Davunetide (aka, NAP, aka AL-108) trial now to focus on PSP


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Davunetide (aka, NAP, aka AL-108) trial now to focus on PSP

Postby Robin » Fri Jun 26, 2009 8:46 pm

In November 2008, CurePSP, through the Pollin CBD Research Fund, awarded a research grant to UCSF and Dr. Boxer to study NAP (AL-108) in CBD. See:
http://forum.psp.org/viewtopic.php?t=7669

Within the last month or so I heard from a CBD family who plans to participate in the trial that UCSF would begin enrollment some time in the fall of 2009. There were to be at least two additional sites participating -- Mayo Rochester and UPenn.

I heard a few days ago from Sharon, a local support group member, that the NAP trial would be open to PSPers. I received confirmation from UCSF today:

"After feedback from the European equivalent of the FDA, we were forced to focus on PSP, although we will still enroll a smaller number of CBD and FTD patients. The study will also be much larger than originally planned because of additional $ raised by the company that manufactures the drug. We are still the lead site and there will likely be 25 North American sites. More details about sites will be forthcoming in the next few months."

UCSF emphasized that they have no further details to provide at this time. They did point me to a press release from Allon Pharmaceuticals, NAP's manufacturer, that came out yesterday. I've copied that below.

One item I will clarify later is whether participating patients must have dementia or cognitive impairment.

Robin



http://allontherapeutics.com/ir_news_25Jun_2009.html

Allon Therapeutics forms Steering Committee for Phase II human trial

VANCOUVER — June 25, 2009 - Allon Therapeutics Inc. (TSX:NPC) reported today that leading neurologists and psychiatrists have joined a special Steering Committee to help the Company design and conduct a Phase II human clinical trial that will evaluate whether Allon’s lead neuroprotective drug candidate, davunetide intranasal (AL-108), has the potential to become the first effective treatment for a number of brain disorders broadly categorized as frontotemporal dementia (FTD). The study will evaluate the effect of davunetide for the treatment of Progressive Supranuclear Palsy (PSP), one type of FTD. A smaller study in other related forms of FTD will be carried out in parallel.

PSP is a degenerative brain disease that is often characterized by progressive difficulty with balance and walking, eye movement abnormalities, and cognitive and personality changes. PSP affects approximately 20,000 people in the United States, a patient population size consistent with an orphan drug designation. The company expects that efficacy in PSP would define the opportunity to use davunetide (AL-108) in other FTD subtypes that are tauopathies.

Gordon McCauley, President and CEO of Allon, said the Company plans to begin the Phase II trial in FTD during the second half of 2009.

“Physicians and researchers who specialize in FTD are enthusiastic about evaluating davunetide intranasal (AL-108) in FTD patients, primarily because about 50% of FTD and related disorders are tauopathies, or tau-related diseases — and Allon’s technology is recognized as the most clinically advanced tau-related therapy,” McCauley said.

The Company identified some of the members of its FTD Steering Committee as:

• Adam L. Boxer, M.D., Ph.D., Director of the University of California, San Francisco (UCSF) Alzheimer’s Disease and Frontotemporal Dementia Clinical Trials Program and Assistant Professor of Neurology at the UCSF Memory and Aging Center, who specializes in Alzheimer’s Disease, Frontotemporal Dementia and related disorders such as Corticobasal Degeneration and Progressive Supranuclear Palsy.

• Rachelle S. Doody, M.D., Ph.D., Professor of Neurology and Effie Marie Cain Chair in Alzheimer’s Disease Research at Baylor College of Medicine, Houston, who specializes in Alzheimer’s disease and memory disorders.

• Murray Grossman, M.D., Professor of Neurology and Psychiatry at the University of Pennsylvania School of Medicine, who specializes in the diagnosis and treatment of non-Alzheimer’s forms of dementia such as frontotemporal dementia, corticobasal degeneration, amyotrophic lateral sclerosis, and Lewy body disease.

