What about the new IV drug aducanumab for a 90+ relative who is starting to exhibit obvious short term memory problems? A buddy asked me about it, marketed as Aduhelm, recently given FDA Accelerated Approval for reducing amyloid in Alzheimer patients.
Caregiving Old Guy will skip over the significant controversy in the approval process, which is easily found elsewhere; several well-known researchers resigned from their FDA scientific work after the green light action, apparently in protest.
Here’s the Prescribing Information [dated 6/2021], in FDA-approved package insert text, first page :
ADUHELM™ (aducanumab-avwa) injection, for intravenous use Initial U.S. Approval: 2021
__________________INDICATIONS AND USAGE _________________ ADUHELM is an amyloid beta-directed antibody indicated for the treatment of Alzheimer’s disease. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with ADUHELM. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s). (1)
_______________DOSAGE AND ADMINISTRATION ______________ • Titration is required for treatment initiation. (2.1) • The recommended maintenance dosage is 10 mg/kg administered as an intravenous infusion over approximately one hour every four weeks. (2.1) • Obtain a recent (within one year) brain MRI prior to initiating treatment. (2.2, 5.1) • Obtain MRIs prior to the 7th and 12th infusions. If radiographic severe ARIA-H is observed, treatment may be continued with caution only after a clinical evaluation and a follow-up MRI demonstrates radiographic stabilization (i.e., no increase in size or number of ARIA-H). (2.2, 5.1) …
___________________ CONTRAINDICATIONS ___________________ None. (4) _______________WARNINGS AND PRECAUTIONS _______________ • Amyloid Related Imaging Abnormalities (ARIA): Enhanced clinical vigilance for ARIA is recommended during the first 8 doses of treatment with ADUHELM, particularly during titration. If a patient experiences symptoms which could be suggestive of ARIA, clinical evaluation should be performed, including MRI testing if indicated. (2.2, 5.1) • Hypersensitivity Reactions: Angioedema and urticaria have occurred. If a hypersensitivity reaction occurs, promptly discontinue the infusion of ADUHELM and initiate appropriate therapy. (5.2)
___________________ ADVERSE REACTIONS ___________________ Most common adverse reactions (at least 10% and higher incidence compared to placebo): ARIA-Edema, headache, ARIA-H microhemorrhage, ARIA-H superficial siderosis, and fall. (6.1)
Five things stand out for CareGivingOldGuy: 1) there is no mention of appropriate stage of Alzheimer’s indicated, and there are no contraindications (so coma, stroke, brain injuries and co-morbidities are not excluded [although one assumes they were excluded from the study cohorts of prodromal, MCI and mild dementia subjects]);
2) although this is an anti-amyloid agent, it doesn’t seem to require the clinical demonstration of amyloid excess (PET scan or spinal fluid) to prescribe it; 3) a 12th dose is mentioned (i.e one year) for scanning, but no limit to duration is mentioned.
4) there is no mention of cognitive consenting issues or age limit (the “oldest old” as some researchers call those >age 85); 5) there is no mention of mandatory or voluntary followup studies, or an FDA REMS (Risk Evaluation and Mitigation Strategy) program.
Even the acne drug isotretenoin (Amnesteem, etc) requires an obnoxious REMS program and pledge from females to not get pregnant, with warnings about suicide.
Since final approval of Aduhelm is conditional on further data collection, not mentioning a followup study seems like a missed opportunity, or reflects a lack of urgency (but to be fair, #4 and #5 above are not usually in package insert text).
What does the text say about efficacy? …”In Study 1, treatment with ADUHELM high dose demonstrated reduced clinical decline, as evidenced by a statistically significant treatment effect on change from baseline in CDR-SB compared to placebo (-0.39 [-22%], p = 0.0120)…”[page 13]
In Study 2: “No statistically significant differences were observed between the ADUHELM-treated and placebo-treated patients on the primary efficacy endpoint, the change from baseline in CDR-SB score at 78 weeks.” [page 17]
In Study 3: “Clinical assessments in Study 3 were exploratory. [the terms “evidence,” “statistically significant,” and “clinically significant” are missing]. Results for clinical assessments were directionally aligned with the findings from Study 1, with less change from baseline in CDR-SB and MMSE scores at 1 year in the ADUHELM 10 mg/kg fixed-dose group than in patients on placebo (CDR-SB: -1.26, 95% CI [-2.356, -0.163]; MMSE: 1.9, 95% CI [0.06, 3.75]).” [page 19]
So.…”reduced clinical decline,” which seems like a failure to stop progressive decline, with no reversal or improvements in performance, seen only in Study 1, not really replicated in two other company clinical trials. That’s one aspect of the controversy, right there in the FDA approved package insert.
The side effect of brain changes on MRI is noted as “ARIA” (Amyloid Related Imaging Abnormalities). Here’s the table from the text:
Back to my buddy: he doesn’t care about the controversy, he’s not the primary caregiver or “care partner,” he doesn’t have power of attorney for healthcare (perhaps his sister does), he never had a conversation with his relative about what that person wants, their concepts of quality of life or how aggressive to be even for resuscitation, and my buddy doesn’t live nearby.
No question, though, that he loves and respects his relative, and is concerned.
The priority might be to start the conversation with the older person about what that person wants as specifically as possible, not what family members want, then get the paperwork done, and go from there! The estimated cost of $50K? He happens to be a financial guy.
Caregiving Old Guy won’t dwell on ideas about therapies that don’t cure but might help someone with quality of life….take palliative chemotherapy or radiation for example. Does Aduhelm improve quality of life? It’s a bit unclear how that was assessed in the trials, if at all.
Interestingly, France stopped financing the FDA-approved dementia drug donepezil years ago, for what they consider lack of efficacy. How Aduhelm figures into American palliative concepts of dementia care remains to be seen.
CC0 cocoparisienne@pixabay
And what about CareGivingOldGuy himself? If he make more typos on this blog, should he go in for a monthly Aduhelm cleanup infusion, like seeing a dental hygienist for cleanings, or seeing the guy who tops off his old car with detergent fluids, just more frequently?
He knows the High Mileage Stuff is probably hype; but getting a new vehicle for cognitive function, or even a reliable trade-in seems so hard right now, and the journey’s destination and timeline remain uncertain, so maybe paying extra is worth it (or is that another definition of emotional blackmail?)….the Car Talk guys would go nuts, since they thought that Americans already do way too many oil changes!
With “carte blanche” prescribing, and little apparent incentive to do the appropriate studies, we may never know how many infusions are too many….
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