustained throughout the trial.

At the time of primary analysis data cutoff on April 7, 2022, the median follow-up for PFS was 15.9 months. Nirogacestat exhibited a manageable safety profile in the DeFi trial, with 95% of all treatment-emergent adverse events (TEAEs) reported as Grade 1 or 2. The most frequently reported TEAEs that occurred in participants receiving nirogacestat were diarrhea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%). Ovarian dysfunction, which was defined by events of amenorrhea, premature menopause, menopause, and ovarian failure, was observed in 75% (27/36) of women of childbearing potential receiving nirogacestat. As of the extended follow-up date of July 20, 2022, these events resolved in 74% (20/27) of the affected participants, including 64% (9/14) of participants who remained on nirogacestat treatment and 100% (11/11) of participants who were off of treatment for any reason.

"There is a great unmet need for patients with desmoid tumors as there are no approved therapies. We are very pleased that nirogacestat provided benefit across all prespecified subgroups in the study, which underscores the potential to broadly serve desmoid tumor patients regardless of tumor location, prior treatments or surgery, or genetic mutation," said Saqib Islam, Chief Executive Officer of SpringWorks. "We look forward to working with the FDA as they review our NDA, and we are excited by the opportunity to make a profound impact on this underserved patient population."

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1 2-sided p-values are shown here to be consistent with NEJM publication standards.

About the DeFi Trial

DeFi (NCT03785964) is a global, randomized (1:1), double-blind, placebo-controlled Phase 3 trial evaluating the efficacy, safety and tolerability of nirogacestat in adult patients with progressing desmoid tumors. The double-blind phase of the study randomized 142 patients (nirogacestat, n=70; placebo n=72) to receive 150 mg of nirogacestat or placebo twice daily. Key eligibility criteria included tumor progression by ≥20% as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) within 12 months prior to screening. The primary endpoint was progression-free survival, as assessed by blinded independent central review, or death by any cause. Secondary and exploratory endpoints include safety and tolerability measures, objective response rate (ORR), duration of response, changes in tumor volume assessed by magnetic resonance imaging (MRI), and changes in patient-reported outcomes (PROs). DeFi includes an open-label extension phase, which is ongoing.

About Desmoid Tumors

Desmoid tumors are rare, aggressive, locally invasive, and potentially morbid tumors of the soft tissues.1,2 While they do not metastasize, desmoid tumors are associated with a high rate of recurrence.2,3,4 Sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis, these soft tissue tumors can be serious, debilitating, and, in rare cases when vital structures are impacted, they can be life-threatening.2,5

Desmoid tumors are most commonly diagnosed in patients between the ages of 20 and 44 years, with a two-to-three times higher prevalence in females.4,6,7,8 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.7,8,9

Historically, desmoid tumors were treated with surgical resection, but this approach has become less favored due to a high recurrence rate after surgery.1,4,10 There are currently no FDA-approved therapies for the treatment of desmoid tumors.

About Nirogacestat

Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors and in Phase 2 clinical development for ovarian granulosa cell tumors. Nirogacestat is an investigational drug for which safety and efficacy have not been established.

Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to growth of desmoid and ovarian granulosa cell tumors. Gamma secretase has also been shown to directly cleave membrane-bound B cell maturation antigen (BCMA), resulting in the release of the BCMA extracellular domain (ECD) from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has several collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities. SpringWorks has also formed research collaborations with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA-directed therapies using a variety of preclinical multiple myeloma models.

The U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for nirogacestat for the treatment of adults with desmoid tumors, which is being reviewed under the FDA’s Real-Time Oncology Review program. The NDA was granted Priority Review designation and has been given a Prescription Drug User Fee Act (PDUFA) action date of August 27, 2023. The FDA also granted Fast Track and Breakthrough Therapy Designations to nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. In addition, nirogacestat has received Orphan Drug Designation from the FDA for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma.

On March 8, 2023 Redx (AIM:REDX), the clinical-stage biotechnology company focused on discovering and developing novel, small molecule, highly targeted therapeutics for the treatment of cancer and fibrotic disease, reported topline monotherapy data from the biliary tract cancer (BTC) module of the RXC004 PORCUPINE2 Phase 2 clinical trial programme (Press release, Redx Pharma, MAR 8, 2023, View Source [SID1234628337]).

RXC004 is an orally active, once daily, porcupine inhibitor being developed as a targeted treatment for Wnt-ligand dependent cancers. The objective of the Phase 2 programme is to provide an initial assessment of the efficacy and safety of the drug both as a single agent and in combination with anti-PD-1 therapy, in patients with certain Wntligand dependent solid tumours whose cancers have progressed following standard of care therapies. The RXC004 Phase 2 clinical development programme consists of two studies, PORCUPINE and PORCUPINE2, which are detailed below.

