Viewpoint Cite This: Biochemistry XXXX, XXX, XXX−XXX
pubs.acs.org/biochemistry
Mavyret: A Pan-Genotypic Combination Therapy for the Treatment of Hepatitis C Infection Published as part of the Biochemistry series “Biochemistry to Bedside” Ashley N. Matthew, Nese Kurt Yilmaz, and Celia A. Schiffer* Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, United States pibrentasvir also selects these mutations, including Y93H, that confer resistance to other NS5A inhibitors.3 However, pibrentasvir maintained good potency against many single-site NS5A mutations, suggesting double or triple mutants need to emerge to confer high levels of resistance against this inhibitor. The other component of Mavyret, glecaprevir (ABT-493), is a P2−P4 macrocyclic NS3/4A protease inhibitor with subnanomolar to low nanomolar activity against all genotypes, including genotype 3.4 NS3/4A protease inhibitors are often susceptible to single-site mutations at residues Arg155, Ala156, and Asp168. Most if not all protease inhibitors are susceptible to mutations at Asp168, which are often present in patients who fail therapy with a protease inhibitor. Notably, this active site residue is not conserved in genotype 3 and is Gln168 instead, contributing to the natural resistance of genotype 3 to most treatments. While potent against 168 variations, including genotype 3, glecaprevir is highly susceptible to A156T and A156V mutations. We have shown that inhibitors containing P2−P4 macrocycles, as in glecaprevir, are susceptible to changes at Ala156, as substitutions with a larger side chain result in steric clash with the inhibitor’s macrocycle.5 Luckily, mutations at Ala156 do not occur alone because of reduced replicative capacity; however, additional mutations could restore the enzymatic fitness, which can lead to clinically viable multi-mutant resistant variants. Thus, both components of Mavyret have good resistance profiles against wild type genotypes and single-mutant variants of HCV. What needs to be considered is the emergence of double, triple, or other multi-mutant variants that may have high levels of resistance to one or both components of this combination. Such multi-mutant variants potentially pose a threat to the longevity and success of HCV treatment. There are already double- and triple-mutant variants that have been isolated from patients who failed therapy with previously FDAapproved combination therapies. Considering the similarity in the inhibitor scaffolds and modes of action, there is a danger that these variants may be cross-drug resistant and not respond to any current treatment option, including Mavyret. As new drugs and combinations are developed, it will be important to understand the mechanisms of resistance for these multimutant variants and incorporate those insights into drug design. Rather than concentrating all effort into inhibitors from the same class with highly similar scaffolds, diversifying the arsenal
Hepatitis C virus (HCV), a virus that infects more than 180 million people worldwide, is the causative agent of chronic liver disease, which often progresses to fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC). According to the World Health Organization, almost half a million patients infected with HCV die each year from cirrhosis and HCC alone. In the last several years, treatment of HCV infections has been revolutionized by the development of small molecular inhibitors that target essential proteins encoded by the viral genome. These inhibitors, known as direct-acting antivirals (DAAs), have improved treatment option and outcomes and eliminated the need for interferon injections. However, the emergence of resistance-associated variants (RAVs) and high genetic variation among the six distinct genotypes of the virus have been presenting challenges, even leading to treatment failure. Newer all-oral DAA combination regimens for HCV infection consist of inhibitors that target the NS3/4A, NS5A, and NS5B viral proteins. Of note, NS3/4A protease inhibitors have become a mainstay of treatment as most new therapies contain an inhibitor from this class. While highly effective against other genotypes, treatment of genotype 3 infections has been the most challenging, especially in patients who failed previous therapy or have cirrhosis. Recently, AbbVie received Food and Drug Administration (FDA) approval for one of the first pan-genotypic combination therapies, Mavyret, consisting of glecaprevir and pibrentasvir, an NS3/4A protease and an NS5A inhibitor, respectively (Figure 1). Given the excellent pan-genotypic response and safety profile in patients, Mavyret was approved for the treatment of genotypes 1−6 in patients without cirrhosis, or with compensated cirrhosis. In patients ̈ or with non-cirrhotic chronic HCV who were treatment-naive had