The Rapid Response Initiative is focused on reducing the time needed to develop therapeutics from years to months. We have been able to condense the timeline by performing many of the steps necessary for drug development as parallel processes. Traditional drug development processes are rigidly linear and span many years. To get a therapeutic to human consumers rapidly during an infectious disease outbreak (either epidemic or pandemic) the best-case scenario for testing in humans has been a year to 18 months. The only way to develop a drug in six months or less, is by running steps in parallel.
The Sasisekharan Lab at MIT and SMART, Singapore, consider the regulatory framework as the driving design constraint. We redesign the traditional linear sequential process to run experiments in parallel. With this approach and the Antibody Engineering methods we have developed, and by working with regulators each step of the way, we can rapidly develop, produce, and evaluate antibody candidates for safety and efficacy in humans.
This framework, supported with advanced instrumentation from Agilent Technologies, has led to biologics development (including GMP manufacturing and non-clinical studies) and first-in-human studies with unprecedented timelines. Using such an approach, a candidate Zika antibody (ZAb_FLEP) was developed in 2017-2018 within nine months and Phase 1a clinical trials were completed.
Yellow Fever Antibody Development
A similar approach was also deployed to develop a potential treatment for Yellow Fever. Yellow Fever, a mosquito-borne disease, tends to appear seasonally in tropical and subtropical regions of South America and Africa. A particularly severe outbreak began in Brazil in January 2018 and endured for several months. We began to develop TY014 in mid-March 2018
Several innovative steps were performed for the development of the anti-Yellow Fever candidate TY014. These included production methods to create small, uniform batches that they could use to perform necessary testing phases at the same time. These tests include studying the drugs’ effectiveness in human cells, determining the most effective dosages, testing for potential toxicity, and analyzing how the drug behaves in animal models. Once deemed safe through these non-clinical studies, the first in-human clinical trials commenced in December 2018.
TY014 was clinically tested in parallel to address safety through dose escalation in healthy human volunteers. Once an appropriate dose was deemed safe, phase 1b trial was initiated, in which the antibody’s ability to clear the virus was evaluated. Although the 1b trial had begun, the 1a trial continued until a maximum safe dose in humans was identified. Because there is a vaccine available for Yellow Fever, we could perform a challenge study. Volunteers were first vaccinated and then 24 hours later, they received either the experimental antibody drug or a placebo. Two days after that, we measured whether the drug cleared the weakened viruses that make up the vaccine. Following treatment, we found that the virus was undetectable in blood samples from the volunteers who received TY014. The treatment also reduced inflammation following vaccination, compared to people who received the vaccine but not TY014. The phase 1b trial was completed in July 2019 and the study published in the New England Journal of Medicine.
SARS-CoV-2 Antibody Development
The COVID-19 pandemic has brought much of the world to a halt. Phase 1 clinical trials to evaluate TY027, a monoclonal antibody that specifically targets SARS-CoV-2, the virus that causes COVID-19 was initiated in June 2020. The development of TY027, including discovery and laboratory and preclinical studies, took only four months.
This four-month timeline is a further improvement from the earlier successful mAb efforts with Yellow Fever, which took seven months from design to first-in-human infusion, and Zika, which took nine months. TY027 is being developed in partnership with several Singaporean government agencies, including the Ministry of Defence, Ministry of Health, and the Economic Development Board. With the successful completion of Phase I, TY027 was being evaluated in Phase 3 studies for the treatment of patients with COVID-19 to slow the progression of the disease and accelerate recovery. However due to limited patients in Singapore at that time the trials were not completed.
The Sasisekharan Lab is collaborating with various groups in the region to establish the Rapid Response Initiative. This includes the Princess Chulababhorn Research Institute, Bangkok, Thailand.
