A new drug shows promise

[Jaque]

https://www.nytimes.com/2021/01/11/heal ... lilly.html

[TheresaB]

I don't have a New York Times account, what does this say? Does the drug address Alzheimer's? Has it been tested in humans, or just mice? Is it another drug that attacks amyloid (which have all failed in the past), if not what's its mechanism? How large was the trial, a decent data set?

[Jaque]

Alzheimer’s Drug Shows Promise in Small Trial
Participants with the disease still declined, but much more slowly than those receiving a placebo, investigators say
https://www.nytimes.com/2021/01/11/heal ... d=em-share
Three scans of the brain of a 62-year-old Alzheimer’s patient, four years after diagnosis.Credit...Zephyr/Science Source

By Gina Kolata Jan. 11, 2021, 11:10 a.m. ET (C) New York Times
In a small clinical trial, an experimental Alzheimer’s drug slowed the rate at which patients lost the ability to think and care for themselves, the drug maker Eli Lilly announced on Monday.
The findings have not been published in any form, and not been widely reviewed by other researchers. If accurate, it is the first time a positive result has been found in a so-called Phase 2 study, said Dr. Lon S. Schneider, professor of psychiatry, neurology and gerontology at the University of Southern California.
Other experimental drugs against Alzheimer’s were never tested in Phase 2 trials, moving straight to larger Phase 3 trials, or failed to produce positive results. The Phase 3 studies themselves have repeatedly had disappointing results.
The findings have not been published in any form, and not been widely reviewed by other researchers. If accurate, it is the first time a positive result has been found in a so-called Phase 2 study, said Dr. Lon S. Schneider, professor of psychiatry, neurology and gerontology at the University of Southern California.
Other experimental drugs against Alzheimer’s were never tested in Phase 2 trials, moving straight to larger Phase 3 trials, or failed to produce positive results. The Phase 3 studies themselves have repeatedly had disappointing results.
The two-year study involved 272 patients with brain scans indicative of Alzheimer’s disease. Their symptoms ranged from mild to moderate.
The drug, donanemab, a monoclonal antibody, binds to a small part of the hard plaques in the brain made of a protein, amyloid, that are hallmarks of Alzheimer’s disease. Patients received the drug by infusion every four weeks.
Participants who received the drug had a 32 percent deceleration in the rate of decline, compared with those who got a placebo. In six to 12 months, plaques were gone and stayed gone, said Dr. Daniel Skovronsky, the company’s chief scientific officer. At that point, patients stopped getting the drug — they got a placebo instead — for the duration of the study.
The small study needs to be replicated, noted Dr. Michael Weiner, a leading Alzheimer’s researcher at the University of California, San Francisco. Still, “this is big news,” he said. “This holds out hope for patients and their families.”
The Eli Lilly trial recruited patients not based on symptoms but on scans showing significant accumulations of amyloid in their brains. The researchers also performed scans for a protein, tau, that forms spaghetti-like tangles in the brain after the disease gets started.
“We needed mild to moderate tangle pathology, but not so many tangles that perhaps the disease is beyond hope,” Dr. Skovronsky said.
The primary endpoint, or goal of the trial, was a measurement that combined performance on mental tests of reasoning and memory with assessments of how well the participants performed in activities of daily living, like dressing themselves and preparing meals.
The main side effect was one regularly seen in patients given experimental monoclonal antibodies to treat Alzheimer’s: an accumulation of fluid in the brain. It occurred in close to 30 percent of patients, Dr. Skovronsky said, but most had no symptoms. The effect was seen on brain scans.

While the trial was going on, Eli Lilly started a second Phase 2 trial, Trailblazer 2, hoping that the initial effort would produce results. Those results are expected in 2023.
Dr. Skovronsky said Eli Lilly would be talking to the Food and Drug Administration and regulatory authorities in other countries about helping patients gain access to the drug.
“Certainly the data are exciting,” he said. “But we will have to see what the regulators say.”
He has been hoping for 25 years for definitive evidence that the amyloid hypothesis is correct.
“This is what we’ve been waiting for,” Dr. Skovronsky said.

[TheresaB]

...By Gina Kolata Jan. 11, 2021, 11:10 a.m. ET (C) New York Times...

