To learn about the safety and effects of an investigational drug called nirogacestat when given to participants with a desmoid tumor/aggressive fibromatosis

Start Date30 Oct 2024

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

[+1]

NCT05949099 / RecruitingPhase 2IIT

Phase II Study of Cryoablation and Nirogacestat for Desmoid Tumor

The primary purpose of this protocol is Systemic therapy with oral study agent, nirogacestat, followed by a single cryoablation procedure.

Start Date15 Aug 2023

Sponsor / Collaborator

Stanford University

[+1]

NCT05573802 / RecruitingPhase 1/2

A Phase 1/2, Dose and Schedule Evaluation Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin Administrated in Combination With Lenalidomide, Dexamethasone and Nirogacestat in Patients With Transplant Ineligible Newly Diagnosed Multiple Myeloma

This is a phase 1/2, open-label study designed to assess the safety and clinical activity of different belantamab mafodotin doses in combination with lenalidomide, dexamethasone and nirogacestat in patients with transplant ineligible newly diagnosed multiple myeloma.
This will be a 2-part study. In part 1 participants will be enrolled in one cohort to receive belantamab mafodotin in combination with lenalidomide, dexamethasone and nirogacestat and will determine the recommended phase 2 dose (RP2D) to be further evaluated for safety and clinical activity in the dose expansion cohort. The RP2D dose will be used in future studies in the transplant-ineligible newly diagnosed multiple myeloma (NDMM) setting. In the dose expansion phase (Part 2) an expansion cohort will be treated with the RP2D. The expansion cohort will randomize participants (1:1) in two groups to evaluate two alternate dose modification guidelines for corneal AEs. Part 2 of the study will also evaluate an alternative dose modification guideline for corneal adverse events (AEs).
Overall, approximately 36 participants will be enrolled in the study. Participant follow-up will continue up to 3 years after the last participant is enrolled (follow-up period range: 3-4 years). The estimated accrual period will be 12 months, corresponding to an approximate total study duration of 4 years.

Start Date14 Jul 2023

Sponsor / Collaborator

Hellenic Society of Cardiology

[+1]

100 Clinical Results associated with Nirogacestat hydrobromide

100 Translational Medicine associated with Nirogacestat hydrobromide

100 Patents (Medical) associated with Nirogacestat hydrobromide

Literatures (Medical) associated with Nirogacestat hydrobromide

01 Jul 2024·The Journal of investigative dermatology

Gamma-Secretase Inhibitors Downregulate the Profibrotic NOTCH Signaling Pathway in Recessive Dystrophic Epidermolysis Bullosa

Article

Author: Condorelli, Angelo Giuseppe ; Marzuolo, Elisa ; Alaggio, Rita ; Odorisio, Teresa ; Scarpelli, Giorgia ; El Hachem, May ; Nobili, Rebecca ; Zambruno, Giovanna ; De Stefanis, Cristiano ; Rota, Rossella ; Castiglia, Daniele ; Diociaiuti, Andrea ; Muglia, Anita

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder caused by mutations in COL7A1. RDEB is hallmarked by trauma-induced unremitting blistering, chronic wounds with inflammation, and progressive fibrosis, leading to severe disease complications. There is currently no cure for RDEB-associated fibrosis. Our previous studies and increasing evidence highlighted the profibrotic role of NOTCH pathway in different skin disorders, including RDEB. In this study, we further investigated the role of NOTCH signaling in RDEB pathogenesis and explored the effects of its inhibition by γ-secretase inhibitors DAPT and PF-03084014 (nirogacestat). Our analyses demonstrated that JAG1 and cleaved NOTCH1 are upregulated in primary RDEB fibroblasts (ie, RDEB-derived fibroblasts) compared with controls, and their protein levels are further increased by TGF-β1 stimulation. Functional assays unveiled the involvement of JAG1/NOTCH1 axis in RDEB fibrosis and demonstrated that its blockade counteracts a variety of fibrotic traits. In particular, RDEB-derived fibroblasts treated with PF-03084014 showed (i) a significant reduction of contractility, (ii) a diminished secretion of TGF-β1 and collagens, and (iii) the downregulation of several fibrotic proteins. Although less marked than PF-03084014-treated cells, RDEB-derived fibroblasts exhibited a reduction of fibrotic traits also upon DAPT treatment. This study provides potential therapeutic strategies to antagonize RDEB fibrosis onset and progression.

