Stamford, CT (Press Release) – Spring­Works Thera­peutics, Inc., a clin­i­cal-stage bio­pharma­ceu­tical com­pany focused on devel­op­ing life-changing med­i­cines for patients with severe rare dis­eases and can­cer, to­day an­nounced that the com­pany has entered into a clin­i­cal trial col­lab­o­ration agree­ment with GlaxoSmithKline to eval­u­ate Spring­Works Thera­peutics’ inves­ti­ga­tional gamma secretase in­hib­i­tor (GSI), niro­gace­stat, in com­bi­na­tion with GlaxoSmithKline’s inves­ti­ga­tional anti-B-cell maturation an­ti­gen (BCMA) anti­body-drug con­ju­gate (ADC), be­lan­ta­mab mafo­dotin (formerly GSK2857916), in patients with re­lapsed or re­frac­tory mul­ti­ple myeloma.

Gamma secretase is an enzyme that cleaves mul­ti­ple transmembrane pro­teins, in­clud­ing BCMA. As evi­denced in pub­li­ca­tions and pre­clin­i­cal ex­per­i­ments, treat­ment with a GSI, in­clud­ing niro­gace­stat, can in­crease BCMA cell surface ex­pres­sion levels on mul­ti­ple myeloma cells¹, poten­tially im­prov­ing the ac­­tiv­ity of BCMA-targeted ther­a­pies, in­clud­ing BCMA ADCs.

“While sig­nif­i­cant ad­vances have been made in treating mul­ti­ple myeloma over the past decade, a sig­nif­i­cant unmet need re­mains for patients who have re­lapsed or are re­frac­tory to avail­able treat­ments,” said Saqib Islam, Chief Exec­u­tive Of­fi­cer of Spring­Works Thera­peutics. “We are delighted to enter into this agree­ment with GlaxoSmithKline, who also invested in our recent Series B financing, and we look for­ward to exploring the poten­tial ben­e­fit of niro­gace­stat and be­lan­ta­mab mafo­dotin for mul­ti­ple myeloma patients. With this col­lab­o­ration, we are pleased to fur­ther ex­pand on our strat­e­gy in build­ing our targeted on­col­ogy port­folio with another industry leader.”

Under the terms of the agree­ment, GlaxoSmithKline will sponsor and con­duct the adaptive Phase 1b study to eval­u­ate the safety, tol­er­a­bil­ity and pre­lim­i­nary ef­fi­cacy of the com­bi­na­tion, and will assume all devel­op­ment costs asso­ci­ated with the study. GlaxoSmithKline and Spring­Works Thera­peutics will also form a joint devel­op­ment com­mit­tee to man­age the clin­i­cal study.

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 June 2018, the FDA granted Orphan Drug desig­na­tion for niro­gace­stat for the treat­ment of desmoid tumors, and in No­vem­ber 2018, the FDA granted Fast Track desig­na­tion for niro­gace­stat for the treat­ment of adult patients with progressive, unresectable, re­cur­rent or re­frac­tory desmoid tumors or deep fibromatosis.

In addi­tion, gamma secretase has been shown to directly cleave membrane-bound BCMA, re­sult­ing in the re­lease of the BCMA extracellular domain, or 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.² Niro­gace­stat’s ability to en­hance the ac­­tiv­ity of BCMA-directed ther­a­pies has been ob­served in pre­clin­i­cal models of mul­ti­ple myeloma.

About be­lan­ta­mab mafo­dotin (GSK2857916)

Belantamab mafo­dotin is an inves­ti­ga­tional anti-B-cell maturation an­ti­gen (BCMA) anti­body-drug con­ju­gate in Phase 2 clin­i­cal devel­op­ment for patients with re­lapsed / re­frac­tory mul­ti­ple myeloma and other ad­vanced hema­to­logic malig­nan­cies expressing BCMA.

In 2017, be­lan­ta­mab mafo­dotin was awarded Break­through Therapy desig­na­tion from the U.S. Food and Drug Admin­istra­tion and PRIME desig­na­tion from the Euro­pean Medicines Agency; these desig­na­tions are in­tended to facilitate devel­op­ment of inves­ti­ga­tional med­i­cines that have shown clin­i­cal prom­ise for con­di­tions where there is sig­nif­i­cant unmet need.

About Spring­Works Thera­peutics

At Spring­Works Thera­peutics, a clin­i­cal-stage bio­pharma­ceu­tical com­pany, we are driven to de­vel­op life-changing med­i­cines for patients with severe rare dis­eases and can­cer. Since our launch in 2017, we have worked to identify and ad­vance promising science, beginning with our licensed clin­i­cal ther­a­pies from Pfizer Inc. We pioneer ef­fi­cient path­ways for drug devel­op­ment, leveraging shared-value part­ner­ships with patient advocacy groups, innovators in industry and academia, and in­vestors so that to­geth­er, we can unlock the poten­tial of science and bring new ther­a­pies to underserved patients. Niro­gace­stat, our gamma secretase in­hib­i­tor for the treat­ment of desmoid tumors is cur­rently in a Phase 3 clin­i­cal trial, and Spring­Works Thera­peutics ex­pec­ts to ini­ti­ate a Phase 2b study of mirda­meti­nib, our MEK 1/2 in­hib­i­tor for neu­rofi­bromatosis type 1 patients with plexiform neu­rofi­bromas, in the third quarter of 2019. Mirdametinib also holds prom­ise as the back­bone for com­bi­na­tion ther­a­pies to treat metastatic solid tumors. At Spring­Works, we ignite the power of promising science to unleash new possibilities for patients. For more in­for­ma­tion, please visit www.springworkstx.com.

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

References

1. Laurent S, Hoffmann F, Kuhn P, Cheng Q, Chu Y, Schmidt-Supprian M, Hauck S, Schuh E, Krumbholz M, Rubsamen H, Wanngren J, Khademi M, Olsson T, Alexander T, Hiepe F, Pfister H, Weber F, Jenne D, Wekerle H, Hohlfeld R, Lichtenthaler S, & Meinl E, Gamma-secretase directly sheds the survival re­cep­tor BCMA from plasma cells, Nature Communications (2015).
2. Chen H, Li M, Xu N, Ng N, Sanchez E, Soof CM, Patil S, Udd K, Bujarski S, Cao J, Hekmati T, Ghermezi M, Zhou M, Wang EY, Tanenbaum EJ, Zahab B, Schlossberg R, Yashar MA, Wang CS, Tang GY, Spektor TM, Berenson JR, Serum B-cell maturation an­ti­gen (BCMA) reduces binding of anti-BCMA anti­body to multiple myeloma cells, Leukemia Research (2019), https://doi.org/10.1016/j.leukres.2019.04.008

Source: Spring­Works Thera­peutics.