Myeloma cell therapies, now in pharma hands, move into spotlight - BioPharma Dive

ORLANDO — Cell therapies, already cleared for use in two types of blood cancer, are proving a powerful treatment option for multiple myeloma, a disease that remains deadly despite a decade of medical advances.

On Friday, the day before the 61st annual meeting of the American Society of Hematology, Bristol-Myers Squibb and biotech partner Bluebird bio unveiled long awaited study results for their CAR-T cancer treatment, called ide-cel. Data from the trial, which showed about three-quarters of treated patients responded to therapy, will support applications to regulators for approval.

The clinical success puts the two drugmakers in front of a half dozen or so companies advancing experimental CAR-T cell therapies and new types of antibodies for multiple myeloma. But while Bristol-Myers and Bluebird currently lead, earlier-stage data from Johnson & Johnson suggest that advantage may be rapidly diminishing.

J&J's therapy, which shares the same target as ide-cel, cleared out cancerous cells in all 29 patients tested, who were very sick and had previously received multiple other drugs. Twenty-five were considered "triple-refractory," meaning their disease evaded three types of treatment. At a median of six months of follow-up post treatment, 27 of 29 remained free of disease progression.

"For everybody to respond like this, it's not something we typically see," said Mark Wildgust, head of global medical affairs for oncology at J&J's Janssen unit. "All these patients are high risk. They aren't the patients you'd expect to see a 100% response rate in."

Twenty patients, or 69%, experienced a complete response, higher than what Bristol-Myers and Bluebird are reporting with ide-cel.

J&J has already fully enrolled a Phase 2 extension of its study, called CARTITUDE-1, and hopes the two parts together can serve as a sufficient dataset to submit to the Food and Drug Administration. A filing for approval could happen as soon as the second half of next year, said Wildgust, which would likely put J&J about six to eight months behind Bristol-Myers and Bluebird if all goes according to plan.

The data were unveiled Saturday at ASH, held in Orlando, Florida. Bristol-Myers and Bluebird's results are not being presented at the conference.

The two CAR-T therapies, as well as others like them, are aimed at a protein known as BCMA, or B-cell maturation antigen. BCMA is almost universally expressed on malignant plasma cells and, critically, very few others. By genetically engineering T cells to seek out and bind to BCMA-expressing cells, drugmakers can create cancer therapies out of the body's own immune cells.

CAR-T technology, when directed against a different protein, has already proved itself in pediatric leukemia and certain types of lymphoma. Multiple myeloma, the emerging body of data from Bristol-Myers, Bluebird, J&J and others suggest, looks set to be next.

Bought into CAR-T

Bristol-Myers is newly involved in CAR-T, having bought Celgene earlier this year for $74 billion and picking up its partnership with Bluebird in the process. (It also gained another BCMA-targeting CAR-T therapy that was in development by Celgene through its acquisition of Juno Therapeutics.)

Ide-cel, formerly bb2121, is particularly important to that deal — one of three drugs linked to an additional potential payout from Bristol-Myers. If all three included in the so-called contingent-value right are approved, Celgene shareholders receive another $9 per share from the pharma.

There are deadlines attached, however. Ide-cel's approval must happen before March 31, 2021 or the CVR is voided.

The positive data announced by Bristol-Myers and Bluebird Friday position the companies well to do so. Among the 128 study participants given a sufficient dose of ide-cel, 73% responded to treatment. For nearly a third, the response to treatment was complete, with no detectable myeloma cells in the bone marrow.

The highest dose — an infusion of 450 million CAR-positive T cells — performed even better, yielding an 82% overall response rate and a 35% complete response rate.

Those figures are particularly notable given how those involved in the study had previously cycled through many other therapies, including immunomodulatory drugs like Revlimid, proteasome inhibitors like Ninlaro and anti-38 blockers like Darzalex. All were refractory to their last prior treatment.

Existing therapies result in complete response rates between 1% and 14% in late lines of treatment like ide-cel is being tested in, wrote Mizuho Securities USA analyst Salim Syed in a note to investors Friday.

But with CAR-T's potency come significant side effects, chiefly a fast-moving immune response dubbed cytokine release syndrome and brain toxicity. More than 80% of patients given ide-cel experienced CRS, although it was classified as severe in only 5.5% of participants. One patient died due to CRS.

Nearly all patients given J&J's CAR-T also experienced CRS. Only two cases of CRS were rated severe, with one death from complications reported as well.

Comparing across data sets is always difficult, especially given differences in enrolled patients. But from what J&J has shown to date, its CAR-T appears competitive to ide-cel. Response rates are likely to fall over time and across larger numbers of patients, however, as happened with ide-cel.

J&J believes its therapy, known as JNJ-4528, can differentiate itself by how it's constructed, with two places on the engineered T cell designed to bind to BCMA. And the company has been able to achieve high efficacy with a smaller dose, infusing 750,000 engineered cells per kilogram into patients.

Durability remains an key question for CAR-T. Responses to ide-cel lasted about 11 months, while the six months of follow-up for JNJ-4528 remains an incomplete picture.

In pharma hands

CAR-T technology originated in academic laboratories and then in smaller biotechs like Kite Pharma and Juno. Increasingly, however, large pharmaceutical companies are driving these therapies forward. Kite was purchased by Gilead Sciences in 2017 and its rival in lymphoma is the Swiss drugmaker Novartis.

Bluebird developed ide-cel through its partnership with Celgene, which had bought Juno and then was acquired by Bristol-Myers. J&J secured its entry into CAR-T through a $350 million deal with Chinese biotech Nanjing Legend, a obscure company until 2017 when it impressed researchers with early results for its version of what J&J now calls JNJ-4528.

The pharma investment reflects CAR-T's commercialization, with Gilead's Yescarta and Novartis' Kymriah now well into their respective market launches.

But the therapies are complex, expensive and require specially trained staff to administer. That's left room for improvement, an open door to companies like GlaxoSmithKline and Amgen, which hope to produce similar efficacy with simpler, antibody-based treatments.

In myeloma, advances in CAR-T follow a steady expansion of the number, and types, of treatments over the past decade. The hope is CAR-T could prove more definitive and offer a chance for patients to live longer without disease progression.

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