After a decades-long odyssey, with plenty of bumps along the way, CEL-SCI (AMEX:CVM) of Vienna, Va. has begun the final clinical lap with its Multikine immunotherapy that could turn into a paradigm shift in the way cancer patients are treated.
“The Multikine Phase 3 study is the first study to ever test the assumption that stimulation of an intact immune system prior to any other cancer therapies will be better for the patient’s survival than the stimulation of the immune system after surgery, radiation and chemotherapy, as is the usual treatment with cancer immunotherapy,” CEO Geert Kersten says in an exclusive interview with BioTuesdays.com.
The primary goal of the Multikine therapy, he says, is to harness the body’s natural ability to kill the local tumor micro-metastases that exist around the tumor and in the local lymph nodes. These micro-metastases are thought to be the cause of most cancer recurrences.
“We believe that the stimulation of an anti-tumor immune response prior to surgery, radiation and/or chemotherapy is the best way to kill tumor micro-metastases and prevent recurrence, thereby increasing overall survival,” he adds. “If you get Multikine after the immune system has been destroyed and your lymphatics are cut up, the drug is unlikely to work.”
Multikine is the first immunotherapy to be tested as a first-line standard of care treatment for cancer. Mr. Kersten points out that if Multikine performs as expected in newly-diagnosed head and neck cancer patients, “we think that all solid tumors that can be reached with a needle are potential targets for this drug. We have great data in cervical cancer and some early data in melanoma that also look good. If we’re right, this will change the way we treat cancer.”
CEL-SCI’s Phase 2 data found that the addition of Multikine before the standard of care resulted in a 33% improvement in the median overall survival at 3 1/2 years post-surgery, when compared with survival results reported in 55 clinical trials published in the scientific literature between 1987 and 2007.
Mr. Kersten dismisses critics who say that the Phase 2 studies were not placebo-controlled and as a result, were not statistically significant. “If it were a statistically significant, placebo-controlled study, we would no longer have to do a Phase 3 study. A 33% benefit would be approved immediately. What people tend to forget is that this is a first-line indication and must be carried into a Phase 3 trial.”
Multikine has been tested in 220 head and neck cancer patients, without any serious adverse events at any dose. In the proof-of-concept Phase 2 studies, 12% of patients had no tumor left after a three-week treatment with Multikine and remaining patients had a 50% reduction in the number of tumor cells before any other treatment. The Phase 2 results were published at ASCO, the Journal of Clinical Oncology and Journal of Oral Oncology.
There’s obviously a lot riding on Multikine.
“This would be the first drug ever to be used ahead of normal therapy to make the first treatment more successful,” Mr. Kersten says. “If that’s the case, you have less cancer recurrence, increased survival and fewer deaths from cancer. Any by reducing recurrence, we can save the health care system a huge amount of money.”
Cancer patients today are given three options: surgery, radiation and chemotherapy. “I don’t know a single person who welcomes them,” he adds. “Everybody wants to avoid them. We can create a fourth option: a non-toxic therapy that works with your body and only takes three weeks before surgery. And in most cases, three weeks is not an unusual delay in treatment, because it takes weeks to schedule surgery. So we’re not even delaying regular therapy.”
CEL-SCI started the Phase 3 trial last month, with the objective of enrolling 880 patients during the next 15 months at 48 centers in nine countries, making it the biggest ever study in head and neck cancer. There will be up to six centers in the U.S., two in Canada, three in Hungary, five in Poland, six in the Ukraine, three in Russia, three in Israel, 15 in India and seven in Taiwan, where there is a high incidence of the disease because of the popularity of chewing betel nut.
“We recognize that this is a changing world and clinical trials should not be run just in the U.S. and Europe,” Mr. Kersten says. “They should be run all over the world.”
Teva Pharmaceuticals (NASDAQ:TEVA), which earlier signed a licensing deal to distribute Multikine in Israel and Turkey, will run the Phase 3 study in Israel, with oversight of the trial’s global CRO. Orient Europharma of Taiwan, which has marketing rights for Multikine in Taiwan, Singapore, Hong Kong and Malaysia, will run the study in Taiwan, also with CRO oversight.
