Genentech has been searching for years to find a way to improve upon rituximab (Rituxan), which set a gold standard 15 years ago as part of the first generation of targeted antibody cancer drugs. Now it looks like Genentech has finally nailed a new and patented version to keep the franchise going for many more years.
South San Francisco-based Genentech is showing today that its experimental drug obinutuzumab (GA101), designed to hit the same molecular target that rituximab does, was able to keep tumors from spreading for a median time of 23 months when given alongside the chemo drug chlorambucil to patients with chronic lymphocytic leukemia. Patients who were randomly assigned to rituximab and the same chemo drug were able to live without their disease worsening for 15.7 months, compared to just 10.9 months for those who got the chemotherapy alone. A summary of the results was posted this afternoon on the American Society of Clinical Oncology’s website in advance of its conference next month.
The results, from a pivotal study of 589 elderly patients too frail to withstand most regimens, were good enough for Genentech to file an application last month to the FDA for clearance to start selling the new medicine in the U.S. The FDA also has granted the application one of its new “breakthrough” designations, which are designed to speed up regulatory reviews of drugs with potential to make the greatest impact. If approved by regulators, and if this success can be repeated in other blood cancers where rituximab has excelled, then the new product could be a huge revenue driver for Genentech and its parent company, Roche. Last year, rituximab generated $7.29 billion in worldwide sales, making it the world’s fifth-biggest selling drug, according to Genetic Engineering and Biotechnology News.
“Rituxan has been a great drug for patients and has provided a lot of benefit,” said Nancy Valente, Genentech’s vice president of global hematology development. “What’s pleasantly surprising, what we’re happy to see, is the improvement with GA101 and chlorambucil is so much greater.”
The new antibody came to Genentech through a circuitous route. Roche acquired GlycArt Biotechnology in 2005, and then Roche acquired all of Genentech in 2009. Genentech has long worked on various iterations on rituximab, particularly through a long-running partnership with Biogen Idec, which has part-ownership of the original molecule and a 35 percent ownership in GA101. Biogen Idec’s participation in GA101 “is purely financial and they have played no role at any point in the development of GA101,” said Genentech spokeswoman Krysta Pellegrino.
What’s different about GA101 is that it was designed through “glycoengineering” to remove a sugar group that would otherwise be attached to the backbone of the Y-shaped protein drug. By doing so, Genentech’s antibody engineers were hoping to amplify a phenomenon they observed with rituximab known as “antibody-dependent cell-mediated cytotoxicity” or ADCC. While rituximab was made to bind specifically with the CD20 target commonly found on the surface of tumor cells, its effect couldn’t be completely explained by the antibody’s direct tumor-killing ability. The binding of the antibody to the target would also send a signal that alerted the immune system to start attacking those tumor cells. Once scientists knew that this immune reaction was partially responsible for rituximab’s success, they sought to create an antibody that would hit the same target, but which might be more efficient at triggering that immune response.
The clinical results proving this concept are still somewhat preliminary. Researchers can’t yet say for sure what kind of impact the new drug will have on patient survival time. And like all drugs, it had side effects. About two-thirds of patients (67 percent) on the new drug combo reported moderate to severe side effects, most of which were infusion reactions the first time patients got the new treatment. About 46 percent of patients on the rituximab regimen reported similar infusion-related side effects, researchers said. Patients on the new drug also reported a higher rate of neutropenia, a depletion of infection-fighting white blood cells, than was seen in the control group. About 34 percent of those on the new drug reported moderate to severe neutropenia, compared with 25 percent who got the older drug from Genentech.
Still, the data package Genentech has sent to the FDA offers some striking evidence of effectiveness. The hazard ratio that compared the new drug group to standard chemo was 0.14. What that means, in a statistical sense, is that patients had an 86 percent lower risk of having their disease worsen during the study if they got the new drug and chlorambucil, compared with chlorambucil alone. Rituxan also showed an advantage on that score when compared with chlorambucil, but the margin wasn’t as wide. The rituximab/chlorambucil combo offered patients a 68 percent lower risk of disease worsening than the chlorambucil alone, researchers said. All the results were statistically significant, meaning it was highly unlikely the advantages observed were the result of chance.
New cancer drugs rarely ever show that big of advantage over standard treatments. Genentech’s Valente called the hazard ratio finding “amazing.” She added: “We’re seeing a clear patient benefit.”
David Miller, an analyst with Biotech Stock Research, simply said “wow” when reviewing the hazard ratio.
“The real comparison, I suppose, is between GA101 and Rituxan,” Miller says. “The hazard ratio won’t be quite that shiny there, but…these are pretty fine data.”
Patients who enrolled in the study had a median age of 73, and were getting their first treatment for chronic lymphocytic leukemia. These patients often have other diseases, and aren’t strong enough to tolerate the standard chemotherapy cocktail regimens that oncologists usually prescribe to younger patients, Valente says. The general population of patients with chronic lymphocytic leukemia are expected to live about a median of six years following their diagnosis, although it’s harder to determine a precise prognosis for elderly patients, she said. While chlorambucil isn’t considered a standard of care on its own, it’s hard to define what the standard of care is in this patient population, because sometimes they go untreated, she said.
The results being presented today suggest that the new Genentech antibody is better than rituximab in this patient group, although the second part of this clinical trial was designed to provide a statistically valid head-to-head comparison, Valente said. Those results should be available later this year, she said.
The infusion reactions did pose a challenge for investigators on the study, and they were managed by prescribing antihistamines and steroid pre-medications, like what patients get with rituximab, Valente said. The study was designed for patients to come in to get an infusion on Day 1, 8, and 15, in the initial phase, followed by treatment every 28 days thereafter. Researchers, after seeing the relatively high rate of infusion reactions on Day 1, allowed for that first-day dose to be split into smaller doses on back-to-back days, to minimize the effect, Valente said.
As you’d expect with a company as big as Roche/Genentech, it has many more trials in the works to see how far it can go with the new antibody. Trials are ongoing in follicular lymphomas, and diffuse large B-cell lymphoma, Valente said. Many studies have been designed to prove that the new drug is superior to the old one, she said.
“This could be a very important product, because if we are successful in making a molecule superior to Rituxan, then we’ve really hit the ball out of the park,” Valente said.