Areas of Focus
The following are indications using PanCytoVir™:
Measles
Measles is a highly contagious, serious disease caused by a virus. Before the introduction of a measles vaccine in 1963 and widespread vaccination, major epidemics occurred approximately every 2-3 years and measles caused an estimated 2.6 million deaths each year.
Unvaccinated young children are at the highest risk of measles and its complications, including death. Unvaccinated pregnant women are also at risk. Any non-immune person (who has not been vaccinated or was vaccinated but did not develop immunity) can become infected.
Measles is still common in many developing countries – particularly in parts of Africa and Asia. The overwhelming majority (more than 95%) of measles deaths occur in countries with low per capita incomes and weak health infrastructures.
Measles is extremely contagious, and 9 out of 10 unvaccinated people will become infected with the virus. Due to the COVID-19 pandemic, many countries have delayed their measles campaigns, which increases the risks of outbreaks around the world – including in the United States. Measles can make its way into the U.S. from anywhere, causing outbreaks in areas where people may be unvaccinated or under-vaccinated. In 2019, measles outbreaks in the United States were all linked to travel-related cases such as infected travelers entering the country or infected U.S. travelers returning from visiting other nations.
We have previously shown that PanCytoVir™ is safe and effective in limiting influenza A virus replication and SARS-CoV-2 replication, along with strong evidence showing inhibition of RSV replication in vitro and in vivo.
PanCytoVir™ is an FDA-approved drug with a well-documented (>7 decades) safety profile for treating gout and hypertension and is a nonspecific inhibitor of OATs that blocks transport by OAT1, OAT3, and URAT1, and has been used to extend the plasma half-life of β-lactam antibiotics and oseltamivir.
Recent published studies have shown that PanCytoVir™ prophylaxis or treatment inhibited viral replication by SARS-CoV-2, RSV, and influenza viruses. We have since extended those studies and shown potent inhibition of the measles virus.
COVID-19 (SARS-CoV-2)
The ongoing pandemic caused by SARS-CoV-2 has caused a global health challenge and has affected over 200 countries with over 11 million cases since 2020.
Respiratory viruses are the most frequent cause of disease in humans, having significant impacts on morbidity and mortality worldwide [21–23]. The most common respiratory viruses are endemic agents such as coronaviruses (CoVs), respiratory syncytial viruses (RSVs), and influenza (flu) viruses. Although vaccines are available for CoV2 and flu, there is a paucity of effective antiviral drugs. For RSV, there is no vaccine available, and therapeutic treatments are very limited.
The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has plagued so far over 200 countries and has resulted in over 11 million cases and 500,000 deaths since the start of 2020.
COVID-19 has accentuated the need for drug discovery, and this has helped propel the need for a better understanding of virus-host cell interactions, with the hope that this
could facilitate drug breakthroughs.
PanCytoVir™ – A new oral tablet formulation of Probenecid
Effective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC90 value are achievable for 24 h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans.
PanCytoVir™ is an FDA-approved drug with a well-documented (>7 decades) safety profile for treating gout and hypertension and is a nonspecific inhibitor of OATs that blocks transport by OAT1, OAT3, and URAT1, and has been used to extend the plasma half-life of β-lactam antibiotics and oseltamivir.
CoVs, like flu, require host cell components to replicate. Recently, it was shown that PanCytoVir™ prophylaxis or treatment inhibited CoV2. Efforts to translate PanCytoVir™ as an antiviral drug in preclinical studies to clinical trials being ongoing for patients infected with CoV2.
The following are indications using TD-214:
Influenza
Influenza type A viruses are categorized based on the combinations of two different proteins: the hemagglutinin (H) and the neuraminidase (N), located on the surface of the virus. The currently circulating type A viruses are H1N1 and H3N2 subtypes. Type A viruses cause pandemics. Currently circulating type B viruses are of two main groups: B/Yamagata and B/Victoria lineages.
Influenza A and B are outbreak-driven, and thus there is no prevalence pattern. In temperate climates, seasonal outbreaks occur mainly during winters, while in tropical regions, influenza may occur throughout the year. Influenza is termed an “unpredictable threat.”
