Never let a good crisis go to waste: a COVID-19 view

As the coronavirus pandemic rages on and more countries being put on lockdown (I’m settling into my third week now in London), it’s a good time to take stock of the growing group of innovative biotechs and pharmas developing and conducting clinical trials on solutions to fight against the devastating effects of COVID-19. After all, social distancing is not a long-term solution, and the efforts these companies are making are our best hope of a way out of this pandemic. As a former bench scientist, I am amazed at the speed science is progressing - a lot of the approaches taken were merely concepts ten years ago, and are now in clinical phase. The below is accurate at the time of writing and is by no means exhaustive, but nonetheless I hope it provides a general sense of where we stand, especially to those outside the biotech / life science industry. 

One of the main concerns in a pandemic is to protect the uninfected. Vaccines are a logical way to go, but the frontrunner this time round takes an unconventional route. Conventional vaccines involve the introduction of deactivated viruses or antigens into the body, so it knows how to produce the necessary antibodies to mount an immune response the next time it encounters the threat. Taking a different approach, Moderna is working on an mRNA vaccine code-named mRNA-1273, which is designed to instruct the body to make both the SARS-CoV-2 antigen and the corresponding antibody against the virus. A major advantage of mRNA vaccines, as compared to conventional vaccine, is that it can be produced in the laboratory from DNA templates less expensively and in a shorter time. Two other biotechs, CureVac and BioNTech, are taking a similar approach. The former, a German mRNA vaccine developer, has been granted a EUR 80 million loan by the European Commission to create vaccines for COVID-19, while the latter is partnering up with Pfizer to co-develop and distribute an mRNA vaccine outside China.  

A shortcut method to create an immune response is to introduce the antibodies directly into the body. Regeneron has isolated hundreds of antibodies from its humanized VelocImmune? mice, as well as collected antibodies from patients who have recovered from COVID-19. From this pool of candidates, it then created an optimized “cocktail” by selecting the most promising antibodies. Another company, Vir Biotechnology, has identified two monoclonal antibodies against the spike protein on SARS-CoV-2. These are expected to go into clinical trials in early summer.

An older and less specific method with a similar concept is to use convalescent plasma, which also contains antibodies against the virus. Hospitals in China and Mount Sinai have trialed this in patients, and it appears to be yielding some positive results. The National COVID-19 Convalescent Plasma Project is currently underway to recruit recovered COVID-19 patients from all over the United States for plasma donation. If you have survived COVID-19 and would like to pay it forward, do sign up here and here.

If one unfortunately gets infected, the attention turns to killing the virus and/or boosting the immune system to fight the virus. Rather than reinventing the wheel, antivirals from existing infections are being repurposed against COVID-19. Gilead’s remdesivir (initially developed for Ebola virus infection but eventually dropped), Abbie’s Kaletra (approved for HIV infection), and Fujifilm’s Avigan (approved for flu infection in Japan) fall under this broad category. However, an innovative class of RNA-based antiviral is also being developed for COVID-19. Existing partners Alnylam and Vir Biotechnology (both ARCH Ventures portfolio companies), who were already working on hepatitis B RNAi therapeutics, are expanding their collaboration to develop and commercialize similar therapeutics for COVID-19. RNAi antivirals use siRNA to target highly conserved regions of SARS-CoV-2, and block them from replicating and causing disease responses.

Gas-based antiviral therapy is also used to treat COVID-19 patients. Cardiopulmonary-focused biotech Bellerophon’s proprietary inhaled nitric oxide (iNO) delivery system, INOpulse?, has been granted emergency use approval by the FDA for the treatment of COVID-19. A promising treatment from the previous SARS outbreak, iNO works by inhibiting viral replication and has demonstrated improvements in arterial oxygenation, a reduction in the need for ventilation support, and an improvement in lung infiltrates in clinical study of SARS patients. Based on the genetic similarities between the two coronaviruses, the FDA has good reason to believe that iNO can provide meaningful benefits for patients infected with SARS-Cov-2, and promptly granted its approval. Mallinckrodt is also submitting trial application to the FDA for INOmax?, a similar nitric oxide treatment previously used for newborns with respiratory failure.

A separate class of treatment is aimed at boosting patients’ immune response to fight the virus. Celularity, an allogenic cell therapy drug spun off from Celgene (now part of Bristol-Myers Squibb after the mammoth USD 74 billion deal), has won FDA permission to commence Phase I/II clinical trial for an off-the-shelf cell therapy candidate named CYNK-001. Trial participants will receive infusions of natural killer cells which are engineered to eliminate the infected cells and limit disease progression. A similar allogenic immunotherapy approach is taken by Allovir (part of ElevateBio) and Baylor College of Medicine, existing partners who are working together to develop T-cell therapies to fight viral infections. Using AlloVir’s Viralym-M therapy, where T-cells from healthy donors are activated with viral fragments and then reintroduced into patients to spark an immune response, the partners are aiming to create an off-the-shelf cell therapy for SARS-CoV-2 and related viruses, such as SARS-CoV and MERS-CoV.

While an appropriate level of immune response is vital to fight off any infection, an overactive immune system can cause downstream cytokine storm (think IL-6, IL-1, TNFalpha) which leads to acute respiratory distress and organ failure - major causes of death for COVID-19 patients. As such, a finely balanced approach towards immune modulation – both upwards and downwards – is important. Here, methods used to temper cytokine storm seen in CAR-T immuno-oncology treatments are borrowed to keep the immune system in check. Regeneron is collaborating with Sanofi to conduct Phase II/III trial for its Kevzara / sarilumab, a fully-human monoclonal antibody that inhibits the IL-6 pathway by binding to and blocking the IL-6 receptor, while Roche is in Phase III trial for its Actemra, another IL-6 inhibitor.

It is unclear when the first regulatory approval will be granted among the candidates above, but Gilead’s remdesivir and Moderna’s mRNA vaccine look to be the frontrunners in the therapeutic and preventive vaccine categories, respectively. Some systemic therapies being investigated for COVID-19, such as anti-interleukin therapies, are relatively aggressive and risky. Due to the compressed timeline, it is possible that their safety profile will not be fully investigated at the point of approval. However, as there are not many alternatives for high-risk patients, these approaches would be our best bet to reduce the number of casualties. On the other hand, the risk-benefit trade-offs for drugs designed to treat the otherwise healthy general public who develop milder COVID-19 symptoms are expected to be more thoroughly assessed before being approved for use. Lastly, given its widespread use in uninfected population, vaccines are expected to undergo significantly more stringent clinical trials with larger test populations, so they will be the last to market – current estimates place the first vaccines to be approved 12 to 18 months away. That said, some emergency use should still be possible for those who are at high risks of infection, such as frontline medical workers.

Winston Churchill once said, “never let a good crisis go to waste”. He was referring to his alliance with Stalin and Roosevelt, which led to the formation of the United Nations after WWII. We are in a world war of sorts now, the common enemy to mankind being SARS-CoV-2. With the help of regulators and investors, the best brains in science and medicine around the globe are fighting to outsmart the virus by neutralizing its threat along its pathological pathway. There is good reason to believe that we will win the war, eventually, likely with a combination of therapeutic approaches above. May the lessons we learn in this crisis serve as a foundation for us to fight the next pandemic, and a reminder that we’re all in this together, regardless of nationalities and political ideologies.