Allon Therapeutics Inc. announced that it has initiated a pivotal phase II/III clinical trial to evaluate the company’s lead neuro-protective drug candidate, davunetide, as a potential treatment for Progressive Supranuclear Palsy (PSP), a rapidly-progressing and fatal degenerative brain disease. On January 4, 2011, the company announced that the study will be conducted under a Special Protocol Assessment (SPA), granted by the United States Food and Drug Administration (FDA). Enrollment in the study began in the fourth quarter of 2010.

Bruce Morimoto, Allon’s vice president of Drug Development, said this trial is a critical step forward in executing the company’s approval strategy for davunetide. “We believe this pivotal trial will generate data in about 2 years, helping form the basis for approval of davunetide in PSP.”

“There is a strong scientific rationale for the development of davunetide in this disease. The extensive preclinical data suggests that davunetide works by reducing the tau pathology which is found in PSP and also present in Alzheimer’s disease as well as other frontotemporal dementias. Our clinical data also confirms that davunetide can have a positive impact on various clinical outcomes,” Morimoto continued.

Matthew Carlyle, Allon’s chief financial officer, commented that Allon is in a strong financial position to execute the pivotal study.

“With the closing of a $10.2 million investment in the fourth quarter, we have the resources available to complete the study as agreed upon in the SPA and are able to move forward aggressively,” Carlyle said.

The pivotal phase II/III double-blinded, placebo controlled trial in PSP will enroll approximately 300 patients randomized 1:1 to receive either placebo or 30 mg of davunetide twice a day for 12 months. The primary outcome measures will be the Progressive Supranuclear Palsy Rating Scale (PSPRS) and the Schwab and England Activities of Daily Living (SEADL) scale. Secondary measures will include Clinical Global Impression (CGI) and brain imaging by Magnetic Resonance Tomography (MRI). Additional exploratory endpoints include cognitive and executive function as well as cerebrospinal fluid (CSF) biomarkers.

This multi-national study is being conducted at premier medical institutions in the United States, Australia, Germany, France, Canada and the United Kingdom. The study Principal Investigator is Adam Boxer, MD, PhD, Associate Professor of Neurology at the University of California San Francisco and Director of the Alzheimer’s disease and frontotemporal dementia clinical trials program at the UCSF Memory and Aging Centre.

Allon previously announced that davunetide received orphan drug designation in the United States (January 12, 2010), the European Union (March 17, 2010), Fast Track Status with the FDA (April 6, 2010), and that davunetide met the primary outcome measure of safety and tolerability, with potential trends from secondary efficacy endpoints, in a pilot study of 12 patients suffering PSP and related tau pathology disorders (October 8, 2010).

PSP is one of a group of progressive disorders called frontotemporal dementias (FTD) that affect movement, speech, and behaviour, and for which there are no approved treatments. Approximately 20,000 and 50,000 persons in the US 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.

Allon has demonstrated a strong scientific and clinical rationale for the potential efficacy of davunetide in PSP. The pathology of PSP and Alzheimer’s is similar in that both diseases involve impairment of the brain protein tau — and davunetide is the most advanced tau therapy in the world.

Research has shown that davunetide reduced tau impairment and preserved memory in mice bred to replicate Alzheimer’s or PSP tau pathology.

In 2008, Allon reported phase II a clinical trial results showing that davunetide had a statistically significant positive impact on memory function in patients with amnestic Mild Cognitive Impairment (aMCI), a precursor to Alzheimer’s. The data was presented July 28 and July 30, 2008 to the International Conference on Alzheimer’s Disease and Related Disorders (ICAD 2008).

On December 7, 2009, Allon reported phase II a clinical trial results showing that davunetide improved memory function of schizophrenia patients and had a positive impact on the ability of these patients to carry out important activities in their daily lives.

On March 30, 2010, Allon announced top-line results from an imaging study of schizophrenia patients showing that 12 weeks of treatment with davunetide resulted in a statistically significant increase in levels of a biomarker that is an important indicator of brain cell health. Allon said statistically significant (p=0.0170) increased levels of N-Acetyl Aspartate (NAA) were measured using magnetic resonance spectroscopy in the brains of the schizophrenia patients treated with davunetide. The scientific literature shows that NAA is an informative biomarker because decreased levels of NAA occur in schizophrenia, and in numerous other neurodegenerative conditions such as brain injury, stroke, and Alzheimer’s.

On October 8, 2010, Allon announced that a pilot clinical trial successfully met its primary endpoint of safety and tolerability with davunetide, in patients with Progressive Supranuclear Palsy (PSP) and other types of frontotemporal dementia (FTD) like corticobasal syndrome, and progressive non-fluent aphasia. Despite the small size and short duration of the pilot clinical trial, the investigators also noted a positive trend on a secondary outcome, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), a cognitive measure of memory, language, and attention.

Davunetide is a fragment of a naturally occurring neuro-protective brain protein known as Activity Dependent Neuroprotective Protein (ADNP). Allon’s laboratory and animal studies have shown that davunetide restores the function of structures in the brain — known as microtubules — which are critical to communication between brain cells and the structure of individual cells.

Allon’s two neuroprotective technology platforms are based on two naturally occurring proteins produced by the brain in response to a range of insults. The platforms are Activity Dependent Neuroprotective Protein (ADNP) and Activity-Dependent Neurotrophic Factor (ADNF).

Because the two platforms are based on different proteins, the drugs from each are different molecules with different therapeutic mechanisms and distinct commercial opportunities. Clinical-stage drugs based on davunetide are derived from ADNP, while preclinical stage drug AL-309 is derived from ADNF. Davunetide is focused on Alzheimer’s disease, cognitive impairment in schizophrenia, and frontotemporal dementia. ADNF drug candidate AL-309 is being developed for the treatment of peripheral neuropathies and is administered orally or subcutaneously.

Allon Therapeutics Inc. is a clinical-stage biotechnology company developing treatments for major neurodegenerative conditions. Allon’s drug davunetide has demonstrated human efficacy in amnestic mild cognitive impairment, a precursor to Alzheimer’s disease, and cognitive impairment associated with schizophrenia. Allon has phase II human efficacy programs pursuing large underserved markets, such as Alzheimer's disease and cognitive impairment associated with schizophrenia, and in orphan markets, such as frontotemporal dementias.