On June 10th, the FDA convened an advisory panel to debate the standing of donanemab, drug maker Eli Lilly’s newest beta-amyloid concentrating on monoclonal antibody for Alzheimer’s illness. The hours-long assembly included slides early on specifying that dialogue factors would come with whether or not the advisory committee thought donanemab was efficient, dosing concerns, and whether or not the advantages of the drug outweighed the dangers. On the finish of the assembly, the panel voted unanimously 11-0 that donanemab is efficient at slowing Alzheimer’s in early-stage illness and that the advantages outweigh the dangers. Whereas this resolution alone doesn’t characterize approval of the drug, the FDA is anticipated to behave on the advice of its advisory panel within the coming months.
Presenting the proof
In March the FDA had initially introduced it might postpone a call relating to approval to additional examine and ask for added data relating to trial information. Arguably the largest trial in query, the TRAILBLAZER-ALZ 2 trial, got here out final 12 months. It concluded that donanemab statistically considerably slowed medical development at 76 weeks in these with baseline low/medium tau and within the mixed low/medium and excessive tau pathology inhabitants.
The advisory panel was convened in June to debate quite a lot of points, together with the excessive charges of uncomfortable side effects (24% mind swelling and 31% mind bleeding within the donanemab teams). Sufferers within the donanemab group had been solely handled till amyloid plaque ranges reached a pre-specified set level at which level therapy was stopped, representing the “limited-duration dosing routine” referred to. Baseline tau ranges had been used to stratify sufferers.
Within the trial outcomes, medical development of Alzheimer’s was slowed in these within the low/medium tau group and within the mixed low/medium and excessive tau group. However the “excessive” tau group alone didn’t have an improved built-in Alzheimer Illness Score Scale rating (iADRS), the first consequence measure within the trial (although members did present enchancment with a secondary consequence measure, the medical dementia ranking scale sum of bins or CDR-SB rating). Sufferers with larger tau burdens can be extra in danger for growing Alzheimer’s to start with. If the drug had been to be authorized, questions surrounding who to supply it to and the way to supply them the drug should be addressed.
The assembly included displays on efficacy and security outcomes by officers at Eli Lilly, alternatives for clarifying questions from the committee, and an open public listening to with audio system unaffiliated with the FDA having the chance to chime in. On the finish of the session, every of the 11 advisory committee members had a chance to share their ideas briefly when discussing their votes.
Reservations
Though the votes of affirmation for donanemab had been unanimous, not all committee members shared an unbounded enthusiasm. For instance, Dr. Nilufer Ertekin-Taner from the Mayo Clinic gave her vote of affirmation with the understanding that the information aren’t clear for all populations of curiosity, together with these with two copies of the APOE4 gene (a powerful Alzheimer’s danger issue), and in African American and Latin American sufferers.
If authorized, donanemab would be part of fellow beta-amyloid concentrating on monoclonal antibody lecanemab (Leqembi™) because the third FDA authorized disease-modifying Alzheimer’s therapy whereas looking for to keep away from the destiny of the primary authorized remedy, aducanumab (Aduhelm™), which has since been pulled from the market by maker Biogen attributable to difficulties producing enthusiasm and acquiring insurance coverage protection for his or her drug. Each lecanemab and aducanumab had been authorized underneath the FDA’s accelerated approval pathway, the place drug approval is predicated not on medical efficacy however on displaying efficacy in attaining a surrogate endpoint. In these circumstances, the endpoint was a discount of beta-amyloid plaques. Critically, nevertheless, the hyperlink between beta-amyloid and cognitive decline is much from sure.
The amyloid speculation and the tau speculation
The speculation that beta-amyloid is linked to cognition, or the amyloid speculation, posits that the buildup of beta-amyloid fibrils underneath pathological circumstances (comparable to with Alzheimer’s illness) results in the event of plaques which might be neurotoxic and result in cognitive decline. Preliminary pleasure for this speculation was linked to the truth that people with Down syndrome who’ve three copies of the amyloid precursor protein gene as an alternative of the common two have the next price of growing Alzheimer’s Illness. This protein is concerned within the technology of beta-amyloid peptides.
Nevertheless, not everybody with Down syndrome who develops beta-amyloid plaques has gone on to develop Alzheimer’s illness. Moreover, in different experiments utilizing genetically modified mice with elevated beta-amyloid manufacturing, nerve cell demise was not noticed as anticipated. Additionally, with the more moderen introduction of imaging for amyloid plaques in people, many sufferers with out recognized cognitive decline have intensive amyloid deposits, whereas many sufferers with Alzheimer’s Illness have few amyloid deposits. There are nevertheless mutations in amyloid genes recognized that are linked to early onset familial Alzheimer’s, although these characterize not more than 10% of Alzheimer’s circumstances.
