Increasing BCMA Surface Expression and Reduced Soluble BCMA Levels with Gamma Secretase Inhibitor Niro­gace­stat May Enhance Clinical Benefit in Com­bi­na­tion with PBCAR269A, an Allogeneic BCMA-Targeted CAR T Cell Product

Durham, NC and Stamford, CT (Press Release) – Pre­ci­sion BioSciences, Inc. (Nasdaq: DTIL), a clin­i­cal stage bio­technol­ogy devel­op­ing allo­geneic CAR T and in vivo gene correction ther­a­pies with its ARCUS® genome edit­ing plat­form, 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 they have entered into a clin­i­cal trial col­lab­o­ration agree­ment. Per the agree­ment, PBCAR269A, Pre­ci­sion BioSciences’ wholly-owned inves­ti­ga­tional allo­geneic chi­meric an­ti­gen re­cep­tor (CAR) T cell ther­apy can­di­date targeting B-cell maturation an­ti­gen (BCMA), will be eval­u­ated in com­bi­na­tion with niro­gace­stat, Spring­Works’ inves­ti­ga­tional gamma se­cre­tase in­hib­i­tor (GSI), in patients with re­lapsed or re­frac­tory mul­ti­ple myeloma.

“Based on recent clin­i­cal data using GSIs in com­bi­na­tion with BCMA-targeted ther­a­pies, it is ex­cit­ing to com­bine these agents in patients who have a need for better ther­a­pies,” said Nina Shah, M.D., study Prin­ci­pal In­ves­ti­ga­tor and Asso­ci­ate Pro­fessor in the De­part­ment of Medicine at the Uni­ver­sity of California, San Francisco. “I look for­ward to the data gen­er­ated from this inves­ti­ga­tional study to see if PBCAR269A plus niro­gace­stat im­proves clin­i­cal out­comes in patients with mul­ti­ple myeloma.”

Gamma se­cre­tase in­hib­ition has been shown pre­clin­i­cally to en­hance the ac­­tiv­ity of BCMA-targeted ther­a­pies by preventing the cleavage and shedding of BCMA from the surface of myeloma cells, which in­creases the cell surface density of BCMA and re­duces levels of soluble BCMA. Via this mech­a­nism, niro­gace­stat may en­hance the ac­­tiv­ity of BCMA-targeted ther­a­pies.¹ Emerging clin­i­cal data also sug­gest that a GSI may in­crease antitumor ef­fi­cacy of BCMA-targeted au­tol­o­gous CAR T ther­apy in patients with re­lapsed or re­frac­tory mul­ti­ple myeloma.^2,3

“In June, we ini­ti­ated our Phase 1/2a clin­i­cal trial of PBCAR269A, which targets BCMA for the treat­ment of re­lapsed or re­frac­tory mul­ti­ple myeloma and has dem­onstrated anti-tumor ac­­tiv­ity in pre­clin­i­cal dis­ease models,” said Chris Heery, M.D., Chief Medical Of­fi­cer at Pre­ci­sion BioSciences. “Pre­clin­ical data from our own pro­gram as well as others have sug­gested the importance of gamma se­cre­tase in­hib­ition to unlock the full po­ten­tial of BCMA targeted ther­a­pies. We look for­ward to fur­ther eval­u­ating this in the clinic.”

Under the terms of the agree­ment, Pre­ci­sion BioSciences will assume all de­vel­op­ment costs of the ex­panded Phase 1/2a study of PBCAR269A to in­clude niro­gace­stat and eval­u­ate the safety and pre­lim­i­nary clin­i­cal ac­­tiv­ity of the com­bi­na­tion ther­apy. Pre­ci­sion BioSciences and Spring­Works will form a joint de­vel­op­ment com­mit­tee to oversee the clin­i­cal study, which is ex­pected to com­mence in the first half of 2021, pend­ing dis­cus­sions with regulators.

“Patients with mul­ti­ple myeloma are in great need of treat­ment ad­vances,” said Saqib Islam, Chief Exec­u­tive Of­fi­cer of Spring­Works Thera­peutics. “We con­tinue to be­lieve that niro­gace­stat has the po­ten­tial to be­come a cornerstone of BCMA com­bi­na­tion ther­apy for these patients and are pleased to work with Pre­ci­sion BioSciences and their lead­ing group of sci­en­tif­ic advisors and clin­i­cal in­ves­ti­ga­tors to eval­u­ate the com­bi­na­tion of our gamma se­cre­tase in­hib­i­tor with their ‘off-the-shelf’ CAR T ther­apy.”

