Pfizer will stop developing its cholesterol-lowering drug bococizumab, an antibody against proprotein convertase subtilisin kexin type 9 (PCSK9). The New York–based big pharma made the surprise announcement November 1, citing “an emerging clinical profile that includes an unanticipated attenuation of low-density lipoprotein cholesterol (LDL-C) lowering over time.” Pfizer also mentioned higher rates of immunogenicity and injection-site reactions with bococizumab than with the two anti-PCSK9 antibodies: Praluent (alirocumab), co-developed by Regeneron Pharmaceuticals of Tarrytown, New York, and Paris-based Sanofi, and Thousand Oaks, California–based Amgen's Repatha (evolocumab) (Nat. Biotechnol. 33, 785, 2015), both approved in 2015. Unlike the fully human Praluent and Repatha, bococizumab is a humanized antibody.

Pfizer was testing the drug's ability to lower lipid in six phase 3 studies and to reduce cardiovascular outcomes such as heart attack and stroke in two other large studies. Several observations suggest its inability to maintain long-term and durable cholesterol lowering is specific to the product and not a class effect. For example, injection site reactions, which were seen at a higher rate than in the placebo group in both phase 2 and phase 3 trials, may have contributed to a higher rate of treatment failures in phase 3 given the longer exposure in those trials, Leerink Swann analyst Geoffrey Porges said in a note to investors. “From a commercial standpoint, if these local reactions persisted or increased in the longer duration and expanded recruitment of the phase 3 trials, then this alone could have compromised the drug's commercial potential,” he said. In earlier trials, bococizumab was also associated with relatively high anti-drug antibodies, which had no impact on drug effectiveness during the six months when they were measured, but could have cast doubt on the drug's effectiveness in the longer term.

Pfizer's decision was a boon to investors in The Medicines Company, which is developing a PCSK9 RNA interference inhibitor licensed from Cambridge, Massachusetts–based Alnylam Pharmaceuticals. On October 18, the Parsippany, New Jersey–based biotech announced positive top-line results from an interim analysis of an ongoing phase 2 study testing the drug, PCSK9si, in atherosclerotic cardiovascular disease, showing a significant and durable reduction in LDL-C. PCSK9si could offer advantages in dosing and cost of goods over the PCSK9-targeting antibody drugs.