- Approved antiviral agents which might have a role in treating COVID-19 include Gilead’s remdesivir, Starpharma’s SPL7013; BioCryst Pharma’s Galidesivir; Pfizer and Merck have programs in this area.
- Remdesivir is primarily a late stage treatment which may reduce time in hospital, but it isn’t a cure.
- Treating early stage disease to prevent progression to serious illness is another approach: examples include Starpharma SPL7013, Sorrento Therapeutics antibodies, possibly Merck/Ridgeback Bio EIDD-2801.
- Drugs (mostly not yet developed) addressing immune system over-reaction for late stage acute disease might have a role. Mesoblast Remestemcel-L is possible but probably too expensive.
- Other possible candidates are many, diverse and speculative.
There are many levels to the coronavirus pandemic and a massive effort is underway to find a vaccine and treatments. Genetic Engineering News summarised 161+ candidates. The US clinical trials website indicates 1,915 trials underway using the keyword COVID-19 (June 3, 2020).
The common cold has no cure/treatment and no vaccine. A coronavirus is responsible for ~20% of common colds.
The initial reports on progress towards a COVID-19 vaccine are coming in, with mixed results. This is a tough problem and it would be extraordinary if a vaccine became available in less than 12-18 months. Even if that happens, it is likely to take considerably longer to have a really effective vaccine. So there is a big need for parallel efforts on treatments.
In this article I highlight some approaches being tried and some companies involved. You can be certain that lots of labs have recently changed their research efforts to engage with COVID-19 drugs. Below I show that there is still much to learn about COVID-19, so a cure is likely to involve a number of twists and turns and there may be multiple kinds of treatments at the end of this saga. Most potential treatments are still vague and hence who to invest in is unclear, except that most big pharma companies are looking for ways to participate with a vaccine and/or a treatment. I highlight two antiviral compounds that are already used to treat viral disease, Gilead’s remdesivir and Starpharma’s (OTCQX:SPHRY) SPL7013, which, although at a very early stage in relation to treating COVID-19, may be of interest to investors.
Potential treatments for COVID-19 fall into various categories, starting with using antibodies from patients who have survived COVID-19, to conventional approaches via antiviral agents that attack other viruses, and also various therapies (mostly monoclonal antibody-based) which bind to various immune system targets to treat the consequences of viral infection rather than the SARS-CoV-2 virus itself.
It is important to be clear what any particular treatment will actually target. The initial stages of COVID-19 are not life-threatening, and clearly a treatment that stops the infection quickly is of interest. The practical window of time during which this kind of treatment can become effective is not straightforward and conclusive evidence of effect might need substantial clinical trials.
For those who progress to severe disease, lung complications are common; the disease becomes ARDS (Acute Respiratory Distress Syndrome) which is a condition that has a high fatality rate. ARDS involves the body’s defences going berserk and hence this is a condition where the SARS-CoV-2 virus might set things up, but the issue is as much about how to send the body’s own defence forces home as it is about attacking the SARS-CoV-2 virus. While the focus of a lot of commentary concerning COVID-19 is on respiratory disease, as a better picture of the organs affected emerges, what a drug treatment needs to look like will become clearer. The fact that patients with prior respiratory disease (e.g., asthma) are not prominent in those needing respirators suggests complexity. Indeed, the profile for a COVID-19 sufferer who proceeds to dangerous disease is more one of a patient with pre-existing blood vessel damage. So high blood pressure, heart disease, diabetes, obesity and the very elderly are key indicators of progression to lethal disease. A really useful summary of COVID-19 has been published in the prestigious journal Science (“How does coronavirus kill? Clinicians trace a ferocious rampage through the body, from brain to toes”). A Harvard University study based on 45,817 COVID-19 deaths in the US to April 22 showed a significant relationship between airborne pollution (PM2.5) and COVID-19 mortality, with a 1ug/meter3 increase in pollution resulting in an 8% increase in COVID-19 death. So COVID-19 is also starting to look like a disease significantly associated with airborne pollution.
What kind of drug is needed to treat COVID-19?
I have provided the above very brief overview of some of the effects of SARS-CoV-2 infection because anyone considering investment in companies searching for a treatment needs to be aware of what needs to be fixed and also what is and what isn’t going to be important in a COVID-19 drug. Beware of investing in hype from ignorant individuals, even if they are well-known public figures.
Viral diseases have until recently been very hard to treat. Often the actual effect of the virus is just a trigger for wider problems caused by its presence. HIV makes sufferers' immune systems weak and they used to die from diseases (e.g. Kaposi’s sarcoma) normally controlled by the body’s immune system.