• Anthony E. Lang, M.D., Director of the Division of Neurology and Jack Clark Chair for Parkinson’s Disease Research at the University of Toronto, and Director of the Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital.

• Bruce L. Miller, M.D., Professor of Neurology at the University of California, San Francisco, A.W. & Mary Margaret Clausen Distinguished Chair, and Clinical Director of the UCSF Memory and Aging Center, which treats patients with diseases that cause dementia, including Alzheimer's disease, corticobasal degeneration, Creutzfeldt-Jakob disease and frontotemporal dementia.

• Lon S. Schneider, M.D., Professor of Psychiatry, Neurology and Gerontology at the Keck School of Medicine of the University of Southern California, whose specialization includes Alzheimer’s disease and dementia.

FTD encompasses several cognitive disorders, including Behavioral Variant-Frontotemporal Dementia, Semantic Dementia and Progressive Nonfluent Aphasia, and the movement disorders, Corticobasal Degeneration and Progressive Supranuclear Palsy. No effective treatment is currently available for FTD, and several FTD syndromes are fatal within three to five years. FTD is often incorrectly diagnosed as Alzheimer’s disease.

In 2008, Allon reported efficacy results from a Phase IIa clinical trial that demonstrated that davunetide intranasal (AL-108) improved short-term and working memory performance in patients with amnestic mild cognitive impairment, a precursor to Alzheimer’s disease.

The pathology of Alzheimer’s disease and many forms of FTD has some similarities, including the presence of altered forms of the brain protein tau. In Alzheimer’s, altered tau forms tangles, part of the well-established plaques and tangles hallmarks of Alzheimer’s pathology. PSP is associated with “pure” tau pathology, unlike Alzheimer’s disease in which both amyloid and tau pathology is identified. This provides additional rationale for the use of AL-108 which targets tau in PSP.

Allon has shown that decreasing the levels of altered forms of tau with davunetide intranasal (AL-108) preserved the memory of mice bred to replicate Alzheimer’s or FTD pathology. Allon’s preclinical studies have also shown that davunetide intranasal (AL-108) preserved the memory and learning function of mice bred to replicate the altered tau pathology associated with FTD. ...
Last edited by Robin on Sun Sep 26, 2010 9:59 pm, edited 1 time in total.
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Postby Robin » Sat Feb 13, 2010 11:27 pm

This trial at UCSF is now recruiting. Trial info was posted to clinicaltrials.gov about two weeks ago. See:
http://clinicaltrials.gov/ct2/show/NCT01056965

This is a 12-week study of davunetide (NAP, AL-108) or placebo is those with PSP, CBD, or two frontotemporal lobar degeneration disorders associated with tau pathology (FTDP-17 and PNFA). The drug and the placebo are both administered via nasal spray.

I noticed these two inclusion criteria may disqualify some:
* Subject resides outside a skilled nursing facility or dementia care facility. Residence in an assisted living facility is allowed.
* Able to ambulate with or without assistance.

And this exclusion criteria may disqualify some:
* Early, symptomatic autonomic dysfunction
* Within 4 weeks of screening or during the course of the study, concurrent treatment with memantine, acetylcholinesterase inhibitors, antipsychotic agents or mood stabilizers (valproate, lithium, etc.) or benzodiazepines (other than temazepam or zolpidem).
* Treatment with lithium, methylene blue, tramiprosate, ketone bodies, Dimebon or any putative disease-modifying agent directed at tau within 90 days of screening.
* Subject not willing to attempt LP [Robin's note: LP probably means lumbar puncture.]

The UCSF trial contacts are:
Mary Koestler, RN, PhD, phone 415 476 0661, mkoestler AT memory.ucsf.edu
Arielle Lasky, phone 415 476 8333, alasky AT memory.ucsf.edu [Robin changed this from Nicholson to Lasky, as clinicaltrials.gov got updated]

Dr. Adam Boxer at UCSF's MAC is the principal investigator.

