In-progress treatments for COVID-19: an attempt to simplify things

Manos Mastorakis|27^th March 2020

Let's jump straight into the main topic of discussion without repeating any of the news you've already heard on promising COVID-19 treatments. This is not intended to add any extra 'noise', but to help us make sense of what's happening in terms of treatments to tackle COVID-19. Hopefully, by the end of this article most of you will feel there's a lot of promise in tackling the pandemic using pharmaceuticals.

Several questions arise when reading articles about the next big thing being investigated against COVID-19:

What is the rationale for this treatment? When will we know whether it works or not? When can we expect this treatment to become available? How promising is this treatment?

You may have read about a large number of drugs (ca. 60) currently or soon to be 'in-the-works' to tackle COVID-19. Some of the most comprehensive articles summarising these can be found here and to keep yourself continuously updated, I recommend this website. Here, we are taking a look at drugs that are already in registered clinical trials, which can be found in the largest clinical trials database, 'clinicaltrials.gov'.

Just a week ago, a search of 'COVID' in this database, yielded 50 clinical trials, whereas now the number of trials has jumped to 110. These trials are either observational or interventional. Examples of observational trials include a trial using AI to differentiate between influenza and COVID-19 patients based on chest X-rays, a trial comparing medical masks to N95 masks, and even a trial exploring the impact of COVID-19 on population's stress. Whilst there are a lot of interesting and useful trials like the above, let's instead focus on the interventional trials testing the efficacy and safety of different drugs.

Of the 95 trials, about half of these are interventional and after a close look, these trials could be largely broken into 3 categories: (1) prevention, (2) antiviral treatment and (3) disease/symptom management.

1. Prevention -

Soon after China made the COVID-19 genome sequence available to the public, on January 10th, researchers were able to design vaccines against the new virus. Although there are more than 10 vaccine candidates expected to initiate trials soon, three are currently already in trials, including Moderna's mRNA vaccine, which dosed its first healthy volunteer last week.

• The bottom line is that a vaccine with the aim of building herd immunity to prevent future infections or reduce the severity of infections may take time (at least 1-1.5 years), but earlier roll-out in the context of trials or as part of Emergency Use for healthcare workers can be expected in the case of Moderna's candidate vaccine

2. Antiviral Treatment -

Antiviral drugs administered shortly after symptom onset can reduce infectiousness by reducing viral shedding in the respiratory secretions of patients (viral load in sputum is known to peak at around 5–6 days after symptom onset and lasts up to 14 days), and targeted prophylactic treatment of contacts could reduce their risk of becoming infected. The table below contains a non-exhaustive list of some of the approaches explored currently in clinical trials:

• The bottom line is that multiple antiviral treatments are being investigated and at least one could become available soon (2020 is not unlikely), forming the first pharmaceutical weapon against COVID-19. Favipiravir (n=35) showed a significantly faster clearance of the virus compared to the control group of Lopinavir / Ritonavir (n=45), respectively. Similarly, hydroxychloroquine in combination with azithromycin also showed a benefit in a small, open-label trial, though due to the small size of these trials, further studies are required.

3. Disease Management -

Part of how COVID-19 is able to cause a severe infection or even kill is that the virus overstimulates the immune system's inflammatory response. This is why approaches to modulate the immune system appear to have a place in the treatment of COVID-19. Below is a list of possible treatments, currently in trials. Many of these are marketed drugs, which means the safety profile of these drugs is well known, but we still need to see a benefit in COVID19 patients.

• The bottom line is that disease management approaches involving pharmaceutical interventions will be crucial mostly in the management of the disease in critically ill patients helping alleviate the pressure in ICUs and reducing mortality rates. Roche's RoActemra/Actemra (tocilizumab), originally prescribed for arthritis, has now been (rapidly) approved in China for patients with lung complications.

Use what, when?

Whilst it is still unclear how antiviral treatments and disease/symptom management approaches may best work, either alone or as combinations, research to understand this is currently ongoing. A group of researchers released a manuscript on a working hypothesis, suggesting which treatments could work at the different stages of the infection (figure below). The researchers propose a typical COVID-19 infection into three stages: Stage 1 (early infection), Stage 2 (pulmonary phase) and Stage 3 (hyper-inflammatory phase), each with separate clinical symptoms and signs (however, it should be noted that the clinical profile of COVID-19 is likely a lot more complicated than that, with many different presentations already observed in practice). Whilst antiviral treatments are suggested to be useful throughout the course of infection (to reduce contagiousness), there is a suggested timing in terms of disease/symptom management treatments, specifically, the "use of anti-inflammatory therapy applied too early may not be necessary and could even provoke viral replication such as in the case of corticosteroids".

The good news -

• Normally, trials take too long to complete. However, more than 50% of the 55 interventional trials are expected to read out this year, which could shed light on what we can expect for most of these treatments, allowing us to double down our resources on the promising ones. Also, although most of these trials are still exploratory at this stage and not sponsored by a pharmaceutical company, they could lead to further studies with the potential to gain marketing authorization further down the line if the data is promising
• Preliminary trials with hydroxychloroquine are promising. Hopefully, the results will be replicated in the larger scale Ph3 trials by Sanofi (PHYDRA enrolling healthcare workers; HYDRA enrolling severely infected patients) expected to complete in Q4 2020. Meanwhile, companies such as Novartis and others are already ramping up production of potentially promising treatments such as hydroxychloroquine to be in a position to provide large amounts of these when necessary
• Many of these trials involve drugs that have been approved in other indications. What this means is that some of the ongoing trials could (on their own) form the basis for a filing to the regulatory authorities for speedy approval. It is possible that the FDA, EMA and other regulatory authorities around the world will work closely together to provide unprecedented speedy approvals for any drug that has strong evidence of its value to patients. Thus, a treatment (or more than one) could potentially be available this year, but it remains to be seen which one(s) will be successful, how, when and where
• Whilst the first volunteer for a Moderna's vaccine, mRNA-1273 was dosed last week, results from this Ph1 trial are expected in a year and a commercial vaccine roll-out would take not before the next 12-18 months. However, the company has announced its intention to make the vaccine available to healthcare workers as part of an Emergency Use Authorization by Fall 2020
• Although a vaccine by the US/EU may need some time to become available, it is quite possible that a COVID-19 vaccine may first come from China as Chinese trials appear to be more advanced at this stage
• We are learning about the disease extremely fast! More 1,000+ publications mention 'COVID-19' after a quick search on PubMed, all within 2020!

Notes

• Any opinions or projections are based on my own analysis/experience unless a source is listed
• The list of trials analyzed is not exhaustive; more trials are expected to be running already and more trials are expected to initiate shortly
• I am not a medical doctor (so excuse any errors in the use of medical terminology above); simply using my scientific background, common sense, passion for drug development and expertise in the Pharma industry to analyse and simplify data
• I welcome any comments, corrections, updates and suggested reading