Unfortunately one of the few experimental drugs being studied in dementia with Lewy bodies (DLB) has failed. The drug is known as intepirdine. The manufacturer is Axovant. Here’s a link to a short news article from this morning:
www.statnews.com/2018/01/08/alzheimers-axovant-intepirdine/
BIOTECH
A new Alzheimer’s drug, once worth billions, is headed for the trash
By Damian Garde
January 8, 2018
Statnews
Robin
This is an interesting, long article in Politico, of all places, on Alzheimer’s (and diabetes) drug development. One focus of the article is on developing biomarkers. Biomarkers are “biological indicators in patients that can be easily measured, and that provide early indicators of whether an experimental drug is actually doing something that’s likely to help the patient. ” Of course we need biomarkers for all neurological diseases, not just Alzheimer’s.
Here are some excerpts from the article:
The effort largely revolves around finding better biomarkers for…diseases—that is, biological indicators in patients that can be easily measured, and that provide early indicators of whether an experimental drug is actually doing something that’s likely to help the patient. A good biomarker can drastically cut the need for massive, long-running, superexpensive trials, by giving researchers a fast, easily measured and reliable answer to the basic question, “Does this drug work?” It can also give basic researchers clues as to which research avenues are most likely to pay off, avoiding dead ends and speeding the early stages of development.
In Alzheimer’s, researchers have tried to judge the effectiveness of experimental drugs by assessing how the drug affects cognitive decline in patients—by giving patients memory tests, for example. The problem is that most experts now believe that by the time cognitive decline has advanced enough to be clearly detected through memory tests, any window for hitting the brain with a drug capable of staving off the disease has long since closed, possibly for two or more decades. Researchers can give people the drug earlier on in life, before symptoms show—but they might have to wait 20 or 30 years to find out if the drug worked, or even if a test subject had Alzheimer’s in the first place. What researchers need is a biological signal that can indicate a patient is developing Alzheimer’s years before cognitive decline shows up, and that can quickly measure whether a drug is slowing the progress of the disease. Though drugs that attack the brain plaques and tangled proteins that characterize Alzheimer’s haven’t worked so far in patients with cognitive decline, notes Lilly’s Skovronsky, plaques and tangles may in fact be the right biomarkers if they can be assessed in pre-cognitive-decline patients. That’s been hard to do in real time because the full extent of damage until recently could be clearly seen only in brain samples taken after the patient’s death.
Here’s a link to the full article:
www.politico.com/agenda/story/2017/12/13/drug-industry-new-developments-000598
The missing Alzheimer’s pill
When it comes to some of the biggest diseases America faces in the future, our drug system is set up to fail. What needs to happen?
By David H. Freedman
Politico
12/13/2017 05:19 AM EST
Robin
This is an article by Karen Wilder, the widow of Gene Wilder who died in 2017 with Alzheimer’s Disease (AD). She writes for ABC News (abcnews.com). Karen Wilder describes her late husband’s symptoms and her role as a caregiver. Though this article is about caregiving for someone with AD, the messages apply to all caregivers. Basically, her messages are that caregivers are overlooked and caregivers can die before their loved ones.
She says: “But let’s not forget that other killer — the silent one that takes its victim even before the disintegration of brain cells does its own dirty work. I am speaking of the crisis that can kill the once-healthy loved spouses, siblings, friends and adult children of Alzheimer’s patients, who devote almost every waking hour of their lives (and also the nights) to caring for a person they love.”
She notes that: “40 percent of Alzheimer’s caregivers die before the patient according to a study done by Stanford Medicine — not from disease, but from the sheer physical, spiritual and emotional toll of caring for a loved one with Alzheimer’s.”
And she says: “It is a strange, sad irony that so often, in the territory of a disease that robs an individual of memory, caregivers are often the forgotten. Without them, those with Alzheimer’s could not get through the day, or die — as my husband did — with dignity, surrounded by love.”
Here’s a link to the article on the ABC News website:
abcnews.go.com/Entertainment/gene-wilders-widow-care-alzheimers/story?id=52045475
Gene Wilder’s widow on what it’s like to care for someone with Alzheimer’s
By Karen Wilder
Jan 2, 2018, 12:36 PM ET
ABC News
Robin
A local support group member whose loved one was involved in this TPI 287 trial at UCSF contacted me a couple of weeks ago to say that she had learned that the trial was not successful. I haven’t been able to find any independently-written article [see updated below!] on the study results (and, of course, clinicaltrials.gov shows nothing) but there is this pharmaceutical company press release.
The TPI 287 study was discussed by Adam Boxer, MD, UCSF at our recent PSP/CBD conference. This was a phase 1 study, which has a safety focus. Researchers are also trying to learn something about efficacy during these studies but that’s not the main point. In the study, 14 patients with PSP and 30 patients with CBS were included. 32 received the drug and 12 received the placebo.
