With the backdrop of Biogen’s BLA filing, and the FDA’s expected response for aducanumab in Alzheimer’s disease in 2020, the link between efficacy and approval seems to have broken. Conditional FDA approvals can’t help when the conditions are ignored.
I met the management of InterMune almost 20 years ago when it was a mid-sized US biotechnology company that had three approved products, two of them interferons. Virtually all of InterMune’s revenues came from one product—Actimmune (interferon gamma 1b), originally licensed from Genentech in 1998.
Actimmune was approved for two rare congenital disorders, but the vast majority of its sales were off-label in idiopathic pulmonary fibrosis (IPF). These were further fueled by the release of “promising” results in IPF from an investigator-sponsored Phase 1 study. In 2000, InterMune announced it would start an accelerated Phase 2/3 program later that same year. The open-label Phase 2 study of Actimmune in IPF completed in 2004 just before InterMune received a subpoena from the US Department of Justice regarding the promotion and marketing of Actimmune. As part of a deferred prosecution agreement charging InterMune with the off-label promotion of Actimmune, a civil settlement of $36.9 million was agreed in October 2006.
In 2003, when the cost of Actimmune was about $50,000 a year per patient, Actimmune generated revenues of $141 million. This was Actimmune’s peak sales year and, as the cloud of the off-label promotion case lingered over the product, its sales declined to $90m by 2006. In order to reverse these declining sales and bring Actimmune in IPF on-label, InterMune started the Phase 3 placebo-controlled INSPIRE study at the end of 2003. But it was not until March 2007 that the study was terminated after a futility analysis determined a higher mortality rate for patients in the Actimmune arm.
At the FDA advisory panel, the agency’s reviewers appeared unconvinced of Exondys 51’s efficacy in even an unvalidated surrogate marker of DMD disease. The presence of parents of DMD patients shouting the benefits of the drug at the panel meeting appeared to persuade the CDER Director to overrule the scientific assessment of the BLA. This reminded me of Phytopharm’s 2001 announcement of its study in canine osteoarthritis (OA). Despite being unable to demonstrate a treatment effect, the owners of the pets “believed that some aspects of OA may have improved.” The tragedy of Exondys 51’s approval is that the drug may have helped a smaller number of the 12 patients treated in the single-arm historically controlled study, but that subset of patients who would benefit remains and the costs—like those of Actimmune in IPF patients—are also borne by patients who don’t benefit (other than from possibly a placebo effect).
Unlike Actimmune in IPF, Exondys 51 is approved by the FDA in DMD patients with amenable mutations, despite (like Actimmune in IPF) the lack of convincing evidence of efficacy. Exondys 51 was approved by the FDA under an accelerated approval that required the conduct of two confirmatory placebo-controlled Phase 3 studies. At the time of the accelerated approval in 2016, these studies were expected to complete in November 2020. The larger of these two studies was supposed to have started in January 2020 and to complete in October 2024.
I was taught in a big pharmaceutical company never to ask a clinical question to which you would not like the answer. The classical case is a label expansion from acute to chronic use. Under the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, chronic use requires a two-year animal carcinogenicity study whose outcome, even for a drug that has been in short-term use in millions of patients, would be uncertain. Typically, pharmaceutical companies don’t risk the (relatively certain) existing sales in an acute indication for a possible label expansion that might demonstrate a carcinogenicity risk and thereby eliminate all sales. So the seven-year lag in InterMune’s announcement of a Phase 2/3 program for Actimmune in IPF before its eventual failure could be seen as successfully eking out sales before an unpalatable clinical answer. In the same way, Sarepta’s eight-year delay for its confirmatory study for Exondys 51 is having the same effect.
Just as Actimmune’s revenues stopped growing four years before its failure in IPF, Sarepta’s fourth-quarter 2019 sales of Exondys 51 grew just 1.1% over the third quarter of 2019. Sarepta’s fourth-quarter Exondys 51 revenues of $100.1 million were in line with analysts’ consensus estimates but its fourth-quarter loss per share of $3.16 ballooned past their estimates of $1.85, having accelerated from the $0.85 loss in the fourth quarter of 2018. The analysts at JMP Securities were not as forgiving as the market when they lowered their price target on Sarepta by 23%. Sarepta’s stock price finished the week down 3% compared to the NASDAQ Biotech Index’s 5% fall.
Biogen (NASDAQ: BIIB) appears all set to submit a BLA for its anti-amyloid antibody aducanumab for Alzheimer’s disease in 2020. This, despite a Phase 3 program previously halted for futility and a later highly contentious post hoc analysis that showed some efficacy in some endpoints in only one of two identical Phase 3 studies.
Sarepta and Biogen have argued that conducting placebo-controlled confirmatory clinical trials after the FDA has already approved a product is unethical from the perspective of patients who would be in the placebo arm of such a study. This is however disingenuous, since ethical objections would typically assume that the active arm is efficacious—something neither InterMune, nor Sarepta, nor Biogen has yet proven. Even if the FDA continues with its laissez faire attitude to drug approvals and confirmatory studies, revenue growth like clinical efficacy seems eventually to be curtailed by real-world evidence.