Discovering and Developing Re-purposed antiviral Drugs for Treatment and Prevention of Zika

The development of new antiviral drugs to combat disease is one of the most exciting areas of discovery medicine in the 21st century. In the last two decades, antiviral drugs have become a mainstay of modern medicine. Drugs are now available to treat diseases caused by many different viruses, including influenza, HIV, herpes, hepatitis B and hepatitis C. According to the World Health Organization, antiviral drugs for HIV have saved almost eight million lives over the last fifteen years. For infectious disease outbreaks, antiviral drugs may be the safest and least expensive treatment or prophylactic option.

Atheric has a rich and diverse pipeline of drugs with activity against:

  • Flaviviruses (Zika, Yellow Fever, others).
  • Alphaviruses (VEE, Chikungunya, others)

Atheric Pharmaceutical researchers have discovered that when repurposed drugs with different mechanisms of action are combined, they are much more effective at inhibiting viral infection, including infection by mosquito-transmitted viruses. Some anti-viral drug combinations have a synergistic effect, which greatly increases the likelihood of success in inhibiting arbovirus replication and spread.  Some of these antiviral drug combinations are also toxic to the mosquitos which spread the virus. These benefits are likely to translate to shorter duration of infection, decreased viral load and, in the case of administering the drugs as a prophylactic, more likelihood of an individual not acquiring the disease. Obviously, this is very powerful strategy for combating the ongoing outbreaks of Zika virus,  Chikungunya,  and Yellow Fever virus infections.

The development of new antiviral drugs to combat disease is one of the most exciting areas of discovery medicine in the 21st century. In the last two decades, antiviral drugs have become a mainstay of modern medicine. Drugs are now available to treat diseases caused by many different viruses, including influenza, HIV, herpes, hepatitis B and hepatitis C. According to the World Health Organization, antiviral drugs for HIV have saved almost eight million lives over the last fifteen years. For infectious disease outbreaks, antiviral drugs may be the safest and least expensive treatment or prophylactic option.

The relatively high mutation rate associated with Zika is similar to that of other RNA viruses, and predicts rapid evolution to escape evolutionary pressure from drug monotherapies. Therefore, it is most appropriate to focus on developing multidrug therapy regimens that combine or cycle active drugs with different mechanisms of action. These drugs should ideally have minimal pharmacokinetic interactions and be safe when cycled or combined.

The Benefits of Re-purposed Drugs

One of the most exciting new approaches for drug development is finding new uses for currently marketed drugs.  This process provides the quickest possible transition from research to approved drugs that physicians can prescribe and patients can use. “Re-purposed” drugs already have a well-known clinical safety profile, which can avoid the lengthy regulatory hurdles and toxicology testing requirements that are needed for new drugs.

With careful selection criteria, testing drugs in combination using a high throughput system and pharmacometric modeling strategies, Atheric has been able to rapidly test and identify many antiviral drugs, which are active against Zika. This innovative approach truly has the potential to revolutionize how new antiviral drugs are discovered.

Why Not a Vaccine for Zika?

Vaccines are a great choice for many infectious diseases, but vaccines are time consuming to develop and pose safety risks for some types of infections, including a Zika virus infection.  A recent report by the National Center for Biotechnology Information (NCBI) at the National Institutes of Health estimates that an extremely accelerated pathway for vaccine approval is 8-10 years.  For example, the West Nile Vaccine that the Director of National Institute of Allergy and Infectious Diseases (NIAID) promised the US Congress in 2002 would be ready within three years, is just finishing up phase I clinical trials 14 years later.

Infectious diseases, such as the Zika virus, that have a high rate of Guillain-Barré Syndrome (GBS) are generally not good candidates for a vaccine, as the vaccine potentially can also cause GBS.  GBS causes a severe form of paralysis and is considered a serious adverse event.

Pregnant women, infants and children are usually excluded from initial vaccine clinical trials, due to safety risks and are usually excluded from new vaccine development, due to unknown risks.  A vaccine for Zika would not be initially approved for use in pregnant women and other at-risk populations, such as children and the elderly.

Antibody Dependent Enhancement (ADE) of either Zika or Dengue is a risk with a Zika Vaccine.  Testing for this risk is going to be time consuming and costly.