With COVID-19 there are timing issues, as by the time they are diagnosed most people have mild symptoms (e.g. mild fever, cough, muscle soreness) that will self-resolve. The life-threatening symptoms appear late (even when a patient is apparently recovering) and death is swift. Even if there was an effective drug, it may be too late to have an effect.
If there could be a pill (or something similar, for example, inhaler) that one takes immediately after being diagnosed that prevents further viral proliferation, this would be a useful drug. Tamiflu and Relenza do this for flu. Merck (MRK) may be beginning to check out a drug for COVID-19 that could fit this category (see below).
So where will drugs to treat COVID-19 come from?
There are basically three approaches.
The first involves the early stages, to prevent the virus getting established. These rely on attacking the ability of the virus to get into cells, because if that can be stopped, then the virus doesn’t grow. Often this means drugs that prevent the virus locking onto the cell.
The second involves trying to control things as they get out of hand. This may involve more of the first stage drugs, but it also includes drugs (like remdesivir) that block the ability of the virus to replicate.
The third approach is less about the virus and more about trying to fix the chaos that it is causing. In the case of SARS-CoV-2, this is all about addressing chaos caused by the body’s own immune system going crazy. This is where immune regulating drugs come in. This third approach is not without problems as calming down an overactive immune system might have the unwanted side effect of allowing the virus to get going again.
Antiviral agents already used on humans
Drugs that have been used in humans as antivirals (not for COVID-19, but for something else) already have resolved issues that drugs that are completely new have to confront (toxicity, side-effects, etc). Here three antiviral agents (remdesivir, galidesivir and SPL7013) that have been used on humans for other conditions are mentioned as possible treatments for COVID-19. Undoubtedly, there are many more antiviral compounds being investigated.
Remdesivir is a small molecule (adenosine analogue) drug from Gilead Sciences (NASDAQ:NASDAQ:GILD). Gilead is best known for its very successful development of treatments which cure Hepatitis C infection, but it also has experience of developing flu treatment Tamiflu and developing drugs (little success) for treating Ebola and Marburg virus. So this company is one of the most experienced biotech companies in antiviral drug therapy. Remdesivir came out of a drug development program in 2009 to find a treatment for Hepatitis C, but it failed to be useful for that disease. It was then used to investigate (without success) treating Ebola virus infection.
Source : Chemical and Engineering News
Remdesivir has been evaluated in two Chinese trials for treatment of COVID-19 disease that has progressed to require hospitalisation. One trial involved patients who had been hospitalised but had not progressed to severe symptoms such as requiring oxygen. The other trial involved patients with severe clinical manifestations such as requiring oxygen. The outcome of these trials was negative but there were some hopeful signs of effect. Subsequent studies have indicated that remdesivir treatment can reduce hospital stay for patients with severe COVID-19. It will be some time before it becomes clear whether an effective treatment with remdesivir will prove worthwhile (e.g., reduce probability of death).
Temporary use of remdesivir has recently been approved as Emergency Use Authorization (EUA) for treatment of COVID-19 based on intravenous injection in adults and children with severe disease by the FDA. Severe disease is defined as patients having low blood oxygen (equal to or less than 94%) or requiring supplemental oxygen or requiring mechanical ventilation.
The basis for approval had the following explanation from the FDA. "Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug's use." This indicates that the approval reflects the urgency of finding treatments for COVID-19 while acknowledging that there are risks in using the drug. The optimal dosing and time of treatment is not yet clear and remdesivir remains an investigational drug which has not been approved by the FDA. Clinical trials of remdesivir continue all over the world. It is acknowledged that much is yet to be discovered concerning side effects of remdesivir use. Liver and kidney function and key biochemistry must be monitored in patients being treated with remdesivir. However, in the absence of anything else, remdesivir is now being used to treat patients in the US, UK, Japan and no doubt it will be used globally, unless more extensive clinical trials show that its overall effect is negative.
Even if remdesivir proves to be an effective treatment for COVID-19, the timeline to broad availability is still not clear due to the need to scale up complex synthesis and then produce millions of doses. Currently Gilead has supplies for initial trials. A discussion in Chemical & Engineering News gives some insight into scaling up manufacture, which is seen by experts as a medium complexity project. Gilead indicated that in April it has sufficient remdesivir to treat 140,000 patients in a 10-day course of treatment and by the end of the year it will have enough material for treating 1 million patients. If the clinical trials are successful, the demand for remdesivir could be substantial if governments choose to stockpile the drug.