In 1997, WHO launched a global web-based tool for influenza virological surveillance where data from National Influenza Centers (NICs) of the Global Influenza Surveillance and Response System (GISRS) and other national influenza reference laboratories collaborating with GISRS are used to track the spread of influenza virus. The tool monitors the evolution of influenza viruses and provides recommendations in
laboratory diagnostics, vaccines, antiviral susceptibility and risk assessment. It also serves as a global alert mechanism for the emergence of influenza viruses with pandemic potential.
The ongoing COVID-19 pandemic has an impact on influenza.
The pandemic has influenced to varying extents health-seeking behaviors, staffing/routines in sentinel sites, as well as testing priorities and capacities in Member States. The various hygiene and social distancing measures implemented by Member States to reduce SARS-CoV-2 virus transmission have also contributed in reducing influenza virus transmission.
In a recent study, a small interfering RNA (siRNA) screen was performed to identify host druggable gene targets for anti-influenza A virus therapy. The host organic anion transporter-3 gene (OAT3), a member of the SLC22 family of transporters, was validated as being required to support influenza A virus replication. PanCytoVir™, a prototypical uricosuric agent and chemical inhibitor of organic anion transporters known to target OAT3, was shown to be effective in limiting influenza A virus infection in vitro (50% inhibitory concentration [IC50] of 5.0 × 10−5 to 5.0 × 10−4 μM; P < 0.005) and in vivo (P < 0.05).
Administration of PanCytoVir™ alone reduced influenza A virus titer in agreement with the finding that OAT3 is important for influenza A virus replication. TD-214, a novel, new chemical entity that safely and efficiently delivers PanCytoVir™ into the bloodstream is currently being evaluated for use as a therapeutic treatment for influenza.
RSV
It is reported in a recent article published in Open Forum Infectious Diseases journal, 2021, that the global burden of RSV study of 2016, estimated that RSV is responsible for 24.8 million acute respiratory tract infections (ARI) episodes and 76,600 deaths each year. Nearly 60%-70% of the children below the age of one have been infected with RSV and 2%–3% of these infections result in hospitalization.
RSV is a leading cause of mortality and morbidity in children aged below five years, particularly in low- and median-income countries. The incidence of RSV is lower in adults, however, it has been increasingly recognized as an important cause of respiratory disease in adults. The articles also have data from 15 participating countries which report the median cases per season and the care level (hospitalized or community care). The data from the 15 countries found that the majority (55%) of RSV cases occurred in the <1-year-olds, with 8% of cases reported in those aged ≥65 years. Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease in children <2 years of age. Increased morbidity and mortality have been reported in high-risk patients, such as premature infants, patients with cardiac disease, and severely immune-compromised patients.
Transmission of the virus occurs through infectious respiratory secretions, such as coughing or sneezing. The virus can also live for hours on objects, so the infection can spread via this route as well. The virus enters the body of a new host through the eyes, nose, or mouth.
There are some groups of people who may be more at risk of contracting RSV, including young children and older adults. Interestingly, RSV does not induce long-term immunity and people can be repeatedly infected. RSV infections are continually a cause of morbidity and mortality around the world in infants, elderly, and high-risk patients. Mainstream therapy remains restricted to supportive care.
RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. PanCytoVir™, was evaluated for prophylactic or therapeutic efficacy to inhibit RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. These studies showed that nanomolar concentrations of all PanCytoVir™ regimens prevent RSV strain A and B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV.
TD-214, a novel, new chemical entity that safely and efficiently delivers PanCytoVir™ into the bloodstream is currently being evaluated for use as a therapeutic treatment for RSV infection.
Dengue
Dengue is a mosquito-borne viral disease that is prone to pandemics. The last 50 years have seen a 30-fold increase in incidence and geographic spread. Nearly all dengue cases reported in the 48 contiguous US states were in travelers infected elsewhere. In the United States, local dengue outbreaks most recently occurred in Hawaii (2015), Florida (2020), and Texas (2013).
The global incidence of dengue fever has gone up drastically. The number of dengue cases reported to WHO in the last two decades has increased eightfold, from 505,430 cases in 2000 to 2.4 million in 2010 and to 5.2 million in 2019. Even the reported deaths between the period 2000 to 2015 have increased from 960 to 4032.
