A month ahead of schedule, Yescarta (axicabtagene ciloleucel, previously KTE-C19) gained a nod from the FDA, representing the second chimeric antigen receptor (CAR) T-cell therapy approved by the agency and the first for certain types of non-Hodgkin lymphoma (NHL). The product was approved to treat adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.

The CAR T-cell immunotherapy Kymriah (tisagenlecleucel, previously CTL-019) from Novartis AG was green-lighted by the FDA in August to treat children and young adults with B-cell acute lymphoblastic leukemia (ALL). (See BioWorld, Aug. 31, 2017.)

Yescarta was developed by Kite Pharma Inc., which in August attracted an $11.9 billion acquisition deal from Gilead Sciences Inc., reckoning the purchase had both near- and long-term therapeutic opportunities in the white-hot immuno-oncology (I-O) space. (See BioWorld, Aug. 29, 2017.)

Gilead, of Foster City, Calif., said Yescarta would list in the U.S. at $373,000, in line with analyst expectations and at a significant discount to Kymriah, priced at $475,000. Analysts cautioned about apples-and-oranges comparisons, however, since Novartis committed to outcomes-based pricing, with treatment reimbursed only when patients respond by the end of the first month. (See BioWorld, Sept. 5, 2017.)

Gilead made no such claim and, unlike Novartis, provided no pricing details beyond a one-sentence statement in its press release. Company officials were in meetings and unavailable for comment, according to a spokeswoman.

In the multicenter ZUMA-1 trial of 101 adults with refractory or relapsed DLBCL – used to support Yescarta's regulatory filing – 72 percent of patients treated with a single infusion responded to therapy, including a complete remission rate of 51 percent. At a median follow-up of 7.9 months, patients who achieved a complete remission had not reached the estimated median duration of response. (See BioWorld Today, March 1, 2017.)

As expected, approval came with a boxed warning for cytokine release syndrome, the systemic response to the activation and proliferation of CAR T cells that causes high fever and flu-like symptoms, and for neurologic toxicities. Other side effects associated with treatment include infections, low blood cell counts and a weakened immune system.

Yescarta also was approved with a risk evaluation and mitigation strategy, or REMS, requiring special certification of hospitals and associated clinics and training of staff that dispense Yescarta. Patients also must be informed of the potential side effects.

To monitor long-term safety, the FDA required the company to conduct a postmarketing observational study of patients treated with the therapy.

In a statement, FDA Commissioner Scott Gottlieb called Yescarta's approval "another milestone in the development of a whole new scientific paradigm for the treatment of serious diseases," transforming "a promising concept to a practical solution to deadly and largely untreatable forms of cancer."

The FDA, Gottlieb added, is "committed to supporting and helping expedite the development of these products." He cited the agency's intention to issue a comprehensive policy that addresses support for development of cell-based regenerative medicine, including clarity on expediting breakthrough products that use CAR T cells and other gene therapies.

Yescarta was granted priority review, breakthrough therapy and orphan drug designations by the FDA and priority medicines regulatory support in the European Union, where a marketing authorization application is under review by the EMA, with potential approval expected in the first half of next year.

Gilead's shares (NASDAQ:GILD) gained $1.58 Thursday to close at $81.59.

'Start of a potential large oncology franchise'

A day following the approval, attention turned to Gilead's roll-out plans and long-term intentions in I-O. The company said the therapy will be manufactured in Kite's commercial manufacturing facility in El Segundo, Calif. Gilead officials previously cited the facility's close proximity to Los Angeles International Airport as a boon for global distribution. They additionally credited Kite's expertise in R&D and manufacturing – which, they said, meshed with Gilead's manufacturing capabilities in southern California – as keys to cementing the acquisition.

Gilead confirmed that Kite's field team is prepared to provide final site certification to 16 centers, enabling them to begin treating patients with Yescarta. Kite, based in Santa Monica, Calif., is working to train more than 30 additional centers, with an eventual target of 70 to 90 centers across the U.S.

"There may be ways that we could enhance the activity of some of these products either through engineering better CAR Ts or perhaps in combination therapy," John Milligan, Gilead's president and CEO, said in August of Kite, referencing its ongoing multicenter phase I/II effort evaluating KTE-C19 in combination with PD-L1 antibody Tecentriq (atezolizumab, Genentech/Roche Holding AG) in refractory DLBCL, which is the most common aggressive NHL, accounting for three out of every five cases. Kite also is advancing Yescarta in second-line DLBCL, mantle cell lymphoma and pediatric and adult ALL.