01 Jan 2024·Biochimica et biophysica acta. Molecular basis of disease

The Notch signaling pathway in desmoid tumor: Recent advances and the therapeutic prospects

Review

Author: Li, Wei ; Weng, Xin ; Zheng, Chuanxi ; Huang, Jianghong ; Xu, Gang ; Zhang, Shiquan

Desmoid tumor (DT) is a rare fibroblastic soft-tissue neoplasm that is characterized by local aggressiveness but no metastatic potential. Although the prognosis is relatively favorable, the unpredictable disease course and infiltrative growth lead to significant impairments and morbidity. Aberrant activation of Wnt/β-catenin signaling has been well-established in the pathogenesis of sporadic DT and familial adenomatous polyposis (FAP) or Gardners syndrome-associated DT, suggesting therapy targeting this pathway is an appealing treatment strategy. However, agents against this pathway are currently in their preliminary stages and have not yet been implemented in clinical practice. Increasing studies demonstrate activation of the Notch pathway is closely associated with the development and progression of DT, which provides a potential alternative therapeutic target against DT. Early-stage clinical trials and preclinical models have indicated that inhibition of Notch pathway might be a promising treatment approach for DT. The Notch signaling activation is mainly dependent on the activity of the γ-secretase enzyme, which is responsible for cleaving the Notch intracellular domain and facilitating its nuclear translocation to promote gene transcription. Two γ-secretase inhibitors called nirogacestat and AL102 are currently under extensive investigation in the advanced stage of clinical development. The updated findings from the phase III randomized controlled trial (DeFi trial) demonstrated that nirogacestat exerts significant benefits in terms of disease control and symptom resolution in patients with progressive DT. Therefore, this review provides a comprehensive overview of the present understanding of Notch signaling in the pathogenesis of DT, with a particular emphasis on the prospective therapeutic application of γ-secretase inhibitors in the management of DT.

01 Oct 2023·Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation

GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS^©): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial.

Article

Author: Bell, Timothy ; Atkinson, Thomas M ; Lim, Allison ; Daskalopoulou, Christina ; Gounder, Mrinal M ; Martindale, Moriah ; Smith, L Mary ; Griffiths, Pip

PURPOSE:

The GODDESS^© tool was developed to assess Desmoid Tumor/Aggressive Fibromatosis (DT/AF) symptom severity and impact on patients' lives. This study evaluated GODDESS^©'s cross-sectional and longitudinal measurement properties.

METHODS:

The Phase 3, randomized placebo-controlled, DeFi study (NCT03785964) of nirogacestat in DT/AF was used to assess GODDESS^©'s reliability, construct validity, responsiveness, and estimate of meaningful change thresholds (MCTs). Other patient-reported outcome (PRO) measures included Patient Global Impression of Severity (PGIS) in DT/AF symptoms, EORTC QLQ-C30, Brief Pain Inventory Short Form, and PROMIS Physical Function short-form 10a v2.0 plus 3 items.

RESULTS:

DeFi participants (N = 142) had a median age of 34 years (range: 18-76) and were mostly female (64.8%), with extra-abdominal (76.8%) or intra-abdominal tumors (23.2%). The GODDESS^© symptom/impact scales showed internal consistency at baseline, cycles 4 and 7 (Cronbach's α > 0.70) and test-retest reliability (intra-class correlation coefficient > 0.85). GODDESS^© scales correlated moderately to highly with PRO measures capturing similar content and differentiated among PGIS and Eastern Cooperative Oncology Group groups. GODDESS^© scales detected improvement over time. For the total symptom score, a 1.30-point decrease was estimated as the within-person MCT and a 1.00-point decrease as the between-group MCT. For the physical functioning impact score, estimated within- and between-group MCTs were 0.60-point and 0.50-point decreases, respectively. Few participants exhibited symptom worsening.

