A month ahead of its PDUFA date, the chimeric antigen receptor T-cell (CAR T) immunotherapy Kymriah (tisagenlecleucel, previously CTL-019) gained FDA approval to treat children and young adults with B-cell acute lymphoblastic leukemia (ALL). Though expected following a unanimous endorsement last month by members of the FDA's Oncologic Drugs Advisory Committee (ODAC), the product from Novartis AG becomes the first gene therapy approval in the U.S.

On a conference call Wednesday, FDA Commissioner Scott Gottlieb called the approval "an important milestone in a long journey we've been on to transform clinical medicine by using modern advances in genomics."

Decades of work by researchers in academic and industry settings to modify cells using the tools of gene therapy "was always held out as a way to alter the course of many vexing diseases, and maybe even deliver the ability to cure deadly disorders," Gottlieb said.

Despite challenges, even tragedies, along the way, "today, a pivotal leg in that journey is complete," he added. "The science has reached a point of superiority, where enough of the components of these endeavors are worked out that we can deliver effective therapy to patients."

Kymriah was approved to treat patients up to age 25 with B-cell precursor ALL that is refractory or in second or later relapse.

The genetically modified autologous T-cell immunotherapy begins with a patient's own white blood cells. The patient's T cells are collected and sent to a manufacturing center where they are genetically modified to include a new gene that contains the CAR that directs the cells to target and kill leukemia cells bearing the CD19 surface antigen. Once the cells are modified, they are infused back into the patient to kill the cancer cells.

Kymriah uses the 4-1BB costimulatory domain in its CAR to enhance cellular expansion and persistence. The therapy was first developed by researchers at the University of Pennsylvania, which partnered with Novartis in 2012 in a research, development and commercialization pact covering the use of CAR T to treat cancer.

Safety and efficacy were evaluated in a single multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory (r/r) B-cell precursor ALL, demonstrating an overall remission rate within three months of treatment of 83 percent.

Following the ODAC meeting, the panel's vote was heralded by the Alliance for Regenerative Medicine (ARM) as a major milestone – a sentiment ARM reiterated Wednesday.

"The FDA's approval of Novartis' CAR T-cell therapy Kymriah is a historic and monumental milestone for patients and the broader regenerative medicine sector," Janet Lambert, ARM CEO, said. "Great potential has become thrilling reality with the approval of what will likely be a cure for patients with B-cell ALL."

Dana-Farber Cancer Institute's Kenneth Anderson, president of the American Society of Hematology, called the approval "an important shift in the blood cancer treatment paradigm. We now have proof that it is possible to eradicate cancer by harnessing the power of a patient's own immune system. This is a potentially curative therapy in patients whose leukemia is unresponsive to other treatments and represents the latest milestone in the shift away from chemotherapy toward precision medicine."

Anderson cautioned, however, that Kymriah will help only a small population of patients.

"More research is needed to make this therapy more effective for a broader population, to reduce the severe side effects that patients experience during treatment and ultimately to find a broader application beyond blood cancers," he said.

Actemra approval also extended to treat CRS

During the ODAC meeting, some FDA reviewers expressed concerns about manufacturing consistency and quality in producing what Basel, Switzerland-based Novartis and the FDA described as a "living drug," with each batch representing hope for a unique, distinct patient with r/r B-cell ALL – and producing it in time for that child or young adult. (See BioWorld, July 13, 2017.)

In the end, ODAC members were convinced that Novartis was peddling something more than hope for a disease that has few options. One of the parents who testified, Tom Whitehead, was the father of Emily – the first patient to receive the immunotherapy. Emily stood beside her father at the committee meeting as living proof of the therapy's success. Moreover, the Novartis CAR T therapy proved to be a life-saving alternative, rather than just a bridge to a bone marrow transplant, which carries a survival rate of just 30 percent.

Kymriah was approved with a boxed warning of cytokine release syndrome (CRS) – a systemic response to the activation and proliferation of CAR T cells that causes high fever and flu-like symptoms – and for neurological events. Other severe adverse events associated with the therapy – generally within days of infusion – included serious infections, low blood pressure, acute kidney injury, fever and hypoxia.

In a related move, the FDA expanded the approval of Actemra (tocilizumab, Genentech Corp.) to treat CAR T-cell-induced severe or life-threatening CRS in patients 2 or older. In trials in patients treated with CAR T cells, 69 percent of those affected with CRS showed complete resolution within two weeks following one or two doses of Actemra.

Approval of Kymriah also came with a risk evaluation and mitigation strategy, or REMS, including elements to assure safe use, and Novartis committed to conduct a postmarketing observational study involving patients who were treated with the product.

