How close are we to a COVID-19 cure? A biotech VC perspective

16th April 2020

An effective treatment for COVID-19 would be a game-changer. With patients crowding hospitals around the world, drugs to reduce the burden on ICUs could save thousands of lives. Equally importantly, as the infection nears its peak in several Western countries, a treatment could be the safety net needed to help reopen economies where COVID-19 has drastically changed our way of life. Indeed, short of a treatment or vaccine, COVID-19 could become the new way of life as a potentially cyclical pandemic that – unlike the seasonal flu or even SARS – appears to be unrestrained by warmer climate at its current scale.

The response from biotech and big pharma has been swift and immense. Umer Raffat and Jonathan Miller at Evercore ISI recently put together a list of at least 250 companies and academic groups working on drugs and vaccines. Clearly the brightest minds in biotech are working on this – but nearly two months into the pandemic, is there a breakthrough in sight?

What we need in a drug

Fig.1: Science

To understand the potential landscape of drugs, it’s helpful to review how COVID-19 causes pneumonia, which kills most who succumb to the virus.

Like other viruses, COVID-19 undergoes endocytosis into the human cell before orchestrating a process to replicate itself, starting by copying its RNA and then hijacking the cell’s ribosomes to manufacture viral proteins. As the packaged virus particles leave the cell, it disintegrates. Loss of functioning respiratory tissue leads to pneumonia and other symptoms, such as anosmia, or loss of smell. Figure 1, taken from Science, shows the necessary steps and sites of action for some of the key drugs being explored today.

The human immune system’s response to combat the virus is thought to be via antibody-mediated cell-mediated cytotoxicity (ADCC), meaning that once an infected cell is tagged with an antibody, the immune system kills the cell. However, it remains to be seen if that alone is sufficient to clear the infection – if not, that would complicate vaccine development substantially.

What should a coronavirus drug be able to do? A valuable coronavirus drug should help clear viral infection and have measurable impact on patient outcomes, e.g. shorter ICU stays, mortality, etc. For sick patients, it could do this by improving clearance of the virus, preventing pneumonia, or its accompanying lung inflammation and cell death, known as acute respiratory distress syndrome (ARDS).

Perhaps the larger target for drug developers is to preventative treatment, but this is also trickier to test. The ultimate goal would be for improved testing and a reliable treatment to bring COVID-19 down to a flu-like illness that can be treated with oseltamivir/Tamiflu.

What’s in the therapeutics pipeline?

There has been widespread coverage on a few COVID-19 treatments, but there is much broader landscape. These can be grouped into drugs that are being repositioned, novel antiviral mechanisms, drugs designed to protect lung tissue in severe cases, and vaccines.

1. Existing antiviral drugs being repositioned - Many of these have been covered widely in the news. Drug repositioning is especially attractive because there is already substantial safety data in humans and often existing preclinical models to test the hypothesis. Indeed, a study by the QBI COVID Research Institute at UCSF found that at least 69 may already fall into this group. However, there has been very little high-quality data, i.e. randomized trials, making the evidence very difficult to assess.

  • remdesivir (Gilead) – remdesivir is an adenosine analog, which means it slows viral transcription, and was originally developed for Middle Eastern respiratory syndrome. As with other similar antiviral treatments, there is a chance it may not be effective in severe, late-stage illness once the virus runs rampant. What has been published so far has only been open label and compassionate use, meaning there were no placebo patients included. Still, the initial results (Figure 2) are promising – among 34 patients who started the drug on the ventilator, 19 (56%) showed improvement. However, Gilead announced on April 15 that it had ended most of its work in China in both mild-moderate and moderate-severe patients, suggesting the drug may not have been found to be effective.
  • lopinavir/ritonavir/Kaletra (AbbVie) – AbbVie’s attempt to retool anti-HIV protease inhibitors failed one of the only published RCTs so far. With 100 patients in each group, there was no change in time to clinical improvement. This does not bode well for other non-targeted therapies of this class, including J&J’s darunavir/cobicistat (Prezcobix). COVID-19 needs proteases to cleave its proteins to become active virus particles, but one issue is that human cells naturally have their own proteases.
  • favipiravir/Avigan (Fujifilm Toyama Clinical) - After trials in Wuhan and Shznehen as a next generation flu drug, favipiravir appears to improve viral clearance and lung condition on X-ray, especially in mild-moderate patients. Originally designed as the next seasonal flu drug, it inhibits RNA polymerase (viral transcription) and has previously been used for Ebola.
  • Several groups are working on convalescent sera treatments, or antibodies from patients who have recovered from COVID-19. These include Takeda, Mount Sinai, and Hopkins. Aside from directly dosing patients with these antibodies, they will aim to identify monoclonal antibodies that can be mass-produced in the lab. There is reason to believe this will work given previous experience with SARS. Importantly, the success of convalescent sera will give clues to how the immune system combats COVID-19 and how easily a vaccine can be made.

