FORGE antivirals engage the patient’s own immunity to naturally defend against viral infection without the emergence of drug resistance
FORGE broad-spectrum antivirals are based on the discovery that certain human proteins, called sirtuins, normally defend the human (host) cell from being invaded by many different virus-types. Sirtuins regulate the metabolism of the host cell. When a virus infects the host cell, the virus redirects the metabolic machinery of its host to support production of virus DNA and proteins. By modulating sirtuin activity, FORGE drugs restore metabolism that favors the host cell and enhances host defense-mechanisms while eliminating productive conditions for virus propagation. Since host-mediated metabolism is essential to provide the necessary building blocks for the virus, the virus cannot evolve resistance mutations around FORGE drugs.
Three features differentiate FORGE sirtuin-targeted antivirals from currently marketed direct-acting antivirals that target a virus protein: (1) no viral resistance detected, (2) effective against a variety of different viruses, and (3) therapeutic utility in multiple areas of significant unmet medical need.
FORGE drugs were initially identified in a screen for drug-like chemicals demonstrating modulatory effects on the enzyme activity of any of the seven human sirtuins 1-7. Sirtuins are evolutionarily conserved enzymes that modify other proteins through de-acylation; FORGE founders demonstrated sirtuins are also evolutionarily conserved viral restriction factors (view publication). Sirtuin modulators are drug-like chemicals that increase or decrease the ability of sirtuins to de-acylate substrates. To optimize sirtuin drugs for antiviral use in the clinic, FORGE leverages our world-class expertise in both sirtuin and virus biology starting with structural information about all seven sirtuins and computer-aided drug-design to model the desired drug selectivity, with the desired sirtuin interaction(s) to be validated through X-ray crystallography. FORGE proprietary and drug-like candidates are first validated as antivirals in cell-based virus growth assays and then in cross-species animal models against diverse viruses spanning enveloped and non-enveloped DNA and RNA viruses. In the clinic, reduction of viremia in patients will provide a predictive disease-modifying biomarker to facilitate early clinical development. Thus, the FORGE sirtuin-based antiviral-platform benefits from the validation of FORGE sirtuin-based drugs in viral assays in culture, in animals, and in the clinic, tracking the desired disease-modifying effect to inhibit virus growth through the entire drug-development process.
FORGE products will have the potential to transform the practice of medicine by offering treatment options that target a broad-spectrum of viral infections responsible for an entire infectious disease condition, such as respiratory infections. Current virus-targeted therapies, such as influenza antivirals, are only effective against the targeted virus, i.e. influenza A or influenza B, and exclude other respiratory viral infections presenting with similar symptoms, such as respiratory syncytial virus (RSV), SARS virus, and others. In the case of respiratory infections, influenza only accounts for ~20% of such infections in a typical season. FORGE is developing a portfolio of first-in-class, broad-spectrum antivirals, that can be safely administered without the problem of virally-acquired resistance. The goal is one therapy to target and cure each infectious disease condition. In addition to a pan-respiratory infections antiviral, FORGE has active programs targeting multiple (opportunistic) infections endangering transplant patients and their graft organs; a brain-penetrant antiviral to treat viral encephalitis; and a liver infections antiviral targeting HBV and HCMV.
Seasonal flu annually causes considerable morbidity and mortality; its overall burden to the U.S. economy is estimated to be $83 B per year. FORGE has leads with activity against influenza A and B, including strains resistant to current drugs. The targeted patients include those receiving the least benefit from seasonal flu vaccines and the greatest risk of complications, infants and the elderly. The expanded profile will include other respiratory viruses (e.g. SARS, MERS, RSV, adenovirus). Superior clearance of virus compared to oseltamivir suggests the FORGE antiviral may prevent person-to-person spread.
Some viruses cause disease primarily in immunocompromised patients, such as transplant patients, who are actively immunosuppressed to protect their grafts. Such viruses are “opportunistic”. Such transplant patients, active immunosuppression is required to maintain the graft. With suppressed immune systems, patients have increased occurrence of infections and must be actively monitored because the symptoms of infection are also suppressed. Viruses like BKV have no effective antivirals. To treat, immune suppression is reduced until the infection clears, putting the graft organ at risk of rejection. FORGE leads are active against 3 opportunistic viruses: cytomegalovirus, BKV and influenza A. The expanded profile will include herpes, polyoma, respiratory, and hepatitis viruses.
A brain-penetrant FORGE antiviral can treat many viruses causing brain-encephalitis or inflammation. Most are rare, but deadly. For example, JCV infection can cause progressive multifocal leukoencephalopathy (PML). PML carries a >20% fatality rate; patients who survive are severely disabled by brain damage. FORGE has leads with potent activity against JCV. Other encephalitic viruses include rabies, West Nile virus, herpes viruses, and childhood viruses like measles, rubella, and Mumps. With increasing non-compliance with public health vaccination policies, these illnesses, while still rare, are increasing in occurrence, and can have devastating outcomes for children and families.
While chronic hepatitis, or liver inflammation, may have no symptoms, it can progress over time to more serious liver ailments including cirrhosis (scarring of the liver), fibrosis (formation of extra fibrous tissue), or even complete liver failure which is fatal. Cirrhosis greatly increases the risk of liver cancer. Recently, there has been a break-through in antiviral therapies that effect a cure for hepatitis C. Along with hepatitis C, hepatitis B and A are the most common viruses infecting the liver; less common but often deadly, is cytomegalovirus. Accumulating scientific evidence predicts a strong role of sirtuin 1 in hepatitis B infection. FORGE has initiated a drug discovery program optimizing its sirtuin-based cytomegalovirus antivirals for liver treatment.
Beyond infectious disease, efficacious sirtuin modulators with clear mechanism of action have multiple indications in the treatment of chronic diseases associated with aging. Multiple sirtuin-based drugs have progressed to phase 2, with over 1,255 patients enrolled in completed trials for cancer, diabetes, sepsis, Huntington’s disease and others. So far, 1st generation drugs are well-tolerated but have yet to achieve efficacy in non-infectious disease indications. FORGE Next Gen sirtuin-drugs provide multiple pharma partnering opportunities across disease areas. FORGE Next Gen sirtuin-drugs benefit from state-of-the-art science with respect to sirtuin 1 through 7 biology (as opposed to primarily sirtuin 1 for the earlier 1st generation drugs) and demonstrate validated disease modifying biological activity.