Molecular Diagnostics Supply Chain and Breakthrough Therapies In Development: An Update!

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the majority of cases result in mild symptoms, some progress to pneumonia and multi-organ failure. As of March 28, 2020, the overall rate of deaths per number of diagnosed cases is 4.6 percent; ranging from 0.2 percent to 15 percent according to age group and other health problems. This is important to highlight as the impact to our bodies is driving various efforts in the development of therapies and diagnostics. Since COVID-19 is considered a novel virus and not seen before, there has been limited therapy development prior to the current pandemic. Additionally, large-scale, high-volume throughput diagnostic capabilities are under development and lagging the increased demand. The technical development of these complementary efforts of diagnosis and therapy require robust supply chains to ensure the timely delivery of quality materials, services, and technologies to healthcare providers and patients.

Current Diagnostics Efforts – The Race Against Time
Real time reverse transcription polymerase chain reaction testing (rRT-PCR) is done on respiratory samples obtained by swabs and results initially made available in 2-4 days. Companies including Charite, Kogenebiotech, Seegene, BGI Group, Roche, Hologic, and Cepheid have since been focusing on quality, testing different parts of the coronavirus genetic profile, and providing results in < 45 minutes, with the ultimate goal of providing instant results or at least, during a routine 15-20 minute medical appointment. The new bottleneck is the high-throughput reference labs, such as LabCorp and Quest Diagnostics, who are preparing for large-scale testing and standardization. A significant improvement over current make-shift drive-thru testing is taking place in parking lots. Quest Diagnostics has cited the ability to process 1,200 tests a day at its facility in southern California, with a short-term goal to quickly ramp up production to 5,500 per day. Without timely test results from these organizations,, debate has started on whether and how doctors should continue caring for patients, especially in traditional and makeshift emergency rooms across the US. Commercial labs are struggling to keep up with government demands and testing processes have exposed various risks, such as shortages of technicians and critical chemicals.

Current Diagnostics Supply Chain Requirements and Components

COVID-19 diagnosis requires three diagnostics elements, namely,

1.Equipment and extraction Kits used for specimen preparation,
2.rRT-PCR test kits, and
3. Reagents
COVID-19 diagnosis uses reagents, which are chemical substances used in laboratory analyses. The reagents extract, purify and stabilize RNA, or ribonucleic acid, in samples taken from patients suspected of having COVID-19.

Qiagen, a global leader in sample and assay technologies for molecular diagnostics, recently manufactured enough of the chemical mixture to supply about 1.5 million COVID-19 tests per month and plans to scale up manufacturing capacity to support more than 6.5 million tests by the end of April, and more than 10 million per month by mid-year, with a target of doubling this output by year-end. Additional components of COVID-19 diagnostics include primer and probe.

Integrated DNA Technologies, a supplier of custom nucleic acids, recently manufactured sufficient primer and probe kits to enable an additional 2.5 million tests and became the first company in the US to have primer and probe kits approved by the CDC for use as a key component of the CDC EUA testing protocol for the diagnosis and detection of COVID-19.

Regeneron Pharmaceuticals recently announced their supply chain efforts to make, distribute, and donate viral transport media (VTM). VTM is a liquid used to preserve patient test swabs until they can be tested, and a critical component of COVID-19 testing kits that has been in short supply. Ramping up production and opening up the distribution & logistics transportation lanes globally by various diagnostics and pharmaceutical companies is enabling more people to be tested in an effort to stop the spread of COVID-19.

Breakthrough Therapies – What Can Be Developed In 12-18 Months?

As previously cited, there are a few parallel efforts in play right now, such as immediate needs for protective personal equipment for healthcare, hospitals and first responders, short-to-medium term diagnostics capabilities, and medium-to-long term therapies availability. While all are critical, the last is the most important in terms of our ability to eradicate the novel coronavirus. Government collaboration is present in all the three elements mentioned above, however the US FDA owns the governance, policy, and public safety on the road towards a therapy, a vaccine, and on-going development of solutions to this pandemic.

Government + NGOs + Industry = A Strong Partnership

The US FDA, under the leadership of Dr. Stephen M. Hahn, has prioritized medical and regulatory staff members to focus on COVID-19 and tasked staff from the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research to provide guidance and technical support. The FDA has established teams, fast-track policies, technical review and created the Coronavirus Treatment Acceleration Program (CTAP). The goal is to reduce the traditional Drug Discovery to FDA Approval timeframe from multi years (and in some cases over a decade) to 12-18 months.

