Double-dealing in immunotherapy

LONDON—AstraZeneca announced two deals in August oriented toward bolstering its offerings in the immunotherapy space. The company struck a $500-million deal with Heptares Therapeutics Aug. 6 that will give it exclusive global rights to an experimental cancer drug. Days earlier, the company announced that MedImmune, its global biologics research and development arm, had entered into a clinical trial collaboration with Mirati Therapeutics to investigate the safety and efficacy of using two experimental drugs in combination to treat lung cancer.

 

The licensing agreement with Heptares, a clinical-stage drug discovery and development company, allows AstraZeneca to develop, manufacture and commercialize HTL-1071, a compound targeting the molecule adenosine in order to stimulate the A_2A receptor found on the surface of T cells.

 

“The A_2A receptor program at Heptares has been an outstanding example of our structure-based drug design approach in action, resulting in a novel clinical candidate, HTL-1071, with a highly attractive profile,” said Malcolm Weir, CEO of Heptares. “Heptares is targeting G-protein-coupled receptors that play a key role in cancer biology through the identification of both antibody and small-molecule therapeutics.”

 

HTL-1071’s potential as an effective cancer treatment is found in its ability to halt one of the processes that prevents T cells from proliferating and destroying cancer cells. Typically, tumor cells use the molecule adenosine to stimulate the A_2A receptors found on T cells, disrupting their anti-cancer response. By blocking A_2A receptors, HTL-1071 may be able to limit the role of adenosine in driving tumor growth.

 

AstraZeneca says it will explore the potential effectiveness of HTL-1071 to treat a wide range of cancers. It will also evaluate its efficacy when used in combination with its existing portfolio of immunotherapies, in particular with its checkpoint inhibitor durvalumab, which works similarly to HTL-1071 by targeting the PD-L1 receptor on cancer cells and stimulating an immune response. Signals from PD-L1 help tumors avoid detection by the immune system. Durvalumab blocks these signals, undermining the tumor’s immune-evading tactics.

 

The financial terms of the agreement call for Heptares, which was acquired by the Japanese pharmaceutical company Sosei last February, to receive an upfront payment of $10 million from AstraZeneca and become eligible to receive more milestone payments based on the completion of certain events during the preclinical and clinical phases. If AstraZeneca successfully commercializes HTL-1071, Heptares could also receive more than $500 million, in addition to significant royalties on net sales.

 

The deal between Heptares and AstraZeneca also provides a framework for the two companies to collaborate on efforts to discover other A_2A receptor-blocking compounds that may have value for cancer immunotherapy.

 

AstraZeneca’s other recent move to expand its immunotherapy portfolio involves a clinical trial collaboration between MedImmune and Mirati Therapeutics, an oncology company focused on genetic and epigenetic drivers of cancer. The two companies plan to conduct Phase 1 and Phase 2 studies in patients with non-small cell lung cancer to evaluate the potential for MedImmune’s compound durvalumab to be used in combination with Mirati’s drug mocetinostat.

 

Mocetinostat, a spectrum-selective histone deacetylase (HDAC) inhibitor, is believed to have the potential to bolster the antitumor effects of checkpoint inhibitors like MedImmune’s durvalumab.

 

“There is a growing body of evidence that mocetinostat may enhance the efficacy of immune checkpoint inhibitors such as PD-L1 antibodies,” said Charles Baum, president and CEO of Mirati. “Mocetinostat selectively targets specific HDACs that may increase the efficacy of durvalumab in patients with non-small cell lung cancer, as well as other tumor types.”

 

Mirati says the research collaboration may eventually extend beyond non-small cell lung cancer to explore the drug combination’s potential to treat other cancers. David Berman, senior vice president and head of the Oncology Innovative Medicines unit at MedImmune, says that his company’s partnership with Mirati is part of its broader effort to develop a “combination-focused immuno-oncology strategy” and a focus on lung cancer as a key disease area. “We continue to follow the scientific evidence to explore novel combination treatments to meet unmet patient need, with durvalumab as the cornerstone,” he said.

 

The terms of the agreement call for Mirati to conduct and fund an initial trial that will begin in 2016. MedImmune will supply durvalumab for the trial, which will be overseen by a joint committee created by the companies. If the studies prove successful, MedImmune will have a limited period of time during which it can negotiate a commercial license to use mocetinostat in combination with durvalumab.

 

In addition to launching new collaborations with Heptares and Mirati, AstraZeneca also announced last month that it is expanding an existing partnership with Isis Pharmaceuticals. The two companies will work together to discover and develop antisense therapies for cardiovascular, metabolic and renal diseases. Antisense drugs are short, chemically modified, single-stranded nucleic acids with the ability to target any gene product of interest.