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Iovance Opens the Door to Cell Therapies in Solid Tumors With Amtagvi

Iovance's Amtagvi

NEW YORK – The US Food and Drug Administration's approval on Friday of Iovance Biotherapeutics' Amtagvi (lifileucel) represents a new era for autologous cell therapies, making them commercially available for solid tumors for the first time.

Researchers, biopharma companies, and, most importantly, patients have been waiting for such an approval for decades. The first-in-class accelerated approval makes Iovance's tumor-infiltrating lymphocyte (TIL) therapy an option for advanced melanoma patients after prior treatment, including with PD-1 checkpoint inhibitors. The FDA made the decision after considering the results of Iovance's Phase II C-144-01 trial in which 31.4 percent of 153 patients responded to Amtagvi, and more than half of these patients were still responding after a year.

Iovance has touted the roughly 30 percent response rate in this melanoma for at least three years, and Steven Rosenberg pioneered the treatment nearly 40 years ago, in the late 1980s, at the National Institutes of Health's Surgery Branch. But the treatment has been limited to the NIH and research settings ever since, partly because regulators at the FDA couldn't decide how, exactly, to regulate the unique treatment.

"We were surprised two-and-a-half years ago that the 30 percent response rate was not sufficient to gain approval for [Iovance's] BLA," said Michael Lotze, a surgeon and immunologist at the University of Pittsburgh Medical Center who had previously been Iovance's CSO. Lotze helped design the manufacturing process for the TIL therapy at Iovance.

A long time coming

Iovance's drawn-out road to regulatory approval, which included consecutive filing delays culminating in the decision to file a rolling biologics licensing application, has less to do with the therapy's efficacy than the fact that it didn't fit neatly into the framework the FDA uses to evaluate a biologic product's potency.

"We and others in the cell therapy community took this to heart," he said of the delays, though he acknowledged that "the FDA focused on 'identify, purity, and potency' to protect consumers."

Because tumor-infiltrating lymphocytes go after targets that differ from patient to patient, it's not possible to create a potency assay that measures Amtagvi's ability to home in on one specific target.

"Every person's TILs from their own tumors have different targets they're going after because their cancers are different," said Jason Bock, CEO of the Cell Therapy Manufacturing Center, an MD Anderson Cancer Center and National Resilience joint venture. "That inherently makes it more challenging to come up with a predefined potency assay. It's an advantage of TIL, but that was the challenge that Iovance and the FDA were wrangling with."

Bock, who previously served as a consultant for Iovance, pointed out that even autologous CAR T-cell therapies, which involve a similarly intensive, patient-specific process of harvesting and reinfusing a patient's cells, are designed to target one predefined antigen, such as CD19 or B-cell maturation antigen (BCMA) on the surface of cancer cells. With TIL therapies, in contrast, "we're targeting whatever the patients' TILs are targeting, but we don't know those targets a priori," he said. "The specificity makes it harder to define TILs as a traditional therapeutic in the FDA's paradigm."

Ultimately, after many regulatory meetings, the FDA reframed how it thinks about potency assays for cell and gene therapies and distilled them in a recent draft guidance for industry. The agency is still fine-tuning its regulatory approach and will continue to sharpen processes as other TIL therapies gain approval, but the FDA seems to have embraced a "potency assurance strategy" for these types of bespoke cell therapies rather than a single potency assay.

Getting Amtagvi off the ground

Bock isn't the only one to draw comparisons between the newly approved TIL therapy product and CD19- and BCMA-directed CAR T-cell therapies. Those therapies, most of which are approved for blood cancers like lymphoma and myeloma, are the only other autologous cancer treatments to enter the market, so their launches could serve as roadmaps for Iovance as it rolls out Amtagvi to patients.

In a conference call to discuss Amtagvi's approval on Friday, Iovance interim CEO Fred Vogt brought up FDA-approved CAR T-cell therapies several times, especially when defending the high price of Amtagvi, which has a list price of $515,000. For comparison, the list price for Gilead's CAR T-cell therapy Yescarta (axicabtagene ciloleucel) is $414,000, and BMS, Novartis, and Janssen have priced their autologous CAR T-cell therapies similarly.

"Based on our payor interactions, we expect coverage similar to approved CAR T-cell products," Vogt said, adding that like those treatments, Amtagvi will require prior authorization. He highlighted Iovance's patient support program, IovanceCares, that the firm launched to help patients with access to Amtagvi, including with the treatment's cost.

Indeed, as is the case for CAR T-cell therapies, the six-digit price tag won't be the only barrier to accessing Amtagvi. The therapy will only be available at authorized treatment centers with specialized staffing, training, and processes in place to administer TIL therapy.

