On May 25, 2023 Theseus Pharmaceuticals, Inc. (NASDAQ: THRX) (Theseus or the Company), a clinical-stage biopharmaceutical company focused on improving the lives of cancer patients through the discovery, development, and commercialization of transformative targeted therapies, reported initial dose escalation data from the ongoing phase 1/2 trial of THE-630 in patients with advanced gastrointestinal stromal tumors (GIST) (Press release, Theseus Pharmaceuticals, MAY 25, 2023, View Source [SID1234632081]).

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Theseus will host a virtual investor webcast today at 5:30pm ET to discuss this update.

"THE-630 has shown strong clinical proof of mechanism through Cohort 6 with a safety and pharmacokinetic profile supportive of continued dose escalation," said Tim Clackson, Ph.D., President and Chief Executive Officer of Theseus. "Importantly, with dose-dependent activity observed against both major classes of KIT resistance mutations, coupled with the increased frequency of stable disease at the higher doses tested thus far, we believe THE-630 could have a best-in-class profile and provide a much-needed alternative to combat the complex resistance that drives rapid progression of GIST. We are also encouraged by the further validation of our PRA, with reductions in ctDNA observed for specific mutations consistent with our preclinical predictions. These data support our ability to reach target exposures in Cohort 8, and we look forward to reporting data through Cohort 8 later this year."

"The emerging potential activity in both classes of resistance mutations in the activation loop and ATP binding pocket is promising, as it is critically important to be active against both to provide a meaningful clinical benefit for patients," said Suzanne George, M.D., Associate Division Chief, Sarcoma Center, Dana-Farber Cancer Institute, and a principal investigator on the phase 1/2 trial.

Reporting data on THE-630 through Cohort 6 (n=23); currently dosing Cohort 7
•As of April 21, 2023, 25 patients have been treated in the dose escalation portion of the trial: 23 patients enrolled in Cohorts 1-6 (3, 4, 6, 9, 12, 18 mg); 2 patients enrolled in Cohort 7 (27 mg).
◦Following the data cutoff, both Cohort 7 patients subsequently cleared the dose-limiting toxicity (DLT) observation period without experiencing a DLT.
•All patients had metastatic KIT-mutant GIST.
•Patients in the trial had a median of 4 prior therapies (range 2 to 8); 70% of patients with ≥4 prior tyrosine kinase inhibitors (TKIs).
◦All patients received prior treatment with imatinib and sunitinib.
◦65% of patients received prior treatment with ripretinib and regorafenib.

Safety profile supportive of continued dose escalation; pharmacokinetics (PK) consistent with once-daily oral dosing
•The observed safety profile is consistent with the class and with preclinical data.
•Treatment-related adverse events (TRAEs) were observed in 65% of patients.
◦Of 89 TRAEs reported, 84 (94%) were grades 1-2 and 5 (6%) were grade ≥3 (3 of which occurred in Cohorts 1 and 2).
◦The most common TRAEs (occurring in ≥10% of patients) included fatigue, increased AST, diarrhea, nausea, dry mouth, and dyspnea.
•In Cohort 2 (4 mg), a 9th-line, 64-year-old patient with hyperlipidemia experienced a myocardial infarction (MI) on study day 6 after being hospitalized for adverse events unrelated to study drug, and subsequently died. The event was considered a DLT as the relationship between THE-630 and the MI could not be incontrovertibly ruled out.
◦No cardiac ischemic AEs of any grade have been reported in the other 22 patients in the study, including at significantly higher exposure levels.
•No additional DLTs or treatment-related serious adverse events have been observed, and the maximum tolerated dose (MTD) has not been reached.
•PK profile approximately linear and consistent with once-daily oral dosing.

