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Imlygic is what’s known as an oncolytic virus—an engineered virus (in this case herpes) that shrinks tumors and then stimulates the immune system to continue recognizing and destroying cancer cells. At least a half-dozen biotechs and academic groups are working on oncolytic viruses, but Amgen is the first to market, meaning it will set the stage for everyone who follows in terms of how oncolytic viruses are embraced as part of the overall cancer-treatment landscape.
Imlygic is injected into melanoma tumors and is designed both to destroy cancer cells at the primary site and to prompt the immune system to hunt down and kill metastatic cells. Herpes, like many viruses, has a natural ability to invade cancer cells and destroy them. But Imlygic was also specially engineered to include a cytokine, or protein, called granulocyte-macrophage colony-stimulating factor (GM-CSF), which draws immune-boosting cells to the tumor, further boosting the drug’s cancer-killing abilities.
Just a few days before the FDA approval of Imlygic, the European Medicines Agency issued a positive opinion on the drug, setting the stage for approval by the European Commission. "Metastatic melanoma continues to be one of the most difficult-to-treat cancers, often requiring the use of multiple treatment modalities,” said Sean Harper, Amgen’s vice president of R&D, in a statement following the ruling. “Despite recent advances, the five-year survival rate for patients who cannot be cured with surgery remains unacceptably low, demonstrating the critical need for additional approaches to control this disease."
It’s been anything but a smooth road to market for Amgen, however. The company got into the oncolytic virus business in 2011, when it paid $425 million, plus $575 in potential milestone payments to acquire Imlygic’s inventor, Biovex. At the time, the FDA had granted “fast track” status to the drug, which was meant to speed up the approval timeline.
Problem was, the Phase III trials of Imlygic were designed to compare the drug to GM-CSF alone, which seemed OK until a whole bunch of game-changing melanoma drugs hit the market. They included the immunotherapy drugs Yervoy (ipilimumab) and Opdivo (nivolumab) from
The Imlygic trials weren’t set up to compare the drug with the new entries. What’s worse, Imlygic didn’t stack up all that impressively to GM-CSF, extending median overall survival by just 4.4 months. An FDA advisory panel knocked down the fast-track plan this past April, after the agency had already pushed back its decision date by three months.
All that said, there were some positive signals that emerged during the advisory panel’s meeting. Amgen presented data showing that patients who had a durable response to Imlygic in the first year of treatment had a 95% reduction in the risk of death. Nearly half of the 2,116 melanoma tumors injected with the drug vanished, along with 212 tumors that weren’t treated but may have benefitted from the drug’s ability to stimulate the immune system. Randy Russell, a melanoma patient who testified at the panel meeting, said he had run out of options when he went into the trial and was amazed that Imlygic made his disease disappear.
Amgen’s data showed that the durable responses to Imlygic were most pronounced in a subset of patients who were in Stage III of the disease, meaning their cancer had only spread to a few lymph nodes. Cowen & Co.’s Schmidt estimates that no more than 10% of patients who are ineligible for surgery would be appropriate candidates for Imlygic in light of that data. “This is because patients with melanoma that is advanced enough to be unresectable, but not advanced enough to require aggressive systemic approaches, are uncommon,” he wrote in a September report. Hence his low sales estimate.
But what’s most important about Imlygic and all the other oncolytic viruses in development is probably not their potential as standalone therapies. Virtually everyone working in the field agrees that the biggest potential for these engineered bugs will be in combination treatments, particularly with other types of immune-boosting treatments. Drugs like Yervoy, for example, are called “checkpoint inhibitors” because they block signals that would normally prevent the immune system from attacking cancer. Combining checkpoint inhibitors with oncolytic viruses may free up the immune system to attack cancer from many different angles.
Towards that end, Amgen is already testing Imlygic with Yervoy and with Keytruda in melanoma. In April, investigators for the company reported that the Yervoy/Imlygic combo produced higher response rates than either drug alone in an early trial.
Imlygic’s availability as a solo therapy will give physicians time to get comfortable with engineered viruses—and that alone could boost the entire field of oncolytic virus development, said former Amgen executive Thomas Zindrick in an interview last week. “The comfort level that will be created for regulatory agencies, but more importantly for physicians working with these agents for the first time, will increase the acceptance and ultimately the adoption of the technology,” said Zindrick, now CEO of Genelux, which is working on a drug derived from the vaccinia virus.
Physicians who treat aggressive melanoma are in constant need of new approaches to battle the disease. "Advanced melanoma remains a complex disease to treat, requiring the use of several modalities over the course of a patient's therapeutic journey," said Howard L. Kaufman, associate director for Clinical Science at the Rutgers Cancer Institute of New Jersey, president of the Society for Immunotherapy of Cancer, and the principal investigator for the pivotal trial of Imlygic in a statement. The drug, he added, "has a unique approach, and provides another option for treating eligible patients with unresectable disease that has recurred after initial surgery."
In the statement, Amgen said it would make Imylgic available within a week at an estimated average cost of $65,000. There will likely be more discussion about the drug later today, when the company announces its third quarter earnings. But for melanoma patients who are more concerned about getting access to new treatment choices than they are about the financials of the companies providing those drugs, the approval of Imylgic will likely be welcome news.
