Increasing BCMA Surface Expression with Gamma Secretase Inhibitor Niro­gace­stat May Enable Deep and Durable Responses to ALLO-715, an Inves­ti­ga­tional Anti-BCMA Allogeneic CAR T Therapy

South San Francisco, CA and Stamford, CA (Press Release) – Allogene Thera­peutics, Inc. (Nasdaq: ALLO), a clin­i­cal-stage bio­technol­ogy com­pany pioneering the de­vel­op­ment of allo­geneic chi­meric an­ti­gen re­cep­tor T cell (AlloCAR T™) ther­a­pies for cancer and 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 they have entered into a clin­i­cal trial col­lab­o­ration agree­ment. This agree­ment will eval­u­ate ALLO-715, Allogene’s inves­ti­ga­tional anti-B-cell maturation an­ti­gen (BCMA) AlloCAR T ther­apy in com­bi­na­tion with Spring­Works’ inves­ti­ga­tional gamma secretase in­hib­i­tor (GSI), niro­gace­stat, in patients with re­lapsed or re­frac­tory mul­ti­ple myeloma.

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 reduce levels of soluble BCMA, thereby enhancing the ac­­tiv­ity of BCMA-targeted ther­a­pies.¹ In addi­tion, emerging clin­i­cal data sug­gest that a GSI may in­crease antitumor ef­fi­cacy of BCMA-targeted au­tol­o­gous CAR T ther­apy in patients with re­lapsed and re­frac­tory mul­ti­ple myeloma.^2,3

“Autologous CAR T ther­apy has shown the poten­tial for engi­neered cell ther­apy to treat mul­ti­ple myeloma and provide sig­nif­i­cant benefits to patients. We be­lieve allo­geneic CAR T ther­apy is the next frontier in ge­net­ic­ally engi­neered cell ther­apy for the treat­ment of cancer,” said David Chang, M.D., Ph.D., Pres­i­dent, CEO and Co-Founder of Allogene Thera­peutics. “The search to find long-lasting and poten­tially curative ther­a­pies for patients with mul­ti­ple myeloma con­tinues to evolve. We are pleased with the progress of our ALLO-715 Phase 1 UNIVERSAL trial and are ex­cited to explore the com­bi­na­tion of ALLO-715 with niro­gace­stat as a means to fur­ther unlock the poten­tial of allo­geneic CAR T ther­apy in this dis­ease.”

Under the terms of the agree­ment, Allogene will sponsor and conduct the Phase 1 study to eval­u­ate the safety, tolerability and pre­lim­i­nary ef­fi­cacy of the com­bi­na­tion, and will assume all de­vel­op­ment costs asso­ci­ated with the study. Allogene and Spring­Works will form a joint de­vel­op­ment com­mit­tee to oversee the clin­i­cal study, which is ex­pected to com­mence in the sec­ond half of 2020 pend­ing dis­cus­sions with regulators.

“Gamma secretase in­hib­ition has emerged as a clin­i­cally val­i­dated mech­a­nism to potentiate BCMA ther­a­pies and we be­lieve that niro­gace­stat has the poten­tial to be­come a cornerstone of BCMA com­bi­na­tion ther­apy for patients with mul­ti­ple myeloma,” said Saqib Islam, Chief Executive Officer of Spring­Works Thera­peutics. “We are delighted to part­ner with Allogene, a pioneer in the allogenic cell ther­apy field, to fur­ther explore niro­gace­stat in com­bi­na­tion with an ‘off-the-shelf’ CAR T ther­apy for these patients where the need for treat­ment op­tions remains great.”

Spring­Works is cur­rent en­rolling patients in a global Phase 3, double-blind, ran­dom­ized, placebo-controlled clin­i­cal trial (the DeFi Trial) to eval­u­ate niro­gace­stat in adults with progressing desmoid tumors.

About ALLO-715

ALLO-715, an AlloCAR T ther­apy targeting B-cell maturation an­ti­gen (BCMA), is cur­rent in Phase 1 de­vel­op­ment as a poten­tial novel treat­ment for mul­ti­ple myeloma. Multiple myeloma is char­ac­ter­ized by ab­nor­mal­i­ties in plasma cells that reproduce un­con­trol­lably in the bone mar­row of people with the dis­ease,⁴ mul­ti­ple myeloma is incurable for most patients, and most patients relapse despite the treat­ments avail­able.⁵ Pre­clin­i­cal study results for ALLO-715 were pub­lished in the journal Molecular Therapy validating the poten­tial for an AlloCAR T to treat mul­ti­ple myeloma and demonstrating the ability for ALLO-715 to sustain potent anti-tumor re­sponses in pre-clinical models. Allogene ini­ti­ated the UNIVERSAL study in the third quarter of 2019.

