Poseida Therapeutics says the lead allogeneic chimeric antigen receptor T-cell (CAR-T) candidate it is co-developing with Roche through an up-to-$6.2 billion-plus collaboration will advance to Phase Ib after generating positive interim clinical data in the Phase I portion of an early-stage trial in patients with relapsed/refractory multiple myeloma (RRMM).
That lead candidate, P-BCMA-ALLO1, is an off-the-shelf, B-cell maturation antigen (BCMA)-targeted allogeneic, T stem cell memory (TSCM)-rich CAR-T therapy. P-BCMA-ALLO1 showed a 91% overall response rate (ORR) and safety results the companies termed “compelling” among 23 heavily pretreated patients in the optimized lymphodepletion arm, called “Arm C,” of the trial’s Phase I portion.
The ORR rose to 100% in B-cell maturation antigen (BCMA)-naïve patients, but was 86% in patients who had received at least one prior BCMA-targeting treatment (all had received prior CAR-T and/or T-cell engagers [TCE]), and 86% in patients who had received at least one prior BCMA-targeting treatment and/or talquetamab.
Researchers for Poseida, Roche and clinical partners presented their clinical data on Friday at the 21st International Myeloma Society (IMS) Annual Meeting, held September 25–28 in Rio de Janeiro.
The data came from the Phase I portion of an ongoing open-label, multicenter Phase I/Ib dose-escalation and expansion trial (NCT04960579) in patients with RRMM. The trial’s primary objectives are assessing the safety and maximum tolerated dose of P-BCMA-ALLO1, with anti-myeloma activity, a secondary endpoint of the study.
Seventy-two unique patients were enrolled as of September 6 as an intent-to-treat (ITT) population, treated across four study arms (S, A, B and C) that included different P-BCMA-ALLO1 doses and lymphodepletion regimen combinations. Study participants were required to have received three or more prior lines of therapy, including a prior proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody.
“Remarkable” overall response rate
“The high overall response rate of 91% is remarkable because most study participants in my center had rapidly proliferative refractory disease, in contrast with those treated in the pivotal clinical trials of FDA-approved autologous CAR-T therapies. Such patients treated in the current trial of P-BCMA ALLO1 would not have qualified for standard of care autologous CAR T therapy,” Bhagirathbhai R. Dholaria, MD, the trial’s lead investigator, said in a statement. Dholaria is an associate professor of medicine, malignant hematology and stem cell transplantation at Vanderbilt University Medical Center.
P-BCMA-ALLO1 is manufactured from healthy donor T-cells using non-viral transposon-based integration via Poseida’s piggyBac® DNA Delivery System, which introduces a human anti-BCMA V H-based CAR and an iCas9 safety switch, as well as produces a highly enriched T stem cell memory product.
“At Poseida we have used our tools to produce allo(geneic) CAR-T, but it’s not just any allo CAR-T,” Kristin Yarema, PhD, Poseida’s president and CEO, told GEN Edge recently. “It’s an allo CAR-T with a very high T stem cell, memory cell component, which has been shown to correlate with depth and durability of response.
“You really can’t get a CAR-T that’s rich in T stem cell memory cells with any kind of viral technology. You need the transposon to do that because it preferentially inserts genes into naive and stem cell memory cells,” Yarema added. “That’s why we think the data that’s emerging from, for example, our BCMA program is so remarkable and stands out among the allo CAR-Ts.”
Other findings for Arm C patients in the Phase I portion:
- 22% achieved complete response (CR) or stringent complete response (sCR), a deeper response category employed in multiple myeloma studies.
- 48% achieved very good partial response or better (VGPR+).
Study participants were required to have received three or more prior lines of therapy, including a prior proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody.
The trial enrolled a heavily pretreated patient population with 43% of patients having received prior BCMA-and/or GPRC5D targeting therapy. Additionally, 33% of study participants were racial minorities—which according to Poseida demonstrated its commitment to studying historically underserved patient populations.
“Competitive” candidate
“Despite Poseida’s patient population having a higher burden of disease and being more refractory (including to BCMA-targeted therapies), we see the ORR with P-BCMA-ALLO1 as competitive with commercial autologous BCMA CAR-T therapies and BiTEs [bispecific T-cell engagers], particularly on an ITT basis,” Sami Corwin, PhD, a William Blair healthcare analyst focused on biotechnology, and two colleagues wrote Monday in a research note.
“We think P-ALLO1-BCMA could be a compelling alternative to Abecma or Tecvayli if it is able to demonstrate compelling PFS [progression-free survival],” Corwin and colleagues asserted.
Abecma® (idecabtagene vicleucel) is a BCMA-directed genetically modified autologous T cell immunotherapy co-marketed by Bristol Myers Squibb and 2seventy bio and indicated for adults with RRMM after two or more prior lines of therapy. Tecvayli® (teclistamab-cqyv), marketed by Johnson & Johnson’s Janssen Biotech, is a bispecific BCMA-directed CD3 T-cell engager indicated for adults with RMRR who have received at least four prior lines of therapy.
“Overall, we view the high response rates seen in the trial, and more specifically in arm C, as very encouraging, specifically since a patient population this severe effectively has not been studied in previous BCMA CAR-T/BiTE trials,” Corwin and colleagues added.