The benefits of this focus include the following :

• Accelerated track within the FDA at all stages of clinical and commercial viability
• Prioritized review of protocols and turn-around time in terms of hours (vs. weeks/months)
• Streamlined collaboration on the review and approval of changes associated with materials, processes, or manufacturing sites

Existing Pipeline of Products in Development to Save Human Lives–

Current US government mandate is to repurpose existing drugs vs. the longer development and evaluation of new ones, in order to battle COVID-19 now. Potential therapies for COVID-19 are undergoing clinical trials to assess their safety and efficacy include those which the World Health Organization (WHO) announced as the most promising to be effective. This global trial is called SOLIDARITY and includes the following:

• Gilead Sciences (Remdesivir): Gilead has initiated two Phase-3 clinical studies to evaluate the safety and efficacy of remdesivir in adults diagnosed with COVID-19 following the U.S. Food and Drug Administration’s (FDA) rapid review and acceptance of Gilead’s investigational new drug (IND) filing. These randomized, open-label, multicenter studies began enrolling patients in March 2020 and will enroll a total of approximately 1,000 patients in the initial phase of the studies, in countries with high prevalence of COVID-19. The first of two studies will evaluate the safety and efficacy of both a 5-day and a 10-day dosing duration of Remdesivir, in addition to standard of care, for patients with severe manifestations of COVID-19. The second study will evaluate the safety and efficacy of the same dosing regimens of Remdesivir in addition to standard of care for patients with moderate manifestations of COVID-19, compared with standard of care alone.
• AbbVie/Abbott
• (Kaletra, lopinavir/ritonavir):

Kaletra is a fixed-dose combination medication for the treatment and prevention of HIV/AIDS. It combines lopinavir and ritonavir. It is generally recommended for use with other antiretrovirals and is used for prevention after a needle stick injury or other potential exposure. AbbVie has taken action through the provision of Kaletra/Aluvia as an experimental option for treatment of COVID-19/. The company is also exploring a potential research collaboration with the Innovative Medicines Initiative (IMI), which is exploring multiple potential COVID-19 treatment options.

• Sanofi (Chloroquine, Generic and Hydroxychloroquine): Sanofi development and now available as a Generic. These drugs are currently authorized at a national level across the globe as treatments against malaria and certain autoimmune diseases such as rheumatoid arthritis. Available as a generic medication, Novartis, Mylan and Teva are taking steps to deliver hundreds of millions of Chloroquine tablets. With over 20 ongoing clinical trials in China. Chloroquine seems to be effective in limiting the replication of SARS-CoV-2, the virus causing COVID-19.
• Bayer (Interferon beta-1b): Systemic interferons and in particular interferon beta are currently authorized to treat diseases such as multiple sclerosis. Interferons, a subclass of cytokines, are produced in the body during illnesses such as influenza in order to help fight the infection and inflammation.

Additional Trials and Future Outlook

Monoclonal antibodies are created when our bodies are invaded by a virus to help fight off a particular infection. Organizations and research institutions in fighting COVID-19 are evaluating many antibody candidates, as well as the manufacturing requirements for large-scale production and distribution. Monoclonal antibodies have been proven effective in fighting many diseases, including cancers, Ebola, rheumatoid arthritis, and Zika. Drugs such as Actemra (Genentech) and Kevzara (Sanofi/Regeneron collaboration) are undergoing Clinical trials and results are pending.

Jannsen Pharmaceuticals, a part of Johnson & Johnson, through the U.S. Department of Health and Human Service, has recently signed a $1B agreement with the government’s Biomedical Advanced Research and Development Authority (BARDA) on an investigational vaccine, Ad26 SARS-CoV-2 (based on technology and manufacturing used to develop an Ebola candidate vaccine). Phase 1 clinical trial activities are scheduled to begin in the 4th quarter of 2020 with the goal of COVID-19 vaccine (emergency use) available early 2021.

BARDA has also announced their collaboration with Moderna Inc., in preparation to Phase 2 and 3 clinical trials of a vaccine known as SARS-CoV-2 mRNA-1273, joint development with National Institute of Allergy and Infectious Diseases, NIAID, part of the National Institutes of Health. Related clinical trials require the enrollment of 100s to 1000s of people to determine the safety and efficacy of the investigational vaccines.

BARDA and government support reflects a commitment to providing technical expertise and monies necessary for manufacturing expansion and the production of the investigational vaccine for these studies. While there is an immediate need to protect our healthcare and first responders with the appropriate PPE to help reduce the spread of COVID-19 between people, the partnerships among governments, NGOs, and industry are greatly appreciated in the mid to long-term battle against COVID-19 through the development, manufacturing, and distribution of improved diagnostics and effective therapies.