A Sirtuin Inhibitor Enters Phase1a Clinical Trials in Europe

HD Lighthouse Contributing Editor's Comment: 

Siena Biotech has begun testing a Sirt1 inhibitor in multiple doses in 96 healthy male and female volunteers in Europe. The randomized, double-blind and placebo-controlled study will assess safety, tolerability and pharmacokinetics preparatory to initiating clinical trials in Huntington’s Disease patients.

The name sirtuin comes from the Silent Information Regulator gene 2 (Sir2), a gene which is associated with aging in yeast and invertebrates. The equivalent gene in mammals is called Sirt1.

Siena Biotech researchers have performed a series of unpublished studies which they report shows the inhibitor to be neuroprotective in cell and animal models. In a mouse model, symptoms were ameliorated and survival times were increased. In addition, Siena reports that the preclinical safety profile indicates that the drug would likely to safe for chronic treatment.

The sirtuin inhibitor was granted orphan drug status from the European Medicines Agency (EMEA) in October and from the FDA in December, 2009. These designations provide regulatory and financial incentives to develop drugs for diseases which affect a relatively small number of people.

Siena licensed the inhibitor from Elixir Pharmaceuticals. Elixir was founded by Cynthia Kenyon and Lawrence Guarante, following their groundbreaking work on lifespan extension in the c.elegans worm and in yeast, respectively.

Increasing the expression of Sirt2 in yeast and worms increases lifespan. Accordingly, initial interest in modifying the expression of Sirt1 as a treatment for Huntington’s Disease focused on enhancing rather than inhibiting it since the onset of neurodegenerative diseases appears to be associated with the aging process, as the defense mechanisms of cells become less efficient. However, the Sirt1 protein is also a deacetylase. Inhibiting it appears to modify the acetylation of the HD protein causing the enhancement of the clearance of the HD protein but not the normal version. It is this function which appears to produce the positive effects in cell and animal models of Huntington’s.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 01-31-2010

Siena Biotech Announces FDA and EMEA Orphan Drug Designations and Phase I Clinical Study of SEN0014196 for the Treatment of Huntington’s Disease

Siena, Italy, January 8th, 2010. Siena Biotech S.p.A. announced today that its orally active, selective SirT1 inhibitor SEN0014196 (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide), which is being developed as a disease-modifying therapy in Huntington’s disease, has obtained Orphan Drug status both from the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMEA).

The European Medicines Agency (EMEA) granted Orphan Designation to Siena Biotech’s SEN0014196 for the treatment of Huntington’s disease on October 28, 2009 whereas the Office of Orphan Products Development of the FDA granted Orphan Drug designation for SEN0014196 on December 7th, 2009. The US Orphan Drug Act is intended to assist and encourage companies in the development of new drugs for the treatment of rare diseases and disorders affecting fewer than 200,000 people in the United States, providing economic and regulatory incentives to sponsors, including reduction of fees, protocol assistance and eligibility for seven-year market exclusivity. In the EU, and upon marketing approval, Orphan Drug Designation entitles to ten year’s market exclusivity and eligibility for protocol assistance and possible exemptions or reductions from certain regulatory fees.

Siena Biotech also announced that SEN0014196 has entered Phase I clinical studies; the compound is being tested in a combined single- and multiple-dose study with a randomized, double-blind and placebo-controlled design to assess safety, tolerability and pharmacokinetics of SEN0014196 in a total of 96 male and female healthy volunteers.

“The Orphan Drug Designations obtained by this molecule brought into clinical trials by Siena Biotech, reaffirms the commitment of our company and its reference shareholder, the Monte dei Paschi di Siena Foundation, to fight diseases still without a cure”, stated Marco Parlangeli, Managing Director of the Monte dei Paschi di Siena Foundation and President of Siena Biotech. "We are excited to bring forward SEN0014196 into the clinic as it has the potential to be the first use of this class of molecules in this devastating disease”.

In a series of preclinical studies, researchers at Siena Biotech have demonstrated the neuroprotective properties of SEN0014196 in a series of in vitro systems as well as its capacity to increase survival and ameliorate psychomotor and histological phenotypes in a widely employed in vivo preclinical model of Huntington’s Disease, indicative of a disease-modifying activity. Additionally, the product exhibits a biopharmaceutical and preclinical safety profile compatible with chronic treatment of Huntington’s Disease.

SEN0014196, also known as EX-527, was in-licensed by Siena Biotech from Elixir Pharmaceuticals Inc., Cambridge, Mass., USA, in 2009. Under the terms of the agreement with Elixir Pharmaceuticals, Siena Biotech has certain exclusive rights to develop and commercialize the compound in all countries of the world.

“We believe that SEN0014196 has all the characteristics to become a breakthrough product for the treatment of this devastating disease, still without a cure.” said Giovanni Gaviraghi, M.D., C.Chem., CEO of Siena Biotech, “We are eagerly awaiting the results of the pivotal clinical studies to assess the disease-modification potential of SEN0014196 and confirm our pre-clinical evidence also in patients.”

About SEN0014196 and SirT1 Inhibition in Huntington’s Disease - The selective SirT1 inhibitor SEN0014196 displays cyto- and neuroprotective activity against toxicity induced by mutant huntingtin in cellular models of Huntington’s Disease increasing survival, amelioration of psychomotor behaviour and improvement in histopathological endpoints in the most widely employed animal models of Huntington’s Disease, pointing towards a potential activity of the compound against this disease in humans. SirT1 is a protein deacetylase capable of modulating mutant huntingtin acetylation. Inhibition of SirT1 by SEN0014196 is expected to increase clearance of the mutant huntingtin without affecting levels of the normal protein.

About Huntington’s Disease - Huntington’s Disease is a monogenetic, autosomal dominant disease that gives rise to progressive neural cell death, characterized by chronic progressive chorea with a degenerative course over a period of 10-25 years, when the patient eventually succumbs to complications such as heart failure or aspiration pneumonia. Huntington's Disease is the most studied and better understood of a class of rare neurodegenerative conditions caused by expansion of CAG repeats in different genes and shares patho-mechanisms with other less studied neurodegenerative diseases. Huntington’s Disease is therefore sometimes described as the model for this class of diseases where some degree of sharing in the underlying mechanisms might exist.

About Siena Biotech S.p.A. - Siena Biotech S.p.A. is an innovative, clinical-stage drug discovery company whose R&D efforts are mainly focused on discovering new drugs for therapeutic intervention against neurodegenerative diseases and in oncology. The company, based in Siena, Italy, is structured around drug discovery technology platforms from target validation to clinical studies. The company has developed an internal portfolio of several innovative R&D projects in three therapeutic areas: Alzheimer’s Disease, Huntington’s Disease and Cancer. The projects are rapidly progressing through the pipeline, in some cases as parts of strategic R&D alliances with major pharmaceutical companies. Siena Biotech has built a wide network of external collaborations, both in the academic and business communities, to add to the scientific excellence of internal R&D, thus creating a sound scientific base for its interactions with patients and physicians. Siena Biotech is the instrumental company of the Monte dei Paschi di Siena Foundation to operate in the field of scientific research and biotechnology, in line with its founding charter and mission.

Source: Press Release