Virus World

ViiV Healthcare announced that it has received a complete response letter (CRL) from the FDA, rejecting its marketing application for its long-acting, monthly injectable therapy for HIV. The combination treatment was touted by ViiV as a next generation HIV therapy, due to the fact that it could free people with the virus from taking daily oral pills. The monthly injection  is a combination of ViiV’s integrase inhibitor cabotegravir and Johnson & Johnson’s non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine.

ViiV – which is majority owned by GlaxoSmithKline – said that it “will work closely with the FDA to determine the appropriate next steps for this new drug application”. In the CRL, the FDA cited concerns regarding the treatment’s chemistry manufacturing and controls process, but there was no issues surrounding the safety of the product. This is a blow to ViiV, which has been vying for market share from Gilead. Both companies make billions of dollars each year from selling daily oral drugs for HIV, so this monthly injectable could have made a significant dent in Gilead’s sales. In previous trials testing the long-acting treatment, ViiV’s injectable was as effective as a standard three-drug oral regime at suppressing levels of HIV. Two trials, named ATLAS and FLAIR, formed the basis of the regulatory filings for the regimen. ATLAS involved patients who had been previously treated with long-acting antiretroviral therapy (ART), and showed that the combination injection matched standard therapy on viral suppression rates. Three patients treated with ViiV’s injectable (1%) demonstrated a failure to suppress HIV, while there were four cases on the oral therapy. FLAIR recruited newly-diagnosed patients and along with data showing non-inferiority to oral treatment, revealed a similar 1% rate of treatment failure, caused by the emergence of treatment resistance strains.

ViiV’s rival Gilead was the first company to bring a single-tablet triple therapy – Biktarvy – to market, and the former has been desperately pushing its own two-drug oral therapies through the pipeline to try and claim more market share. Gilead’s Biktarvy has grown quickly since its launch last year, and will most likely hit a $1bn-plus annual sales rate. According to GlobalData, the overall value of the HIV market is not expected to change dramatically in upcoming years, but there will be a predicted shift towards increased use of simpler, single-tablet regimens as the big-selling products change.

Like an adjustable wrench that becomes the "go-to" tool because it is effective and can be used for a variety of purposes, an existing drug that can be adapted to halt the replication of different viruses would greatly expedite the treatment of different infectious diseases. Such a strategy would prevent thousands of deaths each year from diseases like dengue and Ebola, but whether it can be done has been unclear. Now, in new work, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) show that repurposing an existing drug to treat viral diseases is in fact possible - potentially bypassing the decades needed to develop such a broad-spectrum drug from scratch.

In a new study published in the journal Molecular Therapy, the Temple researchers report that a drug used in the treatment of HIV also suppresses Zika virus infection. In cell and animal models, they show that the drug, called rilpivirine, stops Zika virus by targeting enzymes that both HIV and Zika virus depend on for their replication. These enzymes occur in other viruses closely related to Zika, including the viruses that cause dengue, yellow fever, West Nile fever, and hepatitis C. Dr. Khalili, a senior investigator on the new study, attributed the breakthrough work to a productive collaboration with Temple University colleagues, including Dr. Michael L. Klein, FRS, Laura H. Carnell Professor of Science and Dean of the College of Science and Technology at Temple; and Ilker K. Sariyer, DVM, PhD, and Jennifer Gordon, PhD, Associate Professors of Neuroscience at Temple's Center for Neurovirology.

Historically rare and isolated to parts of Africa and Asia, Zika virus is now present throughout the Americas and occurs in multiple other regions of the world. It has attracted increasing attention in recent years, owing to its damaging effects to the brain and nervous system. The virus is transmitted to humans by mosquitoes. Once in the body, it infects cells and replicates, typically taking up residence in cells in neural tissues. In severe cases, Zika virus infection can cause an autoimmune condition known as Guillain-Barré syndrome, which culminates in muscle paralysis. Infants born to mothers infected during pregnancy may experience delays in neurological development and may be affected by microcephaly (abnormal smallness of the head).

To replicate inside cells, Zika virus requires an enzyme called non-structural protein 5 RNA-dependent RNA polymerase (NS5 RdRp). In the new study, Dr. Sariyer showed that rilpivirine suppresses Zika virus infection in cells by blocking viral replication. Using structural biology and computational studies, Eleonora Gianti, PhD, a research assistant professor in Dr. Klein's laboratory, was able to show that rilpivirine prevents viral replication by binding specifically to the NS5 domain. Dr. Gordon's team carried out experiments in mice, in which animals were infected with Zika virus through their footpads, similar to the way a person becomes infected through a mosquito bite. Mice that become infected with Zika virus normally become very sick within about a week and eventually die. "We found, however, that when treated with rilpivirine, the animals survived," Dr. Gordon said. "Our conclusion is that rilpivirine disrupted the virus's usual course of infection."

Rilpivirine is one of several non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs that have been developed for the treatment of HIV infection. Experiments in which the Temple researchers tested two other NNRTIs in Zika-infected cells revealed similar effects on viral replication, with the drugs specifically inhibiting NS5 activity.

Published on Molecular Therapy (October 11, 2019):

https://doi.org/10.1016/j.ymthe.2019.10.006