The data announced today, the first from the Phase 2 programme, are from 16 previously treated patients enrolled in the advanced BTC monotherapy arm of the PORCUPINE2 study. The primary endpoint was Progression Free Survival at six months. Some patients received durable clinical benefit from RXC004 in this cohort, consistent with clinical activity seen in the Phase 1 trial, and the safety profile of RXC004 in this module was also consistent with the safety data previously reported in the Phase 1 trial. However, the overall results are not sufficient to support the further development of RXC004 as a monotherapy in this treatment setting.

Planned retrospective analysis of all efficacy and biomarker data in this BTC monotherapy cohort will increase the understanding of the single agent activity of RXC004 and will be used to aid interpretation of the ongoing combination module efficacy, where RXC004 is used alongside anti-PD-1 therapy, pembrolizumab.

"Our Phase 2 program is designed to explore the activity of RXC004 both as monotherapy and in combination with immune checkpoint inhibitors, consistent with its postulated dual mechanism of action. Our primary efficacy hypothesis is that in combination it can overcome immune evasion and anti-PD-1 resistance, which could open new patient segments," said Dr Jane Robertson, Chief Medical Officer, Redx Pharma. "While today’s results do not support further clinical development of RXC004 as monotherapy in recurrent BTC, where very few drugs have received regulatory approval as single agents in this hard-to-treat disease, they are nonetheless consistent with the overall hypothesis that RXC004 has potential as an active component of combination therapy. We look forward to the data read out from the combination module with pembrolizumab, that is expected in the second half of this year."

Biliary tract cancer, a cancer with an annual incidence of 51,000 patients1, has an extremely poor prognosis, with only a 2% 5-year survival rate2 and a treatment response rate of less than 5% with standard second-line chemotherapy.

About the RXC004 Phase 2 Clinical Trial Program
The first study in the Phase 2 programme, PORCUPINE, (clinicaltrials.gov NCT04907539) is focused on patients with advanced microsatellite stable metastatic colorectal cancer (MSS mCRC) that has not progressed following treatment with standard of care and is evaluating preliminary efficacy and safety of RXC004 in genetically selected patients with Ring finger protein 43 (RNF43) or R-spondin (RSPO) aberrated, advanced MSS mCRC. A second Phase 2 study of RXC004, PORCUPINE2, (clinicaltrials.gov NCT04907851), for genetically selected pancreatic cancer and biliary cancer, a highly Wnt-ligand dependent cancer is also ongoing.

Given the dual mechanism of action of RXC004, which preclinically was shown to inhibit tumour growth and immune evasion, there is a strong rationale for immune therapy combination. In November 2022, Phase 1 clinical data evaluating the safety and tolerability of RXC004 in combination with nivolumab, in patients with advanced malignancies was presented as a poster at the Society of Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Conference. The data was suggestive of an anti-tumour immune response, which is reported to correlate with an improved response to anti-PD-1 immune checkpoint inhibitors. The results of the study supported a dose selection of 1.5mg once daily to be used in combination modules of both PORCUPINE and PORCUPINE2.

The combination module of the PORCUPINE trial will evaluate RXC004 in combination with nivolumab, (OPDIVO – Bristol Myers Squibb, a PD-1 inhibitor) in MSS mCRC and this module is now open for recruitment in all countries taking part in the trial including the US and the UK. The combination module of the PORCUPINE2 study, (clinicaltrials.gov NCT04907851), will evaluate RXC004 in combination with pembrolizumab, (KEYTRUDA – MSD’s anti-PD-1 therapy) in biliary tract cancer. A clinical trial supply and collaboration agreement was entered into with MSD (Merck & Co., Inc., Rahway, NJ, USA) in December 2022 for the supply of KEYTRUDA, and this module is open for recruitment in all countries taking part in this clinical trial including the UK and Australia.

The person responsible for the release of this announcement on behalf of the Company is Claire Solk, Company Secretary.

For further information, please contact:

Redx Pharma Plc T: +44 (0)1625 469 918
UK Headquarters
Caitlin Pearson, Head of Communications [email protected]

Lisa Anson, Chief Executive Officer

US Office
Peter Collum, Chief Financial Officer

SPARK Advisory Partners (Nominated Adviser) T: +44 (0)203 368 3550
Matt Davis/ Adam Dawes

WG Partners LLP (Joint Broker) T: +44 (0)203 705 9330
Claes Spång/ Satheesh Nadarajah/ David Wilson

Panmure Gordon (UK) Limited (Joint Broker) T: +44 (0)207 886 2500
Rupert Dearden/ Freddy Crossley/ Emma Earl

FTI Consulting T: +44 (0)203 727 1000
Simon Conway/ Ciara Martin

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On March 8, 2023 MacroGenics, Inc. (Nasdaq: MGNX), a biopharmaceutical company focused on developing and commercializing innovative monoclonal antibody-based therapeutics for the treatment of cancer, reported that it has entered into an agreement to sell its royalty interest on future global net sales of TZIELD (teplizumab-mzwv) to a wholly-owned subsidiary of DRI Healthcare Trust for up to $200 million (Press release, MacroGenics, MAR 8, 2023, View Source [SID1234628336]). MacroGenics retains its other economic interests related to TZIELD, including future potential regulatory and commercial milestones.

