SpringWorks Therapeutics (SWTX) Announces Presentation of Clinical Data for Nirogacestat in Combination with BCMA-Directed Therapy at EHA

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SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe and rare diseases and cancer, today announced a joint venture to evaluate the investigational oral drug niroacestat. Presented data from two investigator-sponsored clinical studies. Combined Gamma-Secretase Inhibitor and B-Cell Maturation Agent (BCMA) Therapy in Patients With Relapsed or Refractory Multiple Myeloma (RRMM) at the European Hematology Association (EHA) in Frankfurt, Germany from June 8th It will be announced at the 2023 Congress – 11, 2023. From a Phase 1/2 study sponsored by GSK plc (LSE/NYSE: GSK) evaluating the combination of low-dose belamaf (belantamab mafodotin-blmf), GSK’s antibody-drug conjugate targeting BCMA, and nirogacestat Updated clinical data. Results of a study in RRMM patients will be presented in a poster presentation. Additionally, new findings from a Phase 1b clinical trial sponsored by Janssen Research and Development LLC (Janssen) evaluating the combination of telistomab and nirogacestat, Janssen’s bispecific antibodies targeting BCMA and CD3 data will be presented orally.

“These data provide further validation of the mechanistic approach that supports the ability of nirogacestat to enhance the activity of BCMA-directed therapy across modalities. We are pleased to continue to support our hypothesis that the benefit and risk profile of monotherapy may be further optimized, and that a Janssen-sponsored study demonstrated that nirogacestat and BCMA bispecific It is also encouraging that the initial tolerability, safety and efficacy profile of the combination of sex antibodies has been established,” said Saqib Islam, Chief Executive Officer of SpringWorks. “Our goal is to improve outcomes for patients with multiple myeloma, and developing a robust clinical data set across BCMA modalities and lines of therapy will help us understand where nirogacestat is in the multiple myeloma therapeutic landscape. We believe it will help demonstrate where we have the greatest opportunity to maximize clinical benefit.”

Poster presentation at EHA 2023 conference

Low-dose belantamab mafodotin (veramaf) in combination with niroacestat vs. beramaf monotherapy in patients with relapsed/refractory multiple myeloma (RRMM): a phase 1/2 DREAMM-5 platform substudy 3

Abstract number: P913

Session Date and Time: Friday, June 9, 18:00-19:00 CET (12:00-1:00 PM ET)

This ongoing Phase 1/2 study is substudy 3 of GSK’s DREAMM-5 platform trial (NCT04126200) aimed to determine whether the combination of low-dose veramaf and nirogacestat has an improved ocular toxicity profile and similar efficacy compared to high-dose veramaf alone. Patients were randomized 1:1 to receive veramaf 0.95 mg/kg every 3 weeks (Q3W, low dose) and niroacestat 100 mg twice daily or veramaf 2.5 mg/kg Q3W monotherapy. rice field.

The first results of a pre-planned interim analysis will be presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting. Updated data from a randomized cohort expansion in which 34 patients received low-dose beramaf plus niroacestat and 37 patients received beramaf monotherapy will be presented at EHA. Patients had a median number of previous lines of therapy of 5 (range 3-14). As of the December 9, 2022 data cutoff, patients received a median of 4 cycles of combination therapy (range 1-20) and a median of 3 cycles of monotherapy (range 1-9).

The overall response rate (ORR) for low-dose veramaf (0.95 mg/kg Q3W) plus niroacestat was 29%, with 1 patient (3%) achieving a complete response (CR) and 5 patients (15 %) achieved very good responses. Good partial response (VGPR), 4 patients (12%) achieved partial response (PR). In the veramaf monotherapy arm (2.5 mg/kg Q3W), the ORR was 38%, with no patients achieving CR, 5 patients (14%) achieving VGPR, 9 patients (24%) ) achieved a PR. His ORR was also calculated incorporating his previous ORR of low-dose beramaf and niroacestat from the dose-finding cohort of this DREAMM-5 substudy 3 and the DREAMM-2 beramaf monotherapy study according to a prespecified analysis plan it was done. The ORR across these studies was 36% for the low-dose beramaf plus niroacestat group and 33% for the beramaf monotherapy group.

Safety results showed a significant reduction in high-grade ocular events in the low-dose veramaf plus niroacestat group compared to the high-dose veramaf monotherapy group. Specifically, grade 3 ocular events were 29% with low-dose veramaf plus niroacestat and 59% with veramaf monotherapy (by KVA scale). No grade 4 ocular events or new toxicities occurred in either group.

“These clinical data demonstrate that the combination of niroacestat and low-dose veramaf is as effective as high-dose belamaf monotherapy while significantly reducing the frequency of high-grade ocular adverse events. It suggests that it is possible,” said Jim Cassidy, M.D. , SpringWorks Chief Medical Officer. “We are encouraged by these results and look forward to further evaluating this combination with standard of care in relapsed/refractory multiple myeloma and its potential in early-line therapy.”