This seems to be the crux of the problem — “Interestingly, patients treated with TPI 287 performed worse on the [Clinical Dementia Rating] assessment vs. placebo after 12 weeks.”
Update: A member of our email list forwarded me that independent write-up I was looking for on TPI 287; it’s on Alzforum. Just as the group member said, the trial had negative results. In addition to the worsening in the dementia rating scale (mentioned earlier today), there was also a worsening of falls in CBD and PSP patients. The study was also conducted of the same compound, TPI 287, in Alzheimer’s Disease. The experimental drug was not safe in AD patients at high doses. An excerpt from the Alzforum summary is below.
Robin
www.alzforum.org/news/conference-coverage/least-we-know-these-dont-work-negative-trials-ctad
Excerpt from
At Least We Know These Don’t Work: Negative Trials at CTAD
Alzforum
15 Dec 2017
Abeotaxane
Adam Boxer, University of California, San Francisco, presented his center’s Phase 1 trial of TP1 287. Also known as abeotaxane, this small-molecule taxol derivative stabilizes microtubules. TPI 287 accumulates in the brain, and has been tested primarily to treat central nervous system tumors. Its application to tauopathies grew out of work showing beneficial effects of the microtubule stabilizer epothilone D in tau transgenic mice (Zhang et al., 2012). Testing of epothilone D in AD patients started in 2012 but was discontinued for lack of efficacy.
Boxer’s group examined the safety and tolerability of TP1 287 in 44 people with the primary four-repeat tauopathies cortical basal degeneration (CBD) or progressive supranuclear palsy (PSP), and in 33 people with AD. Participants received abeotaxane by intravenous infusion once every three weeks for nine weeks, with an option for open-label extension up to three months.
In recruiting for the CBD cohort, Boxer screened with amyloid PET to exclude people with AD and to limit the treatment group to people with pure tau pathology. Of 55 diagnosed with CBD, Boxer excluded seven based on positive amyloid scans. He also used CSF biomarkers to confirm diagnoses: AD patients had lower Aβ42 and higher total tau and phospho-tau levels than CBD/PSP group members, who showed elevations in neurofilament and a higher neurofilament light (NfL)/phospho-tau ratio than the AD group.
Participants received tailored doses of 2, 6.3, or 20 mg/meter2 TPI 287, or placebo.
AD patients tolerated the treatment poorly. Boxer told the CTAD audience that he had to stop the high-dose arm because two participants suffered anaphylactoid hypersensitivity reactions, most likely to the diluent for the active compound. In all, seven people in the AD group discontinued treatment. Curiously, the CBD/PSP group tolerated the drug well, even at the highest dose. They suffered no hypersensitivity reactions, and most participants stuck with the trial even through the open-label extension. However, in CBD and PSP patients, the drug caused more falls, a serious concern.
On the exploratory cognitive endpoints, the researchers saw a hint of stabilization of MMSE scores in the AD group, but no change in the ADAS-Cog, and the CBD/PSP cohort had a dose-related worsening on the Clinical Dementia Rating-Sum of Boxes at three months.
Boxer has no future plans for the drug, except to complete the analyses of pharmacokinetics and MRIs. He told Alzforum that investigators learned a lot from the trial. “It shows the importance of testing potential treatments in different tauopathies,” he said. “Animal models don’t tell the whole story, and we have to look at different conditions in humans,” he said.
This is a good summary from Alzforum about research published last Friday out of two of the world’s largest brain banks — the University College London and the Mayo Clinic Jacksonville. Researchers genotyped 1743 patients — 1324 of those patients had autopsy-confirmed dementia with Lewy bodies. They were looking for genome-wide associations in dementia with Lewy bodies (DLB). Basically, they were trying to answer the question — how much of DLB can be explained by genetics?
This breakthrough research was made possible through brain donation. Our nonprofit, Brain Support Network, has helped over 450 families with brain donation. All of those families we’ve helped where the diagnosis was confirmed DLB were involved in this important research! Please let us know if this is interest to your family and we can help make advance arrangements.
“The researchers calculated that, overall, genetic variants account for about 36 percent of the risk for DLB in this sample. This is roughly the same as for PD, but much less than that for late-onset AD.” Previously-known associations were confirmed — APOE, SNCA (synuclein), and GBA. “The APOE locus emerged as the most strongly associated with DLB, with the SNCA gene for α-synuclein next. Interestingly, though, the particular SNCA SNPs were different from the ones associated with PD.” A new loci was discovered — CNTN1.
The study was funded by two UK organizations — Alzheimer’s Society and Lewy Body Society.
Here’s a link to the Alzforum summary:
First Genome-Wide Association Study of Dementia with Lewy Bodies
15 Dec 2017
Alzforum
And MedicalXpress had a good summary of the research as well. Here’s a link to that as well:
medicalxpress.com/news/2017-12-dementia-lewy-bodies-unique-genetic.html
Dementia with Lewy bodies: Unique genetic profile identified
December 15, 2017
MedicalXpress
Robin