Reductions in ctDNA of both classes of KIT resistance mutations, consistent with preclinical PRA predictions
•THE-630 reduced the allele frequency across all major classes of KIT activating and resistance mutations in a manner consistent with preclinical predictions seen in the Predictive Resistance Assay (PRA), including dose-dependent and potent reduction of exon 13 mutation V654A, the most common resistance mutation seen in GIST.
◦Pre- and post-baseline samples were available for 19 patients, including 2 in Cohort 6 (18 mg).
◦KIT mutations were detected in 84% of patients (16 out of 19); 5 patients had more than one resistance mutation at baseline (range 2 to 6).
◦ctDNA reductions were observed more frequently at higher doses, with 6 out of 6 patients treated in Cohorts 4-6 (9 to 18 mg) showing reductions in all KIT mutant variants present at baseline, including activating mutations detected in exons 9 and 11, and resistance mutations detected in exons 13, 14, and 17.
•Based on clinical PK through Cohort 6, and consistent with ctDNA observations to date, THE-630 is projected to achieve exposures consistent with pan-variant inhibition across all major classes of KIT mutations, as predicted by the PRA, in Cohort 8.

Evidence of prolonged stable disease observed
•Disease stabilization was observed more frequently at higher doses, with 8 out of 9 evaluable patients treated in Cohorts 4-6 (9 to 18 mg) achieving stable disease as best response, a disease control rate of 89%.
•A patient with 5 prior lines of therapy and KIT exon 11 and exon 17 (N822K) mutations detected in ctDNA at baseline had prolonged stable disease, receiving THE-630 for 36 weeks (enrolled in Cohort 2 [4 mg] with subsequent escalation to 6 mg and then 9 mg), with strong ctDNA reductions of both mutations observed.
•A patient with KIT exon 11 and exon 13 (V654A) mutations detected in pre-treatment tumor biopsy remains on therapy with stable disease maintained through at least 24 weeks (enrolled in Cohort 5 [12 mg] and subsequently escalated to 18 mg).

"Today’s data provide early clinical evidence that THE-630 could potentially meet a critical need in patients with refractory GIST," said David Kerstein, M.D., Chief Medical Officer of Theseus. "We are particularly excited by the observed dose-dependent reductions in KIT mutations, along with disease stabilization. With the encouraging early safety profile, we look forward to continuing dose escalation to a recommended phase 2 dose for THE-630."

Virtual Investor Event

Theseus will host a virtual investor event to review these initial clinical results today, beginning at 5:30pm ET. The event will be webcast live and can be accessed in the Events section of the Company’s investor relations website at ir.theseusrx.com. A replay of the webcast will be archived and available for 90 days following the event.

Date: Thursday, May 25, 5:30pm ET
Webcast link: View Source
Register for dial-in: https://register.vevent.com/register/BI54a9015fcbd64a6a996a40c017a76abf

About THE-630

THE-630 is a pan-variant tyrosine kinase inhibitor (TKI) of the receptor tyrosine kinase KIT, designed for patients with GIST that have developed resistance to earlier lines of therapy.

THE-630 Clinical Trial Background and Clinical Development Plan

Trial THE630-21-101 is a phase 1/2 open label, multicenter, first-in-human dose escalation and expansion trial designed to evaluate the safety, pharmacokinetics, and anti-tumor activity of oral THE-630 (NCT Number: NCT05160168). The trial is expected to be conducted in two parts: a dose escalation phase, followed by an expansion phase. The patient population of the initial dose escalation phase (phase 1) of the trial will include patients with unresectable or metastatic GIST who had disease progression on or are intolerant to imatinib therapy and have also received at least one of the following: sunitinib, regorafenib, ripretinib, or avapritinib. The primary objective of the dose escalation phase is to determine the safety profile of THE-630, including the dose-limiting toxicities, maximum tolerated dose, and the recommended phase 2 dose.

Once a recommended dose has been determined in the dose escalation phase, the dose expansion phase (phase 2) will enroll patients with unresectable or metastatic GIST into three cohorts defined by prior therapy including a second-line cohort and a fifth-line cohort. The primary objective of the expansion phase is to evaluate the anti-tumor activity of THE-630 in these GIST patient populations.

Data from the phase 1/2 clinical trial is expected to inform further clinical development of THE-630 including the design of the planned registrational trials for THE-630. Theseus is prioritizing the development of THE-630 in second-line GIST, where a pan-variant KIT inhibitor with activity against all major classes of activating, or cancer-causing, and resistance mutations has the potential to deliver meaningful clinical benefit over the current standard of care. Theseus also plans to evaluate THE-630 in fifth-line GIST, where there is currently no available therapy and therefore a significant unmet need.

