Aduhelm & Down Syndrome

Official statement from FDA re: its accelerated pathway approval of Aduhelm

Official NIH statement re: Adehelm

Initial statement regarding Aduhelm's use with adults Down syndrome

Prescription protocol for use of Aduhelm issued by Biogen

Brief web article on Biogen's clinical trials

Web article summarizing the technical information re: clinical trials for aducanumab

Detailed description of aducanumab, issues related to its clinical trials, and other factors

Detailed narrative of insurance issues for families with a member receiving Aduheim

 Commentary on perspective of critics and defenders with analysis of potential costs

Commentary/analysis on financial aspects of paying for Aduhelm and how Medicare might cover its costs June 24, 2021, pp B1, B6.

• Aducanumab has not been studied in patients with Down Syndrome associated Alzheimer’s disease (DS-AD), and there are no data on the efficacy and safety in this special population. ADUHELM has been approved under accelerated approval for the treatment of Alzheimer’s disease (AD) based on reduction in amyloid beta plaques observed in patients treated with aducanumab. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).

• Biogen has been involved with the research community in discussions around the supplemental evidence needed in DS-AD should a drug be approved for sporadic AD (most recently in the Critical Path Innovation Meeting (CPIM) organized by Lumind)

• Biogen welcomes input from experts in DS-AD as well as from the FDA and other Regulatory Agencies to advance research and potential treatments for people with DS-AD

Commentary by Dr. Han Yu on the background of Biogen's work on Aduhelm and what alternative theories purport is responsible for Alzheimer's disease.

Commentary on controversy of FDA's approval of Aduhelm and alternative hypotheses for the cause of Alzheimer's disease

Article on Biogen's drug, Aduhelm, which now has been deemed only appropriate for patients with mild or early-stage Alzheimer’s as it had not been studied in patients with more advanced disease. Previously, the FDA instructions said simply that the drug was approved for Alzheimer’s disease in general.

New story on FDA asking DHHS's Inspector General to undertake review of the basis for the FDA's approval of aducanumab for the treatment of Alzheimer's, including examining the connections between FDA staffers and Biogen. Concerns over the FDA's approval of the drug stems from not only potentially problematic interactions between the agency and Biogen but also uncertainty over the effectiveness of Aduhelm.

Report notes that Medicare will most likely bear much of the cost of Aduhelm for the majority of seniors affected by Alzheimer's. However, those affected will have to pick up 20% of the cost (or about $11,500). State and federal Medicaid spending will cover some costs as Medicaid pays the premium for Medicare beneficiaries. Adults with early-onset Alzheimer's disease (such as those adults with Down syndrome) and enrolled in Medicaid should be covered by state Medicaid programs. However, much of this impact upon Medicare and Medicaid has yet to be determined. [Report authored by Tami Luhby, CNN, and adapted to note impact on adults with intellectual disability]

The Centers for Medicare & Medicaid Services (CMS) has opened a National Coverage Determination (NCD) analysis which permits CMS to 'carefully review and determine whether Medicare will establish a national Medicare coverage policy for monoclonal antibodies targeting amyloid for the treatment of Alzheimer’s disease.' The 30-day public comment period began 7/12/2. CMS also hosted public listening sessions on July 22nd and 27th to receive public comments.

The American Geriatrics Society has noted that before prescribing clinicians should review full prescribing information and know any prior authorization and other requirements for prescribing. Based on their review of the available data, the AGS recommends that clinicians only consider prescribing aducanumab after confirming the patient is a candidate for this treatment, informing them as to what is known about it, and discussing whether the potential clinical benefit outweighs the risks.  This statement provides detailed information for physicians about the medication and its conditions for use.

The NTG in collaboration with a group of experts, and endorsed/supported by a number of national organizations, has issued a preliminary statement on issues related to the use of Aduhelm by adults with Down syndrome.  Posted is the current statement (8/2/21); updates will include additional information and sign-ons. 

A version of the statement, published in Exceptional Parent, can be accessed here. 

