Status: BLA approved in March 2011; EU approved in July 2011

Organizations involved:

Bristol-Myers Squibb Co. – R&D; Tech.; World mark.

Medarex, Inc. – R&D; Tech.; USA mark.

Samsung Biologics - Manuf.

Lonza Biologics plc –Manuf.; Former

Cross ref.: See the entry for other CTLA antibodies -- CTLA-4 Mab, rDNA/Pfizer (tremelimumab) and CTLA4-Ig, rDNA (Abatacept). See also the Monoclonal Antibodies entry (#300)

Description: Ipilimumab is an aqueous formulation recombinant fully human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) IgG1 monoclonal antibody, presumably manufactured using transformed Chinese hamster ovary (CHO) cells. Ipilimumab has a calculated molecular formula of C6472H9972N1732O2004S40 and an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.

Yervoy is supplied in single-use vials of 50 mg/10 mL and 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab plus diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (Tween 80) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7.

Yervoy is the first therapy approved by the FDA to clearly demonstrate a survival advantage in patients with metastatic melanoma. It had been 13 years since the last therapy became available to treat melanoma. That was interleukin-2 (Proleukin), but this only benefits 10%-15% of those with advanced melanoma.

Nomenclature: CTLA-4 Mab, rDNA/BMS [BIO]; immunoglobulinG1, anti-(human CTLA-4 (antigen)) (human g1-chain), disulfide with human k-chain, dimer [CAS]; immunoglobulin G1, anti-(human CTLA-4 (antigen)) (human gamma1-chain), disulfide with human kappa-chain, dimer [CAS]; ipilimumab [USAN]; 477202-00-9 [CAS RN]; MDX-010 [SY]; MDX-CTLA-4 [SY]; MOAB CTLA-4 [SY]; antigen-4(anti-CTLA-4) monoclonal antibody [SY]; MDX-CTLA4 [SY]; cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibody, recombinant [SY]; NSC 720801 [NCI]; NDC 0003-2327-11 and NDC 0003-2328-22

Biological.: See the Abatacept entry above for further background about CTLA-4. In brief, by binding to CTLA-4, ipilimumab inhibits the binding of CTLA4 to B7 ligands, resulting in enhanced T cell activation associated with cellular toxicity (cytotoxic immune responses) against tumors. Ipilimumab is an antibody against human cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), an antigen expressed on activated T-lymphocytes (T-cells) with affinity for B7 co-stimulatory molecules. CTLA-4 is one of the key negative regulators of adaptive immune responses, with a central role in the maintenance of peripheral tolerance and in shaping the repertoire of emergent T cell responses. CTLA4 binding by ipilimumab enhances T-cell activation, enables continued CD28-mediated enhancement of T-cell receptor (TCR) signaling, and blocks B7-1 and B7-2 T-cell co-stimulatory pathways. Blockade of CTLA-4 expressed on activated T-cells can be used alone or in conjunction with a tumor vaccine to potentially enhance antitumor responses.

Companies.: Medarex is jointly developing ipilimumab in collaboration with Bristol-Myers Squibb Co. (BMS), with Medarex providing 35% of development costs. The companies entered into an agreement in Jan. 2005. Medarex pays 35% of development costs related to trials intended to support regulatory approval in both the U.S. and Europe and 50% of costs related to trials intended to support only U.S. regulatory approval. BMS pays for costs related to trials only supporting regulatory approval in countries other than the U.S. Medarex and BMS commited $192 million to the development of ipilimumab across multiple indications:. Medarex could receive up to $205 million from BMS if all regulatory milestones are met. As part of this deal, BMS paid $25 million in cash and purchased $25 million in Medarex stock in 2005. Medarex is potentially entitled to an additional $275 million, if certain sales-related milestones are met.

BMS has worldwide marketing rights. Medarex has an option to co-promote ipilimumab in the U.S. In the case Medarex chooses to do so, it will be entitled to 45% of profits from ipilimumab derived from sales in the U.S.; and it will receive undisclosed royalties. Medarex will receive an undisclosed royalties on sales outside the U.S., with various analysts estimating this to be between 20-30%.

