ARTICLE IN BRIEF
EXPERTS say the different outcomes for two different neurology drugs show that regulatory system is doing what it's supposed to do.
Two neurology drugs had different outcomes — one was approved by the US Food and Drug Administration, and the other was abandoned by the drug company sponsor. The article examines why they had very different pathways.
Two highly anticipated drugs for two neurologic diseases — solanezumab, Lilly's amyloid-busting drug for Alzheimer's disease, and Biogen's nusinersen (Spinraza), approved in December 2016 as the first treatment for spinal muscular atrophy (SMA) — went down very different paths over the last year.
One was abandoned by the drug company sponsor, and the other was approved by the US Food and Drug Administration (FDA), but both are examples of the drug development and approval process working more or less exactly as it should, according to experts interviewed by Neurology Today.
DR. CHANA SACKS: “The assumption might be that at some point, you'll figure out the truth anyway —that we'd ultimately gain the knowledge that the drug [solanezumab] doesn't work. But there's a chance that if the drug had been approved earlier, Expedition 3 would never have been done — or if it had, it would have taken much longer to enroll, and we would have spent years paying for a drug that didn't work. I think this experience demonstrates the importance of understanding whether or not a drug works before it is approved.”
The FDA drug approval process has been criticized recently, in the wake of controversial decisions like the September 2016 approval of eteplirsen (Exondys 51), an exon-skipping drug for Duchenne muscular dystrophy that received FDA fast-track designation, priority review, and orphan drug designation. That decision overruled the opinion of the agency's advisory committee and several senior staff, who believed the drug had been pushed forward despite inadequate evidence of efficacy.
In an article in Neurology Today following that approval, experts noted that patient advocacy groups were very vocal in advocating for the approval of eteplirsen. Indeed, a May 18 article in the Wall Street Journal suggests that a consultant to Sarepta may have helped parents of children with DMD article prepare for the FDA hearings.
On its face, nusinersen has a lot in common with eteplirsen. It also targets a rare and fatal genetic disease of childhood that has no other known treatment. It received fast-track designation, priority review, and orphan drug designation from the FDA. And it is also mind-bogglingly expensive — an estimated $750,000 per year for nusinersen and $300,000 per year for eteplirsen.
But that's where the two pathways diverge.
THE NUSINERSEN APPROVAL
Nusinersen's approval was based on an interim analysis of data from the NURTURE trial, which involved 21 patients with infantile-onset SMA who were younger than seven months at the time of their first dose. That analysis showed that 40 percent of patients treated with nusinersen achieved improvement in motor milestones, whereas none of the control patients did.
“The drug demonstrated a very strong signal of clinical benefit. The results were strikingly positive,” said former FDA Commissioner Robert M. Califf, MD, Donald F. Fortin, M.D. Professor of Cardiology in the School of Medicine at Duke University.
Some questioned the agency's decision to approve the drug for all types of SMA based on this analysis, since NURTURE involved only patients with SMA type 1.
“It's true, the approval was broader than the scope of that trial,” said Bruce H. Cohen, MD, FAAN, director of the NeuroDevelopmental Science Center at Akron Children's Hospital. “But because SMA type 2 and type 3, although they are later-onset and take a milder form, have essentially the same basis as type 1 biologically speaking, the FDA made the decision to allow it to be used in patients of all ages.”
And in April 2017, that decision was borne out. Phase 3 end-of-study data from CHERISH, which assessed nusinersen's safety and efficacy in children ages 2 to 12 who had developed SMA after six months of age — meaning that they were most likely to develop type 2 or type 3 disease — showed statistically significant and clinically meaningful improvement in motor function among this population. Children taking nusinersen improved their mean score on the Hammersmith Functional Motor Scale Expanded (HFMSE) by 3.9 points, while children not on treatment had a mean decline of 1.0, for a total difference of 4.9 points (p=0.0000001).
