W. Malone MD, LLC announced the enrollment of an innovative, rigorous clinical trial designed to rapidly assess the safety and clinical benefit of a combination of two widely available and inexpensive repurposed generic drugs for treatment of hospitalized patients suffering with COVID-19. Under the guidance of Dr. Malone, clinical trials were initiated at Northwell Health system in New York. Malone was a key participant in a multi-faceted collaboration involving physicians and scientists from multiple institutions. This clinical trial provides patients hospitalized with COVID-19 disease the opportunity to volunteer for a clinical trial that may bring new hope to all at risk for infection by the SARS-CoV-2 virus. Malone is reported to be part of efforts to employ computer simulations, Artificial Intelligence and other methods are used to study which drugs could be repurposed to counter threats such as COVID-19, also collaborated extensively with The Office of the Assistant Secretary for Preparedness and Response (HHS) and the Department of Defense; Defense Threat Reduction Agency.
The clinical trial is being conducted at New York State’s largest health care provider and private employer, with 23 hospitals and nearly 800 outpatient facilities, Northwell Health is continually striving to find more innovative and effective ways to improve the health of our patients, our communities, our country, and the world.
About Drug Repurposing for Infectious Disease Outbreaks
When confronting a rapidly moving epidemic or global pandemic caused by a new and highly infectious respiratory virus, time is of the essence, and every day can be measured by thousands more people infected, suffering or dying. The pressing need to rapidly develop drug or vaccine treatments or preventions can be overwhelming. However, those with experience in managing outbreaks are aware of the risks of rushing an unproven drug or vaccine into widespread use before demonstrating both effectiveness and safety; many millions of people could be further damaged if dosed or vaccinated with unsafe medical products. Unfortunately, demonstrating both the safety and the ability to reduce or prevent viral disease for a new drug or vaccine for a new virus takes large amounts of time, money, and risk; usually 10 to 15 or more years, billions of dollars for each candidate, and often ends in failure. The Merck Ebola vaccine was moved through the process from initial human testing to FDA licensure in a record time of five years.
One option for accelerating this process is to focus on identifying drugs that have already been licensed by the FDA for treating other diseases; repurposing them for a new “off label” use. This strategy can save valuable time because the safety, manufacturing processes, and pharmaceutical characteristics of a repurposed antiviral drug candidate has already been demonstrated and reviewed by the FDA. The remaining challenge is to rapidly determine which of the thousands of licensed drugs might be useful for preventing or treating the viral disease, to rigorously test the safety and efficacy of a candidate treatment in properly controlled clinical trials, and to do this as fast as possible. Days lost translate into lives lost.
There are three general approaches for discovering whether the library of old drugs can be useful for treating new viral diseases. One is to test each drug one by one for ability to halt the replication of the virus. This approach is relatively slow and can now be speeded up by using advanced robotics technologies (high throughput screening), but even if a drug blocks a virus from replicating in cells it may not work in animals or humans to stop the disease. This method typically requires time consuming animal testing. Another recently developed method uses advanced high-performance computing to analyze the three-dimensional structure of virus proteins and predict whether a drug may block the ability of a virus to replicate. By using supercomputers or cloud-based computing, this method can select likely drug candidates from the library of all licensed drugs in just hours. A third approach also involves modern computer technology, but sorts through large clinical data sets to identify medical conditions and drug treatments that seem to protect some people from disease relative to others who are not taking the drug (“survival signals”). All three of these approaches are being used by physicians and scientists all over the world in an open cooperative effort aimed at combatting the COVID-19 pandemic.
Discovery of Famotidine as a Possible Repurposed Drug Treatment for COVID-19 Disease
Famotidine is sold as an over the counter, generic, inexpensive oral pill that is commonly used for relief of heartburn, acid indigestion, and sour stomach. In prescription form (oral or IV), famotidine is used for treatment of duodenal ulcer; gastroesophageal reflux disease (GERD), active benign gastric ulcer and certain other conditions involving excess stomach acid. Famotidine is inexpensive, remarkably safe, easily manufactured, rapidly absorbed into the blood and readily distributed throughout the body. Further information including safety information about famotidine can be found here.