I've heard from a few people (including one member here) that Mayo Jax intends to participate in this trial. Presumably this will happen later in 2010.

Robin
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Postby Robin » Mon Apr 26, 2010 11:42 pm

Here's a short update on the 12-person pilot study of NAP (AL-108, davunetide) at UCSF for PSP and CBD, and on the larger trial. I know several in our local support group attempted to get in on the pilot but I only know of two who were offered spots. One with PSP took the spot offered. The other with CBD declined to participate because of the hassle of getting to UCSF.

This rest of the update comes from Arielle Lasky at UCSF. In short, they are looking for one more CBDer for the pilot, and the full trial for PSP only (not CBD) may begin in September. Here's Arielle's email:

"We are wrapping up the pilot... we've screened 12 people but I think there is one screen fail so we are looking for one last patient, and we hope to find a CBD/PNFA since the group is already half PSP. Given that there's one slot left, people who contact us are likely to not get into the trial, however we can keep their information for future studies should that be the case. We are hoping to wrap up the pilot soon, so if people are interested they should contact me ASAP.

We think the larger study will begin at the end of summer, but many details are still being worked out, so we can't make any promises. We will definitely let you know when it's up... and when it's running, there will be a posting on clinicaltrials.gov."

Actually, the larger trial did get posted to clinicaltrials.gov though, of course, it shows as "not recruiting." See:
http://clinicaltrials.gov/ct2/show/NCT01110720
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Postby Robin » Tue Aug 10, 2010 12:21 pm

This short abstract is about treating tau pathologies, which includes Alzheimer's Disease, PSP, and CBD. The author states that their "findings show that ADNP-deficiency leads to tauopathy which is inhibited by the ADNP derived drug candidate, davunetide (originally known as NAP)." (ADNP = activity-dependent neuroprotective protein) "It is hoped that davunetide, a most advanced drug in clinical development will rapidly advance as a first effective treatment for a number of brain disorders broadly categorized as frontotemporal dementia (FTD)."

There is a small trial going on now (for 12 people - PSP, CBD, FTD, etc) at UCSF with davunetide. And hopefully a larger trial involving more people will start recruiting soon. The larger trial will only be for PSP. This may be the case because the diagnostic accuracy for CBD is very low.

Robin



Current Alzheimer Research. 2010 Aug 2. [Epub ahead of print]

Tau Pathology and Future Therapeutics.

Gozes I.
Laboratory for Molecular Neuroendocrinology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Abstract
The current review discusses microtubules and tau in the healthy brain and move on to the underling pathology of Alzheimer's disease (AD) with emphasis on tau and neurofibrillary tangles. Tangles have been associated with cognitive dysfunction causing neurodegeneration in the absence of plaques.

AD, the most abundant tauopathy is characterized by beta-amyloid plaques and tau tangles.

An abundance of tau inclusions, in the absence of beta-amyloid deposits, defines Pick's disease (frontotemporal lobar degeneration), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and other diseases.

Our own focused research is on activity-dependent neuroprotective protein (ADNP). Our findings show that ADNP-deficiency leads to tauopathy which is inhibited by the ADNP derived drug candidate, davunetide (originally known as NAP).

The current review further describes tau as a potential diagnostic marker followed by drug candidates that are aimed at fighting tau pathology. A recent historical perspective is the final comment of the manuscript.

This paper is not a comprehensive review of the literature rather it gives my own point of view in the face of many publications and a great unmet need for future therapeutics. It is hoped that davunetide, a most advanced drug in clinical development will rapidly advance as a first effective treatment for a number of brain disorders broadly categorized as frontotemporal dementia (FTD) and serve as a prototype for future therapeutic development toward modification and remedy of currently intractable neurodegenerative diseases.

