HONG KONG – Osaka, Japan-based Ono Pharmaceutical Co. Ltd. entered a license agreement with Bristol-Myers Squibb Co. for the development and commercialization of its compound, ONO-4578, a selective antagonist of EP4, a prostaglandin E2 (PGE2) receptor. An oral antagonist of EP4 developed using mouse models, ONO-4578 has showed an antitumor effect by improving immunosuppressive tumor microenvironment, and Ono already started a phase I study of the compound in Japan.
"PGE2, a major immunosuppressive factor in the tumor microenvironment, is believed to suppress tumor immunity through PGE2 receptor on immune cell and promote tumor progression," Yukio Tani, director of corporate communications at Ono, told BioWorld Asia. "Preclinical data suggest that modulation of the PGE2 pathway through PGE2 receptor antagonists may complement immuno-oncology therapies, including anti-PD-1 antibody and anti-CTLA-4 antibody."
Under the terms of the agreement, BMS is granted the rights to develop and commercialize ONO-4578 and other compounds from PGE2 receptor antagonist programs worldwide, except Japan, South Korea, Taiwan, China and Association of South-East Asian Nations (ASEAN) countries. The two companies will also jointly discover and develop other compounds from the PGE2 receptor antagonist programs.
In Japan, South Korea and Taiwan, both companies will jointly develop and commercialize the products related to that agreement, under the existing collaboration agreement between the companies in immuno-oncology programs.
Ono and BMS are also considering combining ONO-4578 and BMS' PD-1 inhibitor, Opdivo (nivolumab), for better treatment outcomes.
"We will consider possible combination therapy with several immune-oncology products, including Opdivo," said Tani. "Ono is only responsible for conducting the clinical study of ONO-4578 in Japan."
"To improve long-term outcomes for more patients with cancer, we believe more immuno-oncology-based combinations may be required," said Fouad Namouni, head of oncology development at BMS. "Ono's prostaglandin E2 receptor antagonist programs offer the potential to develop targeted therapies that counteract the effects of an immunosuppressive tumor microenvironment. Researching prostaglandin E2 receptor antagonists in combination with our oncology portfolio has the potential to result in an enhanced response in a broad range of tumors."
Ono is set to receive an up-front payment of $40 million from BMS. The Japanese company will also receive subsequent clinical, regulatory and sales-based milestone payments, as well as royalties.
The two companies previously worked together on Opdivo, which gained approval in Japan in 2014. (See BioWorld Today, July 9, 2014.)
Ono granted BMS its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan in 2011. Three years later, the companies decided to expand their strategic collaboration to include the joint development and commercialization of multiple immunotherapies cancer patients in Japan, South Korea and Taiwan.
"We are considering the best development strategy for each compound, and will establish good partnership for them," said Tani.
In terms of competitors, two other Japanese companies currently have three compounds with the same mechanism as ONO-4578 under clinical development. One is Eisai Co. Ltd.'s in-house oral EP4 inhibitor, E-7046, in phase I testing in the U.S. and EU.
The others are Askat Inc.'s structurally different EP4 antagonists, AAT-007 and AAT-008, both being developed for the treatment of chronic pain and cancer.
Askat is a biopharmaceutical venture company founded in 2013 and based in Nagoya. Most of its compounds are an outgrowth of the research done by the scientists when they were part of Pfizer Inc.'s R&D laboratory in Nagoya.
AAT-007 and AAT-008 have demonstrated potent antitumor activities in animal cancer models, including lung, breast, colon, gastroenterological, prostate, liver and more. According to Askat, the compounds demonstrated synergistic antitumor activity in combination with currently available immunotherapies in preclinical testing.
Last week, Askat entered a worldwide licensing agreement in immuno-oncology with Arrys Therapeutics Inc. from Massachusetts for AAT-007 and AAT-008. Askat will receive up-front, development, and commercial milestone payments potentially exceeding $1.2 billion, as well as royalties.
On Dec. 18, the CFDA accepted an investigational new drug (IND) filed by Chinese company Rmx Biopharma Co. Ltd., licensee of Askat's AAT-007, for pain indications in China. With the CFDA's acceptance of the IND, Rmx will be able to initiate human trials of AAT-007 for the first time in the country.
Rmx will continue to develop AAT-007 for a new chronic pain therapy in China based on the pharmacological efficacies and superior safety previously demonstrated in preclinical studies as well as in human clinical trials in the U.S.
AAT-007 is ready to go in phase I and phase II studies for indications of chronic pain and cancer, respectively, in the U.S. and China.
AAT-008 will soon enter phase I trials worldwide for both indications, too.