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Roche-Curis Vismodegib (Hedgehog) Pivotal Phase 2 BCC Study Commentary


I would like to have a discussion if the AE, SAEs will have a negative effect on the approval of this drug. Keep in mind, other than disfiguring surgury, there is absolutely no other treatment. Is 25% of patients experiencing an SAE enough to get a "no" from the FDA? There's no doubt this drug works for patients in this indication - the Hh pathway in basal cell cancer is mutated in 90% of these patients. Clinical Benefit in ~80% of patients in study. Bear in mind, the following link is efficacy pictures:

http://twitpic.com/6pt7k2

http://www.faqs.org/sec-filings/100108/CURIS-INC_8-K/g60971ex99_1s11gbgd.jpg



Further, 2 million cases of BCC in the US per year and <5% would be available for this drug - which would be 100,000 patients. Assume only 20% of those 100,000 (20,000 patients) get the drug per year. I am assuming based on recent BRAF drug @ $95,000/year, Vismodegib would be at least $75,000 per year. That's a $1.5 billion drug for Roche, just off this one indication in aBCC/mBCC - or at 5%-8% royalty, $75million-$120million/year for Curis off this small indication. Are my assumptions way off here? People continue to say this is a tiny indication, but, numbers wise, so is/was CML, and Gleevec is a multi-billion drug


September 29, 2011 (Stockholm, Sweden) — The investigational drug vismodegib, which has a novel mechanism of action (inhibiting the hedgehog signaling pathway), has shown "substantial clinical benefit" in advanced basal cell carcinoma, in both metastatic and locally advanced settings.

This finding comes from a pivotal trial of the product in 104 patients, presented here at the 2011 European Multidisciplinary Cancer Congress. The results were presented by Luc Dirix, MD, from the Iridium Kankernetwerk, Antwerp, Belgium, from a paper selected as a best abstract for the presidential session.

Vismodegib is "a potential new therapy" for advanced basal cell carcinoma, he told the meeting attendees. It is under development by Genentech/Roche, which has recently filed an approval application with the US Food and Drug Administration for its use in the treatment of inoperable advanced basal cell carcinoma.

The results from the pivotal trial were "totally convincing" and there were some "very spectacular responses" said Caroline Robert, MD, PhD, from the Institut Gustave Roussy in Paris, France, who acted as discussant for the paper.

"Vismodegib is a breakthrough for the treatment of advanced basal cell carcinoma," she said, but cautioned that "long-term tolerance is an issue."

This novel drug is the first in the class of hedgehog pathway inhibitors. This pathway is disrupted in about 90% of basal cell carcinomas; it is also affected in several other cancers, including medulloblastoma.

Advanced Cases Not Operable

Basal cell carcinoma is the most commonly diagnosed human cancer, with more than 2 million cases each year in the United States, Dr. Dirix noted.

Most cases are treated with surgery, he explained. However, a small proportion of patients (less than 5%) progress to locally advanced or even metastatic disease, for which there is currently no standard of care.

In a phase 1 study of 33 patients with advanced basal cell carcinoma, vismodegib showed a 55% response rate and was generally well tolerated (N Engl J Med. 2009;361:1164-1172). The results generated considerable excitement among scientists, and were heralded as a new era in the treatment of basal cell carcinoma.

Those results led to the pivotal phase 2 study conducted by Dr. Dirix's team. Patients recruited to this study had histologically confirmed basal cell carcinoma that was inoperable, or were patients for whom surgery would be significantly disfiguring, he explained. All patients had either locally advanced (n = 63) or metastatic (n = 63) disease, and all received treatment with vismodegib 150 mg orally until progression or until withdrawal from the study.

"Nearly all patients had some tumor shrinkage," Dr. Dirix reported.

Of the patients with locally advanced disease, 43% responded, and "many had huge responses with massive decreases in tumor size," he said. One patient had no evaluable basal cell carcinoma after treatment, he noted.

Patients with locally advanced disease, assessed by independent review, had an overall response rate of 43% (95% confidence interval [CI], 31% to 56%; P < .0001), and patients with metastatic disease had an overall response rate of 30% (95% CI, 16% to 48%; P = .0011).

Median time to progression was 9.5 months for both groups of patients, Dr. Dirix noted.

Adverse events that were reported in more than 30% of patients included muscle spasms, alopecia, taste disturbance, weight loss, and fatigue. Serious adverse events were reported in 26 patients (25%); in 4 patients the serious adverse event was considered to be related to the vismodegib. Fatal adverse events were reported in 7 patients (7%), but none were considered to be related to the drug.

In her discussion of the study, Dr. Robert drew attention to these tolerability findings. Most of the patients in this study could not tolerate the drug for more than 18 months, and overall, 25% of patients stopped therapy because of toxicity, she noted. My thoughts: would you rather suffer from side effects, or have a massive hole in your head? Did patients see tumor shrink dramatically and therefore decided that they were done with the drug because they didn't want to deal with hair loss, muscle spasms, etc etc.

In another study of vismodegib, conducted in 41 patients with Gorlin syndrome, about 30% stopped taking the drug because of adverse events, she added.

Dr. Robert speculated that there might be a use for vismodegib in the neoadjuvant treatment of advanced basal cell cancer, for example with patients taking it for 3 months or so to shrink their tumors and then undergoing surgery. "We need to explore other modalities," she said, and "surgery must always remain in the algorithm."

Dr. Robert also provided interesting insight into how the drug was developed. Cyclopamine, a chemical extracted from the corn lily, was found to be an inhibitor of the hedgehog pathway. Attention was drawn to this plant after it was noticed that sheep that fed on the flowers while they were pregnant gave birth to deformed offspring, with only 1 eye and brain malformations.

The trial was funded by Genentech/Roche, the companies that are developing vismodegib.

2011 European Multidisciplinary Cancer Congress (EMCC): Abstract 1BA. Presented September 24, 2011.