On May 25, 2023 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported preliminary efficacy data from a Phase 1 study of its lead investigational peptide-drug conjugate (PDC) candidate, sudocetaxel zendusortide (formerly TH1902), in patients with advanced solid tumors (Press release, Theratechnologies, MAY 25, 2023, View Source [SID1234632080]). In a June 3 poster session at the 2023 annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, researchers will present early results from Part 1 (dose escalation) and Part 2 (dose expansion) of the multicenter, open-label trial of sudocetaxel zendusortide, in which 36% of heavily pretreated participants experienced a clinical benefit, including two patients with partial responses (PR) and seven achieving prolonged stable disease (SD).

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Based on the results presented at ASCO (Free ASCO Whitepaper), Theratechnologies is engaged with the U.S. Food and Drug Administration (FDA) to amend the protocol of the Phase 1 clinical trial of sudocetaxel zendusortide. The amendments are designed to improve the therapeutic window and allow for more prolonged therapy with sudocetaxel zendusortide, reflecting changes in patient selection and evaluation of alternative dosing regimens.

"The early efficacy data for our lead peptide-drug conjugate, sudocetaxel zendusortide, confirm that it rapidly internalizes and hyper-targets delivery of cytotoxic payload directly into cancer cells," said Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer at Theratechnologies. "We look forward to re-initiating our trial with a revised protocol that increases the likelihood of showing the full therapeutic potential of sudocetaxel zendusortide."

"These preliminary data on safety and antitumor activity have informed the proposed changes to the protocol, with the intention of improving the risk-benefit profile of sudocetaxel zendusortide in the next stage of the trial," commented lead investigator Funda Meric-Bernstam, M.D., Chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.

Study details and results

Part 1 of the study enrolled 18 adults with a confirmed diagnosis of a metastatic or advanced-stage solid tumor that is refractory to standard therapies (average of 8 prior lines of therapies). The starting dose of 30 mg/m2 every 3 weeks (Q3W) was selected based on sudocetaxel zendusortide preclinical data. Among participants in Part 1, one patient with endometrial cancer experienced SD for 233 days (33 weeks), a second patient with prostate cancer had SD that lasted for 119 days (17 weeks), and a third patient with ovarian cancer experienced SD for 295 days (42 weeks).

Eighteen additional patients were enrolled into the 300 mg/m2 Q3W dose expansion cohort (Part 2). In an interim efficacy and safety analysis of the 300 mg/m2 dose cohort from Parts 1 and 2 (n=25), five of six patients (83%) with ovarian cancer had a best overall response (BOR) of either PR (n=1) or SD (n=4). In the triple-negative breast cancer (TNBC) population, three of four patients (75%) had a BOR of SD, with one patient experiencing SD for at least four cycles and continued clinical benefit up to at least 24 weeks. In the two patients with prostate cancer, one experienced a PR.

Sudocetaxel zendusortide doses below 300 mg/m2 were well-tolerated in Part 1 of the trial, which established the maximum tolerated dose (MTD) and dose-limiting toxicities at 360 mg/m2 and 420 mg/m2, respectively. Based on those results, investigators selected a 300-mg/m2 dose for Part 2 (dose expansion) of the basket trial, to determine the safety and efficacy of sudocetaxel zendusortide in patients with multiple tumor types with high expression of the sortilin (SORT1) receptor. At 300 mg/m2, the most common treatment-related adverse events (>20%) were ocular changes, neuropathy, gastrointestinal disturbances, and musculoskeletal complaints, with Grade 3 or greater toxicities at a frequency of ≤12%.

