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NEWS & ANALYSIS NEWS IN BRIEF Myosin inhibitor flexes, myosin FDA approves antibody cocktail for Ebola virus activator flops The FDA has approved Regeneron’s another monoclonal antibody cocktail called Drug developers have long been working on Inmazeb — a mixture of three monoclonal ZMapp, the single monoclonal antibody small- molecule modulators of cardiac myosin, antibodies — for Ebola virus. This is the first mAb114 or the antiviral remdesivir. Of the a protein that controls heart muscle contrac- FDA- approved treatment for the deadly 154 Inmazeb- treated patients, 66% were tions, for cardiovascular applications. In virus, and just the second FDA approval of alive at 28 days. In the ZMapp cocktail arm, October, both inhibitors and activators made a monoclonal antibody product targeting a which was used as a control, 49% of patients the news. Whereas Bristol Myers Squibb (BMS) viral antigen. were alive at 28 days. acquired MyoKardia for US$13.1 billion for the Inmazeb consists of atoltivimab, maftiv- “We hope this will be one of many cardiac myosin inhibitor mavacamten, Amgen imab and odesivimab, three antibodies that demonstrations of how the power of and partner Cytokinetics suffered a setback bind distinct, non-overlapping epitopes on science can be successfully deployed with their myosin activator omecamtiv mecarbil. the Zaire ebolavirus glycoprotein. Maftivimab against dangerous infectious diseases,” BMS acquired MyoKardia primarily is a neutralizing antibody that blocks entry of said Regeneron CSO George Yancopoulos, for rights to mavacamten in obstructive the virus into susceptible cells. Odesivimab about the approval. hypertrophic cardiomyopathy (HCM). This is a non-neutralizing antibody that induces The only other monoclonal antibody chronic heart condition is characterized by antibody- dependent effector functions, against a viral antigen to secure FDA excessive contraction of the heart muscle and recruiting immune cells to the virus. approval to date is MedImmune’s reduced ability of the left ventricle to fill. This Atoltivimab combines both neutralization neutralizing antibody palivizumab, approved can lead to fatigue and shortness of breath, and effector function signalling. in 1998 for the prevention of respiratory and increases the risks of atrial fibrillation, The FDA approval was based on results syncytial virus. The agency has approved one stroke, heart failure and sudden cardiac death. of an umbrella trial, carried out in the monoclonal antibody that prevents a virus Earlier this year, MyoKardia reported Democratic Republic of the Congo during from entering host cells by blocking a host promising results from mavacamten in a the 2018 outbreak of Ebola. The PALM trial target — TaiMed Biologics’ CD4-targeting 251-patient placebo-controlled phase III trial. enrolled patients with confirmed Ebola ibalizumab for HIV. It has approved three Mavacamten met its primary and secondary infection for treatment with Inmazeb, antibodies against bacterial toxins. end points, showing clinically meaningful Multiple SARS-CoV-2- targeting improvements in symptoms, functional status antibodies are currently moving through and key aspects of quality of life, the company the clinic. In October, Regeneron filed reported in The Lancet. BMS plans to submit for an Emergency Use Authorization of the drug for FDA approval in 2021. It will its REGN-COV2, a combination of two also evaluate the drug in other indications, virus- neutralizing antibodies. In preliminary including non-obstructive HCM. data from one trial, REGN-COV2 reduced Amgen and Cytokinetics, by contrast, dis- COVID-19- related medical visits by 57%. closed disappointing results from their myosin Credit: S.Harris/Springer Nature Limited Asher Mullard activator omecamtiv mecarbil for patients with heart failure with reduced ejection fraction. Omecamtiv mecarbil was designed to prolong CRISPR pioneers win Nobel prize showed in Science how this system could be the duration of contraction of the left ventri- used for site-specific DNA cleavage. cle, increasing the volume of blood flow with Emmanuelle Charpentier, of the Max Planck Interest in CRISPR has subsequently each heartbeat. Amgen and Cytokinetics’s Unit for the Science of Pathogens, and Jennifer exploded. “At the most fundamental level, 8,250-patient phase III trial of the drug met its Doudna, of UC Berkeley, won the Nobel [CRISPR] surely is a democratizing tool because primary end point, reducing cardiovascular Prize in Chemistry for their development of it’s simple enough to use that essentially any death or heart failure events by 8% compared the CRISPR gene-editing technology. Their graduate student can use it to introduce with placebo, they reported in October. But it work helped show how the CRISPR–Cas changes in cells of interest. And that’s why missed a key secondary end point, reduction in genetic scissors, evolved by bacteria to cut up we’re seeing the kind of extraordinary advances cardiovascular death. The drug’s effect size on invading bacteriophage, could be repurposed in the pace of fundamental research that’s the primary end point was also small, and com- for both basic research and therapeutic gone on over the last few years with CRISPR pared poorly with other heart failure options, applications. and related technologies,” Doudna told Nature analysts noted. The Nobel Prize committee credited Reviews Drug Discovery earlier this year. “What Amgen and Cytokinetics will present Charpentier with kick-starting the devel- makes CRISPR so exciting to so many people additional data from this trial at the American opment of this technology, with her discovery is the fact that it’s not just a discovery tool. Heart Association Scientific Sessions of the previously unknown tracrRNA molecule It’s potentially the fix as well,” she added. in November. A second phase III trial of in the Streptococcus pyogenes bacteria. At least seven CRISPR-based candidates omecamtiv mecarbil is ongoing, to assess Charpentier reported in 2011 in Nature that — including in vivo, ex vivo and CAR-T cell the drug’s effect on exercise capacity. tracrRNA plays a critical role in the maturation applications — have been advanced into Cytokinetics — which participated of CRISPR RNA. That same year, Charpentier the clinic. Other gene-editing approaches, in MyoKardia’s launch in 2012 — also and Doudna started collaborating together including zinc finger nucleases, TALENs and has a cardiac myosin inhibitor in phase II to study, purify and simplify this gene editing meganucleases, are also still in the running. development for obstructive HCM. machinery. In 2012, Doudna and Charpentier Asher Mullard Asher Mullard NATURE REVIEWS | DRUG DISCOVERY VOLUME 19 | DECEMBER 2020 | 827.