Reaction to the Centers for Medicare & Medicaid Services (CMS) proposed decision to limit coverage of the controversial and expensive Alzheimer’s drug aducanumab (Aduhelm) has been swift and polarized.

The drug’s approval by the U.S. Food and Drug Administration (FDA) on June 7 sparked a firestorm of controversy, including a nationwide investigation into the agency’s drug approval process and the resignations of several members of the FDA’s advisory board.

On Tuesday, CMS announced a proposed plan to pay for aducanumab, a monoclonal antibody (mAB), and other FDA-approved drugs of the same class under its CED (Coverage with Evidence Development) mechanism. This means the class would only be covered for patients on Medicare if they participate in qualifying clinical trials.

Opponents of the plan argue that this approach discriminates against many patients with the disease, while supporters see it as a step to protect patients from broad exposure to a drug with known risks and as yet unproven clinical benefits.

CMS officials intend to complete the restrictive coverage policy for aducanumab and related agents by April 11. The working hypothesis is that these drugs will keep Alzheimer’s at bay by removing amyloid beta from the brain. However, at this time there is no evidence that amyloid reduction has an impact on disease progression or other clinical outcomes.

In the coming weeks, there will be arguments from both sides of the Medicare coverage debate.

Groups such as the Alzheimer’s Association, USAgainstAlzheimers and the pharmaceutical industry argue that CMS policies are discriminatory.

In a statement, the Alzheimer’s Association said the limited payments proposed by CMS would mean that aducanumab and its expected follow-on drugs “would now be available only to a privileged few and those with access to research facilities, which would exacerbate and create further health inequalities.”

George Vradenburg, chairman and co-founder of the UsAgainstAlzheimer patient group, agreed.

“Why is treating Alzheimer’s patients held to a different standard than treating cancer, HIV and other diseases? Is it because we are so many? Is it because we’re old?” Vradenburg said in a statement.

“Medicare has doubts about the FDA — not only in terms of the work that has already been done, but also in terms of the work that the FDA will do in the future,” he added.

Others see the CMS proposal as a necessary step to limit the use of aducanumuab and similar drugs until there is clear evidence that they are clinically beneficial. In its proposed decision memo, CMS highlighted the repeated failure of drugs that clear amyloid but do not impact clinical outcomes.

“To date, no study using an anti-amyloid mAb has unequivocally demonstrated a clinically meaningful improvement in health outcomes (ie, cognition and function),” the CMS collaborators wrote.

CMS coverage of the IBD pathway could serve to spur more research into this class of drugs, the agency noted.

CMS support

As reported by Medscape Medical News, the Phase 3 EMERGE trial, which was the basis of the FDA approval, “demonstrated a slight but statistically significant improvement,” the CMS memo said. On the other hand, EMERGE’s sister study ENGAGE showed no significant benefit.

David Knopman, MD, a Mayo Clinic clinical neurologist and one of three members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee who resigned over the agency’s approval of aducanumab, commented on the CMS decision for Medscape Medical News and said what “is undeniable is that the evidence from the two pivotal aducanumab trials failed to demonstrate clinical benefit.”

“The FDA ultimately concluded that aducanumab had not demonstrated any clinical benefit in the studies, so based their decision to accelerate approval solely on the surrogate biomarker. CMS also recognized this apparent deficiency in the available clinical efficacy data,” added Knopman, who did not attend the aducanumab Advisory Committee meeting due to his involvement in clinical trials of the drug.

Aaron Kesselheim, MD, JD, Professor of Medicine, Harvard Medical School, Boston, Massachusetts, also resigned from the PCNS Advisory Committee in the wake of aducanumab approval.

Kesselheim has also been an outspoken critic of the FDA’s handling of the expedited approval process, including questions about the standards the agency accepts for confirmatory data.

However, Kesselheim said there was little doubt about using tumor growth as a surrogate marker in oncology. In contrast, there are growing doubts as to whether amyloid is the right target for AD drugs.

“If the tumor shrinks or you get a response rate, that’s generally considered a good thing,” he said.

In contrast, due to many amyloid drug setbacks, there is increased interest in other potential targets for AD drugs like tau, he added.

“Amyloid plaque replacement is very, very controversial,” Kesselheim said. “My perception is that because all the drugs that have tried to assess changes in amyloid plaques have failed, the field has come to think of tau and tangles and other things as surrogates.”

Zaldy Tan, MD, MPH, Cedars-Sinai Medical Center, Los Angeles, California also supports the CMS approach to aducanumab and other follow-on drugs.

The IBD pathway ensures that patients receiving the drug are those whose condition qualifies them for treatment. Additionally, it will help efforts to determine through testing which drugs have been developed to treat AD labor, he told Medscape Medical News.

“This is probably the best way. It allows access, but in a controlled way,” said Tan, who serves as the medical director of the Goldrich Center for Alzheimer’s and Memory Disorders in Cedars-Sinai.

Tan said he’s discussing aducanumab with his patients who are interested in the drug, although he doesn’t currently prescribe it. He also alerts her to the possible complications of the drug, which include brain swelling and bleeding. Tan said he emphasizes to his patients what the data shows and what doesn’t.

Biogen’s answer

Biogen and its influential allies, which include Pharmaceutical Research and Manufacturers of America (PhRMA), are trying to persuade CMS officials to revise their proposed stance on aducanumab.

In a statement, the PhRMA said Medicare’s approach to covering the drug usurped the FDA’s role.

“With this proposal, CMS is writing off an entire class of drugs before multiple products have even been reviewed by the FDA, positioning itself, rather than the FDA, as the primary arbiter of clinical evidence,” PhRMA said in a press release.

Biogen argues that the CMS proposal would unfairly cut off access to aducanumab.

Earlier this week, Endpoints News reported that Biogen intends to “flood CMS with comments over the next 30 days to ensure the final version of the proposed policy does not reflect Tuesday’s draft,” citing an internal email, reviewed by the publication.

“Even the largest (randomized clinical trials) in Alzheimer’s disease were limited to a few thousand patients, 30 to 50 percent of whom received a placebo,” Biogen said in a statement.

“The population with access to reimbursement for such IBD would probably only number in the hundreds of patients, so the majority of AD patients continue to decline with no hope of intervention,” she added.

Under the FDA’s accelerated approval process, Biogen is yet to provide solid scientific evidence that aducanumab has clinically significant disease-modifying effects. The Company plans to begin patient screening for a post-launch confirmatory study of the drug in May, with a primary completion date of approximately 4 years from the start of the study.

CMS is accepting comments on its proposed coverage policy until February 10th. Medicare already covers many of the routine costs associated with clinical trials, a policy that has been in effect since 2000. In the case of aducanumab, CMS intends to post the final NCD for amyloid-targeted monoclonal antibody drugs after publication.

Kerry Dooley Young is a freelance journalist based in Washington, DC. She is the core topic lead on patient safety issues for the Association of Health Care Journalists. Young previously covered public health policy and the federal budget for Congressional Quarterly/CQ Roll Call and the pharmaceutical industry and Food and Drug Administration for Bloomberg. Follow her on Twitter @kdooleyyoung.

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