Stamford, CT (Press Release) – Spring­Works Thera­peutics, Inc. (Nasdaq: SWTX), a clin­i­cal-stage bio­pharma­ceu­tical com­pany focused on devel­op­ing life-changing med­i­cines for patients with severe rare dis­eases and can­cer, to­day an­nounced that the first patient has been dosed in a Phase 1b clin­i­cal trial eval­u­ating Spring­Works Thera­peutics’ inves­ti­ga­tional gamma secretase in­hib­i­tor, niro­gace­stat, in com­bi­na­tion with GlaxoSmithKline’s (GSK) inves­ti­ga­tional anti-B-cell maturation an­ti­gen (BCMA) anti­body-drug con­ju­gate, be­lan­ta­mab mafo­dotin, in patients with re­lapsed or re­frac­tory mul­ti­ple myeloma. The niro­gace­stat and be­lan­ta­mab mafo­dotin com­bi­na­tion is being eval­u­ated as a sub-study in GSK’s on­go­ing DREAMM-5 plat­form trial.

Gamma secretase in­hib­ition prevents the cleavage and shedding of BCMA from the surface of myeloma cells. In pre­clin­i­cal models, niro­gace­stat has been shown to in­crease the cell surface density of BCMA and to reduce levels of soluble BCMA, thereby enhancing the ac­­tiv­ity of BCMA-targeted ther­a­pies. Fur­ther, pre­clin­i­cal data eval­u­ating the com­bi­na­tion of niro­gace­stat and be­lan­ta­mab mafo­dotin dem­onstrated syn­­er­gis­tic in­creases in human mul­ti­ple myeloma cell kill­ing as com­pared to be­lan­ta­mab mafo­dotin alone, with an up to ~3,000-fold im­prove­ment in cyto­tox­icity with the com­bi­na­tion.¹

“Spring­Works is focused on ad­vanc­ing a com­pre­hen­sive strat­e­gy to eval­u­ate the ability of niro­gace­stat to po­ten­ti­ate BCMA-directed ther­a­pies across modalities with the goal of making niro­gace­stat a cornerstone of BCMA com­bi­na­tion ther­apy for patients with mul­ti­ple myeloma,” said Saqib Islam, Chief Exec­u­tive Of­fi­cer of Spring­Works Thera­peutics. “We are delighted to have reached this im­por­tant mile­stone of dosing the first patient in this col­lab­o­rative trial with GSK, an industry leader com­mit­ted to ad­vanc­ing BCMA ther­a­pies. We look for­ward to generating clin­i­cal data to test the hypothesis that adding niro­gace­stat to be­lan­ta­mab mafo­dotin could lead to better clin­i­cal out­comes for patients.”

The Phase 1b com­bi­na­tion trial is being ad­vanced pur­su­ant to a global clin­i­cal trial col­lab­o­ration agree­ment that Spring­Works and GSK entered into in June 2019. Under the terms of the agree­ment, GSK is sponsoring and con­ducting the Phase 1b study to eval­u­ate the safety, tol­er­a­bil­ity and pre­lim­i­nary ef­fi­cacy of the com­bi­na­tion, and is assuming all de­vel­op­ment costs asso­ci­ated with the study, other than ex­penses re­lated to the manu­fac­tur­ing of niro­gace­stat and cer­tain ex­penses re­lated to in­tel­lec­tual prop­er­ty rights. Spring­Works and GlaxoSmithKline have formed a joint de­vel­op­ment com­mit­tee to help man­age and oversee the clin­i­cal study.

About the Phase 1b Trial

The Phase 1b trial (NCT04126200), which is a sub-study of GSK’s DREAMM-5 Phase 1/2 plat­form study, is an open-label study to eval­u­ate the safety, tol­er­a­bil­ity and pre­lim­i­nary ef­fi­cacy of niro­gace­stat in com­bi­na­tion with be­lan­ta­mab mafo­dotin in patients with re­lapsed or re­frac­tory mul­ti­ple myeloma. The study will in­clude two parts, a dose exploration phase and a cohort ex­pan­sion phase. The dose exploration phase will eval­u­ate the safety and tol­er­a­bil­ity profile of GSK’s be­lan­ta­mab mafo­dotin when admin­istered in com­bi­na­tion with niro­gace­stat and will identify a rec­om­mended Phase 2 dose for each drug in com­bi­na­tion. The cohort ex­pan­sion phase will eval­u­ate the clin­i­cal ac­­tiv­ity of the com­bi­na­tion in comparison to be­lan­ta­mab mafo­dotin mono­therapy in addi­tional patients with re­lapsed or re­frac­tory mul­ti­ple myeloma.

About Niro­gace­stat

Nirogacestat is an inves­ti­ga­tional, oral, sel­ective, small mol­e­cule gamma-secretase in­hib­i­tor in Phase 3 clin­i­cal de­vel­op­ment for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves mul­ti­ple transmembrane pro­tein complexes, in­clud­ing Notch, which is be­lieved to play a role in activating path­ways that con­trib­ute to desmoid tumor growth.

In addi­tion, gamma secretase has been shown to directly cleave membrane-bound BCMA, re­sult­ing in the re­lease of the soluble BCMA from the cell surface. By in­hib­iting gamma secretase, membrane-bound BCMA can be preserved, in­creas­ing target density while reducing levels of soluble BCMA, which may serve as a decoy re­cep­tor 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 pursuing a com­bi­na­tion ther­apy ap­proach to eval­u­ate niro­gace­stat as a BCMA po­ten­ti­ator across modalities by col­lab­o­rating with industry leaders. To date, Spring­Works has entered into two clin­i­cal col­lab­o­rations to eval­u­ate niro­gace­stat in com­bi­na­tion with GSK’s BCMA anti­body-drug con­ju­gate be­lan­ta­mab mafo­dotin and with Allogene’s allo­geneic BCMA CAR-T cell ther­apy ALLO-715.