The big “if” is whether or not remdesivir proves to be an effective treatment, and being delivered through injection this will enable large numbers of people to be treated. Guesses about the price for treatment have ranged widely to as high as $30,000. Even $4,460 per course seems a lot to pay for a drug whose main benefit might be reducing hospital stay and a non-significant improvement in death rate. Time will tell where this ends up. For a deeper dive on remdesivir, see DoctoRx’s recent article. Also, Robert Honeywell recently wrote about investment in Gilead more generally but in the context of remdesivir treatment for COVID-19. Bram de Haas has provided a bullish case for investment in Gilead based on remdesivir being all there is at the moment and what he sees as enormous pressure to relax social distancing. His thesis is that if there is a treatment this will force reopening of the global economy. I’m cautious about this as the treatment has to have an impact on patients and deaths or it will be a brief reopening followed by a close-down again. Sane governments are aware of this and being cautious. The US, UK and Brazil, all of whom have leaders not noted for evidence-based decision-making are acting more aggressively. Time will tell whether their confidence will be justified. It hasn’t worked for phase 1 of the pandemic.
Successful treatment of other viral diseases (e.g. HepC) has been achieved by therapy with multiple antiviral agents. A recent study indicated that 3 old antiviral drugs in combination produced some effect by shortening the time of illness. This could be the start of a successful approach to treatment, but it won’t be sorted out quickly. Gilead has a lot of experience with this kind of approach.
A hint of how this may play out comes from preliminary results from combining BioSig Technologies (NASDQ:BSGM) and its subsidiary Viraclear Pharmaceuticals’ antiviral merimepodib with remdesivir which led to viral clearance in preclinical studies. Antiviral replication inhibitor Merimepodib, which is delivered by mouth, will enter Phase II trials soon. It had a former life as a Vertex Pharmaceuticals (NASDAQ:VRTX) Hepatitis C drug candidate.
BioCryst's (NASDAQ:BCRX) galidesivir is another broad spectrum antiviral that has a similar target to remdesivir. Animal studies indicate that it has potential for treating viruses such as Ebola, Marburg, Yellow Fever and Zika. Galidesivir is injected either intravenously or intramuscularly. A phase 1 trial indicated that it is safe and well-tolerated in humans. In April, a trial was initiated to assess safety, clinical impact and antiviral effects in patients with COVID-19. It seems possible that galidesivir might be similar to remdesivir for a COVID-19 treatment.
The above makes clear that there is a lot of activity in the small molecule antivirals space and it is very hard to get a sense of where it is heading. However, Gilead, with its track record of success in treating Hepatitis C, is a powerful company in this space.
I’ve recently summarised Starpharma’s approach to adopting its antiviral compound SPL7013 to treating early stage COVID-19.
SP7013 is manufactured at some scale for application as a condom coating and also as the active ingredient for treating Bacterial Vaginosis (BV). The BV treatment is being rolled out in markets in Europe and Asia, but it is likely that production would need to be substantially scaled up if it was to be used as a COVID-19 treatment.
The major unknown for SPL7013 is how quickly effective delivery via inhalation or nasal spray can be achieved, and once this is in place, whether SPL7013 is effective in blocking viral proliferation in the nasal passage and lungs, hence preventing COVID-19 establishment.
If you are seeking to treat the virus as a means of preventing COVID-19 disease progression, there is a timing problem. Too soon and you haven’t been able to detect the infection, too late and the disease is effectively over as far as the virus is concerned.
A recent report from Yale University has shown that analysing primary sewage sludge predicts an outbreak (based on SARS-CoV-2 testing) up to 1 week before it happens. This could provide authorities time to focus on specific areas to mitigate the development of infections, perhaps by combining sewage testing with use of early treatments (involving preventatives and drugs that hinder establishment of infection, like SPL7013).
COVID-19 virus (SARS-CoV-2) detected in primary sewage sludge several days before new COVID-19 cases in NE US metropolitan area. Source: Peccia et al Yale University; medRxiv May 22, 2020, preprint (not yet peer-reviewed) Republished as a Tweet by Brennan Spiegel.
New antiviral drugs
Other big drug companies have accelerated programs on antivirals in the hope of providing a treatment for SARS-Cov-2 virus which causes COVID-19.
Pfizer (PFE) has an as yet unnamed candidate and it is fast tracking scale up of manufacture even before the drug has been tested in clinical trials, a very unusual step which requires deep pockets, but one which reflects the urgency of finding a cure. There are rumours that the Pfizer drug might target the SARS-CoV-2 virus at an early stage of the COVID-19 disease, so it could have a different use than remdesivir.
