According to an analysis published Friday in Nature Reviews Drug Discovery, AstraZeneca's decision in 2011 to embark on a major revision of its R&D strategy has delivered a more than fourfold increase in research productivity at the drugmaker. Company scientists, who authored the report, said that since implementing the so-called 5R framework, success rates from candidate drug nomination to Phase III completion have improved from 4 percent in 2005–2010, which was below the industry average of about 5 percent, to 19 percent in 2012–2016, while the industry average has remained largely unchanged.
"All these improvements have happened with less people, less sites and less money," remarked Mene Pangalos, head of AstraZeneca's innovative medicines and early development unit. The 5R framework helps guide how the company discovers and develops new drug candidates by concentrating on five factors, namely selecting the right target, tissue, safety, patient and commercial potential. "AstraZeneca scientists now work in fewer disease areas, with a focus on a deeper scientific understanding of disease biology and mechanisms," the authors said.
AstraZeneca noted that the "increased focus on a stronger target rationale" has cut the number of projects in the small-molecule discovery portfolio from 287 programmes initiated in 2005–2010, to 76 in 2012–2016. Further, the proportion of back-up programmes in the portfolio decreased from about 28 percent to less than 7 percent.
Meanwhile, the authors indicated that "the focus on biological understanding driving target selection also led to a change in pipeline target class composition." Specifically, kinases have become the predominant target class, jumping from 21 percent to 36 percent of projects, driven by an emphasis on oncology, while the proportion of projects targeting G protein-coupled receptors fell from 25 percent to 5 percent. Additionally, the proportion of projects targeting ion channels declined from 8 percent to 2 percent.
"We're working on far fewer programmes and the probability of success on those programmes is going up," Pangalos noted, adding that "going from 4 percent to nearly 20 percent is something we are all very happy with, but I still want us to do better...we're still failing 80 percent of the time."
AstraZeneca has said that the 5R framework was implemented in time to support Tagrisso (osimertinib) in the later stages of preclinical development. The drug gained full FDA approval last year for certain patients with metastatic EGFR T790M mutation-positive non-small-cell lung cancer (NSCLC). The authors also noted that AstraZeneca's ovarian cancer drug Lynparza (olaparib), whose US label was recently expanded to include BRCA mutation-positive metastatic breast cancer, "benefited from the 5R framework even though the molecule was selected as a candidate drug well before the inception of the 5R framework in 2011."
Meanwhile, AstraZeneca's Imfinzi (durvalumab) received accelerated FDA approval last year in urothelial carcinoma. However, results from the Phase III MYSTIC study unveiled in July 2017 showed that the PD-L1 inhibitor in combination with tremelimumab failed to improve progression-free survival (PFS) in patients with metastatic first-line NSCLC, although more recently, the company reported data from the late-stage PACIFIC trial showing that Imfinzi significantly prolonged PFS in patients with Stage III NSCLC.
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