CONCLUSION:

GODDESS^© was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses.

TRIAL REGISTRATION NUMBER AND REGISTRATION DATE:

NCT03785964; December 24, 2018.

News (Medical) associated with Nirogacestat hydrobromide

01 Jul 2024

·www.biospace.com

SpringWorks Therapeutics Completes Submission of New Drug Application to the FDA for Mirdametinib for the Treatment of Children and Adults with NF1-PN

STAMFORD, Conn., July 01, 2024 (GLOBE NEWSWIRE) -- SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, announced today that the Company has completed the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for mirdametinib, an investigational MEK inhibitor, for the treatment of pediatric and adult patients with neurofibromatosis type 1- associated plexiform neurofibromas (NF1-PN). “We are pleased to be one step closer towards our goal of bringing mirdametinib to patients with NF1-PN in the U.S. and believe that our ReNeu data support the potential for mirdametinib to be a differentiated and best-in-class therapy for both children and adults living with this devastating disease,” said Saqib Islam, Chief Executive Officer of SpringWorks. “We look forward to working closely with the FDA throughout the review process and also plan to regulatory approval in the European Union later this year.” The NDA submission includes data from the pivotal Phase 2b ReNeu trial, which evaluated mirdametinib in patients ≥ 2 years of age with NF1-associated PN causing significant morbidity. Results were presented in an oral presentation at the 2024 American Society of Clinical Oncology Annual Meeting and demonstrated that mirdametinib treatment resulted in significant objective response rates confirmed by blinded independent central review, deep and durable responses, improvement in pain and health-related quality of life as well as a manageable safety pro both the adult and pediatric cohorts.1 The FDA and the European Commission have granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity and Rare Pediatric Disease designation for the treatment of NF1. In the second half of 2024, SpringWorks also plans to Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) for mirdametinib for the treatment of children and adults with NF1-PN. About the ReNeu Trial ReNeu (NCT03962543) is an ongoing, multi-center, open-label Phase 2b trial evaluating the efficacy, safety, and tolerability of mirdametinib in patients ≥ 2 years of age with an inoperable NF1-associated PN causing significant morbidity. The study enrolled 114 patients to receive mirdametinib at a dose of 2 mg/m2 twice daily (maximum dose of 4 mg twice daily) without regard to food. Mirdametinib was administered orally in a 3-week on, 1-week off dosing schedule as either a capsule or dispersible tablet. The primary endpoint is confirmed objective response rate defined as ≥ 20% reduction in target tumor volume during the 24 cycle treatment phase, as measured by MRI and assessed by blinded independent central review. Secondary endpoints include safety and tolerability, duration of response, and changes from baseline in patient reported outcomes to Cycle 13. The treatment phase of the trial is complete and results were presented at the 2024 American Society of Clinical Oncology Annual Meeting. Patients who completed the treatment phase were eligible to continue receiving treatment in the optional long-term follow up portion of the study, which is ongoing. About NF1-PN Neurofibromatosis type 1 (NF1) is a rare genetic disorder that arises from mutations in the NF1 gene, which encodes for neurofibromin, a key suppressor of the MAPK pathway.2,3 NF1 is the most common form of neurofibromatosis, with an estimated global birth incidence of approximately 1 in 2,500 individuals, and approximately 100,000 patients living with NF1 in the United States.4,5 The clinical course of NF1 is heterogeneous and manifests in a variety of symptoms across numerous organ systems, including