Poster presentation details:

Title: "Sudocetaxel zendusortide (TH1902), a novel sortilin-receptor (SORT1)-targeting peptide-drug-conjugate (PDC) in patients (pts) with advanced solid tumors: Results from part 1 (dose-escalation) of a phase 1, open-label study"

Lead author: Funda Meric-Bernstam, M.D., Chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center

Abstract number: 3089

Session Date and Time: Saturday June 3, 2023, Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology, 8:00-11:00 CDT

About SORT1+ Technology and Sudocetaxel Zendusortide (TH1902)

Theratechnologies has established its SORT1+ TechnologyTM platform as an engine for the development of proprietary peptide-drug conjugates (PDCs) that target the sortilin (SORT1) receptor, which is expressed in multiple tumor types. SORT1 is a "scavenger" receptor that plays a significant role in protein internalization, sorting, and trafficking. Expression of SORT1 is associated with aggressive disease, poor prognosis, and decreased survival. It is estimated that SORT1 is expressed in 40% to 90% of endometrial, ovarian, colorectal, triple-negative breast (TNBC), and pancreatic cancers, making this receptor an attractive target for anticancer drug development.

Sudocetaxel zendusortide is the first-of-its-kind SORT1-targeting PDC, and the first to emerge from the SORT1+ Technology platform. A new chemical entity, sudocetaxel zendusortide employs a cleavable linker to conjugate (attach) a proprietary peptide to docetaxel, a well-established cytotoxic chemotherapeutic agent used to treat many cancers. The FDA granted Fast Track designation to sudocetaxel zendusortide as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial. Patient recruitment was voluntarily paused on December 1, 2022, and in alignment with this decision, the FDA placed the trial on partial clinical hold. In May 2023, the Company submitted a proposed protocol amendment to the FDA that is currently under review.

On May 25, 2023 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing first-in-classi therapeutics that combine both targeted and immune-mediated mechanisms, reported that Phase 1 clinical trial data for TPST-1495, the company’s novel dual receptor inhibitor of prostaglandin (PGE2) signaling, will be presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting to be held in Chicago from June 2-6, 2023 (Press release, Tempest Therapeutics, MAY 25, 2023, View Source [SID1234632079]).

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The first-in-human Phase 1a/1b, multicenter, open-label, dose-escalation trial included patients with metastatic or unresectable solid tumors and treatment-refractory disease with no remaining standard therapy to confer clinical benefit.

The data showed that in a diverse and treatment-refractory patient population, treatment with TPST-1495 as a monotherapy and in combination with pembrolizumab resulted in tumor shrinkage and prolonged stable disease in certain patients, as well as a durable confirmed partial response (PR) in a combination therapy patient with microsatellite stable colorectal cancer (MSS CRC), an indication not normally responsive to immunotherapy.

The safety profile for TPST-1495 monotherapy on the recommended once-daily schedule was tolerable, with predominantly Grade 1-2 treatment related adverse events (TRAEs), including abdominal pain (17.9% All Grade and 0% Grade 3+), nausea (20.5% All Grade and 0% Grade 3+), and diarrhea (15.4% All Grade and 2.6% Grade 3+). For the combination with pembrolizumab, the most common TRAEs were nausea (29.2% All Grade and 0% Grade 3+), fatigue (20.8% All Grade and 4.2% Grade 3+) and diarrhea (20.8% All Grade, 0% Grade 3+). No TRAEs of Grade ≥4 were reported.

On the recommended once-daily schedule, the disease control rate (DCR) by RECIST v1.1 was 44% for patients on monotherapy TPST-1495 and 40.9% for patients on TPST-1495 with pembrolizumab (including a confirmed PR in a patient with MSS CRC and a stable disease rate of 36.4%).

TPST-1495 also demonstrated near-linear relationship of exposure-to-dose that was unaffected by combination therapy, and pharmacodynamic activity was observed in assays of both immune activation and PGE2 modulation.

"These results from our first-in-human clinical trial in patients with late-line refractory disease are encouraging and support a tolerable safety profile and clinical activity of TPST-1495 as a novel agent targeting the prostaglandin pathway," said Sam Whiting, M.D., Ph.D., chief medical officer of Tempest. "Based on the well-understood biology of PGE2 signaling, we are enrolling patients in a combination therapy cohort focused on endometrial cancer, and we are exploring TPST-1495 monotherapy to treat the high unmet-need inherited cancer syndrome known as familial adenomatous polyposis, or FAP."