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Under the terms of the agreement with DRI, MacroGenics will receive a $100 million upfront payment for the sale of its single-digit royalty on global net sales of TZIELD. MacroGenics will have the right to receive a 50% share of the royalty on global net sales above a certain annual threshold. In addition, the Company is eligible to receive up to $50 million from DRI upon the occurrence of pre-specified events tied to the advancement of TZIELD for the treatment of newly diagnosed type 1 diabetes. The Company may also receive an additional $50 million if TZIELD achieves a certain level of net sales.

On March 8, 2023 Alpha Tau Medical Ltd. ("Alpha Tau", or the "Company") (NASDAQ: DRTS, DRTSW), the developer of the innovative alpha-radiation cancer therapy Alpha DaRT, reported that the first two patients were enrolled and treated today in its pivotal multicenter trial, known as the ReSTART trial (Recurrent SCC Treatment with Alpha DaRT Radiation Therapy), for the treatment of recurrent cutaneous squamous cell carcinoma (cSCC) (Press release, Alpha Tau Medical, MAR 8, 2023, View Source [SID1234628334]). The patients were treated at the University Cancer Center in Houston, Texas

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The trial is intended to enroll up to 86 participants who have biopsy-proven recurrent cSCC who are not otherwise indicated for surgery or standard radiation therapy, and for whom no curative systemic treatment is available. The primary study endpoints include overall objective response rate, based on best overall response, duration of response at 6-months from initial observation of a response to Alpha DaRT insertion, and safety of the Alpha DaRT treatment. The study’s secondary objectives are to assess the progression-free survival and overall survival at 1-year following Alpha DaRT treatment, overall duration of response, local control, and quality of life. Additional information about the trial can be found at View Source

Alpha Tau CEO Uzi Sofer commented, "Today marks an important milestone for the Company and paves our path forward towards our ultimate goal of U.S. regulatory approval. Moreover, being able to enroll the first two patients simultaneously in one site demonstrates the high unmet need in this patient population and is an important boost in our recruitment efforts. We are hopeful that the results of this study, together with the Breakthrough Device Designation from the FDA for the treatment of this indication, will allow us to gain FDA approval and make the Alpha DaRT treatment available as quickly as possible for patients who suffer from recurrent cSCC. In the coming year, we will continue to focus our efforts on three main areas: swift recruitment in the ongoing ReSTART study, targeting initial results from our internal organ clinical program such as the treatment of pancreatic and prostate cancers, and continued scale-up of our production capacity to allow for smooth and efficient production

We remain committed to bringing new hope to patients in this very difficult to treat population. We would like to thank Dr. Mark D’Andrea and Dr. Lawrence Clarke and the dedicated staff at University Cancer Center in Houston for enrolling and treating the first patients in the ReSTART trial and look forward to the forthcoming results," said Alpha Tau Chief Medical Officer, Dr. Robert Den

Dr. Mark A. D’Andrea, radiation oncologist at University Cancer Center in Houston, commented, "I believe that Alpha DaRT can be a real breakthrough in the treatment of recurrent cSCC. These patients have exhausted the effective treatment options available to them, and Alpha DaRT may give these patients additional hope for a successful outcome. In my experience as a radiation oncologist, treatment with the Alpha DaRT is a quick and straightforward procedure that can often be done in the office setting or procedure room in the clinic without the need for hospitalization or a shielded radiation suite. The procedure is often done using a local anesthetic, with the patient returning after 2 weeks for removal of the sources. The patient should then be able to return to a normal daily routine quickly."

On March 8, 2023 Viracta Therapeutics, Inc. (Nasdaq: VIRX), a precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide, reported that Mark Rothera, its President and Chief Executive Officer, and Lisa Rojkjaer, M.D., its Chief Medical Officer, are scheduled to participate in a virtual fireside chat at the 33rd Annual Oppenheimer Healthcare Conference on Wednesday, March 15, 2023, at 12:00 p.m. ET (Press release, Viracta Therapeutics, MAR 8, 2023, View Source [SID1234628332]).

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A live webcast of the fireside chat will be available on the Investors section of the Viracta website under "Events and Webcasts" and archived for 30 days.