About PBCAR269A

PBCAR269A is an allo­geneic BCMA-targeted CAR T cell ther­apy can­di­date being eval­u­ated for the safety and pre­lim­i­nary clin­i­cal ac­­tiv­ity in a Phase 1/2a multi­center, nonrandomized, open-label, parallel assignment, single-dose, dose-escalation, and dose-expansion study of adults with re­lapsed or re­frac­tory mul­ti­ple myeloma. The start­ing dose of PBCAR269A is 6 x 105 CAR T cells/kg body weight with sub­se­quent cohorts re­ceiv­ing es­ca­lat­ing doses to a max­i­mum dose of 6 x 106 CAR T cells/kg body weight.

PBCAR269A is the com­pany’s third CAR T can­di­date to ad­vance to the clinic and is part of a pipe­line of cell-phenotype op­ti­mized allo­geneic CAR T ther­a­pies derived from healthy donors and then mod­i­fied via a simultaneous TCR knock-out and CAR T knock-in step with the Com­pany’s pro­pri­e­tary ARCUS® genome edit­ing tech­nology. Pre­ci­sion BioSciences op­ti­mizes its CAR T ther­apy can­di­dates for im­mune cell ex­pan­sion in the body by main­taining a high pro­por­tion of naïve and central memory CAR T cells.

The U.S. Food and Drug Admin­istra­tion (FDA) recently granted Fast Track Desig­na­tion to PBCAR269A for the treat­ment of re­lapsed or re­frac­tory mul­ti­ple myeloma for which the FDA pre­vi­ously granted Orphan Drug Desig­na­tion. The PBCAR269A clin­i­cal trial will be con­ducted at mul­ti­ple U.S. sites. For more in­for­ma­tion, visit www.clinicaltrials.gov, study identifier num­ber NCT04171843.

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 eval­u­ating niro­gace­stat as a BCMA po­ten­ti­ator and has four col­lab­o­rations with industry-leading BCMA de­vel­opers to eval­u­ate niro­gace­stat in com­bi­na­tions across modalities, in­clud­ing with an anti­body-drug con­ju­gate, two CAR T cell ther­a­pies and a bispecific anti­body. In addi­tion, Spring­Works and Fred Hutchinson Cancer Re­search Center have entered into a sponsored re­search agree­ment to fur­ther char­ac­ter­ize the ability of niro­gace­stat to mod­u­late BCMA and po­ten­ti­ate BCMA directed ther­a­pies using a variety of pre­clin­i­cal and patient-derived mul­ti­ple myeloma models devel­oped by re­searchers at Fred Hutch.

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 Pre­ci­sion BioSciences, Inc.

Precision BioSciences, Inc. is a clin­i­cal stage bio­technol­ogy com­pany ded­i­cated to im­prov­ing life (DTIL) with its novel and pro­pri­e­tary ARCUS® genome edit­ing plat­form. ARCUS is a highly spe­cif­ic and versatile genome edit­ing plat­form that was de­signed with thera­peutic safety, de­livery, and con­trol in mind. Using ARCUS, the Com­pany’s pipe­line con­sists of mul­ti­ple “off-the-shelf” CAR T immuno­therapy clin­i­cal can­di­dates and sev­er­al in vivo gene correction ther­apy can­di­dates to cure ge­netic and infectious dis­eases where no adequate treat­ments exist. For more in­for­ma­tion about Pre­ci­sion BioSciences please visit www.precisionbiosciences.com.

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, visit www.springworkstx.com and follow @Spring­WorksTx on Twitter and LinkedIn.

Precision Forward-Looking State­ments

This press re­lease con­tains for­ward-looking state­ments within the meaning of the Private Se­cu­ri­ties Lit­i­ga­tion Reform Act of 1995. All state­ments con­tained in this press re­lease that do not re­late to mat­ters of historical fact should be con­sidered for­ward-looking state­ments, in­clud­ing, without lim­i­ta­tion, state­ments re­gard­ing the Com­pany’s timing of clin­i­cal trials and re­­sults there­from involving PBCAR269A and the ex­pected ben­e­fits of producing clin­i­cal trial ma­teri­al at the Com­pany’s in-house manu­fac­tur­ing facility. In some cases, you can identify for­ward-looking state­ments by terms such as “anticipate,” “believe,” “could,” “expect,” “should,” “plan,” “intend,” “estimate,” “target,” “mission,” “may,” “will,” “would,” “should,” “could,” “target,” “project,” “predict,” “contemplate,” “potential,” or the neg­a­tive thereof and similar words and ex­pres­sions.

