Curis, Inc., a drug development company seeking to develop next generation targeted small molecule drug candidates for cancer treatment, announced that its collaborator Genentech, a member of the Roche Group, has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) seeking sales and marketing approval for vismodegib (GDC-0449, RG3616) to treat people with advanced Basal Cell Carcinoma (BCC), which includes metastatic and locally advanced BCC for whom surgery is inappropriate.

Vismodegib is a first-in-class investigational, oral medicine designed to selectively inhibit signalling in the Hedgehog pathway, which is implicated in more than 90 per cent of BCC cases. Curis is eligible to receive an $8 million milestone payment from Genentech upon FDA acceptance of this submission. If the drug receives FDA approval, then Curis will also be entitled to receive an additional milestone payment as well as royalties on any future sales.

“We continue to be impressed by Genentech's development efforts with respect to this molecule and are pleased that, following its successful completion of a pivotal study in advanced BCC, the vismodegib programme has advanced to a US NDA submission,” said Dan Passeri, president and chief executive officer, Curis. “We believe that vismodegib is an excellent example of a targeted cancer drug that has been developed based on an understanding of the underlying molecular biology that drives the disease. We believe that this molecule has the potential to provide an important treatment option for patients with advanced BCC.”

Curis expects that the FDA will notify Genentech whether its NDA submission has been accepted for filing within 60 days of submission. Assuming the FDA accepts the NDA submission, the agency will communicate a PDUFA date to Genentech.

Roche has also indicated that the timing of a European regulatory submission is subject to its ongoing discussions with the European Medicines Agency (EMA). Curis is entitled to receive an additional milestone payment should such submission be made by Roche and subsequently accepted by EMA, as well a milestone payment and royalties on future sales should vismodegib be approved by EMA.

ERIVANCE BCC is an international, single-arm, multi-centre, two-cohort, open-label phase II study that enrolled 104 patients with advanced BCC, including locally advanced BCC (71) and metastatic BCC (33). Locally advanced BCC includes patients whose BCC lesions are deemed inoperable or for whom surgery is deemed inappropriate. Metastatic BCC is defined as BCC that had spread to other parts of the body, including the lymph nodes, lung, bones and/or internal organs. The study was conducted at 31 sites in the United States, Australia and Europe. Study participants received 150 mg vismodegib orally, once daily until disease progression or intolerable toxicity. Tumour responses for metastatic BCC were measured by RECIST criteria and for locally advanced BCC by a novel composite endpoint which included reduction of size of lesions of at least 30% in longest dimension and/or complete resolution of locally advanced BCC ulceration.

The primary endpoint of the study is overall response rate as assessed by an independent review facility, with secondary endpoints including investigator-assessed overall response rate, progression-free survival (PFS), overall survival (OS), and duration of response in all evaluable patients, including locally advanced BCC or metastatic BCC patients. In addition, absence of residual BCC in patients was assessed by sampling biopsies in patients with locally advanced BCC.

The overall response rate in the pivotal phase II trial as assessed by an independent review facility showed vismodegib substantially shrank tumours or healed visible lesions in 43 per cent of patients in the locally advanced cohort and 30 per cent of patients in the metastatic BCC cohort.

The median duration of PFS by independent review for both metastatic BCC and locally advanced BCC patients was 9.5 months. The median duration of response by independent review was 7.6 months for both metastatic BCC and locally advanced BCC patients. The median duration of response as assessed by study investigators was 12.9 and 7.6 months for metastatic BCC and locally advanced BCC patients, respectively.

There was no residual BCC in sampling biopsies of 54% of locally advanced BCC patients.

As of the November 26, 2010, data cutoff date, there were 19 (57.6%) metastatic BCC and 32 (45.1%) locally advanced BCC patients remaining on treatment. The median duration on treatment as of this date was 10 and 9.7 months for metastatic BCC and locally advanced BCC patients, respectively.

The most common adverse events observed in the study (observed in greater than 20% of patients) included muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite, and diarrhoea. Serious Adverse Events (SAEs) were observed in 26 patients (25 percent). Four of these patients (4 percent) had SAEs that were considered to be related to vismodegib, including one case each of: blocked bile flow from the liver (cholestasis), dehydration with loss of consciousness (syncope), pneumonia accompanied by an inability of the heart to pump enough blood (cardiac failure) and a sudden arterial blockage in the lung (pulmonary embolism). Fatal events were reported in seven patients (7 percent); none were considered by investigators to be related to vismodegib. In all fatalities, pre-existing risk factors and comorbid conditions were present.

BCC is the most common cancer in the United States and the most common type of skin cancer, accounting for approximately two million new cases annually. The disease is generally considered curable when the cancer is restricted to a small area of the skin. However, in a small group of people, if the disease is left untreated or does not respond to treatment, the cancer may advance further into the skin, bones or other tissues, or spread to other parts of the body. In such rare cases, the disease can become difficult to treat and life-threatening.

Vismodegib is designed to selectively inhibit signaling in the Hedgehog pathway by targeting a protein called Smoothened. The Hedgehog signalling pathway plays an important role in regulating proper growth and development in the early stages of life and becomes less active in adults. However, mutations in the pathway that reactivate Hedgehog signalling are seen in several different types of cancer. Abnormal signalling in the Hedgehog pathway is implicated in the majority of BCC cases.

Genentech is also evaluating vismodegib in a phase II trial in people with operable forms of BCC, which opened for patient enrollment in October 2010. Additionally, vismodegib is being evaluated by third-party investigators in a number of other cancers and in people with BCC who have Gorlin syndrome, a condition that affects many areas of the body and increases the risk of developing BCC.

Under the ongoing collaboration agreement between Genentech, a wholly owned member of the Roche Group, and Curis, vismodegib (GDC-0449, RG3616) was discovered by Genentech and was jointly validated by the parties through a series of preclinical studies. Pursuant to this collaboration, Genentech and Roche are responsible for clinical development, and Genentech (US), Roche (Ex-US excluding Japan) and Chugai Pharmaceuticals (Japan) are responsible for commercialization of vismodegib. Curis is eligible to receive cash payments upon the successful achievement of specified clinical development and regulatory approval milestones, as well as royalties assuming successful commercialization of vismodegib by Genentech and its sub-licensees, which include Roche and Chugai.