2. Novel antiviral mechanisms – Many of these are earlier but may be the best hope for a definitive therapy. There are some early leads here, but we expect that most of these efforts to mature in clinical trials in the next 6-9 months.

  • APN-01 (Apeiron). ACE1 and ACE2 are two human proteins identified to help the COVID-19 enter cells (Figure 4). Combined with evidence that ACE inhibitors, which are commonly used to treat high blood pressure, increases ACE2 production in cell models, this has led some clinicians to consider pulling ACE inhibitors, but this is likely premature. Apeiron had previously developed its drug for SARS and will now take it into a COVID-19 Phase 2 trial. If successful, APN-01 could buy patients’ immune system valuable time in fighting the disease. While this makes sense in theory, the stoichiometry would need to be efficient.
  • Alnylam/Vir collaboration. Vir is working with Alnylam, one of the major players in using drugs to disrupt RNA, to silence ACE2 using a small interfering RNA (siRNA). By doing so, it is aiming to give the virus less of a foothold into infections. The key here will be safety, as we do not yet completely understand the normal role of ACE2 beyond its important function in regulating blood pressure. The second challenge will be getting delivery of an siRNA therapy outside the liver, which is still unproven but promising.
  • Targeted antibodies – Chinese scientists have reported developing novel antibodies against COVID-19 in the lab. These could ideally be used to induce ADCC and the normal immune response. However, this will take time to identify which proteins can be best targeted, i.e. are well conserved across all strains of the virus. Previous efforts to target other coronaviruses, e.g. SARS and MERS have encountered difficulties in the past.
  • N-803 (ImmunityBio). Natural killer (NK) cells gaining traction in biotech for their ability to kill cancer cells, and ImmunityBio’s approach would be to bring them into targeting infected cells. However, it remains unclear to what extent NK cells participate in clearing cells infected by COVID-19, and, as noted above, if an antibody response will be sufficient. N-803 notably has strong evidence in monkeys for HIV.

3. Lung-protective agents to prevent lung injury/ARDS. The diversity is impressive here in the response from biotech and big pharma. Many of these drugs are also either already on the market or have had substantial clinical experience, meaning that they can be rapidly deployed once there is convincing clinical data. Importantly, most of these would be targeted to the sickest patients with lung injury, but some could have preventative effects as well.