Altogether, although the preliminary enthusiasm for the amyloid speculation was excessive, there are holes. One other protein known as tau has additionally been implicated within the improvement of Alzheimer’s illness. Particularly, when tau is hyperphosphorylated (termed neurofibrillary tangles if they’re fashioned in neuronal cell our bodies), it’s strongly correlated with the event of cognitive signs. Imaging methods to review the patterns of tau pathology in addition to autopsy research of sufferers confirmed a lot better correlation between tau pathology and cognitive standing. The tau speculation has at the moment garnered extra help for direct correlation with cognitive decline in Alzheimer’s illness.
Regardless, interpretation of trial information for all three amyloid concentrating on medicine purported to indicate not simply clearance of beta-amyloid but additionally much less cognitive decline in comparison with placebo. These observations raised many questions, together with the extent to which beta-amyloid is straight associated to cognition, the extent to which modulation of beta-amyloid modulates tau, and – crucially — the extent to which the trials displaying profit had been run properly and had their information interpreted accurately.
What occurred with aducanumab?
Within the case of aducanumab, solely one of many section 3 trials confirmed slight profit, however solely in males over the age of 70 with a duplicate of the APOE4 gene. Although the opposite trial didn’t present profit, a post-hoc evaluation that studied solely these receiving not less than 14 therapy classes with a “excessive” dose of the drug did present some profit.
Though an FDA advisory committee voted closely towards recommending aducanumab through the normal pathway primarily based on medical efficacy, the FDA switched its evaluation to that of the accelerated approval pathway primarily based on the surrogate endpoint that displaying removing of beta-amyloid by itself was adequate after which authorized the drug. This was performed with out session with the advisory committee, main 3 members of the advisory committee to resign. A congressional probe later discovered atypical collaboration between Biogen and the FDA. Biogen finally discontinued improvement of aducanumab in January of this 12 months.
The devils within the particulars
The “Lecanemab in early Alzheimer’s Illness” trial was printed in late 2022 and concluded that lecanemab lowered markers of amyloid in early Alzheimer’s illness and resulted in reasonably much less decline on measures of cognition and performance than placebo at 18 months. Not extensively publicized was that per the trial information, lecanemab didn’t gradual cognitive decline in girls, and in reality enhanced decline in these with 2 APOE4 genes. Curiously, trial information for aducanumab, lecanemab, and donanemab do present discount in phosphorylated tau ranges, protecting open the query of a threshold stage of amyloid which influences tau pathology.
One other situation plaguing the trials had been the nagging query of practical unblinding which can be contributing to the optimistic outcomes. In section 3 trials of amyloid-targeting medicine, 21% to 44% of sufferers on energetic therapy developed mind bleeding or swelling, given the acronym ARIA for amyloid-related imaging abnormalities. A latest evaluation postulated that the event of ARIA would have triggered protocol adjustments that will have unblinded sufferers and people round them to their therapy. This similar evaluation discovered a optimistic correlation between the incidence of ARIA-E (E for edema; mind swelling) and reported efficacy of the medicine in query.
An extra level of criticism was how a sensitivity evaluation aimed to account for practical unblinding within the TRAILBLAZER ALZ-2 Trial, through which sufferers with ARIA-E had their put up ARIA information factors changed with extrapolated information factors from the common course of sufferers receiving donanemab who didn’t develop ARIA-E. It’s also well-known that ARIA usually tend to happen in these with the APOE4 gene mutation and, as beforehand talked about, that APOE4 is extra more likely to result in Alzheimer’s. This could have successfully eliminated people most in danger for growing Alzheimer’s illness from the donanemab group.
Lastly, whereas ranges of statistical significance have been hit within the aforementioned trials, a further level of competition is when these adjustments change into clinically significant. It’s been steered that the edge for a significant distinction is a within-patient change of CDR-SB rating of 1. With this in thoughts, neither donanemab nor lecanemab throughout their respective trial intervals improved scores this a lot. Nevertheless, the CDR-SB scale might also not seize one’s cognition very properly.
So, is it value it?
Now that the FDA advisory committee panel has unanimously voted to offer donanemab the inexperienced gentle, it appears near a positive guess that donanemab will probably be authorized within the subsequent few months. Nevertheless, with the above reservations in thoughts, there stays uncertainty. To drill this down correctly and instill public confidence, extra transparency is required. This contains extra information on within-trial topic stage information. With out elevated transparency, it’s arduous to disregard the reservations relating to donanemab and its predecessors.
If, as is the case with donanemab, sufferers with larger baseline tau pathology don’t see a profit of their iADRS, then these most prone to growing cognitive decline stand to profit the least. An enormous query can be whether it is value it to pre-emptively recommend a drug like donanemab to sufferers with suspected early Alzheimer’s illness earlier than signs progress.
With the reservations mentioned above, the facet impact profile, and the tenuous nature of the amyloid speculation on which the premise of medical efficacy is predicated, it shouldn’t be steered to sufferers presently. However, if already authorized, it’s additionally arduous for clinicians to place a full cease on providing the drug to sufferers asking for it. On this case, so long as clinicians are open concerning the uncertainties, the rest of the decision-making ought to fall to the affected person.