About TPST-1495

TPST-1495 is an orally-available and potent small molecule designed to block the receptors EP2 and EP4 in the prostaglandin pathway, which promote both tumor growth and the proliferation of suppressive immune cell populations. Several malignancies are thought to be prostaglandin driven through expression of high levels of COX-2, the cellular enzyme that produces PGE2, including endometrial, bladder, breast, colorectal, and cervical cancers. PGE2 promotes tumor cell growth through EP2 and EP4 signaling and is strongly immune suppressive. Tempest has conducted multiple IND-enabling studies with peripheral blood mononuclear cells (PBMCs) from healthy adult donors and in several mouse tumor models that demonstrate a significant increase in immune activation and anti-tumor potency by inhibiting both EP2 and EP4, when compared to EP4-only targeted molecules and non-steroidal anti-inflammatory drugs (NSAIDS) such as celecoxib.

On May 25, 2023 Syros Pharmaceuticals presented its corporate presentation (Presentation, Syros Pharmaceuticals, MAY 25, 2023, View Source [SID1234632078]).

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On May 25, 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 additional data from the Phase 3 DeFi trial assessing the impact of nirogacestat, an investigational gamma secretase inhibitor, on pain, tumor volume and T2 hypersensitivity in adults with desmoid tumors will be presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, being held June 2-6, 2023 (Press release, SpringWorks Therapeutics, MAY 25, 2023, View Source [SID1234632077]). Data from the DeFi trial were previously presented at the European Society for Medical Oncology Congress in September 2022 and published in the March 9, 2023 edition of the New England Journal of Medicine.1

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"Pain is the most debilitating symptom reported by patients living with desmoid tumors and reducing this burden is a key treatment goal for physicians. We are pleased with the robust data observed using multiple assessment tools demonstrating clinically significant reductions in pain with nirogacestat treatment," said Jim Cassidy, M.D., Ph.D., Chief Medical Officer of SpringWorks. "We are also encouraged by the substantial reductions in tumor volume and T2 hyperintensity seen in the DeFi study, which are consistent with the significant improvements in progression-free survival and objective response rate previously reported, and further elaborate on the activity profile of nirogacestat in desmoid tumors. We believe that nirogacestat has the potential to be a significant advance for patients and we look forward to our continued discussions with the FDA as they review our New Drug Application."

Poster Presentations at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting

Impact of nirogacestat on pain, a key symptom in patients with desmoid tumors (DT): results from the Phase 3 DeFi study (Poster #: 498)

Abstract #: 11564

Poster Session Date and Time: Saturday, June 3, 1:15 – 4:15 p.m. CT (2:15 – 5:15 p.m. ET)

As previously reported, in the DeFi trial (NCT03785964), nirogacestat met its primary endpoint of significantly improving progression-free survival compared to placebo in adult patients with progressing desmoid tumors (hazard ratio: 0.29 [95% CI, 0.15–0.55]; P<0.001). Nirogacestat also achieved a significant and clinically meaningful reduction in pain severity, a key secondary endpoint, compared with placebo at Cycle 10 (P<0.001). A manageable safety profile was observed with nirogacestat, with 95% of all treatment-emergent adverse events (TEAEs) reported as either 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%).

During the DeFi study, patients also completed three prespecified assessment tools that included pain measurements to characterize the impact of nirogacestat on this symptom. Changes from baseline in pain severity were compared between treatment arms at Cycle 10 per the prespecified exploratory endpoints. Statistically significant and clinically meaningful reductions in pain were observed with nirogacestat compared with placebo at Cycle 10 across all three assessment tools evaluated in DeFi: the Brief Pain Inventory-Short Form (BPI-SF), the GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom Scale (GODDESS-DTSS), and the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30).