Merck has announced a partnership with biotech company Ridgeback Bio to advance development of EIDD-2801 which is orally available (pill rather than injected) ribonucleoside which blocks viral replication. Animal studies on two other coronaviruses (SARS-CoV-1 and MERS) indicate treatment is effective in lowering virus numbers in the lungs and also improving lung function. Merck CEO Kenneth Frazier made two points about a pill form of EIDD-2801 versus remdesivir which is injected. Firstly pills are easier to scale to treat a lot of people. Secondly, a pill can be given in less structured situations than an injection, and so there is potential for giving the pill at an earlier stage of the COVID-19 disease.
Expect to hear more about big Pharma establishing partnerships to fast track potential COVID-19 treatments.
Immune material from the blood of patients who have recovered from COVID-19
This is an expensive and desperation measure for treating COVID-19 based on the assumption that people who have recovered will have some immunity to virus infection and this immunity might be able to be passed on to patients suffering the disease. In a spirit of cooperation in the COVID emergency, a number of global players have set up the CoVIg-19 Plasma Alliance to rapidly advance this stop-gap approach. Companies involved in setting up the alliance include Biotest, BPL, CSL-Behring (OTCQX:CMXHF), LFB, Octapharma and Takeda (TAK). A number of other companies and Foundations (including the Bill & Melinda Gates Foundation) have joined the alliance.
Another approach to a temporary solution, pending development of a vaccine, is being developed by Sorrento Therapeutics (SRNE).This San Diego-Suzhou company is working with the Mount Sinai Health System in New York, to develop an anti-SARS-CoV-2 drug combination based on 3 antibodies that bind to a specific part of the protein which makes up the spikes on the surface of the virus. It is suggested that a single treatment may last for 2 months, although the evidence supporting this claim seems limited. It will be a while before its usefulness is clear as a Phase 1 trial (to determine dose level and safety) will not occur until Q3. The science on choice of the appropriate monoclonal antibodies seems solid, but there are always surprises. An old example from development of an influenza vaccine led to a vaccine that, when tested in pigs, protected from 1 strain of flu but made the pigs more sensitive to infection by another strain. Vaccine development is not straightforward and nor will development of stop-gap drugs based on antibody treatments be any simpler. Investors interested in Sorrento’s approach should be aware that it is at a very early stage and there is no guarantee of a successful outcome. John Reilly has recently written in more detail about Sorrento’s overall business and put the COVID-related developments into perspective. Note that hyped up reports that Sorrento has a cure for COVID-19 are well, rubbish.
The question about Sorrento’s approach is whether it will be more effective than other drugs like Starpharma’s SPL7013 which do a similar thing (blocking viral attachment to target cells). Sorrento’s approach involves injecting antibodies, while Starpharma is more focused on delivery into the nasal passages, lungs and eyes (i.e., initial infection foci for the virus).
Sorrento’s products are monoclonal antibody-based and these are complex and expensive drugs to manufacture and scale up.
Immune system based treatments
When things get tough with COVID-19, a lot of the trouble is with the patient’s own immune system, and the trouble that can be caused when the army (immune system) won’t go back to barracks. Hence there is a big focus on treatments that suppress the immune system, although some researchers caution about this approach as it has the potential also to allow the virus to get out of control. This will be a fine balance and won’t be solved quickly.
Companies developing products for inflammatory diseases are focusing on acute COVID-19 ARDS (Acute Respiratory Distress Syndrome) which is the end stage lethal outcome of “cytokine storm.”
There are a lot of companies and trials starting to investigate this approach, primarily because a lot has been invested in developing monoclonal antibodies to modulate the immune system. In some respects, this is a case of the basic science looking for a commercial application. I think it is too early to make sense of this, but investors wanting to follow up can check out many clinical trials involving this kind of approach. Interleukin 6 (IL-6) is a particular target of interest and Roche (OTCQX:RHHBY) has recently received FDA Emergency Use Authorisation for its Interleukin-6 test for identifying patients at high risk of severe COVID-19 progression. Clinical trials.gov has 50 clinical trials involving use of Roche anti-interleukin-6 receptor monoclonal antibody drug tocilizumab (an immunosuppressive drug used for rheumatoid arthritis) for treating severe COVID-19, for those wishing to follow up on immune system drug treatments.
Another company investigating COVID-ARDS is Mesoblast (MESO) which has a mesenchymal stem cell product, remestemcel-L, which is being trialed for end stage COVID-19, where the fatality rate is extremely high. Remestemcel-L is a very high cost live cell product which, even if it works, would have a limited market because of the very high cost.