In a small clinical trial, an experimental Alzheimer’s drug slowed the rate at which patients lost the ability to think and care for themselves, the drug maker Eli Lilly announced on Monday....

The findings have not been published in any form, and not been widely reviewed by other researchers. ...

The drug, donanemab, a monoclonal antibody, binds to a small part of the hard plaques in the brain made of a protein, amyloid, that are hallmarks of Alzheimer’s disease. ...

Participants who received the drug had a 32 percent deceleration in the rate of decline, compared with those who got a placebo. In six to 12 months, plaques were gone and stayed gone, ...

The small study needs to be replicated, ...

He has been hoping for 25 years for definitive evidence that the amyloid hypothesis is correct.
“This is what we’ve been waiting for,” Dr. Skovronsky said.

Very interesting, more to come! Thank you.

[NF52]

...By Gina Kolata Jan. 11, 2021, 11:10 a.m. ET (C) New York Times...

In a small clinical trial, an experimental Alzheimer’s drug slowed the rate at which patients lost the ability to think and care for themselves, the drug maker Eli Lilly announced on Monday....

The findings have not been published in any form, and not been widely reviewed by other researchers. ...

The drug, donanemab, a monoclonal antibody, binds to a small part of the hard plaques in the brain made of a protein, amyloid, that are hallmarks of Alzheimer’s disease. ...

Participants who received the drug had a 32 percent deceleration in the rate of decline, compared with those who got a placebo. In six to 12 months, plaques were gone and stayed gone, ...

The small study needs to be replicated, ...

Very interesting, more to come! Thank you.

Thanks for posting about donanemab, Jacque! This is a drug we can expect to hear about in the next few years. But given that this is a Phase 2 trial, it's not yet close to submission to the FDA or other countries' regulatory bodies, I would guess. A Phase 2 clinical trial of a drug is primarily to test safety and efficacy (does it work as expected) in a larger group of patients than the Phase I trial.

It's helpful (and frustrating) to realize just how long this process takes AFTER a promising drug is developed: The Phase I trial of donanemab began in 2013, with the Phase 2 trial, called TRALBLAZER-ALZ, starting just over 3 years ago (Dec. 2017). A new trial of donanedab, called TRAILBLAZER-ALZ-2, has just started and is actively recruiting in dozens of locations in the US and abroad. I would encourage anyone who is interested in this drug and who might meet the criteria for MCI or early-stage AD, or has a loved one who does, to check out the Clinical Trials info on criteria and locations Trailblazer-ALZ-2

Here's a helpful overview of the current trial and ongoing recruitment, for those who might be interested, published online yesterday on ALZFORUM The bracketed explanation and underlined/bolded areas are on me!

In December 2017, Lilly began TRAILBLAZER-ALZ... It aimed to enroll 375 participants whose memory had been worsening for at least six months, who met a cutoff on the CogState Brief Battery, and who had a positive flortaucipir PET scan [i.e. positive amyloid in the brain]... Within this range, people have detectable cognitive decline over one to two years, but are not yet at advanced disease stages...
The primary outcome [i.e. measured goal] is change on the Integrated Alzheimer's Disease Rating Scale (iADRS), a combined cognitive/functional measure for early stage AD developed by Lilly.... Secondary measures include the ADAS-Cog13, CDR-Sum of Boxes, MMSE, ADCS-iADL, as well as amyloid and tau PET and volumetric MRI... evaluation of donanemab remains ongoing, with a revised enrollment estimate of 266 participants.