The William Blair analysts added that they believe P-BCMA-ALLO1 had generated the most robust responses in multiple myeloma seen with an allogeneic CAR-T to date: “Given the rapidly changing treatment landscape, in which more patients are likely to be exposed to BCMA-targeting agents earlier in treatment, we think the population of patients refractory to these therapies will continue to grow, as will the need for additional therapeutics for these refractory patients.”
The Phase Ib study will evaluate higher doses of P-BCMA-ALLO1 as well as single dose vs. split dose treatment cycles for the drug. Poseida and Roche said they expect to commence the Phase Ib expansion study for P-BCMA-ALLO1 shortly. When that happens, Poseida expects to receive from Roche a milestone payment of an undisclosed amount.
Poseida has said it expects to read out additional clinical updates for P-BCMA-ALLO1 during the second half, subject to coordination with Roche.
P-BCMA-ALLO1 has received the FDA’s Orphan Drug designation for multiple myeloma and Regenerative Medicine Advanced Therapy (RMAT) designation for adult patients with relapsed/refractory multiple myeloma after three or more prior lines of therapies including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody.
Three candidates, $6.2B collaboration
P-BCMA-ALLO1 is one of three candidates Poseida is co-developing with Roche through their up-to-$6.2 billion-plus collaboration. The other two candidates are:
- P-CD19CD20-ALLO1, a Phase I allogeneic dual CAR-T candidate designed to target both CD19 and CD20 antigens to treat B-cell malignancies.
- P-CD70-ALLO1, a preclinical allogeneic CAR-T candidate designed to target CD70 to treat acute myeloid leukemia.
Roche has paid Poseida $110 million upfront when the collaboration launched in August 2022, a $35 million milestone achieved in September 2022 for the Tier 1 Programs, defined as P-BCMA-ALLO1 and P-CD19CD20-ALLO1; plus developmental milestones of $30 million in the fourth quarter of 2023 and $15 million in the second quarter of this year.
Under their collaboration, Poseida is also eligible to receive research, development, launch, and net sales milestones and other payments potentially totaling up to $6 billion, plus tiered net sales royalties into the low double digits, across multiple programs.
“We continue to view the ongoing collaboration with Roche favorably, as it provides additional nondilutive capital, further validates Poseida’s platform technologies, and provides Poseida with a top-tier oncology partner,” Corwin and three colleagues wrote in an August 6 research note.
P-BCMA-ALLO1 has shown early evidence of encouraging safety and efficacy. In April at the American Association for Cancer Research (AACR) 2024 conference, Poseida presented data from a five-patient subset in the Phase I trial showing that three of the patients who progressed following BCMA-targeted therapy achieved clinical responses with P-BCMA-ALLO1.
Poseida and Roche plan to coordinate the release of data during the second half for P-CD19CD20-ALLO1, while Poseida alone is set to announce a clinical update for a third Phase I candidate the company is developing internally, P-MUC1C-ALLO1 in solid tumors.
P-CD19CD20-ALLO1 is an allogeneic dual CAR-T candidate—the first such drug of its kind, according to the companies—and is designed to treat B-cell malignancies by targeting both CD19 and CD20 antigens. By pursuing a dual-target approach, the companies reason, they can address the limitations that arise from the loss of a single antigen and the variability of tumors.
P-MUC1C-ALLO1 is an allogeneic CAR-T candidate in development for multiple indications that include breast, colorectal, lung, ovarian, pancreatic and renal carcinomas, as well as other cancers expressing a cancer-specific form of the Mucin 1 protein called MUC1-C.
“It’s really going to be a very jam packed second half of the year,” Yarema said.
Terminated rights
Until last week, the collaboration included a fourth candidate, P-BCMACD19-ALLO1, a preclinical allogeneic dual CAR-T candidate designed to target both BCMA and CD19 to treat relapsed/refractory multiple myeloma.
But on Monday, Poseida disclosed in a regulatory filing that it terminated Roche’s rights to co-develop P-BCMACD19-ALLO1 after Roche did not exercise in a timely fashion its option to acquire an exclusive license to the candidate for blood cancers: “The Company plans to continue development of the BCMA/CD19 Program internally.”
Poseida finished the second quarter with a net loss of $31.4 million, up from a $27.5 million net loss in Q2 2023, on revenue that rose 30% year over year, to $26 million from $20 million, primarily reflecting milestone payments and an increase in reimbursed research and development (R&D) expenses under its partnership with Roche.
Those factors also explain Poseida’s near-doubling of revenue during the first half of 2024. Revenue jumped 80% year-over-year, to $54 million from $30 million in H1 2023. However, Poseida still finished in the red, though it reduced its net loss from a year earlier, to $55.6 million from $66.3 million in January–June 2023.
Poseida reported cash, cash equivalents, and short-term investments of $237.8 million as of June 30, including $95 million in milestone and upfront payments generated in the first half of 2024—Roche’s $45 million in milestones plus $50 million upfront from Astellas.
Astellas’ Xyphos Biosciences subsidiary has partnered with Poseida on an up-to-$600 million collaboration to develop convertibleCAR® programs to treat solid tumors by combining the cell therapy platforms from both companies. Astellas has agreed to pay Poseida up to $550 million in potential payments tied to achieving development and sales milestones, plus contingency payments and up to low double-digit tiered royalties as a percentage of net sales.
Poseida says its cash position, plus remaining near-term milestones and other payments from Roche, will be enough to fund its operations into the second half of 2025.
