The FDA’s approval of aducanumab has given Alzheimer’s physicians a new treatment option, but little guidance on how to put it into practice. Clinicians are debating issues such as when to prescribe, who qualifies, and how to ramp up capacity (see Part 3 of this story). They also have to figure out how to communicate the potential risks and benefits to patients and their families, and how long to keep patients on drug. Biogen’s post-market study may answer these questions, but the nine-year timeframe means this is no help for clinicians now. Around the world, physicians are preparing to enter a challenging new phase of Alzheimer’s care.
- Clinicians say they will offer aducanumab to patients despite doubts.
- One quandary is when to stop treatment.
- Other countries are closely watching developments in the U.S.
To Prescribe or Not to Prescribe?
Beyond the logistical challenges of bringing monthly infusions into clinical practice lie ethical ones. Some clinicians doubt the value of aducanumab for their patients. Nonetheless, all clinicians Alzforum contacted said they would offer their patients the option to take it. “I believe that patients and families have a right to this treatment now that it is approved, and also that they should receive accurate information from knowledgeable providers about the risks and benefits to help their decision-making,” Suzanne Craft at Wake Forest School of Medicine in Winston Salem, North Carolina, wrote to Alzforum (full comment below).
Even outspoken critics of the FDA approval are taking this approach. David Knopman at the Mayo Clinic in Rochester, Minnesota, who had urged the FDA to demand a confirmatory trial before approving, told Alzforum, “If my patients and their families express interest, I will discuss the pros and cons with them.” Ditto for the National Institute on Aging’s Madhav Thambisetty, who as a fellow AdComs member had advised against approval but more recently wrote about his first physician consult discussing aducanumab with a son and his dad, whose disease was likely too advanced to benefit from the treatment.
Jason Karlawish at the University of Pennsylvania, Philadelphia, described his reluctance to prescribe aducanumab in an editorial prior to June 7. The approval is now forcing his hand because he also believes in respecting an Alzheimer’s patients’ autonomy. “After discussion with a patient and family about this drug, if they want to take it, I’ll prescribe it,” Karlawish told Alzforum. He noted that the clinical conversation would be quite unusual. “In clinical practice we don’t routinely begin with the point that the drug may not have a benefit,” Karlawish said.
How Long Should You Take It?
Biogen has not specified a maximum length of treatment. In the investor call, Al Sandrock, who leads R&D at Biogen, said that participants in extension studies continued to benefit from treatment for as long as five years, and anecdotally reported feeling worse after the infusions stopped.
At conferences, Biogen researchers have reported that two years of treatment at 10 mg/kg drove people's brain amyloid loads below threshold, but even after that, those on this highest dose continued to decline more slowly on cognitive tests than those in lower-dose groups (see Nov 2018 conference news). It is unclear if this beneficial effect required continued dosing, or was due to complete clearance of amyloid. In biochemical and mouse studies, aducanumab stops the formation of toxic Aβ oligomers, hinting that it could have benefits beyond plaque removal (Sep 2020 news; Nov 2020 news).
In trials of Lilly's investigational antibody donanemab, patients switch to placebo once their brain amyloid has dropped below a set threshold, and continue to take cognitive tests to track their rate of decline. No such data exist for aducanumab. The specter of indefinite dosing distinguishes aducanumab from expensive hepatitis or cancer drugs, which are curative or given for a limited, one-time course, and it has intensified the outcry over its list price.
What if people progress from mild to moderate dementia while getting these infusions? After all, aducanumab is claimed to slow progression by 23 percent over 18 months, not halt or reverse it. Should the doctor stop treatment when a patient worsens? This, too, remains unanswered, and the decision again may be left to insurers.
And how will physicians know for certain if a given patient is responding with a clinical benefit? With cholinesterase inhibitors, AD researchers attempted for some time to establish guidelines for stopping treatment, but the drugs’ small effects on “soft” AD clinical endpoints rendered the effort unsuccessful. “We essentially said we will treat as long as we can,” said Philip Scheltens of Vrije University, Amsterdam. For a treatment of monthly infusions, stopping criteria will be more important, because continued treatment at late stages could prolong suffering, said Liana Apostolova of Indiana University School of Medicine in Indianapolis. Apostolova and Scheltens spoke on June 21 in a four-hour webinar hosted by the Alzheimer's Association, playable here.
