On June 7, 2021, the FDA approved the use of the drug aducanumab [trade name: Aduhelm] to treat persons with Alzheimer’s disease using its accelerated approval pathway. On July 8, 2021, the FDA narrowed the indication to match those individuals who were enrolled into the clinical trials, namely as having a diagnosis of Mild Cognitive Impairment (MCI) or Mild AD dementia. According to information provided about the drug, "Aduhelm is an antibody that targets amyloid-beta. The antibody preferentially binds to the aggregated amyloid-beta. This is because it targets an epitope that is not normally accessible in the amyloid-beta monomer. Through this interaction, Aduhelm could reduce the number of amyloid plaques present in the brain, potentially slowing neurodegeneration and disease progression." [source: Alzheimer's News Today]
In spite of the recognition by the National Institute of Health of Down syndrome as a high risk factor for Alzheimer's disease, no adults with Down syndrome (or with any other intellectual disability) were included in the original clinical trials that were undertaken by Biogen. Thus, questions have been raised whether aducanumab can help adults with Down syndrome and other types of intellectual disability. Questions have also arisen as to the practicalities as well as logistics issues. These questions involve consideration of:
What may be any possible adverse effects from the drug?
How it may be best administered to adults who may not tolerate monthly hospital visits?
What will be the diagnostic process for determining eligibility for atypical adults?
What may be the optimal dosage variance for adults with Down syndrome compared to other adults?
Whether insurers will consider adults with Down syndrome eligible for coverage?
What equity considerations will be supported by DHHS and the Courts?
Whether there will be financial aid for families due to the annual cost of the drug?
How will ancillary costs (pre-prescription PET scans and assessments and post-procedure associated surveillance) be covered for families of adults with Down syndrome?
Will state developmental disabilities agencies be required to initiate referrals for assessments and provide coverage for treatment for adults in their services?
Will there be funding to support specialized intellectual disability assessment centers equipped with infusion chairs and able to provide regular M.R.I. scans to track any potential side effects?
Will there be specialized training of hospital personnel at clinics with infusion chairs about the special needs of adults with Down syndrome?
How will family support groups be funded and managed for families whose off-springs with Down syndrome are participating in Aduhelm treatments?
Will there be time limits on prescriptions for Aduhelm treatments once dementia is determined to be advancing?
Will centers with infusion chairs and other supports set triage parameters on the type and number of adults they will treat?
What will be the parameters of informed consent by adults with Down syndrome to obtain use of the drug?
What has to be done to include adults with Down syndrome in any subsequent clinical trials?
What may be the measures of drug efficacy for most adults with Down syndrome and within what timelines given the syndrome-specific compression of the effects of Alzheimer's?
What point will adults with Down syndrome be eligible for receipt of the drug (that is, will it be able to used as a prophylactic given the inherent risk for Alzheimer's among adults with Down syndrome)?
At this point, it is known that the original clinical trials of aducanumab did not include any participants with Down syndrome or and adults with other forms of intellectual disability. The FDA's accelerated approval did not require biomarker confirmation and only requires a baseline and follow up MRIs. No information is available on consideration of persons with natural early presence of plaques but no overt signs of dementia. The approved outcome is based on clearance of amyloid and does not particularly focus on the cognitive outcomes as which were measured in the original Biogen studies (but not observed to a significant degree). The rate and risk of amyloid-related imaging abnormalities (ARIA) are very prevalent, which is not surprising since the monoclonal antibody is clearing amyloid and as a result the central nervous system (CNS) is reacting. The propensity and additional risk for micro-hemorrhages is expected in many people with Alzheimer's disease and this risk increases with the administration of Aduhelm and potentially is also dependent of the titration of the drug over the months of usage.
This preliminary knowledge raised many questions about the use of the drug with respect to its use with adults with Down syndrome. On July 20, 2021, an article in the Journal of Prevention of Alzheimer's Disease [J Pre Alz Dis] authored by J. Cummings, P. Aisen, L.G. Apostolova, A. Atri.,S. Salloway, & M. Weiner, with the title "Aducanumab: Appropriate Use Recommendations" was published. This article provides a comprehensive look at Biogen's Aduhelm, its history, and basis for use. It noted limitations about using the medication with neuroatypical groups. With respect to the medication's prescriptive use with adults with Down syndrome, the 'Expert Panel" noted that "Individuals with Down syndrome essentially uniformly develop brain amyloid plaques and often have symptoms of dementia in midlife. The presence of amyloid plaques in Down syndrome suggests that treatment with aducanumab may be beneficial. There are many differences between Down syndrome and late onset AD, and the Expert Panel recommends against treating Down syndrome." [p.9] Further, the Panel noted that "Patients with Down syndrome that meet all the other criteria for treatment with aducanumab may become treatment-eligible when additional studies have been conducted and additional data are available." [p.10] To this end, the NIH-funded Alzheimer's Clinical Trials Consortium - Down Syndrome (ACTC-DS) network is poised to address some of these questions in collaboration with Biogen and various regulatory agencies by running safety studies on persons with Down syndrome. That work is pending.
The NTG joined with other interested organizations in examining the scientific basis for the prescription for and treatment by Aduhelm among adults with Down syndrome. Preliminary discussions among scientific and medical colleagues have been held as well as discussions with Biogen. To this end, Dr. Seth M. Keller, the co-President of the NTG, led an effort to issue a collaborative scientific statement regarding the issues surrounding the use of aducanumab by adults with Down syndrome. The statement developed by the NTG Aduhelm and Down Syndrome Medical Advisory Group is posted below.
More recently, issues have arisen related to the prescribing and use of aducanumab within the general population. Given the paucity of data on the cognitive outcomes, a number of potential hospital-based infusion sites have declined participation, and some insurers have stated they will not pay for coverage until more clear outcome data are available. As the FDA has limited application of the medication to only adults with MCI or early stage dementia, any use with adults with Down syndrome would be considered 'off-label' until there are concise results from safety and application studies. The Cummings et al. Expert Panel report noted above (and sourced here) reinforces this caution.
Aduhelm Background Resources
We have assembled what background information is available on Aduhelm below.
Biogen's commentary on the application of Aduhelm to people with Down syndrome (provided in response to a query by the NTG) (June 24, 2021):
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 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.
AGS issues 'Aducanumab: What Clinicians Should Know' (7/16/21)
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 Medical Information Notice RE ADUHELM™ (aducanumab-avwa): Use in Persons with Down Syndrome (Trisomy 21) (8/4/21)
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.”
Talking points for physicians, patients and caregivers considering Aduhelm® infusion and the accelerated pathway for its approval by the FDA (Gandy et al. Molecular Neurodegeneration (2021) 16:74 https://doi.org/10.1186/s13024-021-00490-z) (2021)
"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."
American Academy on Developmental Medicine and Dentistry Position Statement:
"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)