As attendees of last year’s American Society of Hematology (ASH) meeting heard, B-cell maturation antigen (BCMA)-targeting therapies are steadily gaining ground on various fronts, even as companies such as Springworks Therapeutics Inc. bring forward candidates that might boost activity of the class.
The ASH meeting in Orlando, Fla., featured New Brunswick, N.J.-based Johnson & Johnson (J&J) with JNJ-4528, a BCMA chimeric antigen receptor (CAR) T-cell therapy that contains two BCMA-binding domain antibodies. An objective response rate (ORR) of 100% turned up, with a 66% complete response (CR) rate, and 27 of 29 patients still progression-free at the six-month time point in advanced relapsed/refractory multiple myeloma (MM). Patients tested had proven highly refractory to prior therapy, including J&J’s Darzalex (daratumumab, n=29, with five median prior treatments and 85% of subjects triple refractory). An anti-CD38 monoclonal antibody, Darzalex gained its first approval in November 2015. H.C. Wainwright analyst Raghuram Selvaraju stacked J&J’s results against the phase II findings, pointing to an ORR of 73.4%, a CR of 31.3%, and an 8.6-month median progression-free survival (mPFS) in an advanced patient population (n=128), 84% of whom were triple refractory.
Data with bispecifics rolled out, too. Celgene Corp., of Summit, N.J. (now part of New York-based Bristol-Myers Squibb Co.) offered results with CC-93269, a BCMA-targeting CD3 T-cell engaging antibody, which onlookers compared to those with Thousand Oaks, Calif.-based Amgen Inc.’s AMG-420, also taking aim at BCMA and CD3. The CR rate of the two drugs seemed similar, though “we point out that a much higher percentage of patients treated with CC-93269 were refractory to prior therapies, including Darzalex,” Selvaraju wrote in a Dec. 10 note – specifically, 80% vs. 21%. That’s significant because of a paper published in Nature related to the BCMA prospect from London-based Glaxosmithkline plc (GSK), belantamab mafodotin, an antibody-drug conjugate, in patients with relapsed or refractory MM. Patients refractory to Darzalex performed worse than those who did not (39%-43% ORR and 6.8-month mPFS vs. 71.4% ORR and 15.7-month mPFS, respectively). GSK gained priority review status for the compound Jan. 21. Jefferies analyst Peter Welford said in a Jan. 26 report that his firm “continue[s] to believe ocular toxicity could be a concern, limiting adoption to later lines, although GSK's chief scientific officer, Hal Barron, was confident this is manageable, with studies in earlier lines planned and ongoing.” Welford forecast worldwide peak sales of $1.5 billion.
For Selvaraju, it all means that J&J’s drug could turn out a strong competitor to bb-2121, the CAR T candidate for MM in the works by Celgene and Bluebird Bio Inc., of Cambridge, Mass., and that CC-93269 “potentially represents a best-in-class bispecific agent.”
‘High levels’ of excitement: analyst
Enthusiasm for BCMA-focused agents likely will bring about a push to find methods of making them even more efficacious, and this is where Stamford, Conn.-based Springworks enters the picture with nirogacestat, an oral small-molecule, gamma secretase inhibitor. Gamma secretase has been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain (ECD), from the cell surface. Blocking gamma secretase preserves membrane-bound BCMA, increasing target density while reducing levels of soluble BCMA ECD, which can serve as decoy receptors for a BCMA-targeted agent. Nirogacestat has reached phase III trials in desmoid tumors. Those are noncancerous growths that occur in the connective tissue, most often in the abdomen, arms and legs. Also known as aggressive fibromatosis, desmoid tumors can extend into tissues and organs.
Springworks has an agreement with GSK to test nirogacestat in a phase Ib experiment, combining it with belantamab in patients with relapsed or refractory MM. Rationale for the approach was bolstered at ASH when GSK unveiled preclinical data with the combo, showing a dose-dependent increase in half maximal effective concentration across multiple cell lines on a three-day proliferation assay. An increase in antibody-dependent cell-mediated cytotoxicity (ADCC) activity, again in multiple cell lines, was observed on the 24-hour ADCC Jurkat reporter assay. “In our view, there is still reasonable room for a belantamab plus nirogacestat combo, especially given the lack of cytokine release syndrome with belantamab and [the fact that] patients would not have to wait to be treated as they would if treated with an autologous CAR-T therapy,” Selvaraju found.
In December, The Lancet published results from the pivotal open-label Dreamm-2 study of belantamab, which was initially reported to have met the primary endpoint in a positive headline in August. SVB Leerink’s Mani Foroohar noted in a report that “detailed study results show a modest 34% ORR at the 3.4-mg/kg dose and a 31% ORR at the 2.5-mg/kg dose, and consistent with the Dreamm-1 study, the majority of patients experienced some degree of corneal toxicity.” He liked the safety profile but said “we do not believe bb-2121 is at risk of being displaced” by the drug in MM. GSK said in mid-December that it had filed a BLA for the use of belantamab in patients whose prior therapy included an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody.
Wainwright’s Robert Burns said in a Jan. 22 report that he “believe[s] nirogacestat's prospects in MM are not substantially reduced by the Dreamm-2 data. Although the competition in the BCMA-targeted space is heating up – with belantamab potentially at the lower end of the efficacy spectrum – we continue to believe that adding nirogacestat to belantamab or another BCMA-targeted agent may boost overall efficacy.”
Springworks on Jan. 13 made public a deal with South San Francisco-based Allogene Inc. to evaluate ALLO-715, Allogene’s investigational anti-BCMA AlloCAR T therapy in combination with nirogacestat in patients with relapsed or refractory MM. Under the terms, Allogene will sponsor and conduct the phase I study to test the safety, tolerability and preliminary efficacy of the combo and will assume all costs thereof. Allogene and Springworks are forming a joint development committee to oversee the clinical study, due to start in the second half of this year, pending discussions with regulators.
Canaccord Genuity analyst John Newman pointed out in a post-ASH report that J&J’s MM drug and CC-93269 saw “higher-than-expected levels of excitement” at the meeting. The latter and bb-2121 “may be in the strongest competitive position,” in his view, putting BMS in the catbird seat. Patients treated with JNJ-4528 “were likely healthier” than those in the other programs, he said.
BCMA continues to draw interest. Last spring, San Diego-based Poseida Therapeutics Inc. pulled down $142 million in series C financing, most of which came from Novartis AG, of Basel, Switzerland, to advance P-BCMA-101, an autologous CAR T therapy for relapsed/refractory MM.