Spotlight on Market Access Actionable understandings from AIS Health’s in-depth coverage September 16, 2019 Recent Situations Stress That Data Is More Important Than Ever to FDA, Drug Uptake 2 Clinical Trials by Indication: Q2 2019 A pair of drugmakers and the FDA found themselves in the news lately, but it’s safe to say it wasn’t for the reasons they would prefer. Both situations Reality Check: PCSK9 Inhibitors 8 stress the importance of data needed to secure product approvals, and, per- haps, payer and provider uptake. On Aug. 6, the FDA put out a statement addressing “data accuracy issues” with Zolgensma (onasemnogene abeparvovec-xioi), a new gene ther- apy to treat spinal muscular atrophy in people less than 2 years old who have bi-allelic mutations in the survival motor neuron 1 gene, including those who are presymptomatic when diagnosed. The one-time therapy has the distinction of being the most expensive drug in the world, with a price tag of $2.1 million. The FDA approved the drug from AveXis, Inc. on May 24 (SMA 7/1/19, p. 6). On June 28, AveXis — which was acquired by Novartis AG last year — notified the agency that there was “a data manipulation issue that impacts the accuracy of certain data from product testing performed in animals sub- mitted in the biologics license application (BLA) and reviewed by the FDA.” continued on p. 3 Report Reveals That Almost 100 RM/AT Products Are in Phase III Clinical Trials This past quarter saw two new gene therapies: Novartis AG subsidiary AveXis, Inc.’s Zolgensma (onasemnogene abeparvovec-xioi) received FDA approval May 24 for the treatment of spinal muscular atrophy (SMA 7/1/19, p. 6), and bluebird bio’s Zynteglo (autologous CD34+ cells encoding βA-T87Q- globin gene) received conditional marketing authorization from the Europe- an Commission for transfusion-dependent beta thalassemia. While only a handful of therapies in the broader regenerative medicine/ advanced therapy (RM/AT) space are available globally, a new report shows that is likely to change, as there are more than 1,000 products in the pipe- line. Many of these therapies truly are innovative products, but they don’t come cheap and often have complex reimbursement schemes that some pay- ers and providers are struggling with, an issue that will need to be handled soon as more of these therapies are poised to hit the market. © Managed Markets Insight & Technology, LLC | 1 MMIT’s Spotlight on Market Access September 16, 2019 The Alliance for Regenerative Medicine published ◊ 249 cell therapy trials are proceeding: 49 the report, titled Quarterly Global Regenerative Med- are in Phase I, 168 are in Phase II, and 32 are in icine Sector Report: Q2 2019, on Aug. 1. It shows there Phase III. are 1,069 clinical trials using specific RM/AT technol- ◊ 44 tissue engineering trials are happen- ogies, which include gene therapy, gene-modified cell ing: five are in Phase I, 23 are in Phase II, and 16 therapy, cell therapy and tissue engineering. Ninety- are in Phase III. four of those products are in Phase III trials. They also span a variety of indications (see chart More specifically, the report reveals: below). ◊ 366 gene therapy clinical trials are un- While Zolgensma’s $2.125 million price for a derway: 117 are Phase I, 219 are Phase II, and one-time infusion makes it the costliest drug on the 30 are Phase III. planet, other newer RM/AT products are certainly ◊ 410 gene-modified cell therapy trials are not cheap. Spark Therapeutics Inc.’s Luxturna (vore- ongoing: 187 are in Phase I, 207 are in Phase II, tigene neparvovec-rzyl), approved in December 2017 and 16 are in Phase III. for a rare form of blindness, costs $425,000 per eye; Clinical Trials by Indication: Q2 2019 • 643 (60%) of all current clinical trials are in oncology, including leukemia, lymphoma, and cancers of the brain, breast, bladder, cervix, colon, esophagus, ovaries, pancreas, and others. • 60 (6%) are in cardiovascular disorders, including congestive heart failure, myocardial infarction, critical limb ischemia, heart disease, and others. • 57 (5%) are in diseases of the central nervous system, including multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, ALS, and others. SOURCE: Alliance for Regenerative Medicine, Quarterly Global Regenerative Medicine Sector Report: Q2 2019, released August 2019. Download the report at https://alliancerm.org/?smd_process_download=1&download_id=4962. © Managed Markets Insight & Technology, LLC. Contact [email protected]. | 2 MMIT’s Spotlight on Market Access September 16, 2019 Novartis Pharmaceuticals Corp.’s chimeric antigen not in place to have the ability to track the patient once receptor T-cell (CAR-T) therapy Kymriah (tisagenlec- therapy is administered.” leucel), first approved in August 2017, costs $475,000 Download the report at https://bit.ly/31cvh6W. G or $373,000 depending on the type of cancer it’s used in; and Gilead Sciences, Inc. unit