AZD-4320

Mene Pangalos, Ph.D., is set to step down as EVP of biopharmaceuticals R&D early next year. It’s all change at AstraZeneca. In a Friday morning full of announcements, the Anglo-Swedish drugmaker not only revealed its second-quarter earnings results but also disclosed the elimination of several pipeline programs, the purchase of a portfolio of preclinical gene therapies from Pfizer and the upcoming departure of a key, long-serving R&D executive.  On the pipeline side, the most advanced casualty is AZD4573, a CDK9 inhibitor that AstraZeneca took as far as phase 2 as a treatment for hematological malignancies. The company designed the drug to suppress MCL-1 and induce apoptosis in hematologic cancer cells and advanced it into phase 1/2 and phase 2 clinical trials as a monotherapy and combination treatment in 2021.  Now, AstraZeneca has discontinued the studies as part of its second-quarter pipeline update (PDF). The company attributed the decision to stop work in indications including peripheral T-cell lymphoma to its “strategic portfolio prioritization.” The second quarter clearout also affected a phase 1 hematologic cancer program. AstraZeneca kicked AZD0466 to the curb, stopping a pair of phase 1/2 blood cancer clinical trials, after assessing the benefit-risk profile.  AZD0466 is a BCL-22/XL inhibitor that was supposed to solve the shortcomings of another asset, AZD4320.  Dose-limiting cardiovascular toxicity, coupled to physicochemical properties, torpedoed AZD4320 before it reached the clinic. But AstraZeneca identified a path forward, teaming with Starpharma to create an AZD4320-dendrimer conjugate, later codenamed AZD0466, with an improved therapeutic index.  While AZD0466 and AZD4573 are leaving the pipeline at the same time, Susan Galbraith, Ph.D., EVP of oncology R&D at AstraZeneca, said the hematology pipeline remains “very robust.”  The two scrapped oncology assets are “both molecules that address a cell death mechanism for hematology,” Galbraith told Fierce Biotech on an earnings call with journalists this morning. “The therapeutic index for these is relatively narrow and overall the benefit-risk was not viewed to be one that we felt was able to go forward into subsequent trials.” AstraZeneca is also ending development of AZD3366 in cardiovascular disease. The drug candidate,  a recombinant form of human apyrase enzyme, showed anti-thrombotic, anti-inflammatory and tissue-protective properties in preclinical studies but has fallen at the first hurdle in the clinic. News of the pipeline updates emerged alongside details of other changes at the company. Mene Pangalos, Ph.D., is set to step down as EVP of biopharmaceuticals R&D early next year after five years in the role and 14 years at AstraZeneca. The Big Pharma has already found Pangalos’ replacement. Sharon Barr, who has headed up R&D at AstraZeneca’s rare disease unit Alexion since 2013, will fill the post vacated by Pangalos. On the call with the media, Pangalos said he has no job lined up for when he leaves AstraZeneca. Rather, the executive said he plans to “spend more time with my wife, my girls, see my family in Greece.” The idea is to step back and enjoy “a different pace of life,” he added. Barr is departing Alexion just as the rare disease group is getting an expanded preclinical pipeline. In yet another announcement this morning, AstraZeneca revealed that Alexion has agreed a deal worth “up to $1 billion” for “a portfolio of preclinical gene therapy programs and enabling technologies from Pfizer.” The deal, which will see employees move to Alexion, includes a number of novel adeno-associated virus capsids, a delivery technology that Pfizer has pulled back from as part of its recent early-stage R&D pivot.