Alzheimer's disease: new bad meds and a new FDA-approved med that may help

 

A couple of new articles on treatment of Alzheimer’s disease came out in the last couple of weeks. The first is an investigative report on some monoclonal antibodies that delayed symptoms of Alzheimer’s for a few months but at a remarkably high risk of very serious adverse events in an ethically fraught study; the second is potentially redeploying  a schizophrenia drug as a treatment for Alzheimer’s

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New York times had a very recent and remarkably disturbing article on new FDA-approved Alzheimer’s Disease drugs that had significantly more serious adverse effects than benefits: https://www.nytimes.com/2024/10/23/health/alzheimers-drug-brain-bleeding.html?smid=nytcore-ios-share&referringSource=articleShare

 

Details:

-- the drugmaker Eisai in 2021 recruited 2000 volunteers to test their experimental Alzheimer’s drug BAN2401, a monoclonal antibody targeted to eliminate brain beta-amyloid

    -- they recruited 274 volunteers whose genetic profiles made them more prone to developing Alzheimer’s, indicating that they were at especially high risk for developing "brain injuries"; the participants were never told about their genetic profiles....

-- the Times then described several patients who died from this medication from cerebral micro-hemorrhages that were attributable to this medication, noting that more than 100 others suffered from brain bleeding or swelling (though most were mild and asymptomatic, some were serious and life-threatening)

   -- cerebral microhemorrhages had been found in the bapineuzumab studies in 2016, considered to be "treatment-emergent adverse events": ie, these microhemorrhages were known from this prior monoclonal antibody targeting beta-amyloid, causing significant brain injuries with little or no cognitive improvement

-- the FDA earlier this year approved this drug, marketed as Leqembi, for Alzheimer’s disease, noting that there was about a five month decrease in cognitive decline and stating that this benefit outweighed its risks

-- the FDA subsequently approved a second but similar drug by Eli Lilly called Kisunla, this drug company also choosing not to tell their 289 volunteers that their genetic profiles made them vulnerable to brain injuries

    --and, again, dozens experienced what Lily classified as ” severe” brain bleeding

-- both of these drug companies required the recipients to sign consent forms saying that “people with certain genetic profiles faced high-risk of brain injuries from receiving the drugs", but, to reiterate, the participants were never told the results of their genetic profiles!!

-- the New York Times did find that the initial drug Leqembi was approved by an institutional review board that was run by a private-equity-backed company named Advarra

    -- Eisai, the company that made Leqembi and ran the initial trial documenting severe consequences from this medication refused to answer questions or be interviewed by the New York Times

    -- the principal investigator for Lilly, however, did discuss the nondisclosure provision (i.e. that volunteers were not told of their genetic profile), stating that if participants did know of their genetic profiles that might “skew their self-assessments of progress”. This principal investigator did not design the trial but did agree that this process was basically unethical

-- a new retrospective study of patients taking Leqembi and Aduhelm (Aduhelm being a prior FDA-approved drug targeting beta-amyloid: see below) found that their mortality rate was 3 to 4 times higher than for Alzheimer’s patients not taking the drug

-- one of the quite unethical approaches of the drug companies was to recruit people in their senior centers by providing a lot of fun events (showing movies, dancing, miniature golf, improv comedy, all-you-can-eat buffets, etc.), then recruiting participants by advertising for “New at Home Memory Test” and “Free Memory Screens”, noting that “Hope Starts Here”

-- medical trial promoters, largely tied to industry, attended an Alzheimer’s conference and pushed for continuing with developing these beta-amyloid targeting drugs (despite the earlier problems with bapineuzumab, which had significant brain injuries with little or no cognitive improvement), with one member of the group stating “we need to be less risk-averse in Alzheimer’s disease”

-- the European Union and Australia, by the way, recommended against approving these drugs, citing that the temporary delay of cognitive decline did not outweigh the safety risks

 

-- in 2021, Biogen was granted FDA accelerated approval for their drug Aduhelm (also a monoclonal antibody targeting beta-amyloid), which was met with huge backlash in the medical community given its very inconsistent and unclear evidence of clinical efficacy, but quite present severe adverse effects: https://gmodestmedblogs.blogspot.com/2021/07/fda-review-of-new-alzheimer-drug.html . And, Medicare, quite unusually after FDA approval of a drug, refused to approve aduhelm in general for pateints with Alzheimer’s disease but did so only for patients enrolled in clinical trials. And Aduhelm was pulled from the market this year

 

-- the above does raise questions about the FDA approval process, several raised in a prior blog: https://gmodestmedblogs.blogspot.com/2024/06/using-surrogate-markers-for-disease-are.html

-- it seems that conflicts of interest are common in the FDA and that they affect voting patterns of their drug advisory committees: https://pmc.ncbi.nlm.nih.gov/articles/PMC1450069/