An article in the Journal of Prevention of Alzheimer's Disease, authored by Cummings, Aisen, Apostolova, Atri, Salloway, & Weiner, noted that Bioden's new medication, aducanumab, has been approved by the US Food and Drug Administration for treatment of Alzheimer’s disease (AD). Aducanumab is an amyloid-targeting monoclonal antibody delivered by monthly intravenous infusions. The pivotal trials included patients with early AD (mild cognitive impairment due to AD and mild AD dementia) who had confirmed brain amyloid using amyloid positron tomography. As clinicians require guidance on the appropriate use of this new therapy, an Expert Panel was assembled to construct Appropriate Use Recommendations based on the participant populations, conduct of the pivotal trials of aducanumab, updated Prescribing Information, and expert consensus. The Expert Panel recommended that use of aducanumab be restricted to this population in which efficacy and safety have been studied. As aducanumab is titrated to a dose of 10 mg/kg over a 6-month period, the Expert Panel recommended that the aducanumab be titrated to the highest dose to maximize the opportunity for efficacy. Given that aducanumab can substantially increase the incidence of amyloid-related imaging abnormalities (ARIA) with brain effusion or hemorrhage, dose interruption or treatment discontinuation is recommended for symptomatic ARIA and for moderate-severe ARIA. The Expert Panel recommended the use of MRIs prior to initiating therapy, during the titration of the drug, and at any time the patient has symptoms suggestive of ARIA. The Expert Panel also recommended that measures less cumbersome than those used in trials be used for the assessment of effectiveness in the practice setting. The Expert Panel emphasized the critical importance of engaging in a process of patient-centered informed decision-making that includes comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits.

Biogen's notice is offered as an educational resource for healthcare providers in response to an unsolicited request by Dr. Seth Keller, co-President of the NTG. The notice indicates that aducanumab-avwa has not been studied in persons with Down Syndrome associated Alzheimer’s disease (DSAD), and there there are no data on the efficacy and safety in this population. The notice cites the work of Cummings et al (2021)  which acknowledges as that there are many differences between Down syndrome and late onset AD and as such, it is recommended against treating persons with Down syndrome with aducanumab-avwa until more data are available. According to Cummings et al., persons with Down syndrome may eventually become eligible for treatment after additional studies have been conducted and additional data are accrued for this group of individuals. It also cites various sources, including the NTG, recommending the generation of more applicability and use protocols.

Reuters has reported that Eli Lilly "plans to seek U.S. approval for its experimental Alzheimer’s disease drug by year end and believes the treatment could be favored by doctors once it becomes available to patients.” The company “said mid-stage data it plans to submit to regulators for its donanemab showed that the drug more effectively cleared amyloid beta brain plaques than any other treatment.”  Eli expects to have information on cognitive improvement benefits in 2023 following the completion of a trial currently underway.

An article in The Conversation notes that the possible approval of aducanumab by Health Canada highlights a series of debates and concerns about how we approve new drugs. The Fraser Institute, a free-market think tank, would like Health Canada to dispense with its own reviews and automatically accept any drug approved by either the FDA or the European Medicines Agency. Read more: FDA approval of controversial Alzheimer's drug could delay discovery of more promising treatments. Given the contortions that the FDA went through to allow aducanumab on the U.S. market, that might not be such a good idea. The recent report from the House of Commons Standing Committee on Transport, Infrastructure and Communities on Boeing’s 737 Max also highlights the dangers of abandoning regulatory oversight to other governments, in this case Transport Canada’s reliance on the U.S. Federal Aviation Authority. The FDA Advisory Committee, composed of outside experts, almost unanimously recommended rejecting Biogen’s application to market aducanumab. Health Canada also uses expert advisory panels and committees for policy issues and technical advice, but not for opinions about whether to approve a new drug. That means that Health Canada will not be getting any outside expert advice about aducanumab. After the disappointing results of trials on the drug in 2019, Biogen initially decided to abandon work on aducanumab. Subsequently, there are allegations that FDA officials held almost daily back-channel meetings with Biogen throughout the summer of 2019 to determine if there was a way to reinterpret the data and resuscitate the drug.  The acting head of the FDA is requesting an investigation by the inspector general for the Department of Health and Human Services into whether these meetings were inconsistent with the FDA’s policies and procedures. Health Canada also meets with companies before they submit drugs for approval so that sponsors can outline the evidence of effectiveness. If meetings have taken place with Biogen there will not be any public record of what was said in them or even if they occurred. Finally, regardless of whether Health Canada approves or rejects Biogen’s application, we will never see what sort of debate went on inside the agency about the safety and effectiveness of the drug. Health Canada will eventually release virtually all of the data that Biogen submitted, but any internal discussions will remain a secret.

An article by A. Rappeport and M. Sanger-Katz, 'Social Security Seen as Falling Into the Red In 12 Years', in the September 1st (2021) issue of the New York Times, noted that actuaries for the health of the nation's Medicare program may uncertain given the annual expenditures required to cover the cost of Aduhelm.  It was noted the estimates on the program of Aduhelm, " a very expensive Alzheimer's treatment that was recently approved by the [FDA]."  They authors noted that officials were waiting for Medicare to issue guidance on how the drug would be covered before making any calculations.  They noted that "the drug could represent tens of billions of dollars in spending each year."