abnormal pigmentation, skeletal deformities, tumor growth and neurological complications, such as cognitive impairment.6 Patients with NF1 have an 8 to 15-year mean reduction in their life expectancy compared to the general population.3 NF1 patients have approximately a 30-50% lifetime risk of developing plexiform neurofibromas, or PN, which are tumors that grow in an infiltrative pattern along the peripheral nerve sheath and that can cause severe disfigurement, pain and functional impairment; in rare cases, NF1-PN may be fatal.7,8 NF1-PNs are most often diagnosed in the first two decades of life.7 These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood.9,10 Surgical removal of these tumors is challenging due to the infiltrative tumor growth pattern along nerves and can lead to permanent nerve damage and disfigurement.11 MEK inhibitors have emerged as a validated class of treatment for NF1-PN.12 About Mirdametinib Mirdametinib is a potent, oral, CNS-penetrant, allosteric small molecule MEK inhibitor in development as a monotherapy treatment for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and low-grade glioma (LGG), and as a combination therapy for the treatment of several subsets of biomarker-defined metastatic solid tumors. Mirdametinib is an investigational drug for which safety and efficacy have not been established. Mirdametinib is designed to inhibit MEK1 and MEK2, which occupy pivotal positions in the MAPK pathway. The MAPK pathway is a key signaling network that regulates cell growth and survival and plays a central role in multiple cancers and rare diseases when genetically altered. The FDA and the European Commission have granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity and Rare Pediatric Disease designation for the treatment of NF1. About SpringWorks Therapeutics SpringWorks is a commercial-stage biopharmaceutical company applying a precision medicine approach to developing and delivering life-changing medicines for people with severe rare diseases and cancer. OGSIVEO® (nirogacestat), approved in the United States for the treatment of adult patients with progressing desmoid tumors who require systemic treatment, is the Company’s first FDA-approved therapy. SpringWorks also has a diversified targeted therapy pipeline spanning solid tumors and hematological cancers, with programs ranging from preclinical development through advanced clinical trials. In addition to its wholly owned programs, SpringWorks has also entered into multiple collaborations with innovators in industry and academia to unlock the full potential for its portfolio and create more solutions for patients in need. For more information, visit and follow @SpringWorksTx on X (formerly Twitter), LinkedIn, and YouTube. SpringWorks Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, relating to our business, operations, and financial conditions, including but not limited to current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our development and commercialization plans, our preclinical and clinical results, the potential for mirdametinib to become an important new treatment for pediatric and adult patients with NF1-PN, the potential for the results of the Phase 2b ReNeu clinical trial to support an NDA submission and an approval, the timing of our planned MAA submission for mirdametinib, our plans for seeking regulatory approval for and making mirdametinib available to NF1-PN patients, if approved, as well as relating to other future conditions. Words such as, but not limited to, “look forward to,” “believe,” “expect,” “anticipate,” “estimate,” “intend,” “plan,” “would,” “should” and “could,” and similar expressions or words, identify forward-looking statements. