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Gilead, Novartis, Juno likely to compete on access, tolerance of CAR-T therapies

With the first gene-engineering cancer therapy launched just months ago, there are already three strong contenders to treat the most common form of lymphoma — leaving market access and ease of treatment as the essential next steps.

Novartis AG's Kymriah boasts the first chimeric antigen receptor T-cell therapy approval in the U.S. for pediatric acute lymphoblastic leukemia. It was soon followed by the diffuse large B-cell lymphoma, or DLBCL, approval for Yescarta, developed by Kite Pharma Inc. before its Gilead Sciences Inc. acquisition.

And now Juno Therapeutics, Inc. which initially appeared to be out of the CAR-T running after several deaths on an experimental therapy earlier this year, is back with JCAR017 — a new attempt that appears significantly safer.

Researchers on all three therapies presented DLBCL data side-by-side to an overflowing room at the American Society of Hematology conference in Atlanta, Georgia, on Dec. 11.

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While each therapy showed promise and near-comparable response rates among patients with DLBCL, small differences in safety and specificity could be the big markers as to which company will edge out others.

Juno's redemption?

With some of the lowest bad reactions among the three, JCAR017, or liso-cel, bore few resemblances to its predecessor in Juno's lineup. The therapy that is being developed in partnership with Celgene Corp. showed just a 1% rate of serious cytokine release syndrome, a negative immune reaction to the newly infused CAR-T cells, and a 12% rate of neurotoxicity, another reaction that can impact the brain.

Juno also outpaced the others on response to therapy, with 44% of patients showing a complete response, or no detectable signs of cancer, at three months, and half of the high-dose patient group showing a complete response at the six-month mark.

Yet this may not have been enough in a competitive and fast-paced field. The numbers were slightly lower than expected, Barclays analyst Gena Wang wrote in a note.

The Seattle-based biotech's stock was down 14.3% by the close of the market day.

There is hope in its low toxicity, which could bode well for outpatient treatment, or the ability to be treated without a hospital stay. There is also potential for liso-cel to emerge as a differentiated CAR-T product, Wang said.

This could be essential as Juno trails well behind the other two on getting to market, and though it is partnered with Celgene on commercializing the therapy, it is dwarfed by the other CAR-T makers: With a $5.73 billion market capitalization, Juno is just over half the size of Yescarta creator Kite Pharma before it was swept up by Gilead for $11.9 billion.

Dominant players duke it out

As the only approved DLBCL CAR-T therapy on the market, Yescarta had already demonstrated its short-term effectiveness to regulators. The data at the Atlanta conference suggested that the drug is able to keep the cancer at bay, with 41% of patients showing no detectable signs of cancer past a year, an improvement on the six-month rate of 31%.

Kymriah's 30% complete response rate at six months in the Juliet trial and a recent follow-up study with 43% remission at over two years puts it toe-to-toe with Yescarta.

While the two are roughly comparable on response rates, the differences were highlighted in the details.

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At the presentation, Stephen Schuster, the lead researcher on Juliet and other Kymriah trials, and an oncologist at the University of Pennsylvania, openly questioned the higher infection rates shown among Yescarta patients. Schuster suggested that they had to do with a too-high dose of an accompanying therapy, a combination of fludarabine and cyclophosphamide dubbed flu/cy, that is designed to condition the body to receive a cell transplant.

Sattva Neelapu, the presenting researcher on Yescarta's ZUMA-1 trial and an oncologist at the University of Texas' Anderson Cancer Center, argued that the infections could just as easily be due to the patient population. More than 40% of ZUMA-1's patients had failed more than two lines of therapy before, and Neelapu said that these patients' extensive earlier treatments with drugs like Roche Holding AG and Biogen Inc.'s Rituxan could play a role in these rates.

Roll-out realities

In an earlier press briefing on the studies, both Schuster and Neelapu said that a number of patients who did not respond, or only responded for a brief time before relapsing, showed depleted levels of CD19, the antigen protein that CAR-T targets.

Neelapu said that about one-third of Yascarta's failed patients showed this depletion, while the other two-thirds showed high levels of PD-L1, a tumor biomarker. A number of immunotherapies target this antigen, including Roche unit Genentech Inc.'s Tecentriq, AstraZeneca PLC's Imfinzi and Bavencio from Merck KGaA and Pfizer Inc.

All three treatments look highly effective and reasonably durable, RBC Capital Markets analyst Brian Abrahams said in a note projecting growing pains for CAR-T manufacturing and roll-out in the next year, but strong long-term growth for the therapy class.

Abrahams also highlighted Novartis' "gentler" approach with the lower doses of flu/cy and solid outpatient potential — 23% of patients were able to receive the therapy without a hospital stay. While some of these patients were eventually admitted for flu-like symptoms and other side effects, "it was really easy to give [the treatment] as an outpatient," Schuster said.

The ability to use CAR-T as an outpatient therapy will be an increasing focus area as infusion centers deal with the cost burden of treating these patients, Abrahams said.

Barclays analyst Geoff Meacham also highlighted the likely importance of establishing centers, writing in a note that the CAR-T companies providing the most assistance to early adopters will be better positioned.

While Yescarta has solid response rates, its tolerability could come into play here. Cytokine release syndrome can be a somewhat common side effect of the therapy and is usually treated with Genentech's Actemra.

However, neurotoxicity is harder to combat directly. Yescarta had serious neurotoxic events in about 30% of the ZUMA-1 trial population, the highest among the three therapies.

This could pose a problem for outpatient treatment in the future, Abrahams said. At the same time, Gilead has manufacturing efficiency on its side with a 14-day turnaround on engineering the cells, Abrahams noted. Novartis, by comparison, has cut its speed from 30 days in initial trials to 22 days in the latest Juliet trial.

"We believe these products represent the tip of the iceberg on the potential for cell therapies," Abrahams wrote. "While uptake will likely be gradual as physicians and centers grapple with initial complexities of administration and reimbursement, over the long-term we see very high revenue potential opportunities for [Gilead]," he said.

The U.S. Food and Drug Administration is also closely tracking long-term results. In a Dec. 10 panel on this year's lymphoma approvals, medical officer Emily Jen said that the agency has commissioned a post-marketing review of long-term safety and secondary malignancies, or those arising specifically following a cancer treatment.