Two powerful congressional committees investigating the controversial federal approval of Biogen’s Alzheimer’s drug, Aduhelm, have demanded extensive information and documents from the Food and Drug Administration in a letter released on September 2nd, making it clear that the committees’ leaders are troubled by unusual actions the agency took in the course of evaluating and approving the drug.  “F.D.A. granted accelerated approval for the drug despite concerns raised by experts — including the agency’s own staff” and members of its independent advisory committee, the letter said. “We are also concerned by reports of unusual coordination between F.D.A. and Biogen throughout the drug’s approval process,” the committee added.

The New York Times (Thursday, November 18, 2021, p. B3) reported that “The drug maker Biogen said on Wednesday that a panel of drug reviewers in the European Union had indicated that its new Alzheimer’s drug was unlikely to be approved there, the latest setback for a medication that has been mired in controversy since it was approved in the United States in June.  Biogen said a committee of experts that advises the European Medicines Agency had issued a “negative trend vote” — a preliminary signal that typically precedes a recommendation that the drug not be approved — on the company’s application for the drug, Aduhelm, this month. The panel will formalize its recommendation at a meeting next month.  The company’s interim research chief, Dr. Priya Singhal, said Biogen was “disappointed” with the panel’s vote. Biogen said in a statement that it would continue to work with European Union regulators “as it considers next steps” to try to get the drug approved in Europe. ***  In the United States, the federal agency that administers Medicare is reviewing whether to standardize coverage of the drug nationwide, a step that could restrict which patients receive it. A draft decision is expected in January, with a final decision by April.”

"The major controversy and challenge to clinician prescribers is the massive information gap making it nearly impossible to determine how to inform patients and families about this drug including the lack of guidance and contradictory information: (1) Between the FDA Ad Comm advice and FDA approval; (2) That Aduhelm®‘s mechanism of action is based on the presence of elevated brain amyloid, but the prescribing information does not require that abnormality to be proved before initiating treatment; (3)  That accelerated approval is based on a surrogate biomarker yet no requirement to measure that biomarker to manage the therapy; (4) That ignores the mismatch between well characterized clinical trial populations with multiple exclusions and the broad indication for patients who might be treated with the drug; (5) That as of August 30, 2021, there is no peer-reviewed manuscript on the two pivotal trials on which the initial application for approval was based."

"While the “accelerated approval” would dictate post-approval continued clinical trials to determine the presence of a meaningful clinical effect, the 9-year period to accomplish this is obviously useless to patients and prescribers now and exceeds the expected lifespan of many of those who are eligible to undergo treatment. Despite over a decade of research, the reduction in brain amyloid burden has not been consistently associated with meaningful clinical benefit. The current generation of anti-amyloid antibodies is unusually efficient in clearing amyloid, yet there is no evidence for clinical benefit. Indeed, 18 months of treatment with many anti-amyloid agents has shown no change or mild, mostly non-significant worsening. Only in the last few years have antibodies been developed that can effectively remove most if not all detectable amyloid plaques from the brain as detected by amyloid imaging. Of those anti-bodies utilized at a high enough dose to have this effect, only aducanumab has completed phase III trials. Three other antibodies including donanemab, lecanemab, and gantenerumab have completed phase 2 trials. Published phase 2 data from donanemab showed ~ 33% slowing of cognitive decline on a prespecified endpoint. However, as noted, definitive phase 3 trials have not yet been completed so a clinically meaningful effect remains to be proven. The cost of Aduhelm® and the prospects for third party reimbursement remain controversial and relevant. The estimated cost for drug alone is US$ 56,000 per year per patient with total costs for infusions, physician fees, etc., estimated to exceed US $100,000 per year per patient. According to the FDA statistician’s analysis, only patients that carry an APOEε4 allele demonstrated an effect on clinical outcomes, and, ironically, those with APOEε4 alleles are also more likely to experience brain microhemorrhages ARIA-h (for amyloid-related imaging abnormalities - hemorrhagic) and brain edema (ARIA-e). In trials, subjects were excluded based on the presence of an excess number of brain microbleeds and were dropped from further infusion after the 10th brain bleed."

"The AADMD's position regarding the prescription and use of all drugs that have been evaluated by the FDA's accelerated approval pathway (which can be used to fast-track a drug that provides a meaningful therapeutic advantage over existing treatments for a serious life-threatening illness) is that their use should be a shared decision made by a physician, the patient, and any other significant and bona fide contributors to the decision-making process.  As additional information and evidence regarding the drug's safety and efficacy is made available, its applicability to distinct groups of adults (e.g., special populations such as adults with Down syndrome) may receive a definitive endorsement by the AADMD. Until that information is made available, we counsel caution and careful assessment as to whether the drug’s use would be safe and beneficial.  As a matter of policy, the AADMD encourages and supports the ethical and appropriate representation of "special populations" in all clinical trials designed to evaluate the safety and efficacy of any drugs for use with specific populations and recommends that the FDA require the inclusion of adults from distinct groups in any further clinical trials."  (Draft v. 6/8/21)