RBC Capital Markets analyst Brian Abrahams alluded to potential expansions of the Yescarta franchise in a first glance on Gilead. While predicting "modest" 2018 sales of Yescarta, across additional indications that remain in development, "we could see $2.7 [billion] in peak revenue potential – the start of a potential large oncology franchise, ripe for additional complementary acquisitions," he wrote.

"No major surprises on label," Abrahams added. "The indication is specific for third-line treatment, and includes a boxed warning and an extensive REMS profile. We believe physician training in Yescarta delivery and potential for cytokine release syndrome will take time."

In a flash note, Jefferies analyst Michael Yee called Yescarta's pricing in-line and predicted a strong launch that could account for $200 million to $250 million in 2018 revenues.

"One caveat is that GILD has suggested (and based on our channel checks on various centers) that the color in the market is that GILD may start the launch more carefully to ensure top centers do not run into safety issues," he added.

Cowen and Co.'s Phil Nadeau provided quite a bit more introspection than his "quick take" suggested. Like others, Nadeau was unsurprised by the early approval, ahead of the therapy's Nov. 29 PDUFA date, but "there had been some question about whether Yescarta would get a full or accelerated approval," he pointed out, so the full approval "is notable."

Nadeau also lined up with peers on Yescarta's pricing and label. But he was more bullish than most on commercial plans, pointing out that physician checks by Cowen suggested a faster launch than investors might appreciate.

"The panelists think the primary reason for a patient being excluded from CAR eligibility in the commercial setting is likely to be the presence of cardiac disease," he wrote. "Other comorbidities that could exclude patients from access in the commercial setting are likely to be the presence of CNS disease or elderly/poor performance status. Notably, the FDA did not include a contraindication for cardiac disease, secondary CNS disease or performance status on Yescarta's label, meaning physicians will have much discretion in determining which patients are appropriate."

Doing the math, Nadeau said that surveyed physicians estimated 53 percent, or approximately 5,300 relapsed/refractory patients annually will be good candidates for commercial CD19 CAR T-cell therapy.

With Kite and competitor Novartis planning staged roll-outs of their commercial therapies, beginning with centers that participated in their respective trials, and given capacity constraints at those hospitals, "physicians anticipate 1,233 aNHL patients will be treated with a commercial CD19 CAR T-cell therapy in 2018," he wrote. "This is nearly double investors' expectation of 677 patients."

Leerink Partners LLC's Geoffrey Porges threw a bit of cold water on Gilead's coming-out party in I-O, however.

Although he raised the company's price target by $1, to $85, and reiterated a "market perform" on shares based on Yescarta's de-risking, list price and in-line label, "the revenue contribution falls far short of what is required to offset the expected erosion of [Gilead's] core business in the next 12 months due to competition and patent expiries," Porges warned. "The announcement does not provide the justification for the premium that Gilead paid for Kite's cellular therapy platform, and Gilead is depending on broadening to earlier lines of treatment, expanding to other indications and development of additional products to generate an adequate return on the acquisition."

Those plans may or may not pan out, according to Porges, since "we expect additional hematologic malignancy CAR T filings to come in 2018, including a filing for direct competitor Kymriah in DLBCL and a filing from Juno's comparable CD19 CAR T medicine."

Juno Therapeutics Inc. raised $287 million last month in a follow-on offering and concurrent private placement with its partner, Celgene Corp., and opened a new Seattle headquarters, prepping for a filing, potential approval and launch of its lead CAR T candidate, JCAR-017, despite clinical setbacks with another CAR T agent. (See BioWorld Today, Nov. 28, 2016, and Sept. 25, 2017.)

Other competitors are in the wings, including Mustang Bio Inc., which has been galloping forward with its lead CAR T programs, MB-101 and MB-102, and has another CAR T, MB-106, in the clinic in B-cell NHL. The Fortress Biotech Inc. subsidiary raised $94.5 million this year. (See BioWorld Today, Feb. 3, 2017.)

Moreover, Porges pointed out, Gilead's hepatitis C forecast "is being eroded more sharply and sooner than we had anticipated" without equivalent offsets from the company's pipeline and business development efforts. "Gilead's valuation is near an all-time low, and would otherwise justify recommending the stock," he wrote, "but continuing negative revisions and substantial terminal uncertainty make it hard for us to see the stock recovering its multiple in the foreseeable future."