The following results from the assessment tools will be presented at ASCO (Free ASCO Whitepaper):

Nirogacestat significantly reduced pain severity per the BPI-SF "worst pain" score (0–10 range) by 1.55 points, compared with 0.05 points with placebo (P<0.001) at Cycle 10.
Nirogacestat significantly reduced pain per the GODDESS-DTSS pain score (0–10 range) by 1.78 points, compared with an increase in pain of 0.34 points with placebo (P<0.001) at Cycle 10. The GODDESS-DTSS pain score includes questions about worst pain, dull pain, and shooting pain.
Nirogacestat significantly reduced pain per the EORTC QLQ-C30 pain subscale (0–100 range) by 22.36 points, compared with an increase in pain of 7.00 points with placebo (P<0.001) at Cycle 10. This pain sub-scale includes questions about pain and its interference with daily activities.
A statistically significant greater proportion of patients achieved a clinically meaningful pain reduction with nirogacestat treatment compared with placebo at Cycle 10 per the BPI-SF "worst pain" score (P=0.001) and the GODDESS-DTSS pain score (P<0.001).
Reductions in pain were rapid, becoming evident as early as Cycle 2 (the first post-treatment timepoint evaluated), and these reductions were sustained through to the end of the double-blind phase of the DeFi trial.
"Many patients with desmoid tumors live with severe, chronic pain that significantly impacts their quality of life," said Winette T.A. van der Graaf, M.D., Ph.D., Group Leader and Medical Oncologist, Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands and investigator in the DeFi trial. "It is very encouraging that nirogacestat demonstrated a rapid, sustained and consistent reduction in different aspects of pain during the trial, including worst pain, dull pain, shooting pain, and pain interference with people’s ability to perform daily activities."

Tumor volume and T2 hyperintensity changes from DeFi: a Phase 3, randomized, controlled trial of nirogacestat in patients with desmoid tumors (Poster #: 448)

Abstract #: 11514

Poster Session Date and Time: Saturday, June 3, 4:30 – 6:00 p.m. CT (5:30 – 7:00 p.m. ET); Poster Discussion at 4:30 p.m. CT (5:30 p.m. ET).

Exploratory analyses were conducted to evaluate changes in MRI-assessed desmoid tumor volume and T2 signal intensity in the Phase 3 DeFi trial. Specifically, volumetric MRI and T2 hyperintensity of each patient’s largest target tumor were evaluated at screening and every 6 cycles thereafter during the double-blind phase of the study. The use of MRI to assess changes in tumor volume or T2 signal intensity represent a novel imaging technique that could have prognostic or predictive value in patients with desmoid tumors.

Treatment with nirogacestat led to significantly improved median best change from baseline in MRI-assessed tumor volume of the largest target tumor compared with placebo (–59% versus +14%; P<0.001). Treatment with nirogacestat also led to significant improvement in the median best percent change in T2 hyperintensity signal ratio of the largest target tumor compared with placebo (–55% versus –21%; P<0.001).

"The Phase 3 DeFi study is the largest trial to date to prospectively evaluate volumetric MRI and T2 hyperintensity results in patients with desmoid tumors," said Thierry Alcindor, M.D., MSc, Medical Oncologist, Dana-Farber Cancer Institute and investigator in the DeFi trial. "These results are consistent with the significant improvements in progression-free survival and objective response rate achieved with nirogacestat compared to placebo in DeFi and represent an alternative approach to imaging patients with desmoid tumors that may better capture the asymmetric and irregular growth of these tumors."

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, potentially morbid tumors of the soft tissues.2,3 While they do not metastasize, desmoid tumors are associated with a high rate of recurrence.3,4,5 Sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis, these soft tissue tumors can be serious, debilitating, and in rare cases when vital organs are impacted, they can be life-threatening.3,6

Desmoid tumors are most commonly diagnosed in patients between the ages of 20 to 44 years, with a two-to-three times higher prevalence in females.5,7,8,9 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.8,9,10

Historically, desmoid tumors were treated with surgical resection, but this approach has become less favored due to a high recurrence rate after surgery.2,5,11 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. SpringWorks is also evaluating nirogacestat as a potential treatment for patients with ovarian granulosa cell tumors and for patients with multiple myeloma as part of several B-cell maturation agent (BCMA) combination therapy regimens in collaboration with leaders in industry and academia. Nirogacestat is an investigational drug for which safety and efficacy have not been established.

The U.S. Food and Drug Administration (FDA) has accepted the 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.

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 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.