Davunetide Research Update (2/8/11 webinar)

I listened to Dr. Morimoto’s presentation yesterday during the CurePSP webinar. My notes are copied below. I thought the background he gave on animal studies (transgenic mice) was fascinating. Otherwise, there wasn’t anything new for me. I was surprised he didn’t mention the pilot study at all. If any of you listened in and found something interesting, please share!

You can find a video/audio recording of the presentation on the CurePSP website here:
http://curepsp.na5.acrobat.com/p92435146/

You can find a PDF of the slides on the CurePSP website here:
http://www.psp.org/file_download/a84748 … 52e9e8ccf8

Of course the slides won’t contain the Q&A.

Robin

Davunetide Research Update
Presenter: Bruce Morimoto, PhD, Vice President, Drug Development, Allon Therapeutics, Inc.
2/8/11 Webinar

[I didn’t take notes on the background he gave on Allon Therapeutics.]

Drug development is a highly regulated and lengthy process:
Preclinical: lab and animal research
Phase I: early clinical safety testing
Phase II: patient safety; early efficacy
Phase III: efficacy; safety
Ends in new drug application, FDA review, and FDA approval

Description of PSP:
* A degenerative disease involving the brain stem, basal ganglia, and cerebellum. These regions control movement.
* Clinical symptoms (movement problems, cognitive impairment) are the apparent result of the underlying tau pathology in the brain region controlling those functions.

Image from Williams and Lees; Lancet Neurology 2009;8:270-279. Location of pathology in Richardson’s Syndrome. Pathology in upper regions gives rise to cognitive impairment. Pathology in lower regions gives rise to movement problems.

In response to both disease and injury, the brain produces a protein called ADNP (activity dependent neuroprotective protein). Image on right side shows nucleotide sequence.

Davunetide has other names, including:
NAP
NAPVSIPQ Peptide
AL-108
AL-208

Davunetide protects and repairs the cell’s scaffolding (cytoskeleton/microtubules). The image on the right shows that davunetide protected a cell from zinc chloride toxin.

Microtubules form the scaffold within the cell. Microtubules are essential for the neuronal structure and function. As the cell becomes sick through neurodegenerative, the microtubules fall apart. As that happens, you lose the structure of the neuron and the function. It begins to die. Then the tau protein becomes chemically modified and starts clumping up. This gives rise to the pathology of PSP. Images from Stamelou, et al; Brain 2010:133;1578-1590.

Animal model for tau pathology:
* Created mice which progressively develop tau pathologies and spatial memory deficit. (Both a cognitive impairment as well as tau pathology.)
* Transgenic (Tg) mice given two human tau mutations. These mutations are associated with a severe FTD phenotype. (PSP is a type of FTD.)

In a study, animals were administered davunetide intra-nasally. The chemical modification associated with tau protein was analyzed. The study’s conclusion: restoration of normal tau phosphorylation levels. The level of tau went down with davunetide. This was the first hint that davunetide might affect this pathology.

Also analyzed the tangle pathology in the mice brains. The study’s conclusion: davunetide treatment reduces the number of NFTs (neurofibrillary tangles). This means that the total amount of pathology is reduced. It’s a modest improvement but is statistically significant. Shiryaev et al (2009) Neurobiology of Disease 34, 381.

While it’s important that the treatment reduces the pathology, it’s more important that the treatment improves symptoms. The tau double mutant mice, once given davunetide, showed improved learning and memory in the Morris water maze. The tau double mutant mice performed nearly as well as normal mice.

Through these studies, we see that davunetide is having an effect on:
1- the pathway that is leading to the development of the pathology
2- the level of pathology
3- behavior

Human testing of davunetide:
1) Phase 1 clinical safety studies done in (a) healthy young, middle-aged and elderly adults, and (b) Alzheimer’s Disease
2) Phase 2 clinical safety and efficacy studies done in: (a) amnestic MCI (pre-cursor to AD). After 3-month treatment, there was memory improvement. And (b) chronic cognitively-impaired schizophrenia patients. After 3-month treatment, improvement in functional capacity (everyday activities) and possible improvement in memory.

