Innovation and trends in the development and approval of antiviral medicines: 1987-2017 and beyond

Abstract

2017 marked the 30th anniversary of the approval of zidovudine (AZT) as the first HIV/AIDS therapy. Since then, more than eighty antiviral drugs have received FDA approval, half of which treat HIV infection. Here, we provide a retrospective analysis of approved antiviral drugs, including therapeutics against other major chronic infections such as hepatitis B and C, and herpes viruses, over the last thirty years. During this time, only a few drugs were approved to treat acute viral infections, mainly influenza. Analysis of these approved antiviral drugs based on molecular class and mode of action shows that a large majority are small molecules and direct-acting agents as opposed to proteins, peptides, or oligonucleotides and host-targeting therapies. In addition, approvals of combination therapies accelerated over the last five years. We also provide a prospective study of future potential antiviral therapies, based on current clinical research pipelines across the pharmaceutical industry. Comparing past drug approvals with current clinical candidates hints at the future evolution in antiviral therapies and reveals how antiviral medicines are often discovered. Overall, this work helps forecast future trends and innovation in the field of antiviral research and development.

Keywords: Antiviral; Chronic viral infection; Direct acting agent; Respiratory virus; Small molecule.

Fig. 1

Timeline of US FDA Antiviral Drug Approvals: 1987–2017. Chronology of US FDA approvals of all antiviral drugs (see Table 1 for drug name abbreviations) using the criteria described in Section 1.2.1. HIV-1 drug approvals are shown in blue, influenza drug approvals in red, HBV drug approvals in grey, CMV and HSV drug approvals in green, and approvals of drugs for other indications in yellow. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Time and indication of US FDA antiviral drug approvals. (A) Total cumulative number of antiviral drug approvals from 1987 to 2017. (B) Number of approval per year, indicating total (black), HIV-1 (blue), HCV (orange). Blue arrows indicate the peaks of two distinct waves of antiviral approvals, the first for HIV-1 therapies (1996–1998), the second for anti-HCV drugs (2011–2017) (C) Proportion and number of US FDA antiviral drug approvals per indication from 1987 to 2017. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Attributes of approved antiviral drugs. (A) Number of small (blue) versus large (grey) molecules over time in 5-year intervals. (B) Number of monotherapies (blue) versus combination therapies (grey) over time in 5- to 6-year intervals. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Mechanism of action of FDA-approved antiviral drugs: 1987–2017. (A) Proportion and number of virus-targeting agents (blue) and host-targeting agents (orange). (B) Mechanism of action of FDA-approved unique NMEs designated as polymerases (blue); proteases (orange); integrases (grey); non-structural protein 5A [NS5A] (yellow); other mechanism (green); and host-targeting agents (red). We define NME as a drug that contains an active moiety that has never been approved by the FDA or marketed in the US. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 5

Antivirals in clinical development. (A) Number drug candidates in Phase 1 (blue), 2 (orange), and 3 (grey) clinical trials per indication. (B) Number and proportion of virus-versus host-targeting agents, monotherapy versus combination therapy antiviral agents, and small versus large molecules. Experimental drugs are represented with colors, whereas approved antivirals are in grey. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)