Oral presentation at EHA 2023 conference

Tecristamab (tec) + Niroacestat (niro) in Relapsed/Refractory Multiple Myeloma (RRMM): The Phase 1b MajesTEC-2 Study

Session Title: MM Clinical: New Combinations and New Targets

Abstract number: S194

Session Date and Time: Saturday, June 10, 12:30-12:45 CET (6:30-6:45 AM ET)

This ongoing Phase 1b trial (NCT04722146) is part of a multi-arm clinical trial being conducted by Janssen that aims to evaluate the safety, tolerability and preliminary efficacy of nirogacestat in combination with teclistomab in patients with RRMM. Patients in the study had received 3 or more prior therapies or were doubly refractory to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) and had been treated with PIs, IMiDs, and anti-CD38 antibodies. Triple exposed and with progressive disease within 12 months of last treatment. Three dose levels were evaluated: 1) Telistomab 720 μg/kg weekly and concurrent nirogacestat 100 mg twice daily, starting with the first dose of teclistomab (n=8). 2) telistomab 720 μg/kg weekly and niroacestat 100 mg once daily starting after teclistomab step-up dose (n=7). 3) Niloacestat 100 mg once daily starting after weekly step-up doses of 1500 μg/kg (this is the FDA-approved dose) and teclistomab (n=13).

As of data cutoff on December 16, 2022, 28 patients received teclistomab plus niroacestat at three different dose levels. The median number of prior lines of therapy was 4 (range 2-12), and the median duration of treatment was 9.4 months (range 0.13-19.7) for teclistumab and 4.7 months (range 0.16-13.0) for nirogacestat.

The most frequent (>20%) treatment-emergent adverse events (TEAEs) at all doses were neutropenia (82%), cytokine release syndrome or CRS (75%), and diarrhea (64%). ) and injection site erythema (54%). ), decreased appetite (50%), fatigue (42.9%), anemia (35%). Two dose-limiting toxicities were reported in eight patients co-administered with telistomab 720 μg/kg and niroacestat (one grade 3 gastrointestinal hemorrhage and grade 3 diarrhea, grade 3 immune effector cell-associated neurotoxic syndrome (ICANS) 1 case). In addition, 1 patient had grade 3 CRS and 1 patient presented with grade 3 confusional state. These events led to the decision to delay the starting dose of niroacestat in subsequent cohorts. In the Dose Level 2 and Dose Level 3 cohorts, no dose-limiting toxicities or grade 3 CRS or neurological adverse events were reported when nirogacestat was added after a step-up dose of teclistomab and reduced to once daily. bottom.

Overall response rates were 71% at dose level 1, 57% at dose level 2, and 92% at dose level 3. The total ORR across the three dose levels was 78% and all responses were ≥VGPR. The percentages of patients who experienced a complete response (CR) or stringent CR (sCR) were 43%, 57%, and 54%, respectively (total rate of CR or sCR across the three cohorts was 52%).

“This is the first clinical data set combining niroacestat and a BCMA bispecific agent. These data demonstrate a tolerable treatment schedule and promising CR and sCR when niroacestat is combined with this BCMA regimen. We believe it provides important insights into promising early evidence of ORR, including rates,” commented Dr. Cassidy. “Nirogacestat has been evaluated in combination with three other bispecific agents and we look forward to obtaining more data with these combinations.”

About Nirogacestat

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

Gamma-secretase cleaves multiple transmembrane protein complexes, including Notch, thought to play a role in the activation of pathways that contribute to the growth of desmoids and ovarian granulosa cell tumors. Gamma-secretase has also been shown to directly cleave membrane-bound B-cell maturation antigen (BCMA), releasing the BCMA extracellular domain (ECD) from the cell surface. By inhibiting gamma-secretase, membrane-bound BCMA is preserved and target density can be increased while reducing the level of soluble BCMA ECD, which may serve as a decoy receptor for BCMA-directed therapy. The ability of nirogacestat to potentiate the activity of BCMA-directed therapy has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating niroacestat as his BCMA enhancer and has several collaborations with his industry-leading BCMA developers to evaluate niroacestat in cross-modality combinations. SpringWorks is also collaborating with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to use various preclinical multiple myeloma models to modulate BCMA and enhance BCMA-directed therapies further characterize niroacestat’s ability to

The U.S. Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for niroacestat for the treatment of adult desmoid tumors, which is under review under the FDA’s Real-Time Oncology Review Program. The NDA was granted Priority Review designation and given an effective date of August 27, 2023 for the Prescription Drug User Fees Act (PDUFA). The FDA also granted Fast Track and Breakthrough Therapy designation to nirogacestat for the treatment of advanced, unresectable adult patients. , recurrent or refractory desmoid tumors, or deep fibromatosis. Additionally, niroacestat 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.

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