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- Therapeutic Pipeline in 2013
- Potential Conflicts of Interest
Existing and emerging viral central nervous system (CNS) infections are major sources of human morbidity and mortality. Treatments of proven efficacy are currently limited predominantly to herpesviruses and human immunodeficiency virus (HIV). Development of new therapies has been hampered by the lack of appropriate animal model systems for some important viruses and by the difficulty in conducting human clinical trials for diseases that may be rare, or in the case of arboviral infections, often have variable seasonal and geographic incidence. Nonetheless, many novel approaches to antiviral therapy are available, including candidate thiazolide and pyrazinecarboxamide derivatives with potential broad-spectrum antiviral efficacy. New herpesvirus drugs include viral helicase-primase and terminase inhibitors. The use of antisense oligonucleotides and other strategies to interfere with viral RNA translation has shown efficacy in experimental models of CNS viral disease. Identifying specific molecular targets within viral replication cycles has led to many existing antiviral agents and will undoubtedly continue to be the basis of future drug design. A promising new area of research involves therapies based on enhanced understanding of host antiviral immune responses. Toll-like receptor agonists and drugs that inhibit specific cytokines as well as interferon preparations have all shown potential therapeutic efficacy. Passive transfer of virus-specific cytotoxic T lymphocytes has been used in humans and may provide an effective therapy for some herpesvirus infections and potentially for progressive multifocal leukoencephalopathy. Humanized monoclonal antibodies directed against specific viral proteins have been developed and in several cases evaluated in humans in settings including West Nile virus and HIV infection and in pre-exposure prophylaxis for rabies. Ann Neurol 2013;74:412–422
The national and worldwide burden of neurological infections continues to grow. New infections continue to emerge at a rapid pace as humans explore every remote corner of the planet and use animal and human products for treatment and transplantation. Once an infection enters the population, the globalization of human travel helps spread infections quickly. Recent emerging viral outbreaks include those caused by Hanta virus, Marburg virus, influenza strains, severe acute respiratory syndrome coronavirus, enteroviral encephalitis, and West Nile encephalitis. These viral infections frequently involve the central nervous system (CNS).[1-3] As better treatments are becoming available for treatment of cancer and immune-mediated diseases, opportunistic infections are also on the rise. Several herpesvirus infections and progressive multifocal leukoencephalopathy (PML) due to JC virus (JCV) are commonly seen in immune-suppressed individuals. Additionally, there are many patients with undiagnosed meningoencephalitis where an infection is suspected but not confirmed. In 1 study, nearly ⅓ of patients with suspected infections of the nervous system in a tertiary care facility remained undiagnosed.
Currently, except for some of the herpesviruses and human immunodeficiency virus (HIV), there are no treatments of proven efficacy available for CNS viral infections. The absence of treatment contributes to high associated morbidity and mortality, leading to large health care costs with major socioeconomic consequences. There is great need for development of antiviral therapeutics that would be effective in brain infections. However, development of therapeutics for infections of the CNS poses unique challenges. Delivery of drugs to the brain either requires the use of small molecules that follow Lipinski's rules for predicting activity based on pharmacokinetic principles and “likeness” to known active drugs, or requires direct delivery to the brain by invasive procedures such as a lumbar puncture, a reservoir placed in the lateral ventricle, or convection-enhanced delivery. However, if there is sufficient inflammation associated with the infection, it may aid the delivery of the therapeutic agent to the site of infection through the cerebral vasculature.
The lack of animal models for CNS infections (eg, JCV-induced PML) that replicate human disease means that human studies may need to be conducted following in vitro efficacy studies and in the absence of preclinical animal safety and efficacy testing, enhancing the risk of failure or unexpected side effects. For example, a recent multicenter study on the use of mefloquine for PML was stopped prematurely due to lack of efficacy in humans despite promising in vitro studies. It is possible that humanized rodent models could be developed for some pathogenic human viruses, but the process is technically challenging and there are potential ethical limitations related to introducing human brain cells into rodent brain. Conducting clinical trials for viral infections of the nervous system also poses unique challenges. The infections may be seasonal, and outbreaks may occur in regions where imaging and monitoring facilities are not be available. The acute nature of the illness demands quick action and setup. For some viruses, reactivation may not always be pathogenic, which is the case for example with human herpes virus-6 and Epstein–Barr virus (EBV).[9, 10] The rarity of many CNS viral infections means that multicenter studies are essential even for phase II studies to achieve the targeted sample size. Despite these challenges, several multicenter studies have been conducted for PML, herpes simplex virus encephalitis (HSVE), and neurological complications of HIV infection.[11-14] Companies interested in development of therapeutic agents for neurovirology can access clinical expertise through the section on CNS infections of the American Academy of Neurology (www.aan.com), and basic science expertise through the International Society of Neurovirology (www.isnv.org).
Traditionally, drug development has been the purview of pharmaceutical companies, and they have limited interest in rare diseases including many CNS viral infections due to limitations in the ultimate size of the potential market. Recently, pharmaceutical companies have shown an interest in rare diseases only if the drugs can be priced so as to make a profit. The high cost of drug development is largely driven by the large failure rate and the inability to predict efficacy in humans.
Most drug trials for CNS viral infections have been conducted with drugs approved for systemic indications rather than specifically developed for use in the CNS. It is possible that if broad-spectrum antiviral agents were to be developed that penetrate the blood–brain barrier, new therapeutics would become available.
Drug development for CNS viral diseases has a distinct advantage over that for chronic diseases, which is the availability of measurements of viral load as a dependable surrogate marker of disease. It is expected that if the viral load decreases, clinical improvement should follow. Hence, clinical trials could potentially be conducted in smaller sample sizes over shorter periods of time. However, resources for medicinal chemistry, toxicology, pharmacodynamics, and pharmacokinetic studies are limited in academic institutions, and unless these aspects are addressed, the challenge in treating these illnesses may continue into the foreseeable future.
In the following sections, some of the new pharmacological, biological, and immunomodulatory approaches to treatment of CNS viral diseases are briefly reviewed.
Potential Conflicts of Interest
- Top of page
- Therapeutic Pipeline in 2013
- Potential Conflicts of Interest
K.L.T.: board membership, DSMB, LPath; consultancy, PML Consortium, Genentech, Roche, Johnson & Johnson, Pfizer, Janssen Pharmaceuticals, Biogen; expert testimony, Bassett Law Firm; royalties, Elsevier, McGraw-Hill; travel expenses, American Neurological Association; editorial board services, Neurology Today (AAN); editorial board: Archives of Neurology.