  • tociluzmab/Actemra (Roche) and saniliumab/Kevzara (Regeneron) – Roche is enrolling 330 patients for a trial of tocilizumab in COVID-19. Approved in 2010 as an interleukin-6 (IL-6) receptor antagonist to modulate the immune response. These are the same drugs used for rheumatoid arthritis and more recently CAR-T conditioning to prevent cytokine release syndrome.
  • fingolimod/Gilenya (Novartis) – This is an sphingosine-1-phosphate (S1P) receptor modulator that has been used to reduce the autoimmune response in multiple sclerosis, which is being tested in China.
  • pirfenidone/Esbriet (Roche) – Pirfenidone is one of two major drugs used to treat idiopathic pulmonary fibrosis (IPF), a devastating, rapidly progressing lung fibrosis disease. Those recovering from COVID-19 can have decreased lung function due to fibrosis, so this rationale is clear.
  • ruxolitinib/Jakafi (Novartis) – Janus kinase (JAK) inhibitor for myelofibrosis and polycythemia vera, which involve proliferation of white and red blood cells in the bone marrow, respectively. Besides these anti-inflammatory properties, ruxolitinib was also identified to have direct anti-COVID-19 activity in a drug screen.
  • tradipidant (Vanda/Eli Lilly)After recently failing a Phase 3 trial in atopic dermatitis, an autoimmune skin condition, tradipidant could have new life as a NK-1/substance P antagonist in lung injury post-COVID-19.
  • SNG-001 (Synairgen). Synairgen’s inhaled formulation of interferon-beta-1a (IFN-1a), which unlike the other drugs above, would increase the immune system’s responsiveness. The evidence so far in asthma patients – where it has been tested for preventing asthma exacerbations from the common cold – is mixed, but in a more severe population, this mechanism could be powerful.
  • OncoImmune – CD24-Fc – This is a novel anti-inflammatory mechanism drug that suppresses multiple cytokine signals the body produces in response to injury (called danger-associated molecular patterns/DAMPs). It has completed a Phase 2 trial in acute graft versus host disease, a condition after stem cell transplant where the grafted white blood cells attack their new host.

4. Vaccines. If history is any guide, developing a vaccine for COVID-19 will be challenging, but biotech has an arsenal of different approaches. Close to 100 groups are working and at least 5 in Phase 1 trials, with the initial clinical data expected by fall or early winter 2020. Success would be having a vaccine that confers durable immunity in at least 70% of patients. Scaling to the entire population will take time, although serologic testing could help with identifying those who are already immune. In any case, this is all be done in record pace, as the entire process usually takes 10 years.

  • Live attenuated/inactivated vaccine – Because of the challenges of growing live virus, these are some of the most difficult to develop, and Soligenix and University of Hawaii are collaborating on this approach.
  • Virus-like particles – CanSino Biologicals is working on an adenovirus type 5 vector expressing S (spike) protein. These have the potential to be safer than live vaccines and as effective, but are more difficult to manufacture.
  • RNA vaccines – As of March 16, Moderna’s mRNA vaccine has entered clinical testing, just over 2 months after the sequence of COVID-19 was published. This is partially because these vaccines are directly developed from the sequence. Prior to COVID-19, Moderna was already targeting Zika, cytomegaloviruss, and other viruses in the clinic. Fosun and Biontech also have a $135M partnership to develop an RNA vaccine. However, this class of vaccine could be less immunogenic, and it remains to be seen if it will create durable responses.
  • DNA vaccines - Inovio also working a DNA plasmid encoding S protein that will be delivered by electroporation to help the DNA plasmids enter human cells to generate an immune response. This is similar to their approach for their HIV vaccine.
  • Cell-based vaccine. Shenzhen Geno-Immune Medical Institute has introduced two vaccines consisting of human white blood cells (dendritic cells and artificial antigen presenting cells) that have been genetically modified to express parts of COVID-19. Both have now entered Ph1.
  • Repurposed vaccines – multiple trials are underway to test the Bacille Calmette-Guérin vaccine (BCG) for tuberculosis. It has long been known that it can protect against other respiratory infections, and some correlation data by country does show this. The BCG vaccine is especially interesting in that – unlike most vaccines which elicit an adaptive antibody response – it targets the innate immune system. It is also used in treating bladder cancer for this purpose.

Concluding thoughts

A viable therapeutic would dramatically change the tone of the COVID-19 pandemic, giving hope and a path to eradicating the virus, saving lives and livelihoods. Highlighted here is the incredible diversity of tools biotech has called in to the battle against coronavirus from decades of work in the lab and in the clinic.

Importantly, while the FDA is likely to allow a rapid path to approval for drugs and vaccine in this time of immediate need, gathering quality data will be vital. Some examples of concerted efforts include the WHO SOLIDARITY trial, which will test four different agents across 90 countries. This will also ensure that the newfound understanding of biology from clinical trials can be shared with everyone.

The current battle against COVID-19 also underscores the need for policy discussions to facilitate readiness and response to a future pandemic. This could include increased funding for drug development, testing capabilities, and disaster preparation. Building up our arsenal will be critical so we are prepared next time.