Heparin is a widely used anticoagulant and some have suggested that it might have a role in severe COVID treatment which involves small blood clots in the lungs, although an initial study suggests that COVID-19 sufferers might be resistant to heparin’s blood-thinning effect. On the other hand, heparin is a negatively charged complex sugar which might bind to SARS-CoV-2 and prevent infection. Yet another angle on heparin is that sulfated glycans are known to bind key proteins involved with immune system overreaction and there is some evidence that heparin might mitigate the cytokine storm that is major problem in severe COVID-19. So heparin could have multiple possible roles in formulating treatments. This discussion of heparin shows how complex it is to come to grips with treating a disease whose mode of action is still not clear.
Whether heparin or other sulphated glycans might end up having a role in treating COVID-19 remains to be established.
There has been a lot of ignorant chatter about hydroxyquinoline, including the assertion that it can’t hurt, so why not take it? The truth in relation to treating COVID-19 is that hydroxyquinoline might increase your risk of dying. This seems like a good basis for the WHO suspending a major trial of this drug. Combining hydroxychloroquine (or chloroquine) with antibiotics seems to have an even worse prognosis in treating COVID-19.
Where does this leave the candidate treatments?
Above I’ve tried to give a sense of the kinds of therapies that are being investigated for treating COVID-19. It is a moving feast as the long-term impact of suffering SARS-CoV-2 infection (COVID-19) is yet to be fully realised. For most people it looks like a quick recovery and back to normal, but there also seem to be a small percentage of people for whom the effects are long term and new therapies will be needed to address their illness.
COVID-19 is that rare once in a century event that proves that, for all of our sophistication, humanity is still at risk from new pathogens. Given the urgency to recover from economic shutdown, the chequebooks are open for researchers with good ideas. It is that rare time for researchers where even very risky, but plausible proposals are being fast-tracked. And as a result, one can expect that there will be surprises (hopefully good ones) on the way for effective treatments for COVID-19, which may or may not become less critical if/when an effective vaccine is developed.
Biotech investing is risky at the best of times. Chasing a major uplift by investing in a company that becomes prominent with a COVID-19 treatment is even trickier. Some investors like to have a small part of their portfolio with a high risk/high return profile. I suggest that for COVID-19 it is still very hard to see what a successful treatment might look like, although two antivirals already tried in humans - Gilead’s remdesivir and Starpharma’s SPL7013 - might have roles, and Merck’s partnership with Ridgeback Bio on EIDD-2801 is worth keeping an eye on. The drugs need not only to work, but they must be delivered appropriately and be given time to work.
Gilead has a strong track record of success with antivirals and their HepC cocktail cures this disease. The difference between HepC and SARS-CoV-2 is that HepC is a slow and unrelenting disease, which means there is time for a treatment to take effect. COVID-19 in its lethal form is a much more acute disease and the timing for treatment involves a narrow window. It seems unlikely that remdesivir will become the cure for COVID-19, but it may have a role in treating patients without other options, even if it just reduces time spent in acute care. Only with further clinical trials will a treatment path become clear and the scale of opportunity for Gilead investors be understood. It looks like some success is already baked into the current share price, so any adverse results might impact the Gilead share price negatively. However, remdesivir might be as good as it gets (and that might not be very good) to treat the later stages of the disease.
Starpharma’s SPL7013 has promise as an enhanced preventative as well as attacking the early stages of SARS-CoV-2 infection. Getting a handle on who to treat (sewage analysis may help regionalise where to target) as well as achieving effective delivery are key issues for the success of SPL7013.
I’m suspicious of immune-suppressive treatments like those based on Interleukin-6 as they might end up creating as many problems as they solve.
On a final note, this discussion about treatment options for COVID-19 suggests that no miracle cure is going to happen any time soon. Also, notwithstanding political promises of a vaccine before the end of the year, the experts are all being much more circumspect. Taken together, limited prospects for a cure and a probable delay in developing a vaccine (if indeed it becomes possible to develop one) mean that unless governments want to try out what a major outbreak looks like (the US currently), social distancing and the negative impacts on economic activity might be with us for some time. It is worth factoring this into your deliberations about getting back into the market.
I am not a financial advisor, but I have a background in biotech both from a technical and also investor perspective. If my commentary helps you and your financial advisor to think about whether you want to invest in this area, please consider following me. I am a long time investor in Starpharma, so please take note of that in discussion about SPL7013.
This article was written by
Analyst’s Disclosure: I am/we are long SPHRY. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
Seeking Alpha's Disclosure: Past performance is no guarantee of future results. No recommendation or advice is being given as to whether any investment is suitable for a particular investor. Any views or opinions expressed above may not reflect those of Seeking Alpha as a whole. Seeking Alpha is not a licensed securities dealer, broker or US investment adviser or investment bank. Our analysts are third party authors that include both professional investors and individual investors who may not be licensed or certified by any institute or regulatory body.