No Answers For Nine Years?
Many researchers are hoping Biogen’s post-market study will provide clarity. So far, Biogen has been tight-lipped on its design, noting only that it is in talks with the FDA. Some worry the study may not be rigorous enough to provide good data. “If the field leaves the execution of the Phase 4 trial as requested by the FDA to the free market alone, we will see mostly results from a complex patient population, resulting again in blurred and controversial signals,” Bart De Strooper at the U.K. Dementia Research Institute at University College London wrote to Alzforum.
In the cancer field, numerous drugs were approved based on surrogate markers, but post-marketing studies were slow in coming and FDA enforcement was lax. The drugs continued to be prescribed in a knowledge vacuum for years. In April 2021, the FDA reviewed post-market oncology data and concluded two drugs did not work for specific cancers: Keytruda for gastric cancer and Opdivo for hepatocellular carcinoma. The drugmakers stopped marketing their products for those diseases. Only 6 percent of accelerated approvals for oncology therapies have ever been withdrawn (Healio news).
Maria Glymour at the University of California, San Francisco, believes the nine-year timeframe for a confirmatory Phase 4 trial will delay certainty about whether aducanumab helps AD patients. “This feels like we have failed patients and families,” she wrote to Alzforum.
Will the World Follow Suit?
While aducanumab so far is approved for use in the U.S., Biogen has applied in Japan, Australia, Switzerland, the European Union, Canada, and Brazil. Some believe the FDA decision is likely to influence other regulatory authorities. After the FDA ruling, Japanese health minister Norihisa Tamura told the media, “This is a big step forward and a breakthrough method; we’ll make a final decision after a careful review on its safety and efficacy.”
Takeshi Iwatsubo at Tokyo University noted that media coverage of aducanumab approval in Japan has been positive, but said the country is not ready for clinical rollout. “We may have to formulate a guideline for the appropriate use of anti-Aβ antibody drugs,” he wrote to Alzforum. “We do feel much is left to be done prior to the implementation of these drugs.”
Like in Japan, German neurologists and psychiatrists have founded a network to help standardize clinical care. And like Iwatsubo, Jörg Schulz at RWTH Medical School, Aachen, and Johannes Levin of Ludwig-Maximilians-Universität München, hope that if the European Medicines Agency approves aducanumab, it will stratify patient eligibility by disease stage and risk factors, and define stringently how to prescribe aducanumab and monitor patients. For example, APOE4 carriers are known to be at higher risk of ARIA but also had the greatest benefit, according to Biogen’s FDA briefing materials. Clinicians are hoping for guidance on how to deal with this conundrum. “In Europe, we are anxiously waiting for the decision of the EMA,” Schulz wrote to Alzforum. “I hope Biogen will support the learning curve by rigorously controlling access to the drug,” Levin concurred (full comment below).
In post-Brexit U.K., approval will come through that country's own regulatory agency, the MHRA. “So far in the U.K. the professional community is divided, with views ranging across the spectrum from condemnation of FDA to optimism for this being the gateway to a new research era,” Catherine Mummery at the National Health Service told Alzforum. She, too, hopes that any approval will require biomarker confirmation and disease staging (comment below). Other clinicians in European countries, who withheld their names, expressed hope that the EMA will be free to deliberate based on the data before them, without the stakeholder pressure that bore down on the FDA.
Despite the many open questions now, many researchers take the long view. They think approval of the first amyloid-lowering drug could spur the field forward. “I hope this approval, in combination with the advent of blood-based AD biomarkers, will quickly usher in the era of preclinical testing and therapy,” Erik Musiek at Washington University in St. Louis wrote to Alzforum.
Gil Rabinovici at the University of California, San Francisco, called on the field to work together to overcome the many challenges this new therapy will bring. “While the debate on aducanumab over the past few months has been very contentious, I hope that now that the FDA decision is made, we can move forward together to define the critical next steps in AD care and research,” he wrote to Alzforum. This was the overall tenor at the January 21 Alzheimer's Association webinar as well. —Madolyn Bowman Rogers
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