Product Strategy

Atheric’s technology development began in late 2015, when Atheric’s founders recognized that the unmet medical need associated with the ZIKV epidemic in the Americas could only be addressed in a timely fashion by re-purposing existing licensed drugs.  The majority of prior drug development strategies for flavivirus antivirals (including ZIKV) have primarily focused on single-agent therapeutic compounds.  Atheric chose an alternative strategy, focusing on drugs and drug combinations which interfere with the interaction of flaviviruses with host cells: those which block the steps required for viral entry and infection of a cell, in which the virus subverts normal cellular processes to support viral replication.  This combined approach, involving hypothesis-driven drug screening and prophylactic inhibition of host–virus interactions, together with selecting mixtures of drugs with complementary mechanisms of action, has allowed Atheric to rapidly identify antiviral drugs that are extremely potent.

Atheric’s strategy for antiviral drug screening is revolutionary.  Atheric focuses on drugs and drug combinations which interfere with the interaction of viruses and host cells: drugs which block the steps required for viral entry, infection, and maturation of a cell, in which the virus subverts normal cellular processes to support viral replication.  The combined approach, involving hypothesis-driven drug screening and inhibition of host–virus interactions, together with selecting mixtures of drugs with complementary mechanisms of action, has allowed Atheric to rapidly identify antiviral drugs that are highly potent.

There are no current preventions or treatments for diseases caused by ZIKV infections.  ZIKV transmission routes include mosquitos and possibly other insect vectors, mother to fetus and child, men through sexual partners, and blood transfusion.  ZIKV has spread to 48 countries and territories across the Americas, Oceania, the Pacific Islands, and Africa (CDC 2016), with over 1.5 million suspected and confirmed cases (WHO 2016).  In the United States, sexually transmitted or travel-associated cases have been reported in 40 states as well as the District of Columbia.  The Pan American Health Organization Zika incident commander estimates that 500 million people in the Americas are at risk for ZIKV infection (Samarasekera and Triunfol 2016).  The World Health Organization estimates the lifetime U.S. costs associated with care for a microcephalic infant to be $10,000,000 (WHO 2016).  In 1997, the USDA estimated the total cost of care for a case of GBS in the United States at $450,000 (Buzby, Roberts et al. 1997).

Atheric has rapidly identified many different re-purposed drug candidates by:

  • Understanding the cellular interactions that occur during ZIKV infection.
  • Using existing databases to identify repurposed drug candidates.
  • Screening and testing anti-viral activity in cultured cells using multiple viral isolates and sophisticated high-throughput multiplex imaging.
  • Identifying synergistic compound combinations.
  • Down-selecting compounds and compound combinations that are sufficiently bioavailable in humans based on pharmacometric modeling.
  • Animal testing for lead product candidate is underway (Zika).
  • Phase 1 PK studies as well as phase 2a clinical trial designs have been developed.  The Pre-IND application has been submitted to the FDA (Zika).

Our lead anti-Zika product consists of the combination of a well-known anti-malarial drug with another well known anti-parasitic drug. Atheric’s strategy is to discover lead candidate antiviral drugs by determining in-vitro antiviral activity curves and then comparing these to the known BIOAVAILABILITY AND SAFETY OF THE DRUG(S) in patients.  This is a critical step that is often missed by anti-viral drug developers who apply high throughput screening methods, and is one part of the process that makes the Atheric strategy dramatically different.

Funding and Partnering Opportunities:

  • Multiple partnering and licensing opportunities:
  • Opportunity to segment by geographic region, pathogen and indication.
  • Public-private-USG partnerships.
  • Direct wholesale marketing into developed market economies.
  • Partnering to sell into emerging market economies.

     Atheric Pharmaceutical, LLC is a privately held corporation that seeks aligned stakeholders who share our vision of improving human health through the development of breakthrough medicines. We encourage interested parties to learn more about Atheric. For additional information contact our Corporate Development team. 

For further information please contact:

Dr. Robert W Malone

CEO, Chief Science Officer, robert.malone@atheric.com

or +1 (434) 979-0090 or 240-994-3334

 

Atheric Pharmaceutical, LLC is a privately held corporation that seeks aligned stakeholders who share our vision of improving human health through the development of breakthrough medicines. We encourage interested parties to learn more about Atheric. For additional information contact our Corporate Development team by sending us a message using the form below or calling 434-979-0090.

 

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