ALLO-715 uti­lizes TALEN® gene-editing tech­nology pioneered and owned by Cellectis. Allogene has an ex­clu­sive license to the Cellectis tech­nology for allo­geneic prod­ucts directed at the BCMA target. Allogene holds global de­vel­op­ment and com­mer­cial rights for this inves­ti­ga­tional can­di­date.

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 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. 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 GlaxoSmithKline’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 (November 2018 and August 2019).

About Allogene Thera­peutics

Allogene Thera­peutics, with headquarters in South San Francisco, is a clin­i­cal-stage bio­technol­ogy com­pany pioneering the de­vel­op­ment of allo­geneic chi­meric an­ti­gen re­cep­tor T cell (AlloCAR T™) ther­a­pies for cancer. Led by a world-class man­agement team with sig­nif­i­cant ex­peri­ence in cell ther­apy, Allogene is devel­op­ing a pipe­line of “off-the-shelf” CAR T cell ther­apy can­di­dates with the goal of de­livering readily avail­able cell ther­apy on-demand, more reliably, and at greater scale to more patients. For more in­for­ma­tion, please visit www.allogene.com, and follow @AllogeneTx on Twitter and LinkedIn.

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.

Allogene Forward-Looking State­ments

This press release con­tains for­ward-looking state­ments for pur­poses of the safe harbor provisions of the Private Se­cu­ri­ties Lit­i­ga­tion Reform Act of 1995. The press release may, in some cases, use terms such as "predicts," "believes," "poten­tial," "proposed," "con­tinue," "esti­mates," "antic­i­pates," "expects," "plans," "intends," "may," "could," "might," "will," "should" or other words that convey un­cer­tainty of future events or out­comes to identify these for­ward-looking state­ments. Forward-looking state­ments in­clude state­ments re­gard­ing intentions, beliefs, pro­jec­tions, outlook, analyses or current ex­pec­ta­tions con­cern­ing, among other things: the timing and ability to ini­ti­ate and ad­vance a com­bi­na­tion trial for niro­gace­stat and ALLO-715, the poten­tial benefits of the com­bi­na­tion trial, in­clud­ing the ability of niro­gace­stat to in­crease BCMA surface ex­pres­sion to enable a deep and durable re­sponse of ALLO-715, the ability to de­vel­op allo­geneic CAR T ther­a­pies for cancer and the poten­tial benefits of AlloCAR T ther­apy. Various factors may cause dif­fer­ences be­tween Allogene’s ex­pec­ta­tions and actual results as discussed in greater detail in Allogene’s filings with the Se­cu­ri­ties and Ex­change Com­mis­sion (SEC), in­clud­ing without lim­i­ta­tion in its Form 10-Q for the quarter ended Sep­tem­ber 30, 2019. Any for­ward-looking state­ments that are made in this press release speak only as of the date of this press release. Allogene assumes no obli­ga­tion to up­date the for­ward-looking state­ments whether as a result of new in­for­ma­tion, future events or other­wise, after the date of this press release.

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, state­ments re­gard­ing the future re­search and de­vel­op­ment ac­­tiv­i­ties under the agree­ment with Allogene, 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, 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 Sep­tem­ber 30, 2019, 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 et al., Abstract #4401 “Synergistic Activity of Be­lan­ta­mab Mafodotin (anti-BCMA immuno-conjugate) with Niro­gace­stat (PF-03084014, gamma-secretase in­hib­i­tor) in BCMA-Expressing Cancer Cell Lines”, ASH 2019.
2. Cowan et al., Abstract #204 “Efficacy and Safety of Fully Human BCMA CAR T Cells in Com­bi­na­tion with a Gamma Secretase Inhibitor to Increase Bcma Surface Expression in Patients with Re­lapsed or Re­frac­tory Multiple Myeloma”, ASH 2019.
3. Blood. 2019 Nov 7;134(19):1585-1597. doi: 10.1182/blood.2019000050
4. Multiple myeloma - Genetics Home Reference - NIH. Retrieved from https://ghr.nlm.nih.gov/condition/multiple-myeloma#
5. Sonneveld P, Broijl A. Treatment of re­lapsed and re­frac­tory multiple myeloma. Haematologica. 2016;101(4):396-406

Source: Allogene Thera­peutics.