Even with continued jostling inside the larger immuno-oncology space, the oncolytic virus (OV) approach may be more firmly staking its claim to drug-developer interest. Already this year, Johnson & Johnson inked a potentially massive deal to take over Benevir Biopharm Inc. The arrangement disclosed in early May brought the latter $140 million up front and up to $900 million in milestone payments. Rockville, Md.-based Benevir boasts a platform called T-Stealth, designed to engineer OVs to infect and destroy cancer cells.
That agreement, a would-be whopper, put in the shade an earlier big-pharma takeover. Kenilworth, N.J.-based Merck & Co. Inc. in February snatched up Sydney, Australia-based Viralytics Ltd. in a $394 million cash deal. Viralytics became a wholly owned subsidiary of Merck, which gained full rights to Cavatak (CVA-21), an immunotherapy candidate based on an OV (coxsackievirus A21) formulation shown to preferentially infect and kill cancer cells.
Merck and Viralytics had a tie-up already. Cavatak is being evaluated in multiple phase I and II trials, both as an intratumoral and systemic agent, including a combo effort with the anti-PD-1 agent Keytruda (pembrolizumab) that dates back to a 2015 deal. The ongoing phase I/II Keynote-200 study is investigating the Cavatak/Keytruda pairing compared to Cavatak alone in people with late-stage melanoma, prostate, lung and bladder cancers.
There's been more. Last fall, North Chicago-based Abbvie Inc. signed a research, option and license agreement with viral immunotherapy player Turnstone Biologics Inc., of Ottawa. Terms were not disclosed but the pact was touted as the largest on record, which implied it was bigger than the agreement between Oxford, U.K.-based Psioxus Therapeutics Ltd. and Bristol-Myers Squibb Co. (BMS), of New York, which involved $50 million up front plus up to $886 million in milestones. Psioxus is developing enadenotucirev (previously known as ColoAd1), described as a highly potent, broad-spectrum OV therapeutic that may be able to target the "vast majority" of solid tumors. Intravenous delivery of enadenotucirev has been carried out clinically. (See BioWorld Today, Dec. 21, 2016, and Oct. 11, 2017.)
The latter alliance involved a then-preclinical oncolytic therapy, NG-348, which comprises enadenotucirev, a non-naturally occurring group B adenovirus identified in a directed evolution screen, further modified to express the human co-stimulatory receptor CD80 and an antibody fragment that binds the human CD3 component of the T-cell receptor. It has a dual mechanism of action, consisting of cancer cell killing and T-cell activation.
Turnstone, for its part, had in the hopper a dual mechanism as well with its modified Rhabdovirus strain MG1 Maraba, which carries mutations in the genes encoding the viral matrix protein and glycoprotein. The virus is inactive in normal cells but is hypervirulent in cancer cells. It can also be modified to express tumor antigens in order to elicit a cytotoxic T-cell response. In the company's lead program, the virus was engineered to express melanoma-associated antigen 3, a tumor antigen associated with a poor prognosis.
Lower risk, proven expertise
Also last year, the Chinese drug registration authority cleared the phase III trial of a cancer drug in the first open meeting the agency had ever held, clearing the way for late-stage testing of an oncolytic immunotherapy drug developed by Korean biopharma company Sillajen Inc. and its Chinese partner, Lee's Pharmaceutical Holdings Ltd. Sillajen said the company was given the go-ahead by the CFDA to launch an experiment with Pexa-Vec (formerly known as JX-594). The drug is a first-line treatment for advanced liver cancer and was first developed by U.S.-based Jennerex Inc., which was later acquired by Sillajen. (See BioWorld Today, Nov. 27, 2013, and July 25, 2017.)
Most recently in OV, Illkirch-Graffenstaden, France-based Transgene SA wrapped up its transactions with Tasly Biopharmaceuticals. Co. Ltd., of Tianjin, China, specifically the sale of rights in greater China to the OV drug known as TG-6002 and the chronic hepatitis B therapeutic vaccine TG-1050 for $48 million in newly issued shares. "There continues to be an appetite for oncolytic virus immunotherapies," Leerink analyst Jonathan Chang noted in an Aug. 14 report.
Chang covers Woburn, Mass.-based Replimune Group Inc., which is conducting a phase I/II trial in about 150 patients with a range of solid tumors. The study tests RP-1, the company's first product from the Immulytic platform to enter the clinic, alone and in combination with the BMS therapy Opdivo (nivolumab). In the first half of next year, Replimune plans a randomized, controlled phase II study with RP-1 in combination with anti-PD-1 candidate cemiplimab vs. cemiplimab alone in cutaneous squamous cell carcinoma (CSCC). Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., and Paris-based Sanofi SA said in April that the FDA accepted for priority review the BLA for cemiplimab in metastatic CSCC or patients with locally advanced CSCC who are not candidates for surgery. The PDUFA date is Oct. 28, 2018.
Replimune's Immulytic approach uses the herpes simplex virus (HSV) strain along with a fusogenic protein that the company says can enhance the ability of HSV to kill cancer cells by 10 to 100 times by providing a large "bystander" effect. The platform then delivers immune-stimulating proteins directly to tumors and draining lymph nodes, thus augmenting the anti-tumor immune response underway. "Overall, while Replimune is still in the early stages of clinical development, we have a positive long-term view on the stock because of [the company's] experienced management team, clear clinical strategy moving into combination trials, and potential broad applicability to injectable tumors," wrote Leerink's Chang. He also sees a lower risk profile than other OV firms, since its methodology is similar to that used by Thousand Oaks, Calif.-based Amgen Inc.'s melanoma therapy Imlygic (talimogene laherparepvec), approved in 2015 – and Replimune's push is led by the same squad that brought to market Imlygic, also known as t-vec.