Lonza Biologics plc originally manufactures clinical supplies of ipilimumab (at least for Medarex) and initially manufacture commercial supplies for BMS.

In July 2013, BMS entered into 10-year deal with Samsung Biologics for manufacture of ipilimumab at its facility in Songdo Incheon, Korea. At the time, Yervoy was approved in 41 countries.

FDA class: Biologic BLA

Approvals: Date = 20110325, full BLA

indications: [full text of the "Indications:ANDUSAGE" section of the product insert/labeling]:

YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for the treatment of unresectable or metastaticmelanoma

Status: Yervoy was approved in the EU by the EMA in July 2011 for the treatment of adult patients with previously-treated advanced melanoma. The registration dossier for MAA with the EMA was filed in May 2010; and BLA was filed with the FDA in June 2010.

FDA had granted Medarex Fast track designation for ipilimumab in combination with chemotherapy (dacarbazine; DTIC) in previously untreated (first-line) metastatic melanoma patients; as monotherapy in previously treated (second-line) metastatic melanoma patients; and in combination with a melanoma-peptide vaccine, MDX-1379, also from Medarex for second-line treatment of melanoma. FDA granted ipilimumab orphan designation of these indications:. The pivotal Phase III trials involve Special Protocol Assessment agreements (SPAs) with FDA concerning the suitability of the trials to support approvals.

On April 25, 2008, BMS reported that the BLA submission would be delayed. The FDA had requested additional overall survival (OS) data to further demonstrate the benefit of ipilimumab. At the time, the pivotal randomized Phase III trial evaluating the efficacy of ipilimumab in combination with dacarbazine versus dacarbazine alone in patients with untreated unresectable Stage III or Stage IV melanoma was ongoing under Special Protocol Assessment (SPA). However, results reported in Dec. 2007 indicated that one of three trials, a Phase II trial (008), expected to support approval had not met its original endpoint, which was to rule out a best objective response rate of less than 10%. The companies sought FDA permission to change the primary endpoint in this trial from progression free survival (PFS) to OS.

FDA approved Yervoy on March 25, 2011. The product insert/labeling includes black box warnings.

Due to the unusual and severe side effects associated with Yervoy, the therapy was approved by FDA with a Risk Evaluation and Mitigation Strategy (REMS) to inform health care professionals about these serious risks. A medication guide will also be provided to patients to inform them about the therapy's potential side effects.

Tech. transfer: Medarex has received U.S. patents including “Human CTLA-4 antibodies,” 6,984,720, Jan. 26, 2006, assigned to Medarex, with claims including various recombinant CTLA-4 monoclonal antibodies and calculated expiration date of Aug 24, 2020.

Patent applications are still apparently pending, e.g., US2012258094, "METHOD FOR TREATING A RHEUMATIC DISEASE USING A SOLUBLE CTLA4 MOLECULE," and US2012052065, "METHODS OF TREATMENT USING CTLA4 MUTANT MOLECULES."

Bristol-Myers Squibb Co (BMS) has received patents including 5,977,318, "CTLA4 receptor and uses thereof" expiring Nov 2, 2016; 5,968,510, "CTLA4 receptor and uses thereof,"expired Jun 27, 2011; and 5,885,796, “CTLA4 receptor and uses thereof,” expiring expiring Nov 2, 2016. These identify CTLA-4 receptor as a ligand for the B7 antigen and provide the complete amino acid sequence for the human CTLA4 receptor gene. Claim no. 1 is “A monoclonal antibody which recognizes and binds the extracellular domain of CTLA4, wherein said binding prevents the binding of CTLA-4 to the B7 antigen.” BMS has received other CTLA-4-related patents (see the Tech. transfer section of the Abatacept entry).