-- the current FDA commisioner Robert M Califf, MD, MACC has a several year history of being the highly paid head of medical strategy and Senior Advisor at Alphabet Inc (the rename of Google Inc), contributing to strategy and policy for its health subsidiaries Verily Life Sciences and Google Health. There was significant opposition to his appointment for this reason and that he had "millions of dollars in pharmaceutical stock": https://www.cnbc.com/2022/02/15/robert-califf-fda-senate-confirmation.html

 

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The FDA recently approved Cobenfy (a combo of xanomeline and trospium) for oral use in the treatment of schizophrenia in adults (a disease which affects about 1% of Americans, is one of the 15 leading causes of disability, and there is a greater risk of dying at a younger age and nearly 5% die from suicide): https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia . The FDA has not posted the study data or how they synthesized it to make their recommendations. My literature search found the following regarding its potential benefit for dementia:

    -- this drug was approved to treat schizophrenia, finding that there was a meaningful reduction in symptoms from baseline to week 5 per the PANSS (Positive and Negative Syndrome Scale), a 30-item scale that measures symptoms of schizophrenia. xanomeline is a selective agonist of the m1 and m4 muscarinic acetylcholine receptors, (as opposed to the more frequent dopamine and serotonin receptors that are targeted by drugs for schizophrenia)

        -- one of two studies analyzed 125 patients evaluated for the effects of the combination therapy (https://doi.org/10.1038/s41398-022-02254-9) in those with schizophrenia. this study found that cognitive improvement was not statistically greater with this medication. But, post-hoc analyses found that removeing individuals with implausibly high intraindividual variability in their analysis, did find statistically significant cognitive benefit:

            -- for those who were significantly cognitively impaired at baseline and comparing the medication (n=20) to placebo (n=35), there was a highly statistically significant improvement with the medications, with p=0.001 (which is pretty impressive for such a small study group. However, analysis eliminating those with implausibly high intraindividual variability was  not a predetermined study endpoint, limiting the statistical validity of this finding

    -- the medication is renally excreted and the most common side effects are nausea, indigestion, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and GERD

    -- trospium was added to the xanomeline since trospium is a peripherally-active anticholinergic drug to help decease some of the peripheral cholinergically-mediated  adverse effects of xanomeline, such as diarrhea, sweating and hypersalivation . A one year study of 204 patients with Alzheimers found that adding trospium to an acetylcholinesterase inhibitor did not have negative effects on cognition or ADLs in those with late-onset Alzheimer’s disease, and it decreased urinary incontinence

  

-- the major study from almost 3 decades ago not in schizophrenic individuals assessed xanomeline by itself on cognitive function and behavioral symptoms in patients with Alzheimer’s disease (see alzheimer xanomeline helps ArchNeuro1997 in dropbox, or Arch Neurol. 1997;54:465-473):

    -- this was a 6-month randomized double-blind placebo-controlled parallel group trial followed by a one-month single-blind placebo washout. Of the 343 patients in the study, 57% were women, 92% were white, and 54% had 12 or fewer years of formal education

    -- patients received either 75, 150, or 225 mg of xanomeline per day versus placebo for six months

    -- they measured the Alzheimer’s Disease Assessment Scale (ADAS-Cog), the Clinician’s Interview-based Impression of Change  (CIBIC+), the Alzheimer’s Disease Symptomatology Scale (ADSS) and the Nurses’ Observational Scale for Geriatric Patients (NOSGER)

        -- there was a dose-dependent reduction in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations per the ADSS scale

        -- in the NOSGER analysis that assessed memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, there was a significant dose-response relationship with cognitive improvement (p<0.02):

           -- overall results:

 

 

-- the improvements in cognitive outcomes was consistently dose-dependent across the symptoms that were evaluated

  

--  in the high-dose group, 52% of patients discontinued treatment because of adverse events, and these dose-dependent adverse events were predominantly gastrointestinal; 12.6% of patients in the high-dose group also had syncope. 35% in the placebo arm discontinued therapy as well as 19% of patients in the low dose, 48% in the medium dose, and 59% in the high-dose xanomeline groups

 

-- so this study using just xanomeline showed that by itself, there were very impressive decreases in Alzheimer's symptoms 6 months after taking the medication at maximal dose, but  lots of adverse events. one would expect a lower incidence of adverse events by the addition of trospium, without a decrease in cognitive benefits per other studies noted above

 

-- the FDA in its approval of xanomeline/trospium for schizophrenia did exclude certain individuals from taking this medicine: those with urinary retention, moderate or severe kidney or liver disease, gastric retention, untreated narrow angle glaucoma, or history of hypersensitivity to either of its components. They also comment that it should not be recommended for people for patients with mild hepatic impairment

 

So, on the surface and without my access to the actual literature review and thoughts of the FDA, it may be reasonable to try the xanomeline and trospium combination to improve cognitive function and likely decrease some of the adverse effects (off label, studies being done).