According to Jim Ziegler, Iovance's executive VP of commercial, the firm is launching Amtagvi at about 30 authorized treatment centers with already "established TIL service line capabilities." Beyond this, Ziegler said a number of additional centers are in the process of completing their final onboarding in the coming weeks. The firm is aiming to ready more than 50 authorized treatment centers in roughly the next 90 days.

Although neither Ziegler nor Vogt would provide an estimate of how many patients would, or could, be treated at each of these centers, Vogt is optimistic Iovance will be able to treat several thousand patients with Amtagvi annually. "We expect a bolus of patients coming through," Vogt said, adding that Iovance will likely begin to record revenues from Amtagvi during the second half of this year.

Once patients undergo tumor resection at one of the authorized treatment centers, the tissue will be shipped to one of two Iovance manufacturing sites: the Philadelphia-based central Iovance Cell Therapy Center and a nearby site operated by the contract testing development and manufacturing organization WuXi Advanced Therapies (WuXi ATU).

At these sites, the TILs will be harvested from patients' tumor samples and expanded ex vivo. Patients will receive lymphodepleting chemotherapy to prepare their bodies to accept the cell therapy. Once the expanded TILs are shipped back, patients will receive them as a one-time infusion along with an infusion of interleukin 2. The entire process can take more than 34 days, a time frame Iovance hopes to shorten.

And while Ziegler doubled down on his conviction that "Iovance is confident in its ability to deliver a successful launch," the rollout of CAR T-cell therapies hasn't always been smooth, and drugmakers have struggled to quickly make enough treatments to meet patient demand.

Payors' prior authorization schemes may also present roadblocks to patient access. "Working through reimbursement strategies with healthcare systems [and] setting up the infrastructure for commercial TIL production will likely be a challenge," Bock suggested, adding that even though many of the authorized treatment sites, including the nearby MD Anderson, have been administering TIL therapies to advanced melanoma patients already under clinical trial protocols, there are new challenges once a therapy is commercially approved.

"In a clinical trial, the company covers all the costs, and all you do is look at the inclusion-exclusion criteria, and if [the patients] meet that, you enroll them," he said. "For commercial [treatments], there are all these [criteria] on the label of who can be included [and] you need to get preauthorized consent from health insurance companies. … That's a whole new education that has to go on at these hospitals and insurance companies."

With all of these considerations, Bock said he imagines it will be years before Amtagvi can reach a level where it's considered standard of care for melanoma patients in this setting. "There are a lot of logistics to work out, even at well-experienced hospitals," he said.

"We need to find a way to make these therapies more cost-effective, faster, and better available for a broader range of malignancies," Lotze echoed, adding that ultimately, this may require more investment and research into off-the-shelf approaches that don't require lengthy, logistically complex manufacturing processes. Others have begun exploring point-of-care manufacturing models for cell therapies to improve access and reduce costs.

'A rising sea lifts all boats'

Whatever the next iteration of TIL therapy may be, the Amtagvi approval has carved a regulatory path for these types of treatments, and the implications for the field cannot be understated, according to industry observers. "A rising sea lifts all boats, and I expect that this approval will spark additional investment with a clear path to profitability for companies like Iovance," said Lotze, the firm's former CSO.

Other firms, such as Obsidian Therapeutics and KSQ Therapeutics, have been working on engineered TIL therapies, and others may soon enter the scene now that Iovance has shown it is possible to steer such a treatment through the FDA.

It remains to be seen how much Iovance will profit from this new type of cell therapy, which it stuck with despite regulatory challenges. The firm's stock price on the Nasdaq on Wednesday afternoon was $15.94 per share, a more than 65 percent increase since the day before the approval. On Wednesday, Iovance announced a $211 million public offering of its common stock.

Since Amtagvi scored accelerated approval, however, Iovance will need to confirm its efficacy and safety in further studies. The firm is in the process of doing just that, while also evaluating Amtagvi in frontline metastatic melanoma within its Phase III TILVANCE-301 study.

Iovance is also working on making TIL therapy commercially available for patients with non-small cell lung cancer, though the road could be bumpy there, too, after the FDA placed the trial on hold late last year following a serious adverse event. Iovance is working to resume the trial "as soon as possible" and is hoping to have an update in the coming weeks.

"There will be challenges with this first-generation product, but it's so important to define that there's a regulatory path going forward," Bock said. "It will help the companies that already have TIL therapy in development, and it should mean additional investment in TIL. … Second-generation products are going to be the ones that really make inroads into bending the curve in solid tumors."