WO2006107298, METHODS FOR TREATING IMMUNE DISORDERS ASSOCIATED WITH GRAFT TRANSPLANTATION WITH SOLUBLE CTLA4 MUTANT MOLECULES, EP0613944, "Methods for regulating the immune response using CTLA4-binding molecules and IL4-binding molecules, expires in 2014. Trials: Ipilimumab had been in clinical trials for over a decade and advanced Phase II-III trials for over 7 years

In Dec. 2006, Medarex reported ipilimumab was shown safe and induced responses in two separate Phase I and Phase I/II trials for treatment of lymphoma and leukemia. In Feb. 2007, Medarex reported positive follow-up data from an ongoing Phase 1 trial of Cell Genesys’ GVAX immunotherapic vaccine in combination with ipilimumab for treatment of metastatic, hormone-refractory prostate cancer. However, in Dec. 2008 Cell Genesys and Takeda halted developoment of GVAX.

The monotherapy data submitted for BLA approval evaluated ipilimumab in 487 patients with advanced Stage III or Stage IV metastatic melanoma from three clinical trials conducted at multiple centers across North America, Europe, South America and Africa. The trials included an open-label, single arm trial (008) evaluating overall response rate in 155 patients who progressed on or following standard treatment; a randomized, double-blind trial (022) evaluating the efficacy of three dose levels of ipilimumab in 216 patients who were previously treated, relapsed or failed to respond to experimental treatment or were unable to tolerate currently approved therapies; and a randomized, double-blind, placebo-controlled trial (007) in 116 patients comparing the safety of ipilimumab, with or without prophylactic oral budesonide (primarily evaluating the rate of grade 2+ diarrhea). All patients enrolled in these trials were diagnosed with advanced Stage III or Stage IV malignant melanoma..

In Dec. 2007, top-line data were reported from the three registrational trials (008, 022, 007). The results from study 008, conducted under Special Protocol Assessment (SPA), did not meet the primary endpoint -- ruling out a best objective response rate of less than 10%. "However, the totality of data from the registrational program included a clear dose response effect observed in study 022 and best objective response rates across the three studies ranging from mid-single digits to mid-teens as determined by independent radiology review. The objective responses were consistent with previous observations and included complete and partial responses. The majority of the responses were ongoing at the end of the observation period. In contrast to standard cytotoxic therapy, responses at the highest doses were noted to evolve over time; these patterns of response appear potentially unique to this form of therapy... Safety data from the 10 mg/kg cohorts were consistent with results from similar or lower doses of previously reported clinical data."

In June 2008, long-term follow-up and overall survival (OS) results were reported from a Phase II clinical study (MDX010-08) in 72 chemotherapy-naive patients with advanced melanoma of 3 mg/kg of ipilimumab in combination with dacarbazine (DTIC). At four years or later, 11.4% (4 of 35) patients receiving the combination were still alive. The median OS for patients treated with ipilimumab plus DTIC was 15 months. These results compare favorably with data in medical literature, in which median OS ranges from 6 to 9 months for patients with treated or previously untreated advanced melanoma treated with standard chemotherapy. The disease control rate (proportion of patients with complete responses, partial responses or stable disease) for patients treated with ipilimumab in combination with DTIC was 37.1%, or 13 of 35 patients The disease control rate in the ipilimumab alone treatment arm was 21.6%, or 8 of the 37 patients, with median OS of 12 months. A similar ongoing Phase III study performed by BMS was then comparing 10 mg/kg of ipilimumab in combination with DTIC versus DTIC alone in previously-untreated patients with advanced melanoma. Patients originally treated in the MDX010-08 study were subsequently enrolled into study MDX010-028 to determine long-term follow-up data and OS.

In Sept. 2008, updated survival data were reported from three Phase II studies (studies 008, 022 and 007) of ipilimumab in patients with advanced metastatic melanoma (Stage III or IV) who had previously been treated, with a consistent one-year survival rate between 47-51%, i.w., with half of patients who received ipilimumab (10 mg/kg) alive beyond one year. As discussed above, these trials had not met their primary endpoints. Follow-up for survival was up to 24.8, 21.88 and 26.32 months in studies 008, 022 and 007, respectively. A recent meta-analysis of 42 Phase II trials with 2,100 patients had reported a one-year survival rate of a~25 percent for patients with Stage III or IV metastatic melanoma.