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Any forward-looking statements in this presentation are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this presentation, including, without limitation, risks relating to: (i) our expectations regarding the potential clinical benefit of mirdametinib for patients with NF1-PN, (ii) estimates regarding the global birth incidence of NF1-PN and the number of patients living with NF1-PN in the United States and the potential market for mirdametinib, (iii) the fact that topline or interim data from clinical studies may not be predictive of the final or more detailed results of such study or the results of other ongoing or future studies, (iv) the timing of our planned regulatory submissions and interactions, including the timing and outcome of decisions made by the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies, (v) whether FDA, EMA, or other regulatory authorities will require additional information or further studies, or may fail or refuse to approve or may delay approval of our product candidates, including nirogacestat and mirdametinib, (vi) our ability to obtain regulatory approval of any of our product candidates or maintain regulatory approvals granted for our products, (vii) our ability to maintain adequate patent protection and successfully enforce patent claims against third parties, and (viii) our ability to meet any specific milestones set forth herein. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. For further information regarding the risks, uncertainties and other factors that may cause differences between SpringWorks’ expectations and actual results, you should review the “Risk Factors” in Item 1A of Part II of SpringWorks’ Quarterly Report on Form 10-Q for the quarter ended March 31, 2024, as well as discussions of potential risks, uncertainties and other important factors in SpringWorks’ subsequent filings. Contacts Kim Diamond Vice President, Communications and Investor Relations Phone: 203-561-1646 Email: kdiamond@springworkstx.com Samantha Hilson Sandler Senior Director, Investor Relations Phone: 203-461-5501 Email: samantha.sandler@springworkstx.com References Moertel C, et al., ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN). Journal of Clinical Oncology 42, 3016-3016(2024). DOI:10.1200/JCO.2024.42.16_suppl.3016. The American Society of Clinical Oncology Abstract 3016. May 2024. Yap YS, McPherson JR, Ong CK, et al. The NF1 gene revisited - from bench to bedside. Oncotarget. 2014;5(15):5873-5892. doi:10.18632/oncotarget.2194. Rasmussen S, Friedman J. NF1 Gene and Neurofibromatosis 1. Am J Epidemiol. 2000;151(1):33-40. doi:10.1093/oxfordjournals.aje.a010118. CTF: Children’s Tumor Foundation. New and Improved: The way to talk about NF. Press release. May 9, 2023. Accessed February 2, 2024. Lee: Lee TJ, et al. Incidence and prevalence of neurofibromatosis type 1 and 2: a systematic review and meta-analysis. Orphanet J Rare Dis. 2023;18(1):292. Published 2023 Sep 14. doi:10.1186/s13023-023-02911-2) Weiss BD, Wolters PL, Plotkin SR, et al. NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. Journal of Clinical Oncology. 2021;JCO.20.02220.doi.org/10. 1200/JCO.20.02220. Prada: Prada CE, Rangwala FA, Martin LJ, et al. Pediatric plexiform neurofibromas: impact on morbidity and mortality in neurofibromatosis type 1. J Pediatr. 2012;160(3):461-467. Miller: Miller DT, et al. Health Supervision for Children With Neurofibromatosis Type 1. Pediatrics. 2019;143(5):e20190660. Gross A, Singh G, Akshintala S, et al. Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1. Neuro Oncol. 2018;20(12):1643-1651. doi:10.1093/neuonc/noy067. Nguyen R, Dombi E, Widemann B, et al. Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1. Orphanet J Rare Dis. 2012;7(1):75. doi:10.1186/1750-1172-7-75. Needle M, Cnaan A, Dattilo J, et al. Prognostic signs in the surgical management of plexiform neurofibroma: The Children’s Hospital of Philadelphia experience, 1974-1994. J Pediatr. 1997;131(5):678-682. doi:10.1016/s0022-3476(97)70092-1. Ferner R. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. The Lancet Neurology. 2007;6(4):340-351. doi:10.1016/s1474-4422(07)70075-3.