PubMed ID#: 20678069 (see pubmed.gov for this abstract only)
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Postby Lorainemarie » Tue Aug 10, 2010 3:43 pm

Do you ever get sad, Robin? Knowing these advances come too late for our parents?
-Loraine
-Loraine
Image
Mom: Marg-PSP-dx Aug'03-Died May'07 age 81.
Dad: Joe-Primary Progressive Aphasia with Frontal Temporal Dementia-dx Mar'06-Died Nov'06 age 84.
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Postby Robin » Tue Aug 10, 2010 4:40 pm

We are still years away from a good treatment so it doesn't bother me that my dad didn't have access to these trials. I attended a PSP research symposium a month after my dad died. I was really surprised with Dr. Golbe spoke after I introduced myself and said, "see, we need to hurry up with that research." I'm unsure if anyone alive now with PSP will benefit from the research going on now. But I thank everyone in the local support group and around the US who have participated in research studies -- the lithium trial, the NIH-funded genetics study, the 12-person Davunetide trial, the Nypta trial, the TMS study, and the CoQ10 study.

Given the discoveries from the research done on my father's brain (and 1K others), the drug trials going on now for PSP, other research studies, and all we've seen just in the last few weeks on AD research gains, I'm very hopeful something can be found in my lifetime. I am proud that my father and some local support group members can be part of that.
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Postby Robin » Sun Sep 26, 2010 7:39 pm

People in our local support group and others around the US have started to receive informational packets from UCSF about the larger Davunetide trial. UCSF is the lead site. Other US sites include Mayo (Rochester, Jax, and maybe Phoenix).

Screening is occurring now. See:
http://clinicaltrials.gov/ct2/show/NCT01110720
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Postby Robin » Wed Jan 26, 2011 4:18 pm

All US sites participating in the Davunetide trial are currently "recruiting" participants with PSP. This info is from clinicaltrials.gov --
http://clinicaltrials.gov/ct2/show/stud ... ocs=Y#locn

University of Alabama - Birmingham
Contact: Penny Forsythe, LPH, 205-934-1668, adbrain@uab.edu
Principal Investigator: Erik Roberson, MD, Phd

Mayo Clinic, Scottsdale, AZ
Contact: Amy Duffy, 480-301-4750, duffy.amy@mayo.edu
Principal Investigator: Virgilio Evidente, MD

USC Keck School of Medicine, Los Angeles
Contact: Mickie Welsh, 323-442-5982, mwelsh@surgery.usc.edu
Principal Investigator: Mark Lew, MD, FAAN

David Geffen School of Medicine - UCLA, Los Angeles
Contact: Curtis Thiede, 310-206-3356, fthiede@mednet.ucla.edu
Principal Investigator: Yvette Bordelon, MD

UCSD/VA Neurology Service, San Diego
Contact: Deborah Fontaine, 858-622-5800, dfontaine@ucsd.edu
Principal Investigator: Stephanie Lessig, MD

UCSF Memory and Aging Center, San Francisco
Contact: Kathryn Sullivan, (415)476-8333, ksullivan@memory.ucsf.edu
Contact: Mary Koestler, RN, PhD, (415)476-0661, mkoestler@memory.ucsf.edu
Principal Investigator: Adam Boxer, M.D., Ph.D.

Colorado Neurological Institute - Rocky Mountain Movement Disorders Ctr
Contact: Diane Erickson, RN, CCRC, 303-762-6674, derickson@thecni.org
Principal Investigator: Rajeev Kumar, MD

Mayo Clinic, Jacksonville, FL
Contact: Tracy Kendall, CCRC, 904-953-7989, kendall.tracy@mayo.edu
Principal Investigator: Neill Graff-Radford, MD

University of Chicago Medical Center
Contact: Joan Young, CCRC, 773-834-1688, jyoung@neurology.bsd.uchicago.edu
Principal Investigator: Tao Xie, MD

University of Louisville Division of Movement Disorders, KY
Contact: Heidi Wilson, 502-561-3032, heidi.wilson@louisville.edu
Principal Investigator: Irene Litvan, MD