Dr. Robert Malone is an internationally recognized physician scientist (virology, immunology, molecular biology, and drug discovery) and is known as one of the original inventors of DNA and RNA Vaccination. Together with his partner, also a scientist, Dr. Malone co-founded and is president of RW Malone MD, LLC, where he serves as principal consultant. When the sequence of the novel coronavirus (now known as SARS-CoV-2) was publicly disclosed on January 10, Dr. Malone and his colleagues began volunteering their time to find an antiviral treatment, knowing that a successful vaccine licensure would be years away. They began applying advanced supercomputing tools to determine whether any FDA licensed drugs or other nutraceuticals might be used to treat COVID-19 disease. This work by the team has been entirely voluntary, performed as “open source” research aimed at finding a potential repurposed drug treatment for COVID-19 while also demonstrating the usefulness of the system developed in support of DTRA rapid medical countermeasure development objectives. The team chose to focus on a SARS-CoV-2 virus protein that has been overlooked by many large pharmaceutical companies; a protein involved in early stages of virus replication, which also suppresses parts of the immune response to SARS-CoV-2 and other viruses. Of the top ranked drugs identified by applying the drug discovery system developed for DTRA, the team determined that famotidine had the most attractive combination of safety, cost, and pharmaceutical characteristics. The success of the system to identify and rapidly advance a repurposed drug candidate for treatment of COVID-19 disease has demonstrated the usefulness of the DTRA approach. Dr. Malone presented a summary of the findings and recommendations to Dr. Callahan and the ASPR. The mission of the HHS Office of the Assistant Secretary for Preparedness and Response (ASPR) is to save lives and protect Americans from 21st century health security threats
Original Observations out of China
Dr. Michael Callahan is a physician scientist that works as an infectious disease, mass casualty infection doctor at the Massachusetts General Hospital in Boston, MA, and who has developed block-buster anti-infective drugs for the U.S. Government and for Industry, has a joint clinical appointment at a sister hospital in China. Dr. Callahan also serves as a senior executive at United Therapeutics, a publicly traded company that is focused on pulmonary hypertension and oncology. Dr. Callahan is triple boarded in internal medicine, infectious disease, tropical medicine, and is one of the few Command physicians based in the United States who specialize in mass casualty infection therapies. Over the last 17 years, Dr. Callahan has managed treatment of over 1000 Ebola patients across five outbreaks in three countries and previously deployed to 3 bird flu outbreaks and the 2002-03 SARS outbreak in Hong Kong.
With the advent of the outbreak of a novel coronavirus infection during December 2019, Dr. Callahan was granted a leave of absence by United Therapeutics’ CEO Martine Rothblatt to travel to China to assist clinical colleagues in mass infection management of COVID 19 under his joint appointment. Unaware of the work by Dr. Malone, Dr. Callahan worked with Asian colleagues to analyze medical records from over 6,000 hospitalized patients, 1,100 of whom had severe disease. This analysis of clinical data revealed that about 600 of these patients were on antacid therapies, and were found to have relatively mild COVID-19 disease compared to others of similar age and health. The incidence of COVID-19 in China dropped quickly, and Dr. Callahan and colleagues were not able to start a clinical trial to test famotidine as a promising oral therapy for treating COVID-19 disease. Dr. Callahan was then recruited to serve as Special Advisor on COVID 19 to the Assistant Secretary of Public Health Preparedness and Response (ASPR), U.S Dept of Health and Human Services during this pandemic, and his leave of absence from United Therapeutics was extended due to the pressing emergency. Since appointment, has been working within the office of the Assistant Secretary to assist policy and management decisions while also lending his experience on the front lines in intensive care units across the country.
Dr. Malone presented a summary of the team findings and recommendations to the ASPR on 18 March 2020. Both Dr. Callahan and Dr. Malone were previously unaware of each other’s work and agreed to collaborate on this project. As old friends, it is not the first time that they have worked to “save the world”. With convergence of these two independent discoveries, Feinstein/Northwell Health system was contacted to explore the possibility of performing well controlled clinical trials within the Northwell hospital system. Northwell hospital system agreed that this repurposed drug candidate worthy of rigorous evaluation of activity in randomized clinical trials. Because New York decided that the standard of care for hospitalized COVID-19 patients was to include hydroxychloroquine, this was added to the study arms to ensure enrollment of patients and comply with bioethical requirements for inclusion of standard of care in clinical trial designs.
Dr. Malone then wrote the initial clinical protocol. This was reviewed and edited by Dr. Robert Malone together with Drs. Martin Lesser, a biostatician, and Joe Conigliary, a general internal medicine doctor within the Northwell hospital system. Robert was also the primary technical author writing the federal funding contract, which was subsequently funded by BARDA for over 20 million dollars, three days later, to perform this clinical trial. Under this contract, Alchem Laboratories is prime contractor and Northwell health system became a sub-contractor for the BARDA award for advancement of this drug.
The volunteer team includes Dr. Joshua Patel of Molecular Forecasting, Dr. Gideon Shapiro, and Dr. Jill Glasspool Malone. We are grateful for this team and what they have accomplished.
About RW Malone MD, LLC
RW Malone MD, LLC offers premier consulting, analytics and proposal development services that specialize in a unique blend of detail-oriented, efficient and value-oriented processes. This enables the synergy required to move projects and product development teams forward by complementing and supporting core client expertise. Core competencies include pre and clinical trials expertise, clinical trial design and implementation, vaccine and biologics, AI drug development, outbreak disease expertise, expert witness due diligence and proposal development.