Phase 2Clinical ResultOrphan DrugFast Track

10 Jun 2024

·www.fiercepharma.com

GSK, attempting to stage Blenrep comeback, bids adieu to combo studies with SpringWorks' Ogsiveo

GSK is stepping away from a collaboration with SpringWorks Therapeutics as it works to make sure it’s “investing in the right combination approaches” in multiple myeloma, a company spokesperson said. Despite the recent approval of SpringWorks Therapeutics’ Ogsiveo, GSK is calling it quits on prior plans to wed the Pfizer spinout’s drug with its withdrawn cancer med Blenrep. SpringWorks on Thursday received a notice of termination on the partners’ amended collaboration and licensing deal, which was struck on Sept. 6, 2022, according to a Friday securities filing. Under the updated pact, GSK and SpringWorks were working together to develop and potentially market combinations of Blenrep (belantamab mafodotin-blmf) and Ogsiveo (nirogacestat) in multiple myeloma and other BCMA-expressing cancers. As part of the collaboration, GSK made a $75 million equity investment in SpringWorks back in 2022. SpringWorks, for its part, was in line to receive up to $550 million in potential development and commercial milestones. The 2022 deal was a retooled version of a clinical trial collaboration between the companies first set up in the summer of 2019. “We can confirm that we have provided notice to terminate our agreement with SpringWorks Therapeutics and will end all development of belantamab mafodotin in combination with nirogacestat,” a GSK spokesperson said over email. The termination will go into effect after 180 days, at which point GSK will work with SpringWorks on “appropriate steps to wind down existing combination study activities,” the spokesperson added. GSK is stepping away from the collaboration as it works to make sure it’s “investing in the right combination approaches” in multiple myeloma, the spokesperson explained. The move will not affect most of Blenrep’s DREAMM development program, which is exploring the use of the antibody-drug conjugate (ADC) in earlier lines of therapy—including as a potential first-line treatment for multiple myeloma—in combination with other innovative cancer meds and standard-of-care treatments. Still, the phase 1/2 platform trial DREAMM-5—which is testing Ogsiveo and other anti-cancer agents in combination with Blenrep in relapsed or refractory or refractory multiple myeloma—“will close,” GSK’s spokesperson noted. GSK will not enroll any new patients and does not plan to initiate any new trials with Ogsiveo, she explained. In its securities filing from last week, SpringWorks said that it “expects GSK will continue” ongoing clinical trials established under the partnership until completion, singling out a 27-patient study combining Ogsiveo with low-dose Blenrep in multiple myeloma. SpringWorks said it would continue to support follow-through on such trials with drug product supply and future publication efforts around generated data. SpringWorks added that it does not owe any payments or expect to incur other wind-down costs in connection with the terminated deal. While SpringWorks’ GSK deal is winding down, the company’s drug, Ogsiveo, is just beginning to enjoy its commercial run after securing an FDA nod to treat desmoid tumors in November. Ogsiveo is both SpringWorks' first commercial product and the first drug specifically approved for desmoid tumors, which are marked by noncancerous soft tissue growths that often cause severe pain and disfigurement. In the first quarter of 2024, Ogsiveo generated $21 million, according to a recent SpringWorks release. Meanwhile, GSK finds itself in a curious position with Blenrep. Back in November 2022, GSK pulled Blenrep from the U.S. market a little more than two weeks after the ADC had failed to top a pairing of Bristol Myers Squibb’s Pomalyst and dexamethasone in relapsed or refractory multiple myeloma after at least two prior lines of therapy. Still, GSK has kept an eye on a potential Blenrep revival in the U.S. In February, the company laid out detailed results from its phase 3 DREAMM-7 trial showing that Blenrep plus Takeda’s Velcade and the steroid dexamethasone significantly cut the risk of progression or death by 59% versus Johnson & Johnson’s Darzalex and dexamethasone in multiple myeloma patients who’d tried at least one prior therapy. In March, GSK said a combination of Blenrep and BMS’ Pomalyst plus dexamethasone (PomDex) “significantly” beat standard-of-care Velcade and PomDex on progression-free survival in the late-stage DREAMM-8 trial. The Blenrep combo also yielded a positive overall survival trend versus the control at the time of GSK’s analysis, the company added. GSK is “encouraged” by the recent head-to-head Blenrep combo results and believes, if approved, the Blenrep-based cancer cocktails could “redefine the treatment of relapsed or refractory multiple myeloma,” GSK’s spokesperson said at the time.

