Bortezomib

GSK's efforts to bring its multiple myeloma drug Blenrep (belantamab mafodotin) back to the US market ran into trouble Thursday, after an FDA advisory panel voted against two proposed combination regimens due to ongoing concerns about the drug's eye-related side effects and dosing.The Oncologic Drugs Advisory Committee (ODAC) voted 5-3 against the benefit-risk profile of Blenrep when combined with bortezomib and dexamethasone at the proposed dose and in the target patient population, which is adults who have received at least one prior line of therapy. A similar second vote on the combination of Blenrep with BMS's Pomalyst (pomalidomide) and dexamethasone yielded an even more decisive 7-1 rejection.The votes followed the release of FDA briefing documents earlier this week that flagged Blenrep's "unique" eye toxicity, including changes in the corneal epithelium, visual acuity changes, and other ocular symptoms, such as blurred vision and dry eye.Agency scientists also questioned whether GSK had truly identified the best dose. In both pivotal trials, DREAMM-7 and DREAMM-8, many patients needed dose modifications, and a majority of patients were not receiving the intended dosage by the third treatment cycle. FDA staff noted that the only way to manage the side effects was by adjusting dosing, a strategy they warned could be difficult to replicate in real-world clinical settings.'Missed opportunity'"This was a challenging decision because the efficacy data were strong, but the toxicity data were also very strong," said Neil Vasan, who chaired the meeting, and voted 'no' on both counts. "I took a textualist interpretation to [the voting questions] – and I'd like to emphasise the words 'at the proposed dosage.' This was for me the what swayed the decision."In remarks prior to the votes, Vasan said many ODAC participants saw the programme as a "missed opportunity, at multiple levels; missed opportunity from conversations years back when this drug was first developed, a missed opportunity from the initial Phase I data to explore all dosages, a missed opportunity at the Phase III level to perhaps explore more dosages at the RCT level."    Panel member Grzegorz Nowakowski said this was probably "one of the most difficult votes" he's cast as an ODAC committee member. He voted 'yes' on the first question and 'no' on the second."On one hand, from a regulatory perspective, the whole drug development programme probably made all the possible mistakes which could have happened, including the lack of US representation in the pivotal studies, and also the lack of the early dose optimisation, which could avoid a lot of the toxicity discussion which you had here," Nowakowski said. "On the other hand, I'm also a practising haematologist and, you know, the drug is clearly active."FDA decision next weekBlenrep was originally greenlit under accelerated approval in 2020 as a fifth-line monotherapy, but the drug was withdrawn from the US market a little over two years later after failing a confirmatory trial. However, it has been staging a slow comeback, spurred by the DREAMM-7 and DREAMM-8 readouts, winning approvals in the UK and Japan this year, with an EU nod expected soon.But Thursday's negative vote casts doubt on whether the BCMA-directed antibody-drug conjugate will make its return to the US by year-end, as GSK hopes. The agency is set to make a final decision by July 23, and a rejection would deal a major blow to the company's growth growth ambitions.It also marks the second time Blenrep has faced regulatory challenges over ocular concerns (see – Spotlight On: Blenrep facing adcom déjà vu but GSK is coming prepared). The FDA previously recommended that GSK conduct further dose finding, but the company continued to pursue its proposed dose anyway, arguing that efficacy would be negatively impacted. "I think the issue was just that there was not exploration done at lower doses – even before, going back many years," commented Nicole Gormely, division director at the FDA's Division of Hematologic Malignancies.For more, see – Spotlight On: GSK's case for Blenrep's re-relevance in MM gaining purchase.

A pair of Phase III studies of AstraZeneca's anselamimab in patients with light chain amyloidosis failed to achieve statistical significance on their primary endpoints versus placebo, although results for the light chain depleter antibody were more promising in a subgroup of participants.The two trials in the CARES programme enrolled a total of 406 newly diagnosed patients with light chain (AL) amyloidosis, including 281 with stage IIIa and 125 with stage IIIb disease. Participants — who were planning first-line plasma cell dyscrasia (PCD) treatment with cyclophosphamide, bortezomib and dexamethasone — were randomised to receive either anselamimab or placebo once weekly for the first four weeks and then every two weeks until study completion.The primary endpoint is a hierarchical combination of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalisations (CVH) in the overall patient population across both studies.According to Alexion — the UK drugmaker's rare disease unit — top-line results showed that while the main goal was missed, anselamimab showed a highly clinically meaningful improvement in time to ACM and frequency of CVH in a prespecified subgroup of patients, compared to placebo. The company added that the therapy was well tolerated in the trials, with the majority of events balanced between the two arms.Ashutosh Wechalekar, lead principal investigator of the CARES programme, said the results from the predefined subgroup "suggest that anselamimab, by targeting and clearing amyloid deposits, may address a leading cause of organ damage and functional impairment in these patients," adding that "the potential to extend survival and reduce cardiovascular hospitalisations would represent a practice-changing advancement for this patient group."Alexion indicated that a full evaluation of the results is ongoing, while it plans to share the data with regulatory bodies and present them at a forthcoming medical meeting.