Monthly Archives: June 2009

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.

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

This recently-published abstract is on some German research into whether the LRRK2 genetic mutation occurs in PSP. This may be of most interest to those who participated in the 23andMe.com genetics testing.

I learned two things from the abstract:

* LRRK2 mutations “have been shown to be the most common genetic cause of both familial and sporadic Parkinson’s disease. Patients harboring LRRK2 mutations develop late onset PD that in most cases cannot be clinically distinguished from idiopathic PD.”

I thought LRRK2 was only associated with familial PD, and I thought familial PD was typically early-onset PD.

* “LRRK2 mutations have been reported to result in a broad spectrum of neuropathological alterations including progressive supranuclear palsy (PSP)-like Tau pathology.”

The weakness of this research is that the 88 PSP patients involved have a clinical diagnosis of PSP. The authors concluded that “there is no evidence that mutations in exon 31 of LRRK2 are a major risk factor for PSP. Our study, however, cannot rule out that other genetic variations in LRRK2 may be associated with PSP.”

Robin

European Journal of Neurology. 2009 Jun 15. [Epub ahead of print]

Screening for LRRK2 R1441 mutations in a cohort of PSP patients from Germany.

Madžar D, Schulte C, Gasser T.
Department of Neurodegenerative diseases, Hertie Institute for clinical brain research, University of Tuebingen, Tuebingen, Germany.

Background and purpose: Mutations in the leucine-rich repeat kinase gene (LRRK2) have been shown to be the most common genetic cause of both familial and sporadic Parkinson’s disease. Patients harboring LRRK2 mutations develop late onset PD that in most cases cannot be clinically distinguished from idiopathic PD.

Furthermore, LRRK2 mutations have been reported to result in a broad spectrum of neuropathological alterations including progressive supranuclear palsy (PSP)-like Tau pathology.

Methods: We screened a cohort of 88 clinically confirmed PSP patients for mutations in exon 31.

Results: We did not find any of the known mutations or any new variants.

Conclusions: Thus, there is no evidence that mutations in exon 31 of LRRK2 are a major risk factor for PSP. Our study, however, cannot rule out that other genetic variations in LRRK2 may be associated with PSP.

PubMed ID#: 19538213 (see pubmed.gov for this abstract only)