With Glaxosmithkline plc (GSK) having sailed through an FDA advisory panel meeting July 14 centered on its belantamab mafodotin (belantamab), an antibody-drug conjugate (ADC) for multiple myeloma (MM), others in the B-cell maturation antigen (BCMA) space such as Legend Biotech Corp. are further piquing Wall Street’s interest.
Legend, of Somerset, N.J., was rocked by news last weekend by the departure of CEO Yuan Xu for “personal reasons,” which came as a surprise to J.P. Morgan analyst Cory Kasimov, especially so soon after the firm’s triumphal, $423 million-plus IPO, upsized from $100 million. “Not the Sunday afternoon we had in mind,” he wrote in a report. But, like his peers, Kasimov kept his enthusiasm for data generated by the lead compound, partnered with Johnson & Johnson (J&J).
First, GSK. The London-based firm could reach the market ahead of the pack with a BCMA therapy in MM. A decision is due this month, and European regulators issued a positive opinion in July. Belantamab, aka GSK-2857916, has been tested in a pair of trials detailed at the American Society of Clinical Oncology (ASCO) virtual annual meeting recently. One, called Dreamm-2, is a 221-subject open-label, randomized, two-arm experiment to test the efficacy and safety of two doses of the compound in patients with MM who had three or more previous lines of treatment, were refractory to a proteasome inhibitor as well as an immunomodulatory agent, and failed with an anti-CD38 antibody.
The other GSK effort, Dreamm-6, will enroll up to 123 patients. It’s meant to evaluate the safety and tolerability profile of the ADC when given in combination with approved regimens of either Revlimid (lenalidomide, Celgene Corp.) plus dexamethasone (len/dex, arm A) or Velcade (bortezomib, Takeda Pharmaceutical Co. Ltd.) plus dexamethasone (bor/dex, arm B) in participants with relapsed/refractory (r/r) MM. The first part of the study is a dose-escalation phase of up to three dose levels and up to two dosing schedules with the two standard-of-care regimens. Part two will further evaluate the safety and preliminary clinical activity of the drug at selected dose levels and dosing schedules in combination with len/dex or bor/dex.
At ASCO, GSK provided a 13-month update on the Dreamm-2 study that showed median overall survival of 13.7 months and median duration of response of 11 months with single-agent belantamab at the 2.5-mg/kg dose. First results from the Dreamm-6 study show the priority review drug in combination with bor/dex resulted in a 78% overall response rate. No new safety signals surfaced in longer-term follow-up with the drug, and the most commonly reported grade 3 or higher adverse events (AEs, occurring in more than 10% of patients) in patients given the 2.5-mg/kg dose were keratopathy/microcyst-like epithelial changes (46%), thrombocytopenia (22%), anemia (21%), lymphocyte count decreased (13%) and neutropenia (11%). There was more good news. An analysis showed that belantamab was more effective than the combo therapy of Xpovio (selinexor, Karyopharm Therapeutics Inc.) and low-dose dex, tested in the phase IIb study called Storm. The ADC proved its mettle in prolonging lives and response to treatment.
‘Little impact’ on asset
In late June, Stamford, Conn.-based Springworks Therapeutics Inc. dosed the first patient in a phase Ib substudy of another GSK experiment, Dreamm-5. The Springworks effort is evaluating the gamma secretase inhibitor nirogacestat paired with belantamab in r/r MM. Blocking gamma secretase 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 antigen. Preclinical work also found the combo synergistic, yielding increases in human multiple myeloma cell killing as compared to the ADC alone, with up to about 3,000-fold improvement in cytotoxicity. Wainwright analyst Robert Burns said in a June 23 report that Springworks is “well positioned to capitalize on the potential of the burgeoning BCMA-targeted therapeutic class, given its established partnerships” with not only GSK but also South San Francisco-based Allogene Therapeutics Inc., “as well as the ability to further pair nirogacestat with additional BCMA-targeted agents.”
At the FDA’s Oncologic Drugs Advisory Committee meeting, panelists voted 12-0 in favor of belantamab’s profile. A handful of BCMA-bispecific candidates have found their ways to the clinic in recent years, steered by such firms as Amgen Inc., Bristol Myers Squibb Co., Pfizer Inc. and Regeneron Pharmaceuticals Inc. New Brunswick, N.J.-based J&J entered the fray by way of a licensing pact with Genmab A/S, of Copenhagen, Demark. The duo started a phase I study in 2017, and at ASCO this year, J&J rolled out the first findings with teclistamab, a bispecific antibody targeting BCMA and CD3. Data from a phase I/II trial with 78 patients turned up reports severe AEs similar to the BCMA CAR Ts, “although overall cytokine release syndrome (CRS) and duration of CRS is lower with the bispecific T-cell engagers [BiTEs],” Jefferies analyst Biren Amin pointed out in a July 1 report. “The downside for BiTEs is weekly infusion vs. up-front therapy with CARs,” he said. “The patient baseline on prior therapies and triple-refractory status is similar to the BCMA-CAR T trials; however, the trial enrolled fewer patients with extramedullary disease and fewer patients with higher tumor burden. In our view, this initial data of teclistamab supports a path forward,” and the commercial strategy could involve sequential use with the BCMA CAR T drug that Legend has partnered with J&J.
That prospect holds “significant promise” in Amin’s view, based on data from the phase I portion of the Cartitude-1 trial testing LCAR-B38M, which showed encouraging responses in MM patients and “portends a favorable outlook [from the] pivotal phase II trial. We expect to see differentiation on durability and believe median progression-free survival could exceed 18 months, which will raise the bar for BCMA therapies.” He predicted peak worldwide sales of $2.6 billion when he started coverage of Legend with a buy rating.
Even more enthusiastic about Legend’s prospect is J.P. Morgan’s Kasimov, who also added the company to his universe recently. The candidate also known as JNJ-4528 “has the potential to be the best-in-class BCMA-directed therapy in r/r MM (across modalities).” Given the tie-up with J&J, “a formidable player in MM, we anticipate launch of [the compound] in 2021,” he said. If the drug can keep showing a complete response (CR) rate “roughly two higher than any later-stage competitor,” Legend and J&J could gain an edge in marketplace. “Longer term, the BCMA space is competitive and it is too early to make a call on what therapy/modality will reign supreme,” he noted. “That said, we believe it will be hard to top the 100% overall response rate (and 86% stringent CR rate), preliminary signals of durability, and an acceptable safety profile thus far.” The Legend CEO’s move recently gave Kasimov pause. “Our sense is that chairman – and now also CEO – Frank Zhang would like to see more aggressive development around the rest of the pipeline,” he wrote. Zhang’s resignation as CEO of Piscataway, N.J.-based Genscript Biotech Corp., Legend’s previous parent company, may illustrate “his significant commitment to Legend,” Kasimov said, but “this has clearly not been a great start for Legend as a public company. Nevertheless, our current thesis is predicated on JNJ-4528 and, given the promising progress made to date and J&J’s overall responsibility, we believe [the CEO step-down] should have little impact on this asset.”