InterMune Inc. stopped a Phase III trial of Actimmune (interferon gamma-1b) in ovarian cancer due to ineffectiveness and will not plan any further oncology studies of the product going forward, as it falls outside the company's core focus.
A synthesized version of interferon gamma, Actimmune is approved for chronic granulomatous disease and severe, malignant osteopetrosis. The Brisbane, Calif.-based company will continue to test its effectiveness in idiopathic pulmonary fibrosis (IPF), a Phase III program.
Since cancer falls outside its concentration in pulmonary and hepatic diseases, its financial forecasts never included revenue contributions from oncology, and the decision to terminate should not impact its broader plans.
"Obviously, if it were positive, we would have been very happy for patients and very happy for shareholders," InterMune President and CEO Dan Welch told BioWorld Today, noting that no financial analysts built cancer revenue into their models. "That's because we shared that we felt the trial was risky."
He added that the company's relatively small drop in share price - the stock (NASDAQ:ITMN) fell $2.54 Friday, or 12.3 percent, to close at $18.07 - indicated "that the market didn't have expectations of any magnitude."
InterMune based its decision on an independent data safety monitoring board's interim analysis showing that Actimmune conferred no survival benefit in the study. Findings also suggested that Actimmune might exacerbate the dose-limiting toxicities of cytotoxic chemotherapy drugs.
The study compared the combination of Actimmune with the standard regimen of carboplatin and paclitaxel to the two chemo agents alone in advanced ovarian cancer. That plan stemmed from a previous study of Actimmune together with an older chemo regime that produced more positive data, but that wasn't reproduced in this trial.
The primary endpoint was overall survival, but there was a shorter overall survival time in the Actimmune arm compared to carboplatin and paclitaxel alone (p=0.001). More specifically, 169 of the 426 Actimmune group patients died (39.7 percent) compared to 128 of the 421 patients who received chemotherapy alone (30.4 percent). Also, there was no difference in progression-free survival time between treatment groups (p=0.796).
The last patient completed dosing in mid-2004, three years after recruitment began, and fewer than 2 percent of patients in each treatment group died during the treatment period. Patients remain in post-treatment follow-up, which is when the company said the survival time imbalance began. Based on the data available for the interim analysis, the incidence of deaths unrelated to ovarian cancer was less than 2 percent overall and was similar between the treatment groups.
Preliminary exploratory analyses suggested that the difference in survival might be related to dose reductions of carboplatin and paclitaxel, as 24 percent of patients in the Actimmune group did not complete all six chemo cycles, compared to 17 percent of patients in the control group.
Since the trial was based on older standard chemotherapy, the expectations "were quite low," Welch said, "and I think appropriately so." But he added that there was an obligation to run it to its completion for patients and investigators. SEC filings show that the company spent about $15 million per year on the program for the past two years.
More patients receiving Actimmune plus chemo experienced Grade 3 or Grade 4 adverse events and serious adverse events compared to those patients on chemo alone, and more Actimmune-arm patients had treatment-limiting adverse events that led to a decrease in dose, interruption or discontinuation of chemo. The most common was the expected side effect of neutropenia. The combination of agents with overlapping toxicity profiles might explain the higher rate of dose modifications.
In contrast, the company said Actimmune generally has been well tolerated in patients with other diseases and InterMune remains comfortable with its role as monotherapy in its approved indications. In the past year, the product generated $107.3 million in revenue for InterMune.
"We're motoring on and focusing on our other three programs, two of which are in Phase III," Welch said.
The company is optimistic about its ongoing IPF program, with the Phase III INSPIRE trial expected to complete enrollment during the first half of this year to determine whether the drug can improve survival in those patients. The study is expected to conclude late next year, with top-line data to be disclosed in early 2008.
"There have been several studies that have suggested a survival benefit of Actimmune in this patient group," Welch said, noting that about 35,000 new IPF patients are diagnosed annually. They have a five-year survival rate of 20 percent.
Additional resources will go to its Phase III program of the oral small-molecule pirfenidone in IPF, for which InterMune recently finalized a treatment protocol. To test forced vital capacity as the primary endpoint, two concurrent, multinational trials will enroll a total of 550 patients beginning in the first half of this year. Previous studies have shown that pirfenidone improves lung function in those patients, for whom there are no approved drug therapies.
Most are treated with steroids, Welch said, and there is considerable off-label use of Actimmune. Making pirfenidone and Actimmune readily available to IPF patients "would be the dream," he added, with the former improving lung function and the latter extending survival.
Other InterMune resources will be directed to ITMN B, an oral protease inhibitor for hepatitis C virus, for which the company plans to seek permission to begin human studies in Europe in the third quarter. Eventually, InterMune expects to file an investigational new drug application to test it in the U.S., but the Europe-first strategy follows an established track employed by other companies for their hepatitis C programs.
ITMN B and other pills represent the future in that space, Welch said, so late last year, InterMune divested a marketed hepatitis C compound, Infergen. In exchange, it received $135.5 million in cash from Valeant Pharmaceuticals International Inc., of Costa Mesa, Calif. (See BioWorld Today, Nov. 30, 2005.)
InterMune, which posted net income of $59.7 million for the quarter ended Dec. 31, closed its fiscal year with $216 million in cash, cash equivalents and available-for-sale securities. Notably, its spending guidance calls for reducing its selling, general and administrative expenses by $60 million.