previously been treated with pegylated interferon or ribavirin, the sustained virological response (SVR) rate was 83− ̈ patients with 100% across all genotypes.1 In treatment-naive compensated liver disease, 99% of patients achieved SVR with a 12-week course.2 Mavyret was approved as an 8-week course ̈ patients without cirrhosis, shortening the for treatment-naive previous standard of care by an additional 4 weeks. One component of the Mavyret combination, pibrentasvir (ABT-530), has excellent potency across all HCV genotypes and retains potency against common RAVs. Pibrentasvir had EC50 values across genotypes ranging from 1.4 to 5 pM against the HCV replicon in antiviral assays.3 Under the selective pressure of inhibitors, RAVs emerge at positions 28, 30, 31, and 93 in the NS5A protein. In fact, all current NS5A inhibitors are susceptible to mutations at Tyr93. In vitro studies indicate © XXXX American Chemical Society
Received: November 15, 2017
A
DOI: 10.1021/acs.biochem.7b01160 Biochemistry XXXX, XXX, XXX−XXX
Viewpoint
Biochemistry
Figure 1. Two-dimensional chemical structure of Mavyret combination inhibitors, glecaprevir (ABT-493) and pibrentasvir (ABT-530). Glecaprevir and pibrentasvir are an NS3/4A protease and an NS5A inhibitor, respectively, with pan-genotypic activity. This combination therapy has resulted in a sustained virological response of 83−100% across genotypes and was approved by the FDA as an 8-week course, shortening the standard of care by 16 weeks. (2) Forns, X., Lee, S. S., Valdes, J., Lens, S., Ghalib, R., Aguilar, H., Felizarta, F., Hassanein, T., Hinrichsen, H., Rincon, D., Morillas, R., Zeuzem, S., Horsmans, Y., Nelson, D. R., Yu, Y., Krishnan, P., Lin, C.W., Kort, J. J., and Mensa, F. J. (2017) Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, openlabel, multicentre phase 3 trial. Lancet Infect. Dis. 17, 1062−1068. (3) Ng, T. I., Krishnan, P., Pilot-Matias, T., Kati, W., Schnell, G., Beyer, J., Reisch, T., Lu, L., Dekhtyar, T., Irvin, M., Tripathi, R., Maring, C., Randolph, J. T., Wagner, R., and Collins, C. (2017) In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS5A Inhibitor Pibrentasvir. Antimicrob. Agents Chemother. 61, e02558-16. (4) Ng, T. I., Tripathi, R., Reisch, T., Lu, L., Middleton, T., Hopkins, T. A., Pithawalla, R., Irvin, M., Dekhtyar, T., Krishnan, P., Schnell, G., Beyer, J., McDaniel, K. F., Ma, J., Wang, G., Jiang, L.-J., Or, Y. S., Kempf, D., Pilot-Matias, T., and Collins, C. (2017) In Vitro Antiviral Activity and Resistance Profile of the Next-Generation Hepatitis C Virus NS3/4A Protease Inhibitor Glecaprevir. Antimicrob. Agents Chemother., AAC.01620-17. (5) Soumana, D. I., Kurt Yilmaz, N., Prachanronarong, K. L., Aydin, C., Ali, A., and Schiffer, C. A. (2016) Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172. ACS Chem. Biol. 11, 900−909.
of DAAs and considering triple-combination therapy may be required to avoid cases of incurable HCV infection. The approval of Mavyret dual-combination therapy marks another milestone in the treatment of HCV infections. There had been a major effort to develop an all-oral combination therapy with activity against all genotypes. With the approval of Mavyret, this goal has been met. The newer-generation inhibitors and various combinations provide treatment options for patients and improve SVR rates across all genotypes. For many cases, Mavyret has decreased the standard of care from 24 to 8 weeks. More importantly, treatment options for patients with compensated liver disease are now available. One major remaining concern is the possible emergence of drug resistance. The newer inhibitors have better activity against single-site RAVs, but highly resistant multi-mutant strains may become clinically relevant. Preventing the emergence and spread of cross-resistant variants and developing inhibitors with improved potency against such variants may be the next challenge.
■
AUTHOR INFORMATION
Corresponding Author
*Phone: +1 508 856 8008. Fax: +1 508 856 6464. E-mail: celia. schiff
[email protected]. ORCID
Celia A. Schiffer: 0000-0003-2270-6613 Funding
Our work is supported by National Institutes of Health Grants R01-AI085051 and F31-GM119345. Notes
The authors declare no competing financial interest.
■ ■
ACKNOWLEDGMENTS The authors thank Dr. Akbar Ali for informative discussions. REFERENCES
(1) Kwo, P. Y., Poordad, F., Asatryan, A., Wang, S., Wyles, D. L., Hassanein, T., Felizarta, F., Sulkowski, M. S., Gane, E., Maliakkal, B., Overcash, J. S., Gordon, S. C., Muir, A. J., Aguilar, H., Agarwal, K., Dore, G. J., Lin, C.-W., Liu, R., Lovell, S. S., Ng, T. I., Kort, J., and Mensa, F. J. (2017) Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1−6 without cirrhosis. J. Hepatol. 67, 263−271. B
DOI: 10.1021/acs.biochem.7b01160 Biochemistry XXXX, XXX, XXX−XXX
