Broad-spectrum antivirals for treatment of adenovirus & CMV infection

Cidofovir structure (credit: wikipedia)

Cidofovir structure (credit: wikipedia)

Unmet Need

Many current and emerging antiviral drugs have chemical characteristics that result in poor cell penetration, which limits their ability to reach their intended target. These therapeutics cannot be given orally and must be delivered at high concentrations resulting in safety/toxicity issues that limit their widespread use in acute and preventative care settings.

Solution

TSRL, Inc. is developing novel antiviral analogues of proven therapeutics against a broad range of viral infections. Our prelead candidates are prodrugs of cidofovir and closely related acyclic nucleoside phosphonate (ANP) analogues. They are engineered to be orally available with substantially increased cell-based potency against human cytomegalovirus (CMV), including ganciclovir resistant-types, as well as a broad range of adenovirus strains, herpes viruses, polyoma viruses and smallpox.

Our approach has the potential to result in three major product advantages over existing therapies:

  1. Development of ANP therapeutics for treatment of AdV, CMV and other DNA virus infections as an alternative to cidofovir, valganciclovir, acyclovir and other antivirals;
  2. Substantially lower toxicity to kidneys; and
  3. Optimized dosing regimen based on a robust understanding of the pharmacokinetic (PK) to pharmacodynamics (PD) relationship.

Research Status

We are in the process of identifying a lead-candidate from the current set of preleads based on maximal broad-spectrum in vivo efficacy and largest therapeutic index for clinical use. We are in the process of filing patent applications covering compositions of matter and methods of use claims.


Adenovirus & CMV Treatment for Immunocompromised Patients

About Adenovirus

Adenovirus (Credit: CDC)

Adenovirus (Credit: CDC)

Adenoviruses are ubiquitous in human and animal populations and are able to survive outside a host for long periods of time. Transmission occurs by touching the eyes, through aerosolized droplets, or by exposure to infected tissue or blood. Due to their diversity, adenoviruses are a causative agent for many syndromes, including: acute respiratory disease, pharyngoconjunctival fever, epidemic keratoconjunctivitis, acute hemorrhagic cyctitis, gastroenteritis, and viremia as associated with disseminated infection. Typically self-limiting in healthy populations, adenovirus infection is life-threatening in immunosuppressed and immunocompromised patients, including hematopoietic stem cell transplantation (HSCT) recipients, solid organ transplant (SOT) patients, and HIV-infected individuals. Mortality rates can be especially significant in pediatric transplant patients, often exceeding 50% [1]. Studies have shown that 30% of “high-risk” patients develop multiple viral infections, including cytomegalovirus and herpes viruses’ infections like Epstein–Barr (EBV), illustrating the need for a broad-spectrum antiviral agent [2].

Healthcare Impact

To estimate healthcare impact for target populations in the United States we assume successful treatment with our ANP antiviral reduces incidence of AdV disease by 50% in “high-risk” pediatric and adult populations (i.e. HSCT & SOT recipients). Data from the National Marrow Donor Program reveals ~19% of HSCTs or about 3,800 cases total were for pediatric [3]. Applying this percentage to the number of transplants and historical infection rates for all HSCT patients, successful treatment results in 295 and 79 fewer cases of AdV disease annually in children and adults, respectively. Expanding this reasoning to include the SOT population, this number jumps to 992 fewer cases. Assuming an average 21% mortality rate, we can potentially save ~210 lives annually, mostly children, and improve quality of life for five times that number of patients.  

Potential Regulatory Benefits

Orphan Drug Designation, Pediatric Exclusivity, Fast-Track, Accelerated Review

Market Potential

The total global market for an effective, hAdV therapeutic is very difficult to estimate to due lack of available data. As a result, we compare payer prices for reimbursed procedures relative to corresponding healthcare savings in the United States. Using the fraction of HSCT and SOT recipients in the US as a proxy (29%) of the global total, we estimate the total market for an effective HAdV therapeutic to be about $420 million per year. This market is growing due to many factors, including: growth of donor databases, improvements in donor transplantation, and increasing numbers of allogeneic transplants.


References:
[1] T. Kojaoghlanian, P. Flomenberg and M. Horwitz, "The impact of adenovirus infection on the immunocompromised host," Rev. Med. Virol., vol. 13, p. 155–171, 2003.
[2] R. Schreier, "Infections in the Immunocompromised Host," MedScape, 2015.
[3] National Marrow Donor Program/Be The Match, "FY13 Annual Numbers," 2013.