INTREPID Alliance updated review of antiviral compounds in clinical and preclinical development for thirteen priority viruses of pandemic potential

Compounds in Clinical Development⁵

Novel compounds were triaged⁶ 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 where these studies have been completed and no data are available publicly. In both cases, we are unable to make a data-driven triage 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 of the approved antiviral compounds, either alone or in combination with other approved compounds, are now being studied toward other viral indications. These Approved Antiviral-Indication Expansion compounds, which have already demonstrated safety and tolerability to regulatory authorities, are being evaluated against the promising compounds criteria noted above as more data become available. In addition, as noted above, there are also ongoing preclinical exploratory evaluations with approved (15) and investigational (11) antivirals.

Methodology: Global Database and INTREPID’s Initial Triage (1st 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. INTREPID reviews data and publications in the public domain as well as the information with a database licensed from Airfinity. Airfinity is a predictive health intelligence and data analytics firm, who monitors preclinical and clinical development of diverse compounds against 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 U.S., 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 importing 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 database identified 687 diverse compounds, some with multiple viral indications across 12 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 (2nd Edition Posted April 29, 2024)

A triage reported in the Second Edition, 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; Promising Clinical Compounds met these criteria. Compounds excluded from our analysis were antibodies, antibiotics and other anti-infectives, cell-based therapy, human immunodeficiency virus (HIV) or hepatitis C virus (HCV)-specific antivirals, host targets (including immunomodulators), natural products/nutraceuticals/herbals and vaccines.

INTREPID Alliance Clinical Landscape (3rd Edition Posted October 9, 2024)

In this edition, we have also included Poxviridae as the 13th viral family of interest; this added new Approved (n=3, smallpox) and Approved Antiviral-Indication Expansion (n=1, Mpox) antivirals. In addition, a total of 7 new compound/indications have been added to the clinical antiviral landscape; 3 each for COVID-19 and Influenza and 1 for Mpox. Finally, changes in stage of development for 2 antiviral compounds were also noted.

In this edition, we have also included the approved and novel ‘investigational’ compounds that are being evaluated in preclinical studies toward other viral indications. There are 15 approved and 11 novel compounds that fall within the ‘preclinical exploratory’ category.

See the interactive pipeline above and 3rd Edition Landscape for compound names and developer information.

Methodology: INTREPID’s Initial Preclinical Triage

As with the clinical development landscape methodology described above, the INTREPID Alliance triaged a global antiviral R&D database of publicly available information from Airfinity using stringent inclusion and exclusion criteria to arrive at the initial Antiviral Preclinical Development Landscape summary posted today.

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. As of July 12, 2024, the Airfinity database identified 362 diverse preclinical compound/indications for multiple viral indications across the 13 priority viral families of pandemic potential; 157 were associated with an antiviral mechanism of action, 10 were associated with ribavirin, and the remaining 195 were primarily host-targeting (77%) or other categories such as monoclonal antibodies, antibiotics, anthelmintics, natural products/nutraceuticals/herbals, and vaccines (23%).

More About the Preclinical Landscape Analysis

It is worth noting that the amount and type of data available varied substantially and not every preclinical compound cited was a clinical candidate quality compound but rather was a tool compound or representative of a lead chemical series. Our review of preclinical compound/indications includes but is not limited to publicly available data such as:

1. In vitro activity
   1. Biochemical
   2. Cell-based (e.g., replicon, pseudovirus)
   3. Cell-based antiviral (e.g., wild-type, variants)
   4. Resistance
2. Absorption, Distribution, Metabolism, and Excretion (ADME) profile
3. Structure/Sequence
   1. Chemical structure of small molecules
   2. Amino acid sequence for peptides
   3. RNA sequence of nucleic acid-based molecules
4. In vivo Exposure (Animal)
   1. Pharmacokinetics (PK)
   2. Safety & Toxicology
5. In vivo Efficacy (Animal)
   1. Treatment design
   2. Prevention design
6. Prior Clinical Data Availability

Following the initial triage based on these data, using the principles outlined in our Target Compound Profile⁸ and the breadth of preclinical antiviral experience in the INTREPID Alliance, we classified the majority of preclinical antiviral compounds with experimental data into five categories:

1. Hit – High-throughput or compound library screening hit, initial antiviral activity requiring significant optimization; limited or no in vitro data available supporting antiviral mechanism of action (MOA).
2. Early Lead – Limited Structure-Activity Relationship (SAR), antiviral activity associated with MOA, may have limited in vitro/in vivo pharmacokinetic data reported.
3. Late Lead – Potency consistent with candidate quality for the specific MOA, more extensive in vitro characterization (e.g., ADME profile, activity against clinically relevant virus strains/isolates), in vivo PK and/or animal efficacy model data reported.
4. Potential Candidate – In vivo efficacy and safety dataset consistent with preparation for FDA Investigational New Drug (IND), or similar, submission; compound has been reported by the developer as a pipeline clinical candidate and/or in IND (or similar) enabling studies.
5. Archived – Progress on the compound has been stopped (timeframe stopped, >5 years); antiviral evidence is only computational; previously optimized drug from another antiviral/other indication that only has weak activity.⁵

Following the initial triage of the 362 preclinical compound/indications as of July 12, 2024, there were 157 (43.4%) compound/indications preliminarily categorized as antivirals. Further evaluation of the available data resulted in ‘archiving’ many compounds, and a few compounds were re-classified into the clinical landscape.