In 2020, dengue affected several countries, with an increased number of cases in Bangladesh, Brazil, the Cook Islands, Ecuador, India, Indonesia, Maldives, Mauritania, Mayotte (Fr), Nepal, Singapore, Sri Lanka, Sudan, Thailand, Timor-Leste and Yemen. The largest number of dengue cases ever reported globally was in 2019.
There are many mild or asymptomatic infections that are not detected by public health surveillance systems and go unreported. About 50 million to 100 million dengue infections are estimated to occur every year in over 100 endemic countries.
Dengue outbreaks occasionally occur in the continental United States. Dengue is common in the US territories of Puerto Rico, the US Virgin Islands, and American Samoa. Nearly all dengue cases reported in the 48 contiguous US states were in travelers infected elsewhere. In the United States, local dengue outbreaks most recently occurred in Hawaii (2015), Florida (2020), and Texas (2013). Most outbreaks in the United States have been relatively small and limited to small areas. Because the types of mosquitoes that spread dengue are common throughout many areas of the United States, local spread of dengue is possible.
According to the CDC, estimates at flu infections fall between 8,000,000 and 13,000,000 for the 2021-2022 season, with up to 170,000 hospitalizations. These estimates are calculated based on data collected through CDC’s Influenza Hospitalization Surveillance Network (FluSurv-NET) and are preliminary. It is worth noting that seasonal flu and pandemic flu are different – seasonal flu happens annually and usually peaks in the winter months. Pandemic flu has only happened 3 times in the 20th century.
TD-214 is a novel, new chemical entity that safely and efficiently delivers PanCytoVir™ into the bloodstream. PanCytoVir™ is an FDA-approved drug with a well-documented (>7 decades) safety profile for treating gout and hypertension and is a nonspecific inhibitor of OATs that blocks transport by OAT1, OAT3, and URAT1, and has been used to extend the plasma half-life of β-lactam antibiotics and oseltamivir.
Recently published studies have shown that PanCytoVir™ prophylaxis or treatment inhibited viral replication by SARS-CoV-2, RSV, and influenza viruses. We have since extended those studies and shown potent inhibition of the Dengue virus.
Zika
Zika virus (ZIKV) is a mosquito-borne Flavivirus that was first reported in humans in 1952. ZIKV reemerged in Brazil and tropical/subtropical nations. There is a strong relationship between ZIKV and microcephaly, and congenital malformations and neurological syndromes caused by ZIKV. There is also evidence that ZIKV may also be transmitted sexually.
The rapid spread of ZIKV raises increasing concerns for public health, such as the increased frequency of Guillain–Barré syndrome and congenital neurological anomalies. Currently, there is no approved vaccine or therapeutics against the Zika virus (ZIKV). Vaccine candidates are being developed using various platforms and technologies. While many of these are in the early stages, several are based upon previously approved platforms and designs against dengue and other infectious disease agents.
In February 2016, WHO declared Zika a global public health emergency. This was lifted in November 2016. Although the symptoms of the disease are not severe, it is linked to Guillain-Barré Syndrome and is known to cause microcephaly and other congenital brain abnormalities in babies born to infected women. Microcephaly leads to an under-developed brain, resulting in developmental delays that frequently impact a baby’s ability to perform vital tasks. These complications make Zika a disease with a high socioeconomic burden.
As of 2019, WHO reported that of the countries and territories affected by Zika virus, 49 were from the Americas. Since 2017, the number of cases in the U.S. started to decline and there were no confirmed cases in the U.S. in 2018, 2019 and 2020.
TD-214 is a novel, new chemical entity that safely and efficiently delivers PanCytoVir™ into the bloodstream. PanCytoVir™ is an FDA-approved drug with a well-documented (>7 decades) safety profile for treating gout and hypertension and is a nonspecific inhibitor of OATs that blocks transport by OAT1, OAT3, and URAT1, and has been used to extend the plasma half-life of β-lactam antibiotics and oseltamivir.
Recently published studies have shown that PanCytoVir™ prophylaxis or treatment inhibited viral replication by SARS-CoV-2, RSV, and influenza viruses. We have since extended those studies and shown potent inhibition of the Zika virus.
