With Food and Drug Administration approval decisions for the amyloid antibodies lecanemab and donanemab expected this year, the Centers for Medicare and Medicaid Services have clarified how they plan to cover these drugs. In a June 1 statement, the agency confirmed its earlier decision that coverage for traditionally approved anti-amyloid antibodies will be contingent on physicians entering treatment and outcome data into a patient registry (Apr 2022 news). “Clinicians will be able to submit this evidence through a nationwide, CMS-facilitated portal that will be available when any product gains traditional approval, and will collect information via an easy-to-use format,” the agency said.

One such patient registry in development is ALZ-NET, by the Alzheimer’s Association (Aug 2022 conference news). At AD/PD 2023 in Gothenburg, Sweden, the association’s Maria Carrillo said that more than 100 U.S. sites are enrolled, and the first 18 patients have been registered. Other countries, including Japan, Australia, and the U.K., are interested in starting similar programs, she added. For its part, CMS did not name specific registries, but noted that it is working with several organizations that are developing such programs. Qualifying registries will eventually be listed on the CMS website. Researchers will have access to de-identified data from these registries, the agency added.

Advocacy groups criticized the decision.“[It] may limit access to those who are not located in a major metropolitan center, or who may or may not have a trusted local healthcare provider equipped to add electronic data entry to their everyday practice pattern,” the Global Alzheimer’s Platform Foundation said in a statement.

Industry seemed less concerned, with one analyst noting that AD patients on amyloid immunotherapy need high levels of monitoring in any case, due to the risk of ARIA, aka amyloid-related imaging abnormalities. Thus, the therapy will already be restricted in practice to people who can make frequent visits to well-equipped medical centers. Real-world data collection is a growing practice for new medication types.

The FDA’s Advisory Committee meets June 9 to make recommendations on traditional approval of lecanemab (Mar 2023 news). The antibody is already available under the accelerated approval pathway, but this use is not covered by CMS (Jan 2023 news). The FDA is expected to consider an application for donanemab full approval, based on its positive Phase 3 results, later this year (May 2023 news).—Madolyn Bowman Rogers

Comments

  1. Requiring enrollment in registries will not serve CMS's stated goal of increasing the quality of evidence for use of anti-amyloid immunotherapy. Alzheimer's disease researchers will study these medications anyway with high-quality registries and other observational and interventional studies whether or not CMS requires it. CMS adding their own requirements will not increase the speed at which we learn more about anti-amyloid immunotherapy unless CMS plans to pay for the studies (other than listing them on their website). Instead, adding the research requirement will only exclude patients from receiving the medications who cannot or wish not to participate in research.

    CMS may be using its coverage restriction, ostensibly about safety, to control costs. But requiring research participation as a coverage requirement in order to reduce expenses is unethical. If the price is the issue, perhaps CMS should say so, even if they cannot negotiate it down.

  2. There would be a high value in a more objective rating of treatment if CMS would devise standards, such as complete prevention of any deterioration and relevance of rating scale results to real life, that we could all adopt. I hope that is what they plan.

    This is necessary because neither lecanemab or donanemab prevented decline in the reported studies. They only produced a slightly slower rate of decline in questionnaire-type assessments. For example, using the CDR-Box test at 18 months, Van Dyck et al.’s lecanemab active group’s mean score declined by 1.22 points versus 1.66 on placebo (Van Dyck et al., 2023). These are interviews that rate patients in six domains of functioning: memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care. Each domain is rated on a five-point scale: 0 = no impairment; 0.5 = questionable impairment; 1= mild impairment; 2 = moderate impairment; and 3 = severe impairment. In the study, both active and placebo groups set out with a mean score of 3.2, so on average they had mild impairment in just over three of the six domains. So, the mean difference of 0.44 points between groups at 18 months was less than a rating of "questionable" in only one of the six domains. It is so small that its clinical benefit needs to be defined in more practical ways.

    After as long as 76 weeks, Mintun et al.’s patient group given donanemab declined by 6.86 points in the Integrated Alzheimer's Disease Rating Scale and the placebo group by 10.6 points, a difference artfully portrayed as a 40 percent lesser decline (Mintun et al., 2021). There are reasons to think blinding was not always secure in this study, largely due to side effects, so such a small difference is also questionable in that regard.

    In any other disease, treatments as poor as this would have been abandoned, especially given the risk of the potentially severe side effect of ARIA .

    References:

    Evidence for lecanemab in early Alzheimer's disease. Drug Ther Bull. 2023 Mar;61(3):37. Epub 2023 Feb 1 PubMed.

    . Donanemab in Early Alzheimer's Disease. N Engl J Med. 2021 May 6;384(18):1691-1704. Epub 2021 Mar 13 PubMed.

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References

Therapeutics Citations

  1. Leqembi
  2. Donanemab

News Citations

  1. Drilling Down into the CMS Aduhelm Decision—A Primer
  2. Bringing Aduhelm—and Antibodies to Come—Into Practice
  3. Decision Date on Leqembi Traditional Approval Set for July
  4. U.S. FDA Gives Green Light to Leqembi, aka Lecanemab
  5. And Then There Were Three: Donanemab Phase 3 Trial Positive

External Citations

  1. June 1 statement
  2. CMS website
  3. statement

Further Reading