Phase 3License out/inDrug ApprovalADCClinical Result

10 Jun 2024

·firstwordpharma.com

GSK, SpringWorks call it quits on Blenrep combo alliance

GSK's impressive run of Blenrep (belantamab mafodotin) readouts have been hinting at the BCMA-targeting antibody-drug conjugate's possible return to the multiple myeloma market – however, if it does make a comeback, it won't be as a combination with SpringWorks Therapeutics' nirogacestat.In a statement, SpringWorks said it was notified by the UK drugmaker that it was terminating their 2022 non-exclusive license agreement centred on testing Blenrep with the former's investigational oral gamma secretase inhibitor in patients with multiple myeloma.The termination, effective 180 days after GSK's notice on June 6, comes roughly 18 months after the two companies expanded their partnership with an agreement potentially worth $625 million to SpringWorks. That included a $75-million equity investment from GSK and up to $550 million in additional milestone payments.The two first teamed up in 2019, and amended the collaboration in 2021, to cover the initial clinical development of nirogacestat plus Blenrep in patients with relapsed or refractory multiple myeloma. The expanded arrangement signed in 2022 allowed for studying the combo in earlier lines of treatment, including newly diagnosed patients.GSK is expected to continue ongoing trials of nirogacestat plus low-dose Blenrep in the 27 patients currently enrolled until completion, while SpringWorks said it would support those efforts with drug supply and publication plans. No payment obligations are triggered for SpringWorks by the termination, and the biotech retains rights to continue developing and commercialising nirogacestat and its other pipeline programmes. It has ongoing partnerships with Johnson & Johnson, Pfizer and Regeneron Pharmaceuticals and AbbVie to test nirogacestat in various combinations.Blenrep was pulled from the US market in late 2022, and appeared to be heading the same way in the EU, after it failed to demonstrate a survival benefit in later-line myeloma patients. However, subsequent successes in the Phase III DREAMM-7 and DREAMM-8 studies – the latter detailed at the American Society of Clinical Oncology (ASCO) annual meeting earlier this month – have revived the drug's prospects.GSK indicated recently that it planned to file Blenrep as a second-line and later treatment for patients with relapsed or refractory multiple myeloma in the US, EU, Japan and China in the second half. For more, see – KOL Views Q&A: Blenrep could fill important MM treatment gap in community settings, says leading expert.

License out/inASCOPhase 3

100 Deals associated with Nirogacestat hydrobromide

External Link

KEGG	Wiki	ATC	Drug Bank
D10960 D11453	-	-	DB12005

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Aggressive Fibromatosis	US	Springworks Therapeutics, Inc.	27 Nov 2023

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Granulosa Cell Tumor of the Ovary	Phase 2	US	Springworks Therapeutics, Inc.	30 Aug 2022
Granulosa Cell Tumor of the Ovary	Phase 2	CA	Springworks Therapeutics, Inc.	30 Aug 2022
Granulosa Cell Tumor of the Ovary	Phase 2	PL	Springworks Therapeutics, Inc.	30 Aug 2022
Advanced breast cancer	Phase 2	US	Pfizer Inc.	03 Feb 2015
Advanced breast cancer	Phase 2	HU	Pfizer Inc.	03 Feb 2015
Advanced breast cancer	Phase 2	IT	Pfizer Inc.	03 Feb 2015
Advanced breast cancer	Phase 2	PL	Pfizer Inc.	03 Feb 2015
Advanced breast cancer	Phase 2	ES	Pfizer Inc.	03 Feb 2015
Advanced breast cancer	Phase 2	GB	Pfizer Inc.	03 Feb 2015
Advanced Triple-Negative Breast Carcinoma	Phase 2	US	Pfizer Inc.	03 Feb 2015

