AZD-8871

AstraZeneca continues to see cytokines as "an important component" of its immuno-oncology portfolio. Big Pharma involvement in IL-12 is fading fast. Days after Bristol Myers Squibb punted its IL-12 fusion protein, AstraZeneca has jettisoned a gene therapy to dial down its interest in the cytokine for the second time in as many quarters. Late last year, AstraZeneca used its third quarter results to reveal the termination of its involvement with MEDI1191, a Moderna-partnered mRNA prospect that encodes for IL-12. BMS followed suit Monday when it returned the rights to an IL-12 therapy that it picked up from Dragonfly Therapeutics in 2020 for $475 million in “near-term upfronts.” Now, AstraZeneca has tossed out another IL-12 candidate in its fourth-quarter pipeline update (PDF). The latest asset to land on a Big Pharma discard pile is MEDI9253, an oncolytic viral agent engineered to include a transgene encoding IL-12. Responding to a question from Fierce Biotech at an earnings event with the media this morning, Susan Galbraith, Ph.D., AstraZeneca’s executive vice president of oncology R&D, framed the back-to-back IL-12 decisions as issues with the drug candidates rather than the cytokine itself.  “Cytokines, like IL-12, are an important component of the immuno-oncology portfolio that we need to have,” Galbraith said. “It's not a lack of belief in IL-12 as an important cytokine, but the mechanisms of action of those two drugs didn't meet with our specified criteria.” The intensity of intratumoral delivery of the Moderna-partnered mRNA drug meant “a really great level of efficacy” was needed to move forward, Galbraith said. In the case of the oncolytic viral agent, the EVP said that for the candidate to work, “you need to show that the virus gets to the tumor and replicates in the tumor.” In principle, MEDI9253 has two cracks at crushing cancer. First, the oncolytic virus could infect cancer cells, replicate and kill host cells to tame the tumor. Then, production of IL-12, a cytokine that stimulates T-cell activity, could boost the immune response against tumors and thereby unleash another anti-cancer mechanism. Localizing IL-12 production in tumors could overcome problems with toxicity and half-life that have so far stopped developers from turning the cytokine into a viable drug.   AstraZeneca began a phase 1 clinical trial to test the candidate in combination with its PD-L1 checkpoint inhibitor Imfinzi in solid tumor patients late in 2020. The choice of combination was underpinned by preclinical data showing MEDI9253 induces PD-L1 expression and brings immune cells to the tumor microenvironment.  However, the Anglo-Swedish drug developer has decided to tap out before getting to the end of phase 1. The action means three leading drugmakers have pulled back from IL-12 in quick succession, with the latest actions at AstraZeneca and BMS preceded by Merck KGaA’s decision to sell M9241 for $5 million.  While Galbraith continues to see IL-12 as important, the cytokine is no longer a fixture in the Big Pharma's clinical-phase pipeline. Biotechs such as Imunon, Oncosec and Dragonfly now largely have the IL-12 field to themselves. And after decades of work on cytokines including IL-2 and IL-12, the industry is yet to find a way to tame the toxicity, overcome poor druglike properties and unlock the clear potential for efficacy. AstraZeneca delivered the latest blow to confidence in IL-12 alongside other updates to its pipeline. The drugmaker dropped tozorakimab in atopic dermatitis from its midphase pipeline but work is continuing in other indications, with the IL-33 antibody moving into a pivotal acute respiratory failure clinical trial in the quarter and already in phase 3 in chronic obstructive pulmonary disease (COPD). The other midphase casualty of the pipeline cull is a different COPD drug, navafenterol, which AstraZeneca acquired in its 2014 acquisition of Almirall’s respiratory franchise for $875 million upfront. AstraZeneca ran a series of phase 1/2 clinical trials of the M3 antagonist beta2-agonist, also known as AZD8871, from 2015 to 2019 but has now thrown in the towel. Finally, AstraZeneca stopped a phase 1 project that was testing an antisense oligonucleotide targeting FOXP3 in combination with Imfinzi in solid tumors.