John Hopkins Hospital, Baltimore
Contact: Melissa Gerstenhaber, RNC, 410-614-1242, mgerste1@ghmi.edu
Principal Investigator: Joseph Savitt, MD, PhD

Massachusetts General Hospital, Boston
Contact: Amanda Cook, 617-643-7428, ahcook@partners.org
Principal Investigator: Scott McGinnis, MD

Lahey Clinic, Burlington, MA
Contact: Lynn Sullivan, 781-744-1453, lynn.a.sullivan@lahey.org
Principal Investigator: Julie Leegwater-Kim, MD

University of Minnesota Department of Neuology, Minneapolis
Contact: Susan Rolandelli, RN, 612-624-8431, rolon010@umn.edu
Principal Investigator: Paul Tuite, MD

Mayo Clinic, Rochester, MN
Contact: Dina Drubach, 507-293-4726, drubach.dina@mayo.edu
Contact: Kelly Jacobson, 507 255-3160
Principal Investigator: Brad F Boeve, MD

University of Kansas Medical Center, Parkinson Disease & Movement Disorders Center, Kansas City, MO
Contact: Loretta Jenkins, CCRP, 913-588-6924, ljenkins@kumc.edu
Principal Investigator: Rajesh Pahwa, MD

UMDNJ - Robert Wood Johnson Medical Center, New Brunswick, NJ
Contact: Deborah Caputo, 732-235-7945, caputod@umdnj.edu
Principal Investigator: Lawrence Golbe, MD

Columbia University, NYC
Contact: Lynda Mules, 212-305-2077, lm2538@columbia.edu
Principal Investigator: Lawrence Honig, MD, PhD

Univeristy of North Carolina Department of Neurology, Chapel Hill, NC
Contact: Brandi McCullough, 919-966-8172, mcculloughb@neurology.unc.edu
Principal Investigator: Daniel Kaufer, MD

University Hospitals Case Medical Center, NI Movement Disorders Center, South Euclid, OH
Contact: Suzanne Foxhall, 216-983-0796, suzanne.foxhall@uhhospitals.org
Principal Investigator: Steven Gunzler, MD

University of Pennsylvania
Contact: Lauren Massimo, MSN, 215-349-5725, massimol@uphs.upenn.edu
Principal Investigator: Murray Grossman, MD

University of Texas Southwestern Medical Center, Dallas
Contact: Jackie Rabb, 214-648-9358, jackie.rabb@utsouthwestern.edu
Principal Investigator: Kyle Womack, MD

Baylor College of Medicine, Houston
Contact: Anne Daleiden, 713-798-5519, daleiden@bcm.edu
Principal Investigator: Joseph Jankovic, MD

University of Utah Center for Alzheimer's Care, Imaging & Research, SLC
Contact: Ashlie Finlayson, 801-581-3986, ashlie.finlayson@hsc.utah.edu
Principal Investigator: Edward Zamrini, MD


Perhaps they had to get more sites to participate besides UCSF, UPenn, and Mayo in order to reach something like 100 enrolled. Each site is supposed to enroll 3-4 people.

There are sites in other parts of the world -- Canada, Australia, and Europe. Check out clinicaltrials.gov if you want the details!
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Postby Robin » Sun Feb 06, 2011 10:16 pm

There is currently a one-year, phase 2/3 clinical trial of the experimental medication davunetide going on at 35 sites in the US, Canada, Australia, and Europe. Each site is attempting to enroll 4 to 5 people who are in the early stages of PSP. (Probably UCSF is enrolling more than 4-5 people because we have 3 local support group members who are participating.)

A big THANK YOU to all trial participants!

As mentioned elsewhere on the Forum, CurePSP is hosting a webinar next week on davunetide research. The speaker is Dr. Bruce Morimoto is the Vice President of Drug Development at Allon Therapeutics, Inc.