Forward-looking state­ments are based on man­age­ment’s cur­rent ex­pec­ta­tions, beliefs and assump­tions and on in­for­ma­tion cur­rently avail­able to us. Such state­ments are subject to a num­ber of known and un­known risks, un­cer­tainties and assump­tions, and actual re­­sults may differ ma­teri­ally from those ex­pressed or im­plied in the for­ward-looking state­ments due to var­i­ous im­por­tant factors, in­clud­ing, but not lim­ited to: our ability to be­come profitable; our ability to procure suf­fi­cient fund­ing and re­quire­ments under our cur­rent debt in­stru­ments; our op­er­at­ing ex­penses and our ability to predict what those ex­penses will be; our lim­ited op­er­at­ing history; the success of our pro­grams and prod­uct can­di­dates in which we expend our resources; our de­pen­dence on our ARCUS tech­nology; the initiation, cost, timing, progress, achieve­ment of mile­stones and re­­sults of re­search and de­vel­op­ment ac­­tiv­i­ties, pre­clin­i­cal or greenhouse stud­ies and clin­i­cal or field trials; pub­lic perception about genome edit­ing tech­nology and its appli­ca­tions; com­pe­ti­tion in the genome edit­ing, bio­pharma­ceu­tical, bio­technol­ogy and agricultural bio­technol­ogy fields; our or our col­lab­o­rators’ ability to identify, de­vel­op and com­mer­cial­ize prod­uct can­di­dates; pend­ing and po­ten­tial liability lawsuits and penalties against us or our col­lab­o­rators re­lated to our tech­nology and our prod­uct can­di­dates; the U.S. and foreign regu­la­tory landscape appli­cable to our and our col­lab­o­rators’ de­vel­op­ment of prod­uct can­di­dates; our or our col­lab­o­rators’ ability to ob­tain and main­tain regu­la­tory ap­prov­al of our prod­uct can­di­dates, and any re­lated restrictions, lim­i­ta­tions and/or warnings in the label of an ap­prov­ed prod­uct can­di­date; our or our col­lab­o­rators’ ability to ad­vance prod­uct can­di­dates into, and suc­cess­fully design, implement and com­plete, clin­i­cal or field trials; po­ten­tial manu­fac­tur­ing prob­lems asso­ci­ated with the de­vel­op­ment or com­mer­cial­i­za­tion of any of our prod­uct can­di­dates; our ability to achieve our antic­i­pated op­er­at­ing efficiencies at our manu­fac­tur­ing facility; delays or dif­fi­culties in our and our col­lab­o­rators’ ability to en­roll patients; if our prod­uct can­di­dates do not work as in­tended or cause un­de­sir­able side effects; risks asso­ci­ated with appli­cable health­care, data privacy and se­cu­ri­ty reg­u­la­tions and our compliance there­with; the rate and degree of mar­ket ac­ceptance of any of our prod­uct can­di­dates; the success of our existing col­lab­o­ration agree­ments, and our ability to enter into new col­lab­o­ration arrangements; our cur­rent and future rela­tion­ships with third parties in­clud­ing suppliers and manu­fac­turers; our ability to ob­tain and main­tain in­tel­lec­tual prop­er­ty pro­tec­tion for our tech­nology and any of our prod­uct can­di­dates; po­ten­tial lit­i­ga­tion relating to in­fringe­ment or misappropriation of in­tel­lec­tual prop­er­ty rights; our ability to ef­fec­tively man­age the growth of our op­er­a­tions; our ability to attract, retain, and motivate key sci­en­tif­ic and man­age­ment per­son­nel; mar­ket and eco­nom­ic con­di­tions; effects of nat­u­ral and man­made di­sas­ters, pub­lic health emergencies and other nat­u­ral catastrophic events effects of the out­break of COVID-19, or any pan­dem­ic, epi­demic or out­break of an infectious dis­ease; insurance ex­penses and exposure to uninsured liabilities; and other im­por­tant factors discussed under the cap­tion “Risk Factors” in our Quar­ter­ly Report on Form 10-Q for the quar­ter­ly period ended June 30, 2020, as any such factors may be up­dated from time to time in our other filings with the SEC, which are accessible on the SEC’s website at www.sec.gov and the Investors & Media page of our website at in­vestor.precisionbiosciences.com.

All for­ward-looking state­ments speak only as of the date of this press re­lease and, 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.

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 June 30, 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. Synergistic ac­­tiv­ity of be­lan­ta­mab mafo­dotin (anti-BCMA immuno-conjugate) with PF-03084014 (gamma-secretase in­hib­i­tor) in Bcma-expressing can­cer cell lines. Blood. 2019;134(supplement_1):4401. doi.org/10.1182/blood-2019-123705.
2. Cowan AJ, Pont M, Sather BD, et al. 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. Blood. 2019;134(supplement_1):204. doi.org/10.1182/blood-2019-129405.
3. Pont MJ, Hill T, Cole GO, et al. γ-Secretase in­hib­ition in­creases ef­fi­cacy of BCMA-specific chi­meric an­ti­gen re­cep­tor T cells in mul­ti­ple myeloma. Blood. 2019;134(19):1585-1597. doi:10.1182/blood.2019000050

Source: Pre­ci­sion BioSciences and Spring­Works Thera­peutics.