Kymriah was granted priority review as a breakthrough therapy.

Price tag: $475,000 for one-time treatment

Chatter about the approval quickly turned from the precedent-setting scientific and regulatory achievement to the more mundane, especially pricing. In a media call, Novartis officials said the therapy will be priced at $475,000 per one-time treatment.

"We carefully considered the appropriate price for Kymriah," Bruno Strigini, CEO of Novartis Oncology, explained. "We looked at many factors, including the medical and clinical value [and] the value to patients, the health care system and society, both in the near term and long term."

The company considered the cost of allogeneic stem cell transplant as the current standard of care, which Strigini pegged at $540,000 to $800,000 in the U.S. in the first year of treatment. Novartis also examined the findings of a health technology appraisal conducted by the U.K.'s National Institute for Health and Care Excellence that suggested "cost-effective" pricing of $600,000 and $750,000 for the CAR T therapy.

Novartis set the Kymriah price "recognizing our responsibility to bring this treatment to patients," Strigini said, at a rate that offers "sustainability" of the technology as well as "a return on our investment."

Novartis officials said they are committed to ensuring that eligible patients have access to Kymriah and are working with payers to ensure coverage for patients.

To that end, the pharma and the Centers for Medicare & Medicaid Services (CMS) said they are working together to improve efficiencies in existing regulations that will allow Novartis to provide outcomes-based pricing. In that way, treatment is reimbursed only when patients respond to Kymriah by the end of the first month.

CMS issued a statement indicating that it will issue guidance to biopharma manufacturers about engaging with the agency in similar innovative payment arrangements. CMS also plans to work with states on other options and to help them manage the cost of emerging gene and cell therapies and cures.

Christiana Bardon, partner of the MPM Oncology Impact Fund and the founder and managing member of Burrage Capital, said the Kymriah price tag was "right where I thought it would be" and applauded the value-based pricing move.

"This is a really smart move by Novartis to correlate the payment to the success in outcomes to patients," Bardon told BioWorld.

The model also leaves room for success from a business perspective, she said, suggesting the manufactured cost of goods "may be well south of $100,000" and could, over time, drop even more as new technologies transform CAR T delivery into an "off-the-shelf business model."

The coincidental timing of Gilead Science Inc.'s acquisition of CAR T rival Kite Pharma Inc. in an $11.9 billion deal "also tells us that they think they can make a really interesting business model out of this," Bardon added. (See BioWorld, Aug. 29, 2017.)

Kite's most advanced candidate, the CAR T therapy axicabtagene ciloleucel (axi-cel, previously KTE-C19), is under priority review by the FDA with a PDUFA date of Nov. 29, potentially positioning it to treat refractory aggressive non-Hodgkin lymphoma (NHL), including refractory diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma and primary mediastinal B-cell lymphoma.

Kite also reported solid results in the phase II ZUMA-1 trial in patients with chemo-refractory aggressive B-cell NHL, achieving the primary endpoint of objective response rate, or rates of tumor response (complete response plus partial response) following a single infusion of axi-cel, with a score of 82 percent (p < 0.0001). (See BioWorld Today, March 1, 2017.)

But even if response rates in other indications fell to 60 percent, or lower, the concept of value-based pricing is that "only the patients who benefit from the therapy have to pay for it," Bardon said. "And, of course, we're all motivated to make sure response rates are as high as possible for patients."

In the end, targeted therapy, priced appropriately, could offer an even better business model than a broad-brush treatment approach, she added, citing chemotherapy as an example.

"Chemotherapy is cheap," Bardon acknowledged. "But in, say, melanoma, out of 100 patients, chemotherapy has a response rate of less than 10 percent. We're treating 100 patients for eight patients to benefit, yet everyone pays. With CART T, we're treating 100 patients and 80 are getting a benefit, and only those 80 pay. In some ways, it makes absolute sense."

Novartis plans to implement an initial network of 20 treatment centers, including five that will be open within one month. By year-end, the company expects to have a network of up to 32 fully FDA-certified centers in place, with the ability for future expansion. With the FDA's endorsement, Novartis is managing the onboarding and training of centers.

Kymriah will be manufactured for each patient using his or her own cells at the company's facility in Morris Plains, N.J. To date, the company has manufactured CAR T cells across multiple indications for more than 250 patients from 11 countries.

The company said it plans additional filings for Kymriah this year in the U.S. and EU, including applications to treat adult patients with r/r DLBCL.

On Wednesday, Novartis shares (NYSE:NVS) fell 88 cents to close at $82.74. Shares of Gilead (NASDAQ:GILD) gained $5.49, or 7.3 percent, to close at $81.23.