BiotechTracker: Curis Approaches the Starting Gate

BiotechTracker: Curis Approaches the Starting Gate

September 02, 2003 On Friday at the Salk Institute in San Diego, CSO Lee Rubin reviewed Curis’s (NASDAQ: CRIS) preclinical hedgehog program. Curis is the leader in developing drugs that impact the hedgehog signaling pathway. Its small molecule hedgehog antagonist (inhibitor) has potential to treat various cancers, and its small molecule hedgehog agonist has potential in both neurodegenerative disease and stroke.

Hedgehog, first identified in fruit flies, is a critical protein in neural development in organisms from flies to humans. Sonic hedgehog and its relatives activate a signaling pathway involving patched and smoothened to induce nerve cells to proliferate and differentiate, among other biological effects.

Curis’s lead program is currently CUR-61414, which will enter clinical trial development for the treatment of basal cell carcinoma, the most prevalent form of skin cancer. Trials were supposed to begin in 2001, but progress was slowed because of the decision to switch from an injected to a topical formulation of the drug. In June of this year, Curis partnered with Genentech (NYSE: DNA) to develop the drug.

Curis plans to file an IND for CUR-61414 for the treatment of basal cell carcinoma "soon." The weakness of IND is that Curis has not performed animal studies showing that the drug is effective. Most of the data supporting the IND come from cell culture studies.

Dr. Rubin reviewed data demonstrating that the hedgehog signaling pathway is activated in most human basal cell carcinomas. One familial form of the diseases is caused by a mutation in the patched-1 protein. Patients with this condition are also predisposed to medulloblastoma, a much more serious form of cancer that also appears to involve aberrant hedgehog signaling. So, CUR-61414 has potential to treat both the prevalent but largely benign basal cell carcinoma, and also deadly but rare medulloblastomas.

Aberrant hedgehog signaling is not correlated with the development of other tumors, but Curis believes that CUR-61414 or other hedgehog inhibitors may nevertheless be efficacious in treating a variety of tumor types. This is because established tumors tend to activate the hedgehog pathway. This has been shown to have direct effects on tumor cells, inducing proliferation, as well as angiogenic effects mediated by nearby stromal cells. Recent preclinical studies show that hedgehog inhibition has promise for treating small cell lung cancer and other cancers where hedgehog is overexpressed.

If inhibiting hedgehog sounds good, activating it may be even better. Curis originally pursued small molecule hedgehog agonists as treatments for neurodegenerative diseases because of the role of hedgehog in inducing neural cell proliferation and differentiation. Progress in this area has been slow, but now Curis has several small molecule agonists that may revive efforts to treat diseases including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis (ALS, Lou Gehrig disease).

In developing its hedgehog agonists, Curis scientists have also discovered a somewhat surprising neuroprotective effect associated with the compounds in mouse models. These studies imply that the compounds have the potential to treat stroke, although the mechanism for this effect is not fully understood. In animal models, hedgehog agonists are able to minimize damage even when administered six hours after the stroke.

An important question is whether hedgehog antagonists used to treat cancer would accelerate neurodegeneration, and whether hedgehog agonists used to treat stroke or neurodegenerative disease would accelerate tumor formation. Curis scientists haven’t seen any evidence of such adversities in animal models, although preclinical models are notoriously poor at predicting human adverse effects. Still, topical treatments that limit the systemic exposure of hedgehog agonists (such as CUR-61414 in basal cell carcinoma) or short treatments such as those needed to treat stroke may yield acceptable risk / benefit profiles.

Two catalysts should benefit Curis in the coming weeks and months. First, acceptance of CUR-61414’s new IND by the FDA will lead to initiation of its first clinical trial program. Second, upcoming publications in the journal Nature alluded to by Dr. Rubin will raise the level of excitement about Curis’s hedgehog program.

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