INTREPID Alliance updated review of antiviral compounds in clinical development for twelve priority viruses of pandemic potential

Novel Compound Classification

Novel compounds were triaged^iv into one of three classifications: Promising, Watch & Wait, and Archived. The basis for these classifications is as follows:

1. Promising

   These are compounds that have met the following criteria:

   • The first-in-human (FIH) clinical study has been completed at relevant dose levels and dosing duration, and the data are available publicly.
   • The proof-of-concept (POC) study is either ongoing or completed and data are available publicly. POC demonstration will be by viral endpoint, symptom alleviation, etc. POC in an animal model may be applicable for certain viral diseases.
   • There are adequate pharmacokinetic/pharmacodynamic (PK/PD) data to support Phase 2/3 dose selection and administration.
   • Safety and tolerability are consistent with the target dose/exposure and there are no significant clinical signals.
   • Other criteria such as chemical structure, synthesis, scalability, etc. are taken into account where data are available.
2. Watch & Wait

   These are compounds in which the FIH and POC studies have just started or are ongoing or these studies have been completed and no data are available publicly. In both cases, we are unable to make an evidence-based, data-driven decision at the time of this analysis.

3. Archived

   These are compounds for which clinical development has been discontinued or there has been no recent information for greater than 5 years. These may potentially be used in the setting of a new previously undescribed pandemic.

Approved Compounds and Indication Expansions

Antiviral compounds that have been approved by either a stringent regulatory authority or other national authority have been limited to either COVID-19 and Influenza. Seven distinct compounds, either alone or in combination with other approved compounds, are now being studied against 13 other viral indications. These Approved-Indication Expansion antiviral compounds, which have already demonstrated an acceptable safety and tolerability profile, will be evaluated against the promising compounds criteria noted above as more data become available.

Methodology: Global Database and INTREPID’s Initial Triage (First Edition Posted on January 24, 2024)

The INTREPID Alliance triaged a global antiviral R&D database using stringent inclusion and exclusion criteria to arrive at the initial Antiviral Clinical Development Landscape summary posted on January 24, 2024. The database was licensed from Airfinity, a predictive health intelligence and data analytics firm, who monitors preclinical and clinical development of diverse compounds against 12 viral families that pose the greatest risk of pandemic potential. Airfinity sources information on clinical stage candidates from global trial repositories, such as those from NIH, WHO, and other national-level repositories including the US, UK, EU, China, India, etc., as well as media/press releases, biopharmaceutical pipeline websites, preprints and peer-reviewed publications by keyword matching and scraping. The information about preclinical candidates is also sourced from publications and biopharmaceutical pipeline websites through keyword matching and scraping. Some compounds are also added based on data presented at conferences (e.g., ICAR, ECCMID, IDWeek) attended by Airfinity analysts. Historic approvals are collected from government websites (and other available sources) with the earliest approvals collected from 1980. After scraping and import of the data, compounds are manually checked and annotated by Airfinity subject matter experts and analysts to ensure all associated data points are accurate and up to date. The information from Airfinity is updated monthly.

Data are generally categorized by compound, developer or sponsor, antiviral mechanism of action/target, viral family, viral disease (e.g., indication) and phase of development. Compounds that are already commercially available for 1 or more indications are further classified by the type of regulatory authority granting the approval per stringent authority (S.A.) or other national authority (O.N.A.). As of November 16, 2023, the Airfinity data base identified 687 diverse compounds, some with multiple viral indications across the 12 priority viral families of pandemic potential; 387 were preclinical and 300 were in the clinical phase of development and/or approved by a global regulatory authority.

INTREPID Alliance Triaging and Inclusion/Exclusion Criteria (Second Edition Posted April 29, 2024)

A triage, using inclusion and exclusion criteria, of the clinical phase and approved compound/indications identified 60 distinct antiviral compounds associated with 78 compound/indications, as reported above. Consistent with INTREPID’s mission of advancing small molecule antiviral development, compounds included were small molecules, peptides, and RNA-based compounds with known direct antiviral mechanisms of action, in vitro/in vivo activity, first-in-human (FIH) single ascending dose and multiple ascending dose data completed, and no major safety signals observed; as noted above, Promising Clinical Compounds met these criteria. Compounds excluded from our analysis were antibodies, antibiotics and other anti-infectives, cell-based therapy, HIV or HCV-specific antivirals, host targets (including immunomodulators), natural products/nutraceuticals/herbals and vaccines.

Next Steps

INTREPID Alliance will next release a list of preclinical stage compounds that may have utility against 12 viral families identified as having potential to result in a pandemic.

INTREPID will offer advice and consultation to help accelerate the selected antiviral compounds that have the strongest potential to positively alter the course of future pandemics. In addition, the INTREPID Alliance engages reactively with academic and biotechnology entities to understand their ongoing activity; compounds and compound/indications identified through this mechanism will be added in future iterations of the antiviral landscape.

Treatments are considered an integral part of any effective pandemic response, with antivirals playing an important role in saving lives. INTREPID will also engage with policymakers and public health bodies to ensure that antivirals are incentivized and integrated appropriately into global and local efforts to be better prepared against future pandemics.

i International Pandemic Preparedness Secretariat, 100 Days Mission: Implementation Report – 2023. (January 2024).
ii Compounds included small molecules, peptides, and RNA-based compounds with known direct antiviral mechanisms of action, in vitro/in vivo activity, first-in-human (FIH) single ascending dose vs. multiple ascending dose data completed and no major safety signals observed.
iii 12 priority viral families identified by the INTREPID Alliance Scientific Working Group using the NIH/NIAID priority viral family list; World Health Organization priority disease areas; and Airfinity database of antivirals.
iv In addition to the collective antiviral drug development experience of INTREPID member companies, guidance documents from Regulatory Authorities such as the US FDA routinely used by drug developers, and publicly available Target Product Profiles such as the NIH/NIAID Target Product Profiles for Antivirals, were used to inform the clinical phase triage.