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Clinical Development of Viekira Pak to Mavyret

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HCV: The Journey from Discovery to a Cure

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 32))

Abstract

Viekira Pak (ombitasvir/paritaprevir/ritonavir and dasabuvir) was one of the first interferon-free direct-acting antiviral (DAA) regimens to be approved for the treatment of genotype 1 HCV infection. The research and development team at Abbott/AbbVie based their approach to HCV cure on the use of three DAAs to avoid emergence of resistance, anchored by a potent protease inhibitor and NS5A inhibitor. Clinical trials were designed to answer multiple questions within a single study, in order to advance the regimen as quickly as possible in a highly competitive environment. The global phase 2 and 3 development program allowed for rapid identification of optimal treatment regimens and durations for populations defined by HCV subtype, prior treatment experience, and the presence of specific comorbidities such as cirrhosis and orthotopic liver transplant. The clinical trial program also clarified the limitations of this first-generation DAA regimen, including activity that was limited to genotypes 1 and 4 and the need for ribavirin for some patients, which defined a target product profile for a next-generation regimen. This continued research and development activity ultimately led to the approval of the pangenotypic regimen glecaprevir/pibrentasvir (Mavyret).

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Notes

  1. 1.

    In addition to its approval in combination with peginterferon and ribavirin for 12 weeks for genotype 1 or 4, sofosbuvir was approved in combination with ribavirin alone for genotypes 2 and 3 and for interferon-intolerant patients with genotype 1, the first approved interferon-free all-oral therapy for chronic hepatitis C.

  2. 2.

    ABT-072 and ABT-333 were closely related members of the same chemical series, with identical binding sites and similar antiviral activity. There was never any intention to combine these two drugs; rather the plan was to advance whichever one proved to have better properties. Although ABT-072 had a half-life that permitted once-daily dosing, due to formulation challenges, ABT-333 was ultimately selected.

  3. 3.

    A number of polymorphisms near the IL28B gene (also known as the interferon lambda gene) were found to be associated with the probability of achieving SVR following treatment with interferon. One of the most frequently studied was the IL28B single-nucleotide polymorphism rs12979860. For this polymorphism, patients homozygous for the C allele (CC) had the most favorable prognosis; those with a TT genotype had the worst prognosis, and heterozygotes (CT) had an intermediate prognosis [7]. Highly effective DAA regimens ultimately obviated the need for IL28B genotype testing.

  4. 4.

    To everyone’s greater surprise, a second subject relapsed at a follow-up visit 36 weeks after the end of treatment. This finding raised considerable discussion about the mechanism behind a delayed relapse, whether patients with the IL28B CC genotype might be uniquely prone to manifesting relapses at a later time point due to more robust immunologic control and whether SVR resulting from an interferon-free regimen might be less durable than that resulting from interferon. The latter question appears to have been conclusively answered in the negative.

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Compliance with Ethical Standards

Funding Daniel E Cohen did not receive any compensation for this chapter.

Conflict of Interest

Daniel E Cohen is an employee of AbbVie.

Ethical Approval

All clinical trials were approved by the independent ethics committee or institutional review board for each trial center and were conducted in accordance with the Good Clinical Practice Guidelines and the ethical principles of the Declaration of Helsinki.

Informed Consent

All study participants (or their legal guardians) provided written informed consent prior to any study procedures being performed.

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Authors and Affiliations

  1. Department R48U, AbbVie, Inc., North Chicago, IL, USA

    Daniel E. Cohen

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Correspondence to Daniel E. Cohen .

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  1. Arbutus Biopharma, Inc., Warminster, PA, USA

    Michael J. Sofia

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Cohen, D.E. (2019). Clinical Development of Viekira Pak to Mavyret. In: Sofia, M. (eds) HCV: The Journey from Discovery to a Cure. Topics in Medicinal Chemistry, vol 32. Springer, Cham. https://doi.org/10.1007/7355_2018_60

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