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03785964 (DeFi \| DeFi, CTgov)	Phase 3	Aggressive Fibromatosis	142	Nirogacestat oral tablet (Double-Blind Phase - Nirogacestat)	mbgsyztcgq(daidpmhdkd) = orhkccqwij rsnfthulcs (wnymvjcddz, oezeqracwh - bakhjchmgw) View more	-	12 Jun 2024
				Placebo Oral Tablet (Double-Blind Phase - Placebo)	mbgsyztcgq(daidpmhdkd) = rdkovfxyar rsnfthulcs (wnymvjcddz, fteorzxayj - cndelvwveo) View more
NCT03785964 (DeFi, ASCO2024) Manual	Phase 3	Aggressive Fibromatosis APC Mutation	29	Nirogacestat (APC mutations)	fbhzjxkqrh(jnixbbmjxj) = rruyaepwwi pzvtbhslni (mpxcdvtwlc ) View more	Positive	24 May 2024
				Placebo (APC mutations)	fbhzjxkqrh(jnixbbmjxj) = amizjiizfx pzvtbhslni (mpxcdvtwlc ) View more
NCT03785964 (DeFi, ASCO2024) Manual	Phase 3	Aggressive Fibromatosis CTNNB1	142	Nirogacestat (Tumor size ≤10 cm)	wnbeycetsb(gdtjssqxyb) = fcefdyqtjc rzbtzzbtwp (qcjasbpwnk, 0.11 - 0.70) View more	Positive	24 May 2024
				Nirogacestat (Tumor size >10 cm)	wnbeycetsb(gdtjssqxyb) = udiwbaqzhp rzbtzzbtwp (qcjasbpwnk, 0.13 - 0.80) View more
NCT03785964 (DeFi, ESMO_SRC2024) Manual	Phase 3	Fibroma	144	Nirogacestat 150 mg	eoqhaqypaa(qyclwaatmy) = ucnnzxjpcw hiclbsdano (pzethckwya )	Positive	15 Mar 2024
				Placebo	eoqhaqypaa(qyclwaatmy) = unzsrmbbyr hiclbsdano (pzethckwya )
NCT03785964 (DeFi, FDA) Manual	Phase 3	Aggressive Fibromatosis	142	OGSIVEO	ppmxlujmmk(tflgvhdbaz) = meuqkkxwzw hrsoyrvgtr (rtjnmdjixh ) View more	Positive	27 Nov 2023
				Placebo	ppmxlujmmk(tflgvhdbaz) = zmftkbdkul hrsoyrvgtr (rtjnmdjixh, 8.4 - NR) View more
NCT03785964 (DeFi , Biospace) Manual	Phase 3	Aggressive Fibromatosis	142	Nirogacestat	grakvovfhr(ekzialhxou) = Nirogacestat significantly improved mean physical functioning score from baseline per the GODDESS DTIS PF domain compared with placebo at the pre-specified time point. The GODDESS DTIS PF domain captures varying degrees of vigorous and moderate daily activity, including moving and reaching. wjevvhepgz (ydtcinlzol ) View more	Positive	01 Nov 2023
				Placebo
NCT03785964 (DT/AF, ASCO2023) Manual	Phase 3	Aggressive Fibromatosis	122	Nirogacestat	mvkskaaxcx(vpkrrpztub) = reetwabaqa aojcuxddto (bfbbahfuab, –100.0 - 517.2) View more	Positive	31 May 2023
				Placebo	mvkskaaxcx(vpkrrpztub) = taeruukrec aojcuxddto (bfbbahfuab, –88.6 - 441.7) View more
NCT03785964 (Pubmed \| Br Dent J)	Phase 3	Aggressive Fibromatosis	142	Nirogacestat	wzgebpuiut(bgqwavuxtr) = sejkznhdmh dzpmzsnmzc (tidbwkbngx ) View more	Positive	09 Mar 2023
				Placebo	wzgebpuiut(bgqwavuxtr) = ubsxxbstvh dzpmzsnmzc (tidbwkbngx )
NCT03785964 (DeFi, ESMO2022) Manual	Phase 3	Aggressive Fibromatosis	142	Nirogacestat	lvusdbfuvt(pvrkpwadvl): HR = 0.29 (95% CI, 0.15 - 0.55), P-Value = <0.001 View more	Positive	11 Sep 2022
				Placebo
NCT01981551 (ASCO2022) Manual	Phase 2	Aggressive Fibromatosis	17	nirogacestat 150 mg	eptoygwvqs(vsoochyajw) = zacfqclnjn bafnngruyr (csvlrdiadw )	Positive	02 Jun 2022

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