I don't think donanemab will be used much but I disagree with many of your points. Donanemab won't expand the market in a measurable manner but will split the space with lecanemab. Unless longer term trials (which would be OLE- i.e. from AACI Exp 3 study, as well as IPTW historical comparisons with ADNI database) show that there is more stability over many years rather than just modest reduced progression over 1.5 years, this will always be a niche drug. I'd rather 3 year controlled data but that will never happen in AD. These are such niche drugs that I doubt any PET center is being stressed by AD patients.
My belief is that both lecanemab and donanemab have modest clinical benefit in early patients but they come with considerable administration and safety baggage. I believe lecanemab, but not aducanumab, approval was appropriate and I expect the FDA to approve donanemab. I am hopeful one of the oral small molecules will show definite benefit.
Donanemab is not a worse debacle than Aduhelm. The Ad Board voted 1-10 against and yet the FDA approved Aduhelm. 3 Ad board members quit in protest. One of two P3 trials outright failed in every measure except AB plaque removal. I don't know a single doctor who has used Aduhelm or thinks it has more than negligible benefit. Only a few hundred patients received commercial drug, many of them free drug and it is now not marketed. On the other hand, most recognize that lecanemab has modest benefit countered by significant risk.
The iADRS is basically a combination of the ADAS-Cog13 and the ADCS-iADL (MCI subset of ADCS-ADL), so it's not completely novel. It has been proposed as a substitute for the CDR-SB that may be more sensitive for the MCI to mild AD transition. The Ad Board did not seem too concerned, likely because there was still separation and significance for the two components when evaluated separately -- ADAS-Cog and iADL.
Tau is an interesting point. Like Amyloid PET, tau PET is expensive and small cities may not have capabilities. Interpretation is simple (easier than amyloid PET) so any radiologist can interpret in a couple minutes. It is FDA approved to demonstrate NFT but not covered. It is not used much outside of research studies. The presence of Tau has been correlated to more rapid conversion from MCI to AD. Indeed, only 15% of patients who are PET amyloid positive, Tau neg patients convert from MCI to mild AD over two years compared to 50% of tau positive patients. Higher tau is observed as AD progresses. People can be MCI x many years of stability but once one is mild AD, progression proceeds near universally, albeit at different rates for different patients. This brings up a real dilemma in neurology clinical trials - not just AD. Every trial has patients that are so mild that they are not expected to progress over the time of the trial (i.e. will enter the trial as MCI and 76 weeks later are still MCI - this could easily be > 50% of the patients!). They also have patients that are 'too far gone' (high tau) to have a benefit (i.e. some mild AD patients, especially educated ones, have MMSE in MCI range but are further along in neurodegeneration and less likely to respond to a drug). The vast majority of tau negative patients will go 76 weeks and be stable on iADRS (or other) with placebo and hence there is no likelihood of showing a benefit with drug in this timeframe -- they add noise to a study with no potential of signal, not a desired subject for a study. So, I understand Lilly was trying to increase the likelihood of a response by eliminating patients who are going to mostly go 76 weeks without change and trying to limit the number of patients who are further along (high Tau) and unlikely to respond based on P2 data. It is still positive amyloid pos / tau neg patients will get a benefit with Amyloid clearance in the brain - just not a benefit that could be proven over 76 weeks. As a clinician, to help make choices, I would love to see their pTau blood biomarker data in comparison to Tau PET and for stratification to see if this simple cheap test could predict who might benefit. I do not think Tau PET will be a requirement in the FDA approval package.
Very early (Amyloid positive, Tau low to medium) patients but not very very early AD patients were selected (amyloid positive but tau negative) for Expedition study. These patients have MCI and can be detected. They correspond to CDR global 0.5. MCI without Amyloid is unlikely to be AD (more likely depression, sleep apnea, some other dementia). Problem is many MCI patients stay MCI x many years before further progression - even when amyloid proven. This group is over-represented by the Tau negative patient
I didn't understand this "If the researchers who believe that amyloid beta and tau are the key elements in the brain’s immune system are, in fact, correct, then that would be a surefire guarantee no patient with AD was selected." Patients selected were amyloid and tau PET positive and if biopsied >90% would show clear AD pathology
"Is there any chance in hell that any healthcare benefit provider will pay to treat a patient who is perfectly healthy has no symptoms and under these guidelines would have no chance in hell of having AD?" The selected patients were MCI --- they had symptoms and were not cognitively normal. MCI patients work, drive, play golf, go on vacations, etc but are not performing at normal cognitive levels. Insurance will put up barriers of course. That seems to be how they interpret their job description and lecanemab is more difficult to approve than most drugs. I have only 2 lecanemab patients. Both are in 60's, work and have an active life. I don't do that much AD but most of my patients are not candidates. The 2 patients both understand our goal is to give them more time in MCI before AD affects them even more. They and their families understand the risk and are willing to take the risk. The expense of this drug is far less than most cancer drugs (with many extending life by just a few months on average) and rare disease drugs that may not make much of a difference (Acadia's trofinetide 600K a year for child to have slightly better behavior; ALS drugs and Muscular Dystrophy drugs with limited benefit not proven in larger trials.)
I think the amyloid clearance on PET and stopping treatment is an issue with donanemab, but a minor one. Hopefully more data becomes available from the OLE to help guide physicians in the future. Given the data, I would consider a 72 week PET scan and discontinue if amyloid cleared if able to get this covered. ARIA safety issues are seldom a problem after 24-36 weeks so 72 weeks has no more risk than 48.