Side effects observed in previous davunetide studies:
* nasal passage complaints such as runny nose, nasal or sinus congestion, throat or sinus pain. These were potentially related to the intranasal administration.
* headache
* dizziness. Note that many PSP patients already have gait instability, episodic dizziness, and/or history of falls.
* nausea
* excessive sweating

Rationale for study of AL-108-231 in PSP:
1) In preclinical (animal) studies, davunetide reduces the tau pathology that is seen in PSP. And reducing the pathology in animals results in an improvement in behavioral outcomes.
2) In clinical studies, davunetide is: well-tolerated with modest side effects; gets into brain; improved memory in aMCI patients (pre-Alzheimer’s Disease); and improved ability to conduct daily tasks in cognitively-impaired schizophrenia patients.

Study design for AL-108-231:
* multicenter, multinational: approximately 300 PSP patients will be treated for 1 year at about 47 clinical sites in US, Canada, Australia, Germany, UK and France.
* Placebo-controlled: 1:1 ratio
* couble-blind

Key patient qualifications:
* probable or possible diagnosis of PSP with no other neurologic disease
* 41 to 85 years old
* reliable caregiver
* patient and caregiver must be fluent in local language so that interviews can be completed
* reside outside skilled nursing home or care facility at the start of the study
* ability to take 5 steps with walker or minor assistance
* parkinson medications must be stable for 90 days and other medications must be stable for 30 days

Study assessments
* Patient and caregiver interviews: safety (adverse events, con meds) and efficacy (disease severity, daily living, cognitive, mood)
* Lab tests including nasal examination, blood tests, MRI scan, lumbar puncture (optional), eye movement (optional at some sites), DNA collection (optional)

31 sites in North America: coordinating center in North America is UCSF. Dr. Adam Boxer is the study physician.

15 sites in Europe: half the sites in Germany are up and running; half the sites in the UK are up and running; the French sites should be up and running in another month or so.

1 site in Australia: Dr. David Williams in Melbourne. Open for recruitment.

For more information:
* see clinicaltrials.gov, study NCT01110720
* contact Allon Therapeutics: Sue Anne Crocker, [email protected]

Q&A: [I re-ordered these]

Question: Do you expect that davunetide will un-do damage that has already been done?

Answer: Our expectation is to prevent additional damage from occurring. We don’t expect to un-do damage that has already been done.

Question: In the 12-week pilot, there was no evidence to suggest efficacy. Does this concern you?

Answer: No. We were not expecting to see any kind of efficacy in the 12-week pilot study. It was a small study: a total of 12 patients. Not only PSP patients but also CBS patients.

Question: Will the drug help eye movements?

Answer: We don’t know. We are including this in the study since one of the distinguishing characteristics of PSP is eye movement problems. How does the eye movement dysfunction relate to some of the other impairments in PSP?

Question: What do we expect in terms of improvements?

Answer: We don’t know. Our best guess is that it’s going to take about 12 months before we see any affect from the treatment. The gains will be modest. We need a large sample size and a lengthy study period to be sure we are seeing improvements.

Question: I infer that only the Richardson’s Syndrome type of PSP patients are included. What can you say to a family dealing with another type of PSP as to the justification for this?

Answer: Inclusion criteria is really looking at the Richardson’s Syndrome type of PSP. In a clinical trial, we need to look at a similar population of patients.

Question: Is the study relevant to FTDs?

Answer: Tau pathology isn’t unique to PSP. CBS and PNFA have tau pathology. Alzheimer’s also has tau pathology.

We need to show that davunetide is effective in PSP before we can look into other conditions.

Question: Are MSA patients included in this study?

Answer: No, PSP only.

Dr. Morimoto’s Comment: Lots of questions about specific situations. Go to clinicaltrials.gov and find the site nearest you. Ask that site about your specific situation.

Dr. Morimoto’s Comment: A number of visits need to be made to the particular site. It’s up to the site to determine if you live close enough or not. Anecdotally, a number of people are travelling a long distance to participate.

[I had a few questions that didn’t get asked. They are: ]

Question: Is it reasonable to think that 47 sites can enroll 6-7 patients each to get to 300 patients? When do you anticipate the 300th patient will enroll?

Question: When might we see published data from this study?

Question: Since the Alzheimer’s market is bigger than the PSP market, why aren’t you testing this first in the AD market?