With T-cell engagers already established as late-line therapies for certain blood cancers, Regeneron has released early data on two of its agents as it works to reach patients earlier in their treatment journeys.
In essence, Regeneron is trying to move Lynozyfic and odronextamab into earlier lines of treatment by testing less onerous regimens than its rivals in the space.
For odronextamab, which is approved in Europe as Ordspono in third-line diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), Regeneron is testing the CD20xCD3 bispecific in two separate phase 3 trials in first-line DLBCL and second-line FL, respectively. At the American Society of Hematology (ASH) annual meeting, the New York pharma unveiled data from the dose escalation or safety lead-in stages of the trials.
As for Lynozyfic, initial results unveiled at ASH from a phase 1/2 trial have given Regeneron the confidence to test the BCMAxCD3 bispecific as a first-line maintenance therapy in newly diagnosed multiple myeloma.
The early data support Regeneron’s hypothesis that the bispecifics can achieve desirable responses in early lines of treatment and that the company can offer “less onerous treatment options to patients” compared with its competitors, Andres Sirulnik, M.D., Ph.D., Regeneron’s clinical development unit head of hematology, said in an interview with Fierce Pharma.
Ordspono findings
For the Olympia-3 trial in previously untreated DLBCL, Regeneron is hoping Ordspono can replace rituximab (R) in the traditional R-CHOP combination regimen. The proposed Regeneron regimen is different from another approach by Roche, which is evaluating the Swiss pharma’s CD20xCD3 bispecific Columvi on top of its Polivy-R-CHP cocktail in the phase 3 Skyglo study.
“We don’t require [Polivy] in order to achieve depth of response,” Regeneron’s odronextamab global program head, Aafia Chaudhry, M.D., said in an interview with Fierce.
In part 1a of the Olympia-3 study, Ordspono, at the higher 160-mg dose studied and used alongside CHOP, led to complete responses (CRs) in all 13 patients tested after a median follow-up of 7.8 months, according to results presented at ASH.
For now, the antitumor effect appears to be durable, as about 90% of patients were estimated to remain in complete remission and progression-free by the data cutoff.
The lower 80-mg dose posted a CR rate of 44% among nine patients at a median follow-up of 9.2 months. It was also used alongside CHOP in the study.
With fewer drugs than Roche’s Skyglo regimen, Regeneron’s simplified course offers less potential for additive toxicities and could help lower cost burdens, Chaudhry argued. In Skyglo, both Polivy and Columvi are patent-protected antibody drugs, while CHOP is a combination of cheaper chemotherapies.
But, even without rituximab, Regeneron’s regimen comes with a lot of side effects. Serious treatment-emergent adverse events (TEAEs) happened in all but one patient (92.3%) in the 160-mg dose group. Neutropenia was the most prominent side effect, with a 77.3% treatment-related incident rate across the two dose groups, all at grades 3 or 4.
That level of adverse events is common with patients who are on chemotherapy, Chaudhry said. The events are “predictable [and] generally manageable,” she said, and, while some patients experienced dose reductions, no one permanently discontinued Ordspono due to TEAEs. The 160-mg dose recorded one (7.7%) TEAE leading to death.
Cytokine release syndrome, a side effect of interest for all T-cell engagers, appeared to be mild for many patients who tried the regimen. Of all 22 patients tested, 12 (54.5%) experienced CRS, including three (13.6%) at grade 2, with no higher-degree events.
Regeneron has recently completed enrollment in part 1b of the Olympia-3 trial, which, besides the 160-mg once-weekly dosing included in part 1a, will also examine a different dose of 160 mg every three weeks, with results expected next year. Once an agreement is reached with regulators, Regeneron plans to start enrollment in the critical part 2 of the study.
As for second-line FL, Regeneron is again trying to go without rituximab by pairing Ordspono with lenalidomide (Revlimid) alone rather than with the traditional Rituxan-Revlimid combo known as R2, an approach that AbbVie has taken for its Genmab-partnered Epkinly.
Part 1 data of the phase 3 Olympia-5 trial unveiled at ASH linked the selected 80-mg dose of Ordspono and lenalidomide to an overall response rate of 84.6% among 26 patients and a CR rate of 69.2%.
Nearly all patients experienced grade 3 or above TEAEs. There was one death of hemorrhagic stroke in the 80-mg dose group, but it was not considered treatment-related. One patient in the lower 40-mg dose group died after influenza infection.
After the FDA’s full approval for Epkinly’s R2 combo in second-line FL in November, the accelerated approval pathway for Ordspono in the U.S. as a later-line treatment appears closed because the unmet need no longer exists. Regeneron recently got an FDA complete response letter for its third-line FL application no thanks to manufacturing issues at a legacy Catalent plant now owned by Novo Nordisk. Chaudhry, acknowledging the regulatory hurdles presented by Epkinly, said Regeneron is considering all options and will announce its decisions on any potential filings in the future.
Lynozyfic ambitions
Meanwhile, staying true to its strategy of simplifying treatment, Regeneron tried testing Lynozyfic as a monotherapy in patients with newly diagnosed myeloma in the phase 1/2 Linker-MM4 trial.
Regeneron decided to conduct this study because first-line myeloma treatments today are built on multidrug combinations, high-dose chemotherapy, with or without transplant, Karen Rodriguez-Lorenc, therapeutic area lead for hematology oncology who has led Lynozyfic’s development, said in an interview with Fierce.
“It’s very burdensome as a treatment,” Rodriguez-Lorenc said, “So what we were asking is, [Lynozyfic] in late lines of therapy is giving such a good efficacy, is this going to be even better in initial line of therapy?”
According to phase 1 results unveiled at ASH after a median follow-up of 9.2 months, Lynozyfic at 200 mg achieved a CR or better outcome in 43% of 21 patients. At that dose level, all nine patients who were evaluable for minimal residual disease (MRD) tested negative at a detection threshold of one malignant cell in 100,000.
In terms of safety, CRS, the most common TEAE observed, occurred in 44% of patients across all three doses tested, with 200 mg associated with the highest rate for the side effect. All were grade 1 events.
The rate of infections at grade 3 was 33%, with no more serious events, and Rodriguez-Lorenc said Regeneron was happy to see how infections decreased over time, because this dynamic suggests the infections were related to myeloma rather than the agent.
Encouraged by the early data, Regeneron is collaborating with the European Myeloma Network to launch a phase 3 trial in first-line transplant-ineligible patients. However, the study, coded Linker-MM6, won’t study Lynozyfic as a monotherapy.
While Regeneron is encouraged by the drug’s benefit-risk profile, the 43% CR or better rate is no match to existing combo therapies. In the phase 3 Imroz trial, Sanofi’s quadruplet combination of Sarclisa with bortezomib, lenalidomide and dexamethasone (VRd) recorded a 74.7% CR or better rate in first-line transplant-ineligible patients.
For the Linker-MM6 trial, patients will first receive Johnson & Johnson's Darzalex, lenalidomide and dexamethasone (DRd) as induction followed by Lynozyfic as maintenance therapy compared with continued DRd.
A separate study of the BCMAxCD3 bispecific is being planned for transplant-eligible patients, Rodriguez-Lorenc said.
“The only thing that we promise is that we are not going with a very onerous profile,” Rodriguez-Lorenc said.