-- the marketed combination pill is Cobenfy, with drug company recommendations for schizophrenia to start with xanomeline 50mg and trospium 20mg twice a day for at least 2 days, then increase to xanomeline 100mg  and trospium 20mg twice a day for at least 5 days, then can increase if tolerated but to get more response to xanomeline 125mg and trospium 30mg twice a day (of note, the highest dose of xanomeline alone in the above Alzheimer study was 225 mg, and was associated with lots of adverse effects in 59% of participants; though the current maximal dose of the combination pill here is even higher at 250 mg and was associated with similar adverse effects, but though nausea was the most common at 19%: https://reference.medscape.com/drug/cobenfy-xanomeline-trospium-4000430 , presumably by adding the trospium did ameliorate some of these)

    -- an observation to justify this decision to try off-label use of xanomeline/trospium is that the FDA clearly approved some pretty terrible and remarkably expensive drugs for Alzheimer's, Alzheimer's is often hugely impairing to individuals/their families/their communities, and we do not really have much of an alternative medication available, especially if the current ones such as donepezil fails to help. at least there seems to be 6 month or more benefit in the xanomeline study cited above. and the cholinergic adverse effects noted in that study that only used xanomeline do not seem to be nearly as bad as with the monoclonal antibodies, seem to be better with trospium added, and should be reversible on stopping the med if they occur. In fact, there really should be a head-to-head comparison of xanomeline/trospium and donepezil, since both act on the cholinergic system, and donepezil has similar adverse effects though in <10% of individuals (which could mean that a stronger cholinergic med, one with more cholinergic adverse effects, might be better for the dementia??)

    -- or, awaiting the results of future studies, which are apparently planned

 

So,

-- one pretty clear conclusion from the above is that yet again we are using surrogate markers as true representatives of a disease process. It has been clear for years that the accumulation beta-amyloid in the brain is not the direct, specific pathway through which clinical Alzheimer’s disease develops. In fact some people with Alzheimer’s do not have any beta-amyloid  accumulation. It has also been clear that cholinesterase inhibitors that do not lead to depletion of beta-amyloid but do seem to help in the decreasing the progressive Alzheimer’s process.

    --And, as per prior blogs on the use of surrogate markers, they are often misleading: https://gmodestmedblogs.blogspot.com/2024/06/using-surrogate-markers-for-disease-are.html

-- there may be benefit from targeting patients who are genetically at high risk for Alzheimer’s disease (e.g. those with APOE4), and this might make sense, however patients with two copies of this genetic variant comprise only 2 to 3% of the general population and 15 to 20% of those with Alzheimer’s; those with only one copy of APOE4 make up about half of Alzheimer’s patients: i.e., this genetic marker is a reasonable target but clearly is not the only risk factor for the development of Alzheimer’s

    -- BUT, the Leqembi trial found that patients who had two copies of APOE4 were actually at a much higher risk of brain bleeding and edema (34.5%);16% of those with only one copy had brain bleeding and edema (ie, we should not use these monoclonal antibodies in these folks)

-- it should be noted that there is an inherent conflict of interest that researchers face: they have the imperative to recruit people into their studies. In this light, one very concerning development is that institutional review boards, those entrusted with approving a proposed study, were initially university-based ethics boards. BUT IRBs have evolved since 2021 such that 92% of drug trials submitted to IRBs were reviewed by two private-equity-controlled companies: Advarra and WCG!!!  Seems like we have lost a lot of patient protection

-- there are other potential determinants of the development and progression of Alzheimer’s disease, including the role of astrocytes/microglial cells which are involved in neuroinflammation and immune regulation in the CNS, perhaps these are more direct predecessors of Alzheimer’s?? (https://pmc.ncbi.nlm.nih.gov/articles/PMC6138241/ or https://www.sciencedirect.com/science/article/abs/pii/S1568163722000642?via%3Dihub )

-- And, and, and, as with many diseases, the real public health issue is prevention and not treatment. And there are several well-known nonpharmacologic approaches that seem to lessen the development of Alzheimer’s:

    -- cognitive activity and social supports may decrease dementia risk: https://gmodestmedblogs.blogspot.com/2019/07/mental-and-social-activities-dec.html

    -- vitamin D supplementation in those deficient may improve cognition: https://gmodestmedblogs.blogspot.com/2018/11/vitamin-d-decreases-cognitive-impairment.html

    -- multivitamins may also help improve cognitive function https://gmodestmedblogs.blogspot.com/2022/09/multivitamins-may-improve-cognition.html

    -- exercise is also associated with improved cognition: https://gmodestmedblogs.blogspot.com/2020/01/exercise-and-cognitive-health.html

    -- avoiding sugary beverages seems to help: https://gmodestmedblogs.blogspot.com/2017/05/sugary-beverages-and-alzheimers.html

    -- and other lifestyle interventions may also help: https://gmodestmedblogs.blogspot.com/2015/12/lifestyle-interventions-and-cognition.html

 

geoff

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