A bombshell hit the news yesterday (11/20/22) about a breakthrough treatment for Alzheimer’s disease. But the drug company announced the same news two months ago in the form of a press release. Today’s story was merely about a formal presentation of the results at an Alzheimer’s conference that added some important safety data. Here’s my blog post from September.
The drug is called lecanemab, and as its last three letters indicate, it’s a monoclonal antibody – in this case directed against the beta-amyloid protein. That’s present in an abnormal, aggregated form in brain cells in Alzheimer’s but not in PSP. In the trial, the antibody solution was infused intravenously every two weeks for 18 months and compared with a group of participants receiving placebo infusions. The news was that lecanemab slowed the rate of worsening of Alzheimer’s by 27%. This is great news from the PSP standpoint because it’s the first time that a monoclonal antibody was shown to slow progression of any neurodegenerative condition, even if it’s a different one. We call that a “proof of principle.”
Today’s new information on the drug’s safety was most notable for a potentially serious issue called hemorrhagic encephalitis. That’s where areas of the brain tissue undergo swelling and/or bleeding. That combination is evidence of inflammation, the equivalent of a very sore arm after a Covid shot. Among the 898 participants with AD who received active lecanemab over the 18 months of the trial, 13% had swelling, but for the 897 receiving placebo, the figure was 2% – a major difference. For bleeding, the proportions were 17% for lecanemab and 9% for placebo – a minor difference. Fortunately, none of those participants suffered important or permanent symptoms from the swelling or bleeding, which in most cases would not even have been suspected without the trial’s routine brain MRIs, and in all cases resolved in a few weeks. However, one wonders how serious the problem could hypothetically be in a tiny percentage of people — too small a fraction to be detected in the 897 on lecanemab in this study.
The group on active lecanemab was a bit more likely than the placebo group to report a variety of serious side effects unrelated to brain swelling or bleeding: 14% vs 11%; and the lecanemab patients were more likely to drop out of the study because of other, assorted side effects: 7% vs 3%.
Now the FDA and Medicare/Medicaid have to decide if they’ll approve this treatment or if the cost (whatever that might turn out to be) and side effects outweigh the benefit. Or, they may require another large trial first.
So, the takeaway for those with PSP is that it’s possible to modestly slow the rate progression of a neurodegenerative disease with a monoclonal antibody treatment with probably only mild risk. The numbers about the hemorrhagic encephalitis are not to be ignored. But I think that if a hypothetical treatment for PSP gave similar risk and benefit, and the out-of-pocket cost is affordable, I think the majority of people with PSP would ask where to sign up.
PSP Blog 
Dr. Golbe-
Thanks for your ongoing updates on lacenemab. These findings beg the question that you alluded to in your September post on lacenemab. Since the PSP trials with the C-terminal Tau directed Mabs have failed (I think pre-COVID?), why have they not been quickly followed up with N-terminal Tau targeting versions? Maybe I’m anticipating what’s already in the works somewhere. I’m always mystified by the reasoning that must go on in the R&D strategy meetings at Pharma companies focused on neurological diseases. Do you go for the “home run” with Alzheimer’s (large costly trials and even more costly if you fail!) or target the orphans like PSP which require smaller trials but if promising, give you an opening to the bigger prize. As a patient with PSP, you’re right that I would 1st in the queue if a trial were to be announced!
Dr. Swanson: The antibody being developed by UCB Pharma is directed against tau’s N terminal. It’s being tested only in Europe, where an open-label trial in 19 patients to assess safety should be completed about now and a double-blind trial in 25 patients has not yet started to enroll. I haven’t heard anything about testing in North America, but I assume that would happen for a larger, Phase 2B or 3 trial if the two current European trials give favorable results. Dr. Golbe
Hi Dr. Golbe, Do the UCB Pharma trials of their antibody directed against tau’s N terminal involve PSP patients or Alzheimer’s patients (or perhaps both)? I am having trouble finding reference to this effort on their website or elsewhere. Thank you.
Dear ME3:
Those trials are not mentioned on UCB’s website probably because that program is at too early a stage (I’m guessing here). But clinicaltrials.gov lists them:
https://clinicaltrials.gov/ct2/results?cond=Progressive+Supranuclear+Palsy&term=bepranemab&cntry=&state=&city=&dist=
If that link doesn’t work, go to http://www.clinicaltrials.gov and search on “progressive supranuclear palsy” and “bepranemab”.
Hello Dr. Globe, my husband Mark was diagnosed with PSP in October 2021 by Dr Irene Litvan at UC
San Diego. He was previously misdiagnosed with Parkinson’s April 2020. My question is : Is the drug listed above, lecanemab available anywhere for him to take, even as a trial? Or any other medication that he would benefit from? Right now he only takes Carbidopa Levodopa but it doesn’t have much effect.
Dear Kelly:
Unfortunately, lecanemab wouldn’t work for PSP. It’s a monoclonal antibody directed at the beta-amyloid protein, not at tau. Alzheimer’s disease, which is what lecanemab is now approved for, has both beta-amyloid and tau, but PSP has only tau. You mention that your husband has seen Dr. Litvan. She is one of the few neurologists in the US participating in the NIO752 trial. Maybe your husband would meet enrollment criteria for that. More information is available here: https://clinicaltrials.gov/study/NCT04539041?intr=aso&cond=Progressive%20Supranuclear%20Palsy&rank=1#locations
Hi Dr. Golbe, We check daily for new blog posts from you and cannot express how much we continue to appreciate everything you are doing. Thank you. My husband Pedro was diagnosed with PSP by Dr. Adam Boxer at UCSF in September of 2021. Dr. Litvan and team at UCSD were kind enough to consider him for their NIO-752 study, and even requested a waiver to allow his intrathecal injections of the medicine to be CT imaging-guided. (Pedro has stenosis in his lumbar spine which makes “blind” injections more difficult but image-guided CSF extractions have worked perfectly for him.). Unfortunately, Novartis declined the UCSD team’s request since they apparently have plenty of candidates and a preference to not deviate from their standard protocol in any way. On the brighter side, it seems that Novartis continues to expand the patient base for this trial. Is it reasonable to infer that this implies that they are encouraged by initial results? If we are not mistaken, the first patients were dosed with NIO-752 as early as autumn of 2021. In the meantime, you had mentioned the likelihood of some additional anti-tau ASO trials and we eagerly await news from these. All the best, and thank you again.
Dear me3:
Thank you once again for your kind feedback.
I’m not sure how to interpret Novartis’ expansion of the study’s enrollment mid-stream. It probably simply means that they haven’t seen any important toxicity so far and want to give the trial the greatest possible chance of demonstrating benefit if any exists.
LG