Just as I don't rely on corporate press releases for medication news and analysis, I don't like getting research info from a drug manufacturer. It's too bad that a researcher from UCSF wasn't invited to give the presentation. The speaker certainly won't be revealing anything that isn't yet published so I don't expect to learn anything.

UCSF - PILOT STUDY

In the summer 2010, UCSF completed a 3-month pilot study on davunetide. (The last visit of the last patient was in mid-August.) In November 2010, I attended a PSP Research Symposium in San Diego where Dr. Adam Boxer spoke about the pilot study. Here are some notes about Dr. Boxer's presentation.

Davunetide (NAP) had an effect on tau in preclinical mouse models. There are three clinical FTLD syndromes that are strongly associated with tau pathology -- PSP, CBS, and PNFA (progressive nonfluent aphasia). The pilot study enrolled 12 patients. Fourteen patients were assessed for eligibility. Enrolled patients included 6 PSP, 3 CBS, and 3 PNFA (progressive nonfluent aphasia). Dr. Boxer's presentation confirmed something I had suspected -- the PSP patients all have Richardson's syndrome, which is the most common type of PSP. It did not include those with PSP-parkinsonism, the second most common type.

The goals of this pilot study were to show that davunetide was safety and tolerable. This was a randomized (2 drug : 1 placebo), double-blind, placebo-controlled trial. The drug and the placebo were administered via a nasal spray. The baseline demographics show how early stage these patients are (as they could still handle their activities of daily living, for example).

Through this pilot study, davunetide was found safe and well-tolerated. There were no serious adverse events. There was excellent compliance (probably because it was a nasal spray).

The groups were not well-balanced at baseline. Five of the six PSP patients were in the treatment group receiving Davunetide.

There was no evidence to suggest efficacy. The clinician's global impression was that most patients were stable and there was no huge change over a 12-week period. Perhaps more change will be seen in the longer study. Or more change will be seen in more homogenous groups.

The pilot study is described on clinicaltrials.gov. The trial ID# is NCT01056965.

MULTI-SITE STUDY

The goal in the 35-site phase 2/3 clinical trial is to enroll 300 patients. I'm unclear how they will reach this goal if each site is to enroll 4 to 5 patients. This larger study is enrolling PSP patients only. The drug to placebo ratio in this larger study is 1 to 1.

Dr. Boxer said it will take one year to enroll fully. And it will take two years "for data." This means that if all goes well, we'll get data in 2013. As Dr. Boxer said: "Fingers Crossed."

PRESS RELEASES

I don't tend to get much useful info from corporate press releases but you may want to know about these...

When the data was analyzed from the pilot study, Allon Therapeutics, the maker of davunetide, put out a press release in mid-October 2010, announcing that the drug was found to be safe. Here's the press release:
http://www.dddmag.com/news-Allon-Comple ... 01110.aspx

There was some press in early January 2011 about the larger phase 2/3 clinical trial as a result of a press release from Allon Therapeutics. Here's the press release:
http://www.marketwire.com/press-release ... 376548.htm

Here's the info in the January 2011 press release on PSP:

"PSP is one of a group of progressive disorders called frontotemporal dementias (FTD) that affect movement, speech, and behavior, and for which there are no approved treatments. Approximately 20,000 and 50,000 persons in the U.S. and EU respectively have PSP. Approximately half of FTDs, including PSP, are tauopathies, which are pathologies that involve impairment of the tau protein in brain cells. Allon expects that demonstrating efficacy in PSP will define the opportunity to use davunetide in other FTD subtypes that are tauopathies."

"PSP is often characterized by progressive difficulty with balance and walking leading to falls, eye movement abnormalities, and cognitive and personality changes. Patients are typically diagnosed when they are between 45 and 75 years of age. PSP is associated with progressive disability and death often three years following diagnosis. The disease is slightly more common in men than women, but there are no known geographical, occupational, or racial patterns."
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