Celgene, headquartered in Summit, New Jersey, and MedImmune (Gaithersburg, Maryland), a wholly owned subsidiary of AstraZeneca, have entered into a strategic collaboration to develop and commercialize MEDI4736, an anti-PD-L1 inhibitor, for hematologic malignancies.

Although the program will initially focus on non-Hodgkin’s lymphoma, myelodysplastic syndromes and multiple myeloma, the initiators believe that immuno-therapies represent a potentially disruptive approach to treating hematologic malignancies and could expand to include other immuno-therapies over time.  Currently, MEDI4736 is not approved in any country for any indication.   Studies are planned to start in the second half of 2015.

Incidence of hematologic malignancies
According to the World Health Organization (WHO) approximately 1.75 million patients globally suffer from hematologic malignancies, include lymphoma, leukemia, multiple myeloma and myelodysplastic syndromes, in 2012. Many of these patients are in need of new treatment options. The global incidence of hematologic malignancies continues to rise. By 2030, the incidence of blood cancer overall is predicted to rise by 46%, and that of non-Hodgkin’s lymphoma and multiple myeloma by 50 and 60%, respectively.

PD-L1, which is expressed on multiple tumors, inhibits cancer immunity. MEDI4736 is an engineered anti PD-L1 antibody and allows T-Cells to recognize and kill tumor cells.[3] Courtesy: AstraZeneca/Medimmune.
Programmed cell death ligand 1
MEDI4736 is a human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1), which is expressed on multiple tumors and helps tumors avoid detection by the immune system. [1] The trial drug is an antibody engineered with a triple mutation in its Fc domain to remove antibody-dependent cell-mediated cytotoxicity.[2]

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Programmed death-1 (PD-1) checkpoint inhibitors have demonstrating prolonged tumor regressions and improvements in survival in melanoma and renal cell cancer, but also in cancers not historically thought to be immunogenic, including lung and ovarian cancer.[2]

Turning the immune system on
The immune system plays a crucial role in the control and eradication of cancer. However, a number of mechanisms immune suppressions may lead to the prevention of effective antitumor immunity.  Tumor cells may, for example, use PD-L1 to turn off the immune system just as it begins to mount a response against them. MEDI4736 helps turn the immune system back on, allowing it to continue its attack on cancer. The trial drug is currently being evaluated in several disease states, including lung, melanoma and head and neck cancer.

Phase I trial in solid tumors
Results from a phase I study with MEDI4736 presented by Lutzky et al during the 2014 Annual Meeting of American Society of Clinical Oncology (ASCO) demonstrated significant success, confirming that this trial drug may be a major component of treatment for patients with a variety of malignancies. The study with a 3+3 dose escalation design included 26 patients. Treatment-related adverse events occurred in 34% of all patients, but there was a remarkably limited toxicity of grades 1 to 2 (mainly of diarrhea, fatigue, rash and vomiting).  Based on the results of the Phase I trial, the researchers found that MEDI4736 proved to be clinically effective, inducing four partial remissions and five additional minor responses in patients with melanoma, as well as non-small cell lung cancer (NSCLC). [3]

Programmed death-1 (PD-1) checkpoint inhibitors are considered to be a paradigm-shifting treatment for patients with solid tumors.  Clinically exploitable immune sensitivity have also been recognized in hematologic malignancies, making them a natural target for this type of treatment.  And, so far, preliminary study results in hematologic malignancies confirm the potential therapeutic usefulness.  For example, clinical trials with nivolumab (Opdivo®; Bristol-Myers Squibb Company), which is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy®; Bristol-Myers Squibb Company) and, if BRAF V600 mutation positive, a BRAF inhibitor, have had remarkable therapeutic activity and offer an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin’s lymphoma. These results raise the hope that programmed death-1 checkpoint inhibitors may also alter the treatment landscape in hematologic malignancies. [4][5]

Move to hematologic malignancy
“The potential of rationally combining immunotherapies such as MEDI4736 with existing and novel hematology compounds creates new opportunities for patients with blood cancers to live longer, better lives,” said Jacqualyn A. Fouse, Ph.D., President, Global Hematology and Oncology for Celgene.

Jacqualyn A. Fouse, Ph.D., President, Global Hematology and Oncology for Celgene Corporation. Courtesy: Celgene Corporation.

“This strategic collaboration leverages the deep expertise of AstraZeneca/MedImmune in immuno-oncology along with the experience of Celgene in the study and treatment of blood cancers. This collaboration advances Celgene’s already deep, diverse scientific platform to include checkpoint inhibitors, an area of significant promise in hematology.”

“We are excited about our strategic collaboration with Celgene, a globally recognized leader in treatments for hematological cancers. This agreement is a great example of how we are accelerating the development of medical innovation in our portfolio in collaboration with other experts, in order to bring life-enhancing new medicines to patients faster,” noted Bahija Jallal, Ph.D, Executive Vice President at MedImmune.  “Together with Celgene, we are designing a programme for our anti-PD-L1 that will explore its full clinical potential as a game-changing treatment that could activate the patients’ immune system to fight and change the course of blood cancers in this area of high unmet need.”

Agreement
Under the terms of the agreement, Celgene will collaborate with AstraZeneca to develop the anti-PD-L1 antibody MEDI4736 in hematology and make an upfront payment of $450 million. Celgene will lead clinical development across all new clinical trials within the collaboration and be responsible for all costs associated with these trials until December 31, 2016, after which it is responsible for 75% of these costs.

As part of the agreement between the companies, Celgene will also be responsible for the global commercialization of approved MEDI4736 indications in hematology, and will receive royalty rates starting at 70% of worldwide sales from all uses in hematology. Royalty rates will decrease gradually to 50% over a period of four years after the first date of commercial sales. This collaboration agreement will become effective upon the expiration or termination of the applicable waiting periods under all applicable antitrust laws.

Strategic Collaboration
This strategic collaboration will initially focus on the development of MEDI4736 as combination therapy with Celgene’s pipeline of products and other novel agents for hematologic disorders. Over time, the collaboration could expand to include other assets.