Nirogacestat has re­ceived Orphan Drug Desig­na­tion from the U.S. Food and Drug Admin­istra­tion (FDA) for the treat­ment of desmoid tumors (June 2018) and from the Euro­pean Com­mis­sion for the treat­ment of soft tissue sarcoma (September 2019). The FDA also granted Fast Track and Break­­through Therapy Desig­na­tions for the treat­ment of adult patients with progressive, unresectable, re­cur­rent or re­frac­tory desmoid tumors or deep fibromatosis in No­vem­ber 2018 and August 2019, re­spec­tively.

About be­lan­ta­mab mafo­dotin (GSK2857916)

Belantamab mafo­dotin is an inves­ti­ga­tional anti­body drug con­ju­gate comprising a humanized anti-B cell maturation an­ti­gen (BCMA) mono­clonal anti­body con­ju­gated to the cyto­toxic agent auristatin F via non-cleavable linker.² The drug linker tech­nology is licensed from Seattle Genetics; mono­clonal anti­body is pro­duced using POTELLIGENT Technology licensed from BioWa.

Belantamab mafo­dotin is not cur­rently approved for use any­where in the world.

About Spring­Works Thera­peutics

Spring­Works is a clin­i­cal-stage bio­pharma­ceu­tical com­pany applying a pre­ci­sion med­i­cine ap­proach to acquiring, devel­op­ing and com­mer­cial­iz­ing life-changing med­i­cines for underserved patient pop­u­la­tions suffer­ing from dev­as­tat­ing rare dis­eases and can­cer. Spring­Works has a dif­fer­en­ti­ated port­folio of small mol­e­cule targeted on­col­ogy prod­uct can­di­dates and is ad­vanc­ing two poten­tially reg­is­tra­tional clin­i­cal trials in rare tumor types, as well as sev­er­al other pro­grams addressing highly prevalent, ge­net­ic­ally defined can­cers. Spring­Works’ stra­te­gic ap­proach and op­er­a­tional excellence in clin­i­cal de­vel­op­ment have enabled it to rapidly ad­vance its two lead prod­uct can­di­dates into late-stage clin­i­cal trials while simultaneously entering into mul­ti­ple shared-value part­ner­ships with industry leaders to ex­pand its port­folio. For more in­for­ma­tion, please visit www.springworkstx.com.

Follow Spring­Works Thera­peutics on social media: @Spring­WorksTx and LinkedIn.

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, in­clud­ing, without lim­i­ta­tion, state­ments re­gard­ing Spring­Works’ clin­i­cal trials and its strat­e­gy, business plans and focus. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “po­tential,” “continue,” “target” and similar ex­pres­sions are in­tended to identify for­ward-looking state­ments, although not all for­ward-looking state­ments con­tain these identifying words. Any for­ward-looking state­ments in this press re­lease 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 press re­lease, in­clud­ing, without lim­i­ta­tion, those re­lated to Spring­Works’ fi­nan­cial re­­sults, the timing for com­ple­tion of Spring­Works’ clin­i­cal trials of its prod­uct can­di­dates, whether and when, if at all, Spring­Works’ prod­uct can­di­dates will re­ceive ap­prov­al from the U.S. Food and Drug Admin­istra­tion, or FDA, or other foreign regu­la­tory author­i­ties, un­cer­tainties and assump­tions re­gard­ing the im­pact of the COVID-19 pan­dem­ic on Spring­Works’ business, op­er­a­tions, clin­i­cal trials, supply chain, strat­e­gy, goals and antic­i­pated timelines, com­pe­ti­tion from other bio­pharma­ceu­tical com­pa­nies, and other risks identified in the section entitled “Risk Factors” in Item 1A of Part II of Spring­Works’ Quar­ter­ly Report on Form 10-Q for the quarter ended March 31, 2020, as well as dis­cus­sions of po­ten­tial risks, un­cer­tainties and other im­por­tant factors in Spring­Works’ sub­se­quent filings with the Se­cu­ri­ties and Ex­change Com­mis­sion. Spring­Works cautions you not to place undue reliance on any for­ward-looking state­ments, which speak only as of the date they are made. Spring­Works disclaims any obli­ga­tion to pub­licly up­date or revise any such state­ments to reflect any change in ex­pec­ta­tions or in events, con­di­tions or cir­cum­stances on which any such state­ments may be based, or that may affect the like­li­hood that actual re­­sults will differ from those set forth in the for­ward-looking state­ments. Any for­ward-looking state­ments con­tained in this press re­lease rep­re­sent Spring­Works’ views only as of the date hereof and should not be relied upon as rep­re­senting its views as of any sub­se­quent date.

References

1. Eastman, S., Shelton, C., Gupta, I., Krueger, J., Blackwell, C., & Bojczuk, P. M. (2019, De­cem­ber). 4401 Synergistic Activity of Be­lan­ta­mab Mafodotin (anti-BCMA immuno-conjugate) with PF-03084014 (gamma-secretase in­hib­i­tor) in Bcma-Expressing Cancer Cell Lines. Poster session pre­sented at the 61st American Society of He­ma­tol­ogy Annual Meeting & Exposition, Orlando, FL.
2. NCI Drug Dictionary - Anti-BCMA Anti­body-Drug Conjugate GSK2857916. National Cancer In­sti­tute. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-bcma-antibody-drug-conjugate-gsk2857916. Accessed May 2020.

Source: Springworks Thera­peutics.