Update: Hedgehog Small Molecule Agonist Neurological Disorders Programs

[Guest guest]

Hedgehog Small Molecule Agonist Neurological Disorders Programs

Under Collaboration with Wyeth

http://www.curis.com/pipeline_detail.php?id=4

The Hedgehog signaling pathway is essential for the formation of

normal nerves and nerve networks in the central and peripheral

nervous systems. Our scientists and academic collaborators have

shown that treatment with a Hedgehog protein appears to accelerate

the restoration of nerve function in models of nerve trauma and

disease. This finding suggests that the Hedgehog pathway may have a

potential therapeutic effect in treating certain human neurological

disorders.

Our scientists have developed a series of small molecule Hedgehog

agonists that, in preclinical models, have shown to be capable of

activating the Hedgehog pathway. Many of these small molecule

Hedgehog agonists are orally available and can cross the blood brain

barrier, a protective barrier formed by blood vessels and brain

tissue that prevents most substances in the blood from entering the

central nervous system. Small molecules that cross this blood brain

barrier can potentially reach and treat the central nervous system,

therefore making them attractive product development candidates for

certain brain disorders.

In 2004, our scientists presented a series of abstracts at the

annual meeting of the Society for Neuroscience demonstrating

positive preclinical results using the Hedgehog small molecule

agonists in models of stroke, Parkinson's disease, and spinal cord

injury. A third party has also reported on the use of a small

molecule Hedgehog pathway agonist to promote the generation of new

motor neurons in vitro. Thismotor neuron report was published in the

Proceedings of the National Academy of Sciences U S A.2004 May 4;101

(18):7123-8. Motor neurons are nerve cells that are most typically

found in the spinal cord, and their purpose is to establish

functional connections with other tissues, usually muscles, to

control movement and other functions. Damage to motor neurons can

occur as result of injury, such as spinal cord injury, or as a

result of disease, such as spinal muscular atrophy or a myotrophic

lateral sclerosis, also known as ALS or Lou Gehrig's disease.

We believe that the positive effects of the Hedgehog agonists in

neuronal disease models are due to neuro protection that is induced

by activation of the Hedgehog signaling pathway. Neuro protection is

the prevention of theprogressive death of cells in the brain caused

by disease or injury. In addition, we believe that activation of the

Hedgehog pathway results in an increased proliferation of stem cells

in the brain. We are currently exploring the possibility that this

may enable us to develop drugs that can promote the replacement of

cells lost as a result of injury ordisease.

In January 2004, we entered into a collaboration agreement with

Wyeth to continue the development of these drug candidates for the

treatment of neurological disorders and other potential indications.

Wyeth is one of the world's largest research-driven pharmaceutical

companies with broad expertise in the development of drugs to treat

neurological disorders and other diseases. Under the terms of the

collaboration, Wyeth paid us an up-front license fee and is

obligated to provide two years of research funding. In addition, if

clinical development of any Hedgehog agonist technology-based

products is successful, Wyeth is obligated to pay us clinical

milestone payments and royalties on product sales.

Wyeth has agreed to assume all future responsibility for clinical

development of the Hedgehog small molecule and protein agonists as

systemic treatments for neurological and other disorders. As part of

the agreement, we have retained development and licensing options

for certain therapeutic applications of Hedgehog agonist

technologies, including topical applications for hair growth and

local delivery applications for treatment of cardiovascular disease.

Wyeth has a right of first negotiation to obtain an exclusive

license to the cardiovascular applications of the Hedgehog agonist

technology. If Wyeth declines its option, or if we are unable to

reach an agreement with Wyeth on terms within the contractually

specified period, we are free to seek another collaborator for this

program.