Infinity Expands Development Program for Oral Smoothened Antagonist Targeting Hedgehog Pathway

Infinity Pharmaceuticals, Inc. recently announced it is expanding its clinical development program for IPI-926, a novel, oral small molecule that inhibits Smoothened, a key component of the Hedgehog pathway. As part of this expansion, Infinity plans to initiate an exploratory Phase II clinical trial in patients with myelofibrosis, an incurable malignancy of the bone marrow characterized by the replacement of normal bone marrow by fibrotic tissue and the production of blood cells in other organs, such as the spleen and liver.

The single-arm, Phase II trial is designed to evaluate the safety and efficacy of IPI-926 administered orally once daily in up to 45 patients with myelofibrosis. The primary endpoint of the trial is hematologic response rate. The trial is expected to begin in the third quarter of 2011.

“The important role of the Hedgehog pathway in pathogenic fibrosis leads us to believe that IPI-926 may have application across a range of malignancies, including pancreatic cancer and myelofibrosis, in which malignant cells create a dense, fibrotic, protective microenvironment via the Hedgehog pathway signaling to the stroma,” said Pedro Santabarbara, MD, PhD, Chief Medical Officer at Infinity. “While other agents in development for the treatment of myelofibrosis reduce spleen size, there is still a significant need for novel treatment options that can directly target the malignant fibrosis underlying this disease.”

Infinity scientists and their academic collaborators have led the way in validating the role of Hedgehog pathway signaling in the tumor-stroma interaction in pancreatic cancer. Earlier this month, Infinity presented encouraging Phase Ib results for IPI-926 in combination with gemcitabine in patients with metastatic pancreatic cancer. Data from the study showed that IPI-926 was well tolerated and clinically active. Partial responses were observed in five out of 16 patients, for a 31% response rate. Infinity continues to explore other potential indications for IPI-926 and plans to initiate multiple investigator-sponsored trials this year.

Myelofibrosis, an incurable malignancy of the bone marrow, is characterized by the replacement of normal bone marrow by fibrotic tissue and the production of blood cells in other organs, such as the spleen and liver. The primary manifestations of myelofibrosis are severe anemia resulting in weakness and fatigue, as well as massive enlargement of the spleen (splenomegaly) and liver (hepatomegaly), which result in abdominal pain and ultimately liver failure. The 5-year survival rate for myelofibrosis is approximately 40%.

There are limited treatment options for patients with myelofibrosis, and there are no approved therapeutic agents that directly target the fibrosis that underlies this disease.

Malignant activation of the Hedgehog pathway is responsible for a broad range of cancers. IPI-926 targets the Hedgehog pathway by inhibiting Smoothened (Smo), a key signaling component of the Hedgehog pathway. Smo inhibition represents a significant anticancer opportunity for addressing a number of difficult-to-treat cancers by disrupting malignant activation of the pathway.

IPI-926 is currently being evaluated in multiple trials, including a Phase II trial in combination with gemcitabine in previously untreated patients with metastatic pancreatic cancer and a Phase II study as a single agent in patients with chondrosarcoma. A Phase II trial of IPI-926 as a single agent in patients with myelofibrosis is planned to begin in the third quarter of 2011. IPI-926 was well-tolerated and showed clinical activity in a Phase Ib trial in patients with metastatic pancreatic cancer and in a Phase I trial in patients with advanced solid tumors, including a cohort of patients with basal cell carcinoma. These clinical trials build upon a robust set of supporting data that provide a strong rationale for evaluating the potential of IPI-926 for treatment across a broad range of cancers.