As of fall 2008, more than 2,000 patients had been treated in trials with ipilimumab as a monotherapy or in combination with other agents. Patients in the ongoing Phase III study (BMS study CA184-024) are randomized to receive induction therapy with 10 mg/kg of ipilimumab in combination with DTIC or placebo. Eligible patients are permitted maintenance dosing with ipilimumab or placebo after the induction phase has been completed. Ipilimumab was/is in three separate pivotal studies for metastatic melanoma as a second-line monotherapy treatment, as a first-line treatment in combination with dacarbazine (comparing ipilimumab plus dacarbazine to dacarbazine alone in patients with stage III or IV melanoma; the second Phase III trial for this indication), and as a second-line treatment in combination with a melanoma-peptide vaccine, MDX-1379, from Medarex. Ipilimumab was/is also in multiple Phase II trial for other tumor types, as well as in combination studies with chemotherapy, immunotherapy and vaccines.

In June 2010, Phase III results were reported showing that patients with advanced melanoma who received ipilimumab lived 34% longer than those who received the immune-stimulating gp100 peptide vaccine. In the study, which involved 125 centres internationally, the safety and effectiveness of ipilimumab plus placebo (137 patients), ipilimumab plus the gp100 vaccine (403), and the gp100 vaccine plus placebo (136) in patients with stage III/IV melanoma were compared. This was the first randomised study to find an improvement in overall survival for advanced melanoma, which currently has few treatment options. This was the first time a therapy prolonged survival for patients with stage IV melanoma. Two-year survival was 24% among the patients who received ipilimumab and 22% among those who received combination treatment, versus 14% for patients who received the gp100 vaccine alone. Ipilimumab was generally well tolerated but 10%-14% of patients experienced sometimes severe side effects, such as rash and colitis, compared to about 3% of the vaccine patients. The addition of gp100 vaccine to ipilimumab did not improve outcome. BMS reported that plans for further development of ipilimumab/gp100 vaccine combination in favor of monotherapy./

In June 2010, trials were underway with ipilimumab in earlier stage melanoma patients, and were planned in combination with targeted agents such as Plexxicon/Roche's BRAF inhibitor PLX4032 (RG7204). Ipilimumab is also in ongoing trials in other malignancies, including prostate and lung cancer.

The most common adverse events in trials of ipilimumab have consisted of flu-like symptoms such as fever, chills and nausea. These events were expected and generally responded to standard medical therapy.

Ipilimumab and some other anti-cancer monoclonal antibody treatments shows some peculiarities. Unlike standard chemotherapy, side effects can be a good sign, because they correlate with a strong antitumor response. Progressive disease may not always be a sign of treatment failur. Instead of stalling or shrinking, lesions may actually grow or increase in number during the course of ultimately successful treatment with ipilimumab. This unpredictability has led researchers to develop and adopt a system of immune-related response criteria (see " New response criteria for immunotherapy to capture response patterns in advanced melanoma patients treated with ipilimumab: Results from two phase II trials," Cancer Immunity, Vol. 8 Suppl. 2, p. 25; 15 December 2008), an alternative to the WHO's partial/complete response criteria for response to anticancer treatments.

In terms of supporting the BLA approval, Yervoy's safety and effectiveness were established in a single international study of 676 patients with melanoma. All patients in the study had stopped responding to other FDA-approved or commonly used treatments for melanoma. In addition, participants had disease that had spread or that could not be surgically removed. The study was designed to measure overall survival, the length of time from when this treatment started until a patient's death. The randomly assigned patients received Yervoy plus an experimental tumor vaccine called gp100, Yervoy alone, or the vaccine alone. Those who received the combination of Yervoy plus the vaccine or Yervoy alone lived an average of about 10 months, while those who received only the experimental vaccine lived an average of 6.5 months.

The types of adverse events (AEs) attributed to Yervoy are generally mechanism (immune)-based. Yervoy can result in severe and fatal immune-related adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system. However, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. Adverse events associated are managed with protocol-specific guidelines, including the administration of systemic corticosteroids, dose interruption/discontinuation and/or other immunosuppressants.

Randomised, double-blind Phase III study results were published in the New England Journal of Medicine in June 2010. Based on the survival (Kaplan-Meier) curve, the 1 and 2-year estimated survival rates for patients treated with Yervoy were 46% and 24% respectively vs. 25% and 14% in the comparator arm with some patients alive at 3 and 4 years.