ABANDONING SOLANEZUMAB
Solanezumab took exactly the opposite path. Exactly one month before the FDA announced its approval of nusinersen on November 23, 2016, Eli Lilly announced that it was abandoning its long, expensive investment in solanezumab after a third phase 3 clinical trial showed the drug had no benefit in patients with mild Alzheimer's disease.
Two initial trials, Expedition 1 and Expedition 2, had shown no significant benefit for patients taking solanezumab, on either a cognitive test or a functional measurement. “Like other Alzheimer's disease trials before them, these trials included patients with mild-to-moderate disease,” said Chana Sacks, MD, an instructor in medicine at Harvard Medical School who co-authored a May 2017 editorial about solanezumab in the New England Journal of Medicine.
“Although the drug clearly failed to meet its primary endpoint in the first two trials, when Lilly did a prespecified analysis pooling the two trials, it appeared to show that for patients with mild disease, there was a 34 percent reduction in cognitive decline,” she said.
Hence, Expedition 3, a 39-center phase 3 trial in 2,100 patients with mild AD and demonstrated brain amyloid burden. That trial has not yet been published — and may never be — but Lilly announced that the drug had failed to meet both primary and secondary endpoints, and ultimately abandoned other trials involving solanezumab.
Solanezumab's failure — although a loss for Alzheimer's patients and their families, for Eli Lilly, and possibly for the amyloid theory of Alzheimer's treatment — was nonetheless a sign of “a regulatory system that worked,” wrote Dr. Sacks, along with Jerry Avorn, MD, chief of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women's Hospital, and Aaron Kesselheim, MD, JD, MPH, the director of Harvard's program on regulation, therapeutics and law.
The results of Expedition 1 and Expedition 2 were reported in 2012 at the American Neurological Association annual meeting. In the intervening years, there has been an increasing push toward loosening the FDA's efficacy requirements for new drugs, with some even arguing that the FDA should approve all drugs determined not to be toxic and let the marketplace sort them out.
“It is worth considering what might have happened if a more antiregulatory stance had been in place in 2012 and the pooled outcome assessments of Expedition 1 and Expedition 2 suggesting benefit in the subgroup of patients with mild Alzheimer's disease had been enough to support FDA approval — particularly since no major safety concerns had been raised in those trials,” Dr. Sacks and her colleagues wrote.
DR. ROBERT M. CALIFF said the experience with solanezumab “is very instructive about the risk of approving things too early. On the other hand, with a disease like Alzheimer's, waiting until you've convincingly proven benefit might take long enough and cost so much money that no one will invest in developing new treatments. We need a lot of public policy discussion around that issue.”
They calculated that had that been the case, a drug that we now know to be ineffective would have cost patients and payers — primarily Medicare, given the age of the Alzheimer's population — a conservative estimate of almost $10 billion over the past four years.
“The assumption might be that at some point, you'll figure out the truth anyway — that we'd ultimately gain the knowledge that the drug doesn't work,” said Dr. Sacks. “But there's a chance that if the drug had been approved earlier, Expedition 3 would never have been done — or if it had, it would have taken much longer to enroll, and we would have spent years paying for a drug that didn't work. I think this experience demonstrates the importance of understanding whether or not a drug works before it is approved.”
DR. BRUCE H. COHEN: “The FDA is stepping away from old standards that have served it well, but may in some cases have been too rigorous, especially for orphan diseases. But everyone is struggling with the ethics of what that might lead to.”
“This experience is very instructive about the risk of approving things too early,” agrees Dr. Califf. “On the other hand, with a disease like Alzheimer's, waiting until you've convincingly proven benefit might take long enough and cost so much money that no one will invest in developing new treatments. We need a lot of public policy discussion around that issue.”
The very different experiences of solanezumab and nusinersen both serve as an example of the regulatory system doing what it's supposed to do — but they also highlight the pressures on the FDA today, in the wake of the 21st Century Cures Act and general public pressure for better drugs, faster.
“The FDA is stepping away from old standards that have served it well, but may in some cases have been too rigorous, especially for orphan diseases,” said Dr. Cohen. “But everyone is struggling with the ethics of what that might lead to.”
