DAVUNETIDE

Davunetide, according to Allon Therapeutics, is derived from a naturally-occurring neuroprotective brain protein known as activity dependent neuroprotective protein (ADNP). Allon reports that human clinical and pre-clinical data suggest that davunetide works on microtubules, structures in the brain critical to communication between cells, and central to the tau pathway. In various investigations, davunetide has shown statistically significant impacts on memory, activities of daily living, and as a biomarker of brain cell function and integrity.

A recent preclinical study found that intranasal davunetide administration significantly improved motor function and brain pathology in a mouse model that replicates certain characteristics of Parkinson's disease. The results demonstrated that davunetide-treated mice showed a 38 percent decrease over control groups in the number of errors per step in the beam transversal test. The lead study author, Marie-Francoise Chesselet, MD, PhD, talks with Practical Neurology about what the study means.

What should neurologists take away from the davunetide preclinical PD study?

A short treatment with intranasal davunetide improved the motor deficits and decreased aggregates in a mouse over-expressing alpha-synuclein. According to Dr. Chesselet, “This suggests that davunetide can interfere with alpha-synuclein induced pathology and motivates a more extensive pre-clinical trial that is currently ongoing.”

How do these findings compare with similar research in the PD field and what do you feel was uncovered by this latest study?

“This is the first time that a small molecule has been shown to improve behavioral deficits in a mouse model of Parkinson's disease that better reproduces the pathophysiology of the disorder than previously used models that used toxins to kill dopaminergic neurons,” Dr. Chesselet notes.

In view of the recent failure of clinical trials of drugs that showed pre-clinical efficacy in toxininduced models, she suggests that many in the field are turning to new models based on information gained from more recent studies on the genetics and pathology of PD.

“The model used in this study is based on evidence that multiple copies of the gene encoding alpha-synuclein cause familial forms of PD and that the protein, although not mutated in sporadic PD, is a major component of Lewy bodies in the brain of patients with sporadic PD. Alpha-synuclein has also been shown to be strongly associated with PD in genome-wide association studies of sporadic PD,” Dr. Chesselet explains. “This provides a compelling case for performing pre-clinical studies of potential neuroprotective strategies in models based on alpha-synuclein over-expression, however not all available models are suitable for such studies.

“The mice over-express the human, wild-type protein to mimic as closely as possible sporadic PD. They lose dopamine in the striatum by 14 months of age and then show l-dopa responsive deficits but also show much earlier dysfunction reminiscent of non-motor symptoms of PD. At a young age, the mice show deficits in sensorimotor function but only in challenging tests, and these deficits can be used to assess drug effects on the pathological processes induced by excess alphasynuclein.”

The study that Dr. Chesselet led showed that deficits induced by alpha-synuclein in young mice, before they lose DA neurons, can be improved by davunetide, “suggesting it has potential for neuroprotection in PD.” She adds, “The current study will test whether a longer treatment is more effective and also whether davunetide can prevent the loss of DA that occurs in older mice. If successful, it will suggest that the drug can interfere with the pathophysiological process of PD and stop or slow its progression even though the treatment will likely be given to patients after they have already lost neurons.”

What's next? What will be the focus of phase II/III studies and what do you hope to learn, or what issues do you hope will be resolved?

According to Gordon McCauley, chief executive officer of Allon Therapeutics, Allon announced in November 2010 the receipt of additional funding from the Michael J. Fox Foundation to further the preclinical research of davunetide in the PD setting. The newly funded research project will focus on the impact of davunetide on a key pathology in PD, namely alpha-synuclein, and serve to assess the potential of davunetide for clinical development in PD.

Currently, Allon Therapeutics is enrolling patients in a pivotal Phase II/III clinical trial evaluating davunetide as a potential treatment for progressive supranuclear palsy (PSP). This study will enroll approximately 300 patients randomized 1:1 to receive either placebo or 30mg of davunetide twice daily 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 MRI. Additional exploratory endpoints include cognitive and executive function as well as cerebrospinal fluid (CSF) biomarkers. The study will be conducted under a Special Protocol Assessment (SPA), granted by the FDA, which means that the design of this pivotal trial is appropriate to be used for drug approval in the US.