In 2nd-half 2011, Hoffmann-La Roche conducted a Phase I/II trial with Yervoy in combination with its oral BRAF inhibitor, vemurafenib. However, further trials were not planned.

Medical: Yervoy is administered intravenously (3 mg/kg). The recommended complete course of treatment includes 4 infusions over 3 months.

Common side effects that can result from autoimmune reactions associated with Yervoy use include fatigue, diarrhea, skin rash, endocrine deficiencies (gland or hormone), and inflammation of the intestines (colitis). Severe to fatal autoimmune reactions were seen in 12.9% of patients treated with Yervoy. When severe side effects occurred, Yervoy was stopped and corticosteroid treatment was started. Not all patients responded to this treatment. Patients who did respond in some cases did not see any improvement for several weeks.

Yervoy poses a risk of serious sideeffects, including severe to fatal autoimmune reactions in 12.9 percent of patients treated with Yervoy, as well as a range of milder side effects. FDA decided that the benefits of Yervoy outweigh its risks, because no other treatment had been shown to prolong a patient’s life.

Disease: See also the other products used (indexed) for melanoma treatment. Melanoma comprises just 5% of all skin cancers, but it is the most deadly. Melanoma is the leading cause of death from skin disease. An estimated 68,130 new cases of melanoma were diagnosed in the U.S. during 2010 and about 8,700 people died from the disease, according to the National Cancer Institute. Late-stage melanoma is devastating, with very few treatment options for patients, none of which had previously prolonged a patient's life. Unlike most other solid tumours, melanoma affects younger, middle aged people. The median age at diagnosis for melanoma is 57 and the median age at death is 67.6.

High unmet needs still persist for this tumor type, despite three decades of extensive R&D, five-year survival of advanced patients remains below 20%. Melanoma is characterized by high relapse rates and poor survival for patients with stage III and IV disease as a result of the lack of efficacious therapies in both the adjuvant and metastatic settings. The incidence of malignant melanoma is expected to continue to rise in the near future. According to the World Health Organization (WHO), the number of cases worldwide is increasing faster than that of any other cancer.

Market: Depending on approvals and other factors, ipilimumab may compete directly against a similar CTLA-4 monoclonal antibody, tremelimumab (see related entry), from Pfizer. The market uptake of ipilimumab in both the first- and second-line settings for metastatic malignant melanoma will increase drug-treatment rates as physicians, who previously had little to offer melanoma patients, try new therapies instead of offering patients no treatment or enrollment into a clinical trial

A full course (4 infusions over 3 months period) of Yervoy cost about $120,000. If 9,000 malignant melanoma patients are treated with at least 1 course of ipilimumab, it can reach $1 billion in sales. The 2Q11 sales were 95 million.

Total 2012 sales were $706 million. Year 2011 sales were originally projected for >$400 million. However, 2011 sales were about $360 million. The U.S. launch was rather successful, with $95 million in sales in 2nd quarter 2011. Sales have been projected by some analysts to eventually reach $600 million.

Thomson Reuters has projected peak sales of $1.43 billion.

The National Institute for Health and Clinical Excellence (NICE), U.K., in Oct. 2011 decided against recommending payment by the National Health Service for Yervoy for advanced malignant melanoma in people who have received prior chemotherapy. NICE acknowledged that Yervoy met the criteria for being a life-extending, end-of-life treatment, but considers that "the magnitude of additional weight that would need to be assigned to the original quality-adjusted life year (QALY) benefits for people with advanced melanoma would be too great for ipilimumab to be considered a cost-effective use of NHS resources" (i.e., they considered it too expensive). Clinical specialists had told NICE's independent appraisal committee that only 30% of people treated with ipilimumab would have improved survival, with only 10% potentially experiencing long-term benefits. So far, no patient characteristics or biomarkers have yet been identified to help identify the small group of people most likely to gain long-term benefit from receiving ipilimumab.

In Nov. 2012, NICE recommendeed use of Yervoy within its Final Appraisal Determination (FAD).