Any open label study without controls is subject to the reasonable criticism that any benefits seen are due to the placebo effect. Neurologic and Psychiatric disease trials can have large (33%) placebo effects (e.g. migraine, depression).
This is very unlikely to be the case with the 1 year results of the open label trial of Simufilam in 200 patients with Alzheimer’s disease. “47% of patients improved on ADAS-Cog over 1 year, and this group improved by 4.7 points”
It is based on my clinical experience with a drug for Alzheimer’s disease released 30 years ago — Tacrine (Cognex). Initially it was touted as helping Alzheimer’s disease (e.g. improving thinking and memory) although later it was held to slow the decline. The local medical school advertised it aggressively (primarily as a marketing device).
So I put my Alzheimer patients on Cognex. I wanted them to get better. They wanted to get better, and their families and caregivers certainly did. Just about all of them thought it might have helped on followup visits in the first month. I couldn’t see much difference. By the second month, they weren’t sure, and later in the first year they didn’t think it helped, and most weren’t using the drug after 1 year.
Not only that, but I was in a call group with 4 other neurologists, and they saw exactly the same thing. I was practicing in an area with a catchment area of over a million people, and every local neurologist I talked to had the same experience. People thought that “Cognex helped” for a month or two and then they didn’t
This a classic example of a placebo effect. Moreover it occurred in a therapeutic trial for Alzheimer’s disease. Crucially, the placebo effect was quite transient and absent at 1 year.
This is why the Simufilam results mentioned above are not a placebo effect.
Those not interested in neuropharmacology can stop at this point. There were excellent clinical and theoretical reasons for the use of Tacrine.
Clinically it was apparent that drugs that blocked the effects of the neurotransmitter acetyl choline on one type of its receptors (muscarinic) profoundly impaired memory. Scopolamine is one such drug. One of the earliest and most invariable symptoms of Alzheimer’s disease is deficient memory.
That’s the clinical part. Here’s the theory. So logically, increasing acetyl choline should help memory. How to do this? Well there are enzymes that break acetyl choline down (the acetyl cholinesterases). So by inhibiting cholinesterases, acetyl choline levels in the brain should increase, and memory should be improved.
Impeccable logic and theory. Unfortunately, like many such it didn’t work.
Chemiotics II 
Comments
So this drug works or at least seems to work and is worthy of approval. May this drug help many people and continue to not have any negative side effects!
Thank you so much for your down to earth analysis. It helps hearing real world neurologist experience and bringing it all back to patients. 102 people out of 216 improved significantly at a year. That simply does not happen and is incredible. Keep up the blogging. We love it.
Placebo effects especially in neurodegenerative conditions can last incredibly long, into one year. You are using your anecdotal experience to say the placebo effect doesn’t exist??? The duration and intensity of placebo is heavily reliant on baseline characteristics amongst many other things. In addition there is published data that the placebo effect has increased over time. The only way to really test the efficacy is with placebo control so CMS will be very telling.
Alfred –“You are using your anecdotal experience to say the placebo effect doesn’t exist???” Not at all. I’m saying that the placebo effect of Cognex in Alzheimer’s disease DOES exist, but that it only lasts a month or two not a year and this is likely to be the case for any placebo effects of Simufilam in Alzheimer’s disease as well.
I agree that the CMS study will be very telling as it is blinded.