Ipilimumab

Ipilimumab (also known as MDX-010 or MDX-101), marketed as Yervoy, is a drug used for the treatment of melanoma, a type of skin cancer. It is a U.S. Food and Drug Administration (FDA) approved human monoclonal antibody developed by Bristol-Myers Squibb, and works by activating the immune system.

Additionally, ipilimumab is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC) and metastatic hormone-refractory prostate cancer.

Approvals and indications
Ipilimumab was approved by the FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery.

Adverse effects
Ipilimumab treatment has been associated with severe and potentially fatal immunological adverse effects due to T cell activation and proliferation. Most of the serious adverse effects are associated with the gastro-intestinal tract; they include stomach pain, bloating, constipation or diarrhea, but also fever, breathing or urinating problems. A "risk evaluation and mitigation strategy" has been set up to inform prescribers of the potential risks.

Interactions
The combination of ipilimumab and leflunomide may lead to increased hepatotoxicity. Over 90 other drug interactions are known, but none of them severe.

Mechanism of action
Ipilimumab is a fully human antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on cytotoxic T lymphocytes that is believed to play a critical role in regulating natural immune responses. The absence or presence of CTLA-4 can augment or suppress the immune system's T-cell response in fighting disease.

Ipilimumab is designed to block the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells.

Clinical trials
, there are two fully human anti CTLA-4 monoclonal antibodies in advanced clinical trials. Ipilimumab, which is an IgG1 isotype, and tremelimumab (from Pfizer) which is an IgG2 isotype.

Melanoma
On December 10, 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma. The three studies tested 487 patients with advanced skin cancer. One of the three studies failed to meet its primary goal of shrinking tumors in at least 10.0% of the study's 155 patients. Side effects included rashes, diarrhea and hepatitis.

In 2010 a study was presented that showed a median survival of 10 months in advanced melanoma patients treated with ipilimumab, compared with 6 months for those treated with gp100, an experimental vaccine (total n=676). Additionally, one year survival was 46% in those treated with only ipilimumab, compared with 25% in those treated with gp100, and 44% for those receiving both. The Phase III clinical studies on the drug were controversial for their unconventional use of a control arm (as opposed to using a placebo or standard treatment). The study tested ipilimumab alone, ipilimumab with gp100, and the vaccine alone. Patients had a higher survival rate with ipilimumab alone, however it is not fully clear whether the vaccine caused toxicity, which would make the drug perform better by comparison. However it gained FDA approval in early 2011. In August 2011 it was approved for use in the UK.

Prostate cancer
, Medarex was performing a Phase I/II dose escalation clinical trial of ipilimumab in metastatic hormone-refractory prostate cancer (HRPC). , some of the patients with advanced prostate cancer had their tumors drastically shrink, promoting further trials.

On June 19, 2009, the Mayo Clinic reported two prostate cancer patients involved in a Phase II study using MDX-010 therapy who had been told initially that their condition was inoperable but had their tumors shrunk by the drug such that operation was possible and are now cancer-free as a result. This press report however was criticized as being somewhat inaccurate and entirely premature. The clinical trials were still at an early stage and were being run alongside other treatments – which could be the real explanation for the tumor shrinkage. It was far too early to say whether ipilimumab has made any difference at all.

Lung cancer
Medarex is running a Phase II trial of ipilimumab in addition to platinum-based chemotherapy (carboplatin) in patients with small cell and non-small cell lung cancer. It is scheduled to run from February 2008 to December 2011.