Ipilimumab (IPI) is a new drug from Bristol-Myers Squibb (BMS) marketed under the name YERVOYTM (1). It is a human monoclonal antibody, a ‘biotechnology-derived’ recombinant protein known as a biologic. Made by fermentation within specialized plants, drugs such as these are based on natural antibodies, slightly changed to give them the long-acting characteristics of the natural form as well as the ability to target proteins on specific cells.
Many of these biologics have been hugely successful, including high-profile medications like Remicade® (Crohn’s Disease), Tysabri® (Multiple Sclerosis), Herceptin® (Breast Cancer) and Erbitux® (Colon Cancer). Some of these drugs find their way into the news. Erbitux® for instance, landed Martha Stewart in jail for insider trading. Tysabri® was recalled and then rereleased after a ~1% rate of a fatal brain infection was found. IPI’s story is still evolving, but will likely make the news as well. To appreciate the drug’s potential, it’s important to understand its history.
Cancer Drugs, Failing Forward
IPI binds to the cell-surface receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) on suppressor T-lymphocytes, a white blood cell. This receptor keeps an eye on the immune system, dampening responses when it’s overactive. For drug development potential, an investor may see this specific-drug, specific-target as a breakthrough opportunity. But such biologics pose investment hurdles and the first-to-market rarely wins. Cancer drugs prove this, as the treatment field has crawled and experienced many surprises and setbacks. In fact, it took many failures over a 30-year period of clinical research to get IPI. But now it’s a blockbuster in cancer treatment.
Drugs like IPI are exciting to follow as they offer hope to patients with few available treatments. Also, failures can actually help move the field forward. Sometimes the real win isn’t just a drug’s approval, it’s the energizing effect it has on research and what it can teach us about the disease. Such events catalyze breakthroughs in cancer immunotherapy, many of which are happening now.
The Price of Progress
When IPI binds to CTLA-4 it blocks a signal which normally inhibits immune reactions. The release of restraint increases T-cell activation, important because these cells are programmed to think melanoma cells are “self” and should be left alone (2). When inhibition is released by IPI, T-cells can hunt down and attack tumor cells.
What keeps T-cells from attacking the rest of the body? FDA scientists worried about this, but knew advances came at a high price. Industry-based drug development costs a great deal of money. On top of time spent, patient’s lives can be the currency of research. The real heroes are the patients willing to try new drugs, helping researchers learn what might work in the future.
Reviewers weighed risks with the reality that those with advanced melanoma had little hope. In fact, there have only ever been two available treatments for the disease and both had a slight effect in arresting the disease. So despite the risks, patients volunteered for clinical research and data accrued across Phase I, II, and randomized Phase III trials.
(Clinical) Trials and Errors
IPI’s mechanism of action had never been tried. It offered some surprises during clinical trials. At first, doctors worried about uncontrolled tumor growth following treatment. Everyone watched and waited, thinking IPI would likely fail like previous immunotherapies. But the immune system began inhibiting tumor growth and patients experienced benefits. Eventually, durable responses and increased survival emerged from the data.
Unchecked immune response was still a concern however. While IPI extended life, patients reported ‘severe’ autoimmune reactions (15%); some deaths occurred during studies as well. Through a special risk management program called REMS, IPI’s package insert presented immune reactions to oncologists. The REMS program helped manage the drug’s risks, improving safety. The insert showed doctors proper administration, helped identify patients unable to tolerate the drug, and presented corticosteroid treatment options in the event of a reaction.
Following phase III trials, the risk vs. benefit analysis showed that IPI improved survival in patients with metastatic melanoma (the first agent to do so). In 2011, it was approved for marketing in the US; the EU approved it shortly after. The drug can now be given as a monotherapy (3mg/kg every 3 weeks for 4 doses) to treat advanced (unresectable or metastatic) melanoma.
IPI’s story reads like many high-risk drugs’ stories read. Numerous research projects supported drug development and many more failed than succeeded. For IPI, setbacks included slower-than-expected response times and severe immune reactions. But the roadblocks helped improve the chances for patients with untreatable melanoma. In addition, research yielded new insights on the immune system, stimulating research on the use of immunotherapy for other diseases. Several promising drugs, with similar actions as IPI, are now in development.
For more information about this area of drug development, read the review article in Nature by Thomas A. Waldmann, “Immunotherapy: past, present and future” (Nature Medicine 9 (3): 269–277, 2003). Also, Steven Rosenberg, head of surgery at the NIH National Cancer Institute, wrote Transformed Cell, telling the story of his role in cancer immunotherapy.
- Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Graziani G, Tentori L, Navarra P. Pharmacol Res. 2012 Jan;65(1):9-22.
- Releasing the brake on the immune system: ipilimumab in melanoma and other tumors. Tarhini A, Lo E, Minor DR. Cancer Biother Radiopharm. 2010 Dec;25(6):601-13.