In the rare blood disorder light chain amyloidosis, standard treatment is a drug combination used for a blood cancer. It’s the only treatment, and that’s a problem because many patients find this regimen doesn’t help enough for this potentially fatal disease. In that context, early data for a Regeneron Pharmaceuticals blood cancer drug look particularly promising.
In a small clinical trial that enrolled previously treated light chain amyloidosis patients in need of another therapy, results show 90% of participants achieved a complete hematological response — no evidence of the disease. Dr. Hans Lee, director of myeloma research at the Sarah Cannon Research institute, described these results for Regeneron’s drug, linvoseltamab, as “a paradigm shift for patients.”
Lee, an investigator in the linvoseltamab study, presented the preliminary Phase 1 data Friday during the annual meeting of the American Society of Clinical Oncology in Chicago. He noted that the Phase 2 portion of this Phase 1/2 clinical trial is ongoing with the potential to support a regulatory submission seeking FDA approval.
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Linvoseltamab is already commercially available under the brand name Lynozyfic following its accelerated FDA approval last summer as a fifth-line treatment for multiple myeloma. This cancer and light chain amyloidosis, also called AL amyloidosis, are both diseases that start in plasma cells. That’s why multiple myeloma drugs are used to treat light chain amyloidosis, a disease in which abnormal plasma cells produce misfolded proteins called light chains. The resulting protein buildup in the heart, brain, kidneys, and liver causes dysfunction that can progress to organ failure.
Regeneron’s drug is a bispecific antibody designed to target two proteins, BCMA on rogue plasma cells and CD3 on T cells, an approach that gets the T cell to kill the disease-driving cell. The open-label light chain amyloidosis study enrolled 20 previously treated patients. With a median follow-up of 9.5 months, 100% of patients showed a very good response or better to the study drug; 90% achieved a complete response. In an interview, Karen Rodriguez Lorenc, Regeneron vice president, therapeutic area lead for hematology oncology, said patient response to linvoseltamab was rapid, with results showing levels of the problem protein falling quickly.
“In 15 days, we are seeing a drop of the free light chain,” she said. “It’s even happening while the patient is receiving the step-up dosing, so the efficacy is really encouraging.”
No dose-limiting toxicities were reported in the trial and the safety profile was consistent with tests of the intravenously infused medicine in multiple myeloma, Lee said in the presentation. There were two deaths in the study, both due to heart complications. Lee said investigators determined that the fatalities were unrelated to the study drug.
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Tests of monoclonal antibodies in light chain amyloidosis have been unsuccessful. Last year, Prothena discontinued development of birtamimab after this antibody failed a Phase 3 study. Months later, AstraZeneca’s anselamimab also failed in Phase 3. At this year’s ASCO meeting, AstraZeneca presented detailed results from the failed Phase 3 study as well as encouraging results in a subgroup of patients with kappa light chain amyloidosis, a subset of the disease driven by misfolded kappa proteins. Clinicians speaking at the ASCO plasma cell disorders session said the drug could help such patients but acknowledged that more clinical testing may be needed. AstraZeneca has not said what its plans are anselamimab in kappa light chain amyloidosis.
The Prothena and AstraZeneca antibodies were designed to reduce or eliminate proteins deposits in tissues and organs. Rodriguez Lorenc said the linvoseltamab results so far suggest a bispecific antibody is superior to monoclonal antibodies in treating light chain amyloidosis. In the same interview, Andres Sirulnik, Regeneron’s senior vice president, hematology, noted that rather than eliminating protein deposits, linvoseltamab is going after the source of the disease, likening the approach to turning off a faucet.
“Once you turn the faucet off, which is essentially getting rid of a malignant plasma cell, you’re not shedding large quantities of misfolded protein that deposits in the organ,” he said. “The key is to turn the faucet off, to turn the malignant cell off.”
The test of linvoseltamab in light chain amyloidosis is part of a broader program for the drug. Clinical trials are ongoing that could support moving this drug into earlier lines of multiple myeloma treatment. But Sirulnik also said there’s potential to expand the reach of this drug even further. Plasma cells are a type of B cell, and rogue B cells drive many types of autoimmune disorders.
A growing number of biopharmaceutical companies are taking B cell-depleting approaches from cancer and adapting them into potential new treatments for autoimmune diseases. Sirulnik said Regeneron is testing linvoseltamab in systemic lupus with renal disease and end-stage renal disease in patients unable to receive a donor kidney because they have autoantibodies that would attack the transplanted organ.
“We believe there is significant potential beyond malignancy and plasma cell-related disorders,” Sirulnik said.
Photo: Michael Nagle/Bloomberg, via Getty Images