Kite Pharma, Inc.’s by Angela Maas Yescarta (axicabtagene ciloleucel), approved in October This story was reprinted from AIS Health’s monthly 2017 to treat large B-cell lymphoma, costs $373,000. publication RADAR on Specialty Pharmacy. For more Many of these products’ manufacturers are offering information, visit https://aishealth.com/product/ various reimbursement schemes, including rebates if a specialty-pharmacy. therapy doesn’t work, other outcomes-based deals and multiyear pay-over-time payment options. But experts Issues Stress Data’s Importance note that many barriers to successfully executing these continued from p. 1 deals exist. According to a July 26 memorandum by Wilson “In principle, spreading the cost over a five-year W. Bryan, M.D., director of the FDA’s Office of Tissues period and putting the cost installments at risk based and Advanced Therapies, “AveXis appears to have upon efficacy is a good approach,” says Winston Wong, become aware of the data manipulation as early as Pharm.D., president of W-Squared Group, about March 14, 2019,” but rather than informing the agency, Zolgensma. “However, the devil is in the details. Do we which was evaluating Zolgensma’s BLA at the time, the have the systems in place that have the capability to company first conducted its own internal investigation, administer a five-year contract?” reporting its findings to the FDA after the investigation was completed. Had the FDA known of the issue before “In principle, spreading the cost over it approved Zolgensma, “I believe that the approval would have been delayed” beyond its Prescription Drug a five-year period and putting the cost User Fee Act (PDUFA) date of May 31, he wrote, add- installments at risk based upon efficacy ing that he believed the FDA still would have approved is a good approach.” the BLA. “Based on the information available at this time, In addition, he asks, “Who is responsible for the the Phase 3 clinical trial results continue to provide billing of the installment, and who is actually making compelling evidence of the effectiveness of Zolgensma, the annual payment? Is it the insurance carrier in all along with sufficient evidence of safety to support an cases, or is that passed on to the self-funded employer? overall favorable benefit-risk profile,” wrote Bryan. Under the payment installment option, how does the “It is the manufacturer’s responsibility to sub- provider, who has to obtain the product, get reim- mit complete and accurate information in marketing bursed?” applications for evaluation by the FDA. If we become According to Wong, “We do not have the systems aware of a concern with data submitted to the agency in place to handle the tracking and processing of as part of our review of a product application, it is in installment billing over a period of five years, as well the best interest of patients, their caregivers, and the as having the ability to track patients once they have public that we disclose such information, to the extent left the health plan,” which “will be a major obstacle permitted by law,” said the FDA in its statement. It to overcome for any value-based agreement where said that it “remains confident that Zolgensma should payment will be dependent upon continued efficacy remain on the market.” of the therapy. From the manufacturer perspective, a However, the agency said, it is “carefully assessing value-based contract implies that no payment would be this situation” and could “take action, if appropriate, made if the patient relapses or passes on. Systems are which may include civil or criminal penalties.” Accord- © Managed Markets Insight & Technology, LLC. Contact [email protected]. | 3 MMIT’s Spotlight on Market Access September 16, 2019 ing to Bryan’s memo, “a complete assessment of the through all appropriate criminal, civil, and regulato- impact of the data manipulation will require additional ry actions against the company. Anything short of a investigation, discussions both internally within CBER forceful response would signal a green light to future [i.e., the FDA’s Center for Biologics Evaluation and pharmaceutical behavior.” The situation, they wrote, Research] and with AveXis, will probably require that “smacks of the pharmaceutical industry’s privilege and AveXis submit and FDA review one or more BLA sup- greed.…It is an outrage that after knowingly misleading plements, and may take at least several months.” the FDA in a rush to make a profit,” Novartis in its Aug. In response to the FDA statement, Novartis issued 6 press release refused “to acknowledge any culpability a press release Aug. 6 that read, in part, “we maintain or remorse. Instead, the company doubled down on its that the totality of the evidence demonstrating the greed-driven behavior.” product’s effectiveness and its safety profile continue to provide compelling evidence supporting an overall favorable benefit-risk profile.