In January 2021, Lilly announced by press release that TRAILBLAZER-ALZ met its primary endpoint, with donanemab slowing decline on the iADRS by 32 percent compared to placebo at 18 months (news link TK). The company claimed improvement on all secondary endpoints of cognition and function, although not all were statistically significant. Treatment resulted in an average reduction in amyloid plaque by 84 centiloids, from 108 at baseline. Safety was similar to earlier trials. ARIA-E developed in 27 percent of treated patients, with six percent becoming symptomatic....
In October 2020, Lilly began recruiting for TRAILBLAZER-ALZ 2, a Phase 2 safety and efficacy trial in 500 people with early Alzheimer’s. Inclusion criteria are similar to TRAILBLAZER-ALZ, i.e., participants must have had a progressive and gradual memory decline for at least six months, MMSE scores between 20 and 28, and meet criteria on amyloid and tau PET scans. Participants will receive donanemab or placebo, with the primary outcome being change in CDR-Sum of Boxes after 18 months. Secondary measures include the MMSE, ADAS-Cog13, iADRS, and ADCS-iADL, amyloid and tau PET, and volumetric MRI, plus pharmacokinetics and measures of anti-donanemab antibodies. The trial is set to run through early 2024 at 87 sites in the United States, Canada, Japan, The Netherlands, and Poland.

So here's my only slightly-informed analysis of this press release:

* POSITIVE: Donanemab, an Eli Lilly drug, slowed decline on IADRS, a test developed by Eli Lilly to measure cognitive skills and activities of daily living by 32% after 18 months compared to those on the placebo.

And yet That is similar to the improvements seen in the aducanumab trial that was just panned by the FDA. The test that showed benefit was developed by Eli Lilly itself. Most trials use composite measures (like combining measures of memory, language, spatial skills, motor skills) that have been developed by others and used multiple times in other studies. The secondary endpoints, which did use widely trusted measures of cognition and functional skills, did not show a statistically significant change. That means it is equally likely that the improvement was by chance. That may explain why for their current trial, they are switching to looking for improvement on the CDR-sum of boxes, which has been used widely as a measure of increase of impairment.

*POSITIVE:The drug removed amyloid plaques from the brains of those who got donanemab.

And yet: Amyloid plaques have been questioned by some researchers, who note that removing the plaques has been shown in many failed anti-amyloid plaque trials, without changing the course of the progression. One strong theory is that plaques not the fuse that lights AD; rather it may be amyloid beta oligomers that clog synapses and trigger breakdown of neurons and/or growth of tau tangles. Aducanumab, for example, targeted both amyloid plaques and oligomers with mixed results. Newer trials, like the AHEAD trials of BAN2401 and the ALZ-801 trial target oligomers to a much greater extent. So the jury is out on whether Lilly's target will be the correct one long term.

SIDE EFFECT * ARIA-E developed in 27% of patients, with 6 percent being symptomatic.
Thoughts: ARIA-E stands for Amyloid-Related Imaging Abnormalities-Edema. It refers to something seen in the aducanumab study, earlier studies with BAN-2401 and other anti-amyloid infusions and is of uncertain significance as a side effect. It often is found only when doing an MRI, as spots that show fluid. One theory is that the removal of amyloid plaques put stress on the blood-brain barrier, or on blood vessels themselves, and they show temporary leaks. (This is an amateur's explanation!) Those who have symptoms (6% in this study) typically have mild headaches, vision disturbances, or dizziness. A few, who are more likely to be ApoE4 carriers in all the recent studies, have confusion and other changes in abilities that require suspending the drug and treating the person with IV steroids. The symptoms appear to resolve, although some recent reports were presented after COVID had suspended in-person cognitive testing. As a comparision, aducanumab had about a 40% incidence of ARIA-E, while BAN2401 had about a 9% incidence, with 15% in those with ApoE 4 (in a small total group). So an incidence of 27% without specifics on ApoE 4 incidence is an unanswered question. It may be that ARIA-E is like getting a reaction to a COVID vaccine: Something that is rarely a problem and worth the peace of mind of preventing a major risk (for some of us). We just don't know yet.

Bottom line for me: It sounds promising, but this is still a trial that needs 500 volunteers (probably split 50/50 between donanedab and placebo by random assignment) for an 18-month trial, with results probably not available until 2024. Trials work very hard to find participants; they don't all join on the first day!).

[Family Tree Guy]

Lilly has not yet published their data (but they said they intend to). From reading various summaries, they appear to have applied a very unusual screening criteria for study inclusion: they excluded patients with elevated levels of pTau. I think this is likely a relatively small subset of AD patients, (high amyloid, but not high pTau). I am very curious about their patient demongraphics, Like most AD studies, Biogen's Aducanumab studies had ~65% E4 carriers. It will be interesting to see Lilly's demos.