CEL-SCI’s portion of the Phase 3 trial will cost $26 million, Mr. Kersten says, adding that the company structured the deals with Teva and Orient Europharma so that they would pay for their rights by participating in the trial.
The company is using the same treatment regimen in the Phase 3 trial that it used in the final proof-of-concept Phase 2 trial. “We think that’s important, because it should be indicative of what we expect in the Phase 3 trial,” which needs to show a 10% overall survival advantage in patients that receive Multikine before standard of care versus the standard of care group, he adds. The FDA has designated Multikine as an orphan drug, so only one pivotal trial is needed.
The incidence of head and neck cancer worldwide is about 650,000 people, of which around 150,000 are in the U.S. and Europe, with the lion’s share in the Far East. “This is another reason to run a global pivotal study,” Mr. Kersten suggests.
“You might think that head and neck cancer is a declining problem, because people are consuming less alcohol and smoking less. But this doesn’t seem to be the case, because we now have increasing incidence, even in younger people. And key opinion leaders have told us that there is nothing on the horizon to treat newly diagnosed head and neck cancer patients, so we are tackling an unmet medical need.”
Calling Multikine a “multi-billion dollar market opportunity”, he says the “cool thing is that we didn’t have to sell out to any of the big guys. Everyone recognizes that a Phase 3 study may fail, so therefore, you must have a huge upside to compensate for the potential risk. Once you bring in a Big Pharma partner, your upside is minimal in comparison to retaining the main marketing rights. That’s the difference in the value creation in the end.”
CEL-SCI still owns the U.S. and European marketing rights for Multikine. “How hard is it going to be to sell a product that is standard of care, has increased survival and is non-toxic? We don’t need any of the big guys to sell this. We can sell Multikine ourselves, at least for head and neck cancer,” he promises.
Multikine belongs to a new drug class called combination immunotherapy, because it has both active and passive immune activity. Combination immunotherapy most closely resembles the workings of the natural immune system in the sense that it works on multiple fronts in the battle against cancer. The drug is a mix of cytokines, which are small proteins, released by cells that have a specific effect on the interactions between cells. The cytokine mixture includes interleukins, interferons, chemokines, and colony stimulating factors, all of which stimulate the body’s healthy immune response.
CEL-SCI’s clinical history with Multikine dates back to the mid-1980s, but the technology required to manufacture the biological drug in commercial quantities became available only in 1993. After completing a series of Phase 1 and Phase 2 studies, the tech bubble burst in 2000, and biotech financing dried up. In 2005, Canadian regulators were the first to clear Multikine for Phase 3 testing, followed by the FDA in 2007. A year later, the company took possession of its manufacturing plant just in time for the financial meltdown.
CEL-SCI’s $25 million GMP plant outside of Baltimore has an annual capacity to make 20,000 treatments of Multikine and can be expanded to 60,000 treatments a year. The plant was designed to fill biologics in “true cold conditions” of 4 degrees Centigrade, which avoids any loss of biological activity. “Building and validating the plant almost killed us—we’re a much stronger company for it,” he maintains.
“What kept us going was a deep-seated belief that the immune system has to be the key to solving cancer and you have to administer an immune system drug before any other therapy. And the disease can’t be as simplistic as a lock-and-key principle with receptors but has to be something very complex that approximates nature,” he recalls.
“We were persistent, and we didn’t take shortcuts. But it wasn’t blind optimism. When we were down and out, we would review the data. It was never emotional. It was always cool and reasoned. Yes, we are right. This will work. Of course, we had no idea how long it would take.”
Why did it take so long to get into Phase 3?
“It’s very simple,” he says. “Money, money, money. Because our drug is a complex biologic, the argument against us in the 1990s was that we’d never be able to manufacture this product in a manner that’s reproducible from batch to batch. We didn’t know how difficult it would be, but we thought we could do it and we did.”