Ramantamig

In a newly released draft guidance, the FDA laid out how drugmakers can lean on minimal residual disease (MRD) and complete response (CR) as primary endpoints to accelerate multiple myeloma therapies toward approval.The FDA noted that overall response rates (ORRs) with new therapies now routinely exceed 60-70% in relapsed disease and 90% in newly diagnosed patients. That success has blunted the usefulness of ORR as a metric to decide accelerated approvals because proving statistically significant differences now means companies have to conduct "infeasibly large" trials. "More sensitive response assessments will allow for continued expeditious drug development," the FDA said.MRD are the tiny traces of cancer cells that can linger in the bone marrow even after a patient appears to be in remission. An FDA advisory panel in 2024 unanimously endorsed using MRD negativity as a surrogate endpoint for myeloma trials after two meta-analyses showed that MRD-negative status strongly correlates with better progression-free survival (PFS) and overall survival (OS).According to the draft guidance, MRD data from single-arm trials can support accelerated approval, though "randomised trials are preferred, as they provide robust assessments for comparative safety" and allow ongoing evaluation of longer-term outcomes like PFS or OS. Sponsors should also "adequately justify the assumed magnitude" of treatment difference for MRD negativity between arms, with MRD assessed at a threshold of at least 1 in 105 residual tumour cells. Additionally, the FDA noted that MRD as an endpoint is appropriate only in specific patient populations and disease settings, saying there isn't enough data currently to consider it in the maintenance therapy or in populations such as smouldering multiple myeloma.Meanwhile, the FDA said CR is a recognised prognostic biomarker, as patients who achieve CR have better long-term outcomes, based on pooled analysis of clinical trial data. While the principles that underpin using MRD as an endpoint also apply to CR, there are some specific considerations, including the need for adequate follow-up in order to establish the durability of CR.J&J 'excited' about optionJohnson & Johnson — which markets several myeloma therapies, including CD38-targeting antibody Darzalex (daratumumab), BCMA-targeting CAR-T cell therapy Carvykti (ciltacabtagene autoleucel) and bispecific antibodies like Tecvayli (teclistamab) and Talvey (talquetamab) — welcomed the new guidance on an earnings call Wednesday."Much of the evidence behind that, frankly, was pioneered by J&J over the years, so we're excited that [MRD] is an option," said John Reed, executive vice president, innovative medicine, R&D. "A place where this could be particularly apropos is with our new trispecific antibody for myeloma, ramantamig (JNJ-79635322), which brings the features of both [Tecvayli] and [Talvey] into a single molecule."However, as this only applies to the US, Reed said the company will still have to deliver PFS and OS data for other territories, "so I suspect that will continue to be an element of our protocols."Comments on the draft can be submitted to the FDA until March 23.

With Carvykti (ciltacabtagene autoleucel) producing "science fiction-like" efficacy, Johnson & Johnson is pulling back the curtain on another CAR-T therapy — one that targets two antigens simultaneously. The company on Friday provided a first look at clinical data for JNJ-4496, an investigational dual-targeting therapy that binds CD19 and CD20 antigens on malignant B-cells.JNJ-4496, formerly known as C-CAR039, incorporates a 4-1BB costimulatory domain intended to enhance binding strength and persistence while potentially addressing common resistance mechanisms. J&J acquired rights to the asset in 2023 through a $245-million upfront deal with Cellular Biomedicine Group, since renamed AbelZeta.Presented at the European Hematology Association (EHA) conference, the Phase Ib study is evaluating JNJ-4496 in patients with relapsed or refractory large B-cell lymphoma (LBCL) who have not previously received CAR-T cell therapy.Among 22 evaluable patients treated at the recommended Phase II dose of 75 million CAR-T cells, those who had received only one prior line of therapy (n=10) achieved an objective response rate (ORR) of 100% after a median follow-up of four months, with 80% reaching a complete response. The remaining 12 who had undergone two or more prior therapies showed a 92% ORR, with 75% achieving a complete response.Safety data from 25 patients in the recommended dose cohort showed no cases of Grade 3 or 4 cytokine release syndrome. Two patients experienced immune effector cell-associated neurotoxicity syndrome (ICANS), including a Grade 1 event as well as a Grade 3 event in a patient with central nervous system lymphoma. The most common severe side effect was neutropenia, occurring in 72% of patients."As we continue to unlock the full potential of CAR-T cell therapies through novel next-generation approaches, these promising data reinforce earlier long-term findings and highlight the potential of JNJ-4496 to improve outcomes for patients," commented Jeffrey Infante, the company's vice president of early clinical development and translational research.The lymphoma results come as J&J basks in Carvykti's momentum. At the recent American Society of Clinical Oncology (ASCO) meeting, the company presented long-term data for the BCMA-directed CAR-T, which is partnered with Legend Biotech, showing that 33% of heavily pretreated multiple myeloma patients remained progression-free for at least five years following a single CAR-T infusion, with no subsequent treatment. For more, see – Spotlight On: With GSK's Blenrep waiting in the wings, J&J touts game-changing Carvykti data.J&J also reported initial Phase I results at ASCO for JNJ-5322, a trispecific antibody targeting CD3, BCMA and GPRC5D that achieved an ORR of 86.1% in relapsed multiple myeloma among the 36 patients who received the recommended Phase II dose. Findings from the study will also be presented at EHA.