Covid-19 Update (Part 2 of 3): What Have we Learnt in the Last Six Weeks?

We wrote in early April to explain the types and functions of therapeutic and vaccines and tests, their pros and cons, attempting to tackle Covid-19. We continue to track global developments on these in real time for your reference here. Six weeks later, we are writing an update on what we have learnt more broadly scientifically in the intervening period and how our understanding is progressing.

This is the second in a three-part blog series:

I. Disease pathogenesis and risk factors
II. Therapeutic and vaccine progress
III. Viral mutation rate emerging strains and serology testing

Headline Findings

1. Moderna, which was the first to enter the clinic with an mRNA based vaccine, has reported promising early data from its Phase I trial, but in results from a very small number of individuals so far. The vaccine was well tolerated and caused patients to develop an antibody response to the virus at comparable or higher levels to that seen in the plasma from recovered patients. The antibodies from 8 immunised individuals could neutralise the live virus in laboratory assays. The company hopes to start a Phase III trial in July.

2. CanSino Biologics, who entered the clinic in March with its recombinant adenovirus vaccine candidate, has published the results of a Phase I trial. The vaccine stimulated neutralising antibodies and a T cell response in patients however it is too early to know whether this confers protection. The company is currently undertaking Phase II trials.

3. The first anti-viral therapeutic, Remdesivir, has received FDA emergency approval. An early Phase II study using “triple combination” therapy of lopinavir-ritonavir (viral protease inhibitor), ribavirin (nucleoside analogue) and interferon beta-1b (a cytokine to stimulate the immune response) has shown promising early data that warrants further investigation at Phase III. Despite early endorsement there has been no definitive data on the efficacy of chloroquine and hydroxychloroquine.

4. The first neutralising antibody therapies plan to enter the clinic in June and large-scale convalescent plasma trials are underway in the UK and the US.

5. Innovative therapeutic approaches classes such as mesenchymal stem cell therapy to treat acute respiratory distress and recombinant ACEC2 proteins are being trialled.

Progress on Therapeutics and Vaccines

The following section describes updates in the therapeutic and vaccine space since our last post in early April. For a summary and background of therapeutic strategies against Covid-19 please see our previous post here.

Anti-Viral Drugs

On 29th April the first emergency use approval was granted by the Food and Drug Administration (“FDA”) for Remdesivir – an antiviral drug developed by Gilead Sciences to treat Ebola. Early reports of trial data were confounding, with a study in China on 158 patients not showing statistical significant differences between the control and treatment groups [1]. Analysts pointed out the sample size was small due to challenges in recruiting patients as the epidemic waned in China, and the drug was delivered up to 12 days after symptom onset which is late in the disease development. An independent Phase II trial led by the National Institute of Allergy and Infectious Diseases (“NIAID”) concluded Remdesivir resulted in a 31% faster recovery time compared the placebo (11 days vs 15 days) [2], which prompted FDA engagement. Figure 1 shows the results published in the New England Journal of Medicine and shows an incremental but significant increase in survival of patients treated with Remdesivir compared to placebo[3].

Figure 1: Comparison of Covid-19 patients treated with Placebo vs. Remdesivir. Source: Beigel et al., NEJM May 2020.

Encouragingly, a Phase II trial of “triple combination” therapy of lopinavir-ritonavir (viral protease inhibitor), ribavirin (nucleoside analogue) and interferon beta-1b (a cytokine to stimulate the immune response) on 86 treated patients in Hong Kong showed the median time to a negative test was reduced from 12 days to 7 days compared to the placebo group and warrants evaluation at Phase III (Figure 2)[4].

Figure 2: SARS-CoV-2 viral load in the placebo group (blue line) vs patients treated with lopinavir-ritonavir, ribavirin and interferon beta-1b. Source: Hung et al., Lancet 2020.

Chloroquine and Hydroxychloroquine received significant early endorsement, buoyed by initial positive reports and ready availability. Unfortunately, a recently published New England Journal of Medicine paper that investigated 1446 patients in New York indicated no significant association between hydroxychloroquine use and clinical outcome[5]. A study published in the Lancet that evaluated 14,888 treated patients compared to 81,144 controls could not confirm a benefit and found treatment was associated with increased risk of in hospital mortality and de novo ventricular arrhythmia[6]. Cardiac side effects following treatment with hydroxychloroquine and chloroquine have been reported in other studies[7]. On Monday, the 25th May the WHO confirmed they would be temporarily pausing trials involving hydroxychloroquine[8].

Neutralising Antibodies & Convalescent Plasma

Many biotech companies and pharmaceutical companies have continued to develop antibody products to neutralise the virus, by targeting the viral Spike protein. Companies are favouring ‘cocktail-based’ approaches to avoid viral evasion through mutagenesis, and some are engineering the antibodies to reduce the risk of Antibody Dependent Enhancement (“ADE”), a phenomenon we wrote about in a previous blog. Regeneron anticipates its antibody cocktail will enter the clinic in June, AstraZeneca are selecting a candidate and plan to enter the clinic between July and September[9], Eli Lilly has formed partnership with AbCellera and Junshi Biosciences and Sorrento has formed a partnership with Mount Sinai in New York, to name a few of the ongoing efforts.

Convalescent plasma received emergency use FDA approval in late March and Phase III trials are due to begin in May. In late April, the UK Blood and Transplant service launched a widespread programme to collect convalescent plasma as part of a UK based trial called “REMAP-CAP,” which once scaled up will be able to treat 5,000 patients per week.

Other Therapies

Over the last month more companies are pursuing cell therapies or innovative other therapeutic approaches. Mesoblast reported that its allogenic mesenchymal stem cell product resulted in 83% survival of severe patients in a small trial in New York[10] and is now preparing for a larger scale trial. Healios and VCanBio has also announced cell therapy based trials for ARDS patients[11],[12]. Apeiron Biologics is undertaking Phase II trials for its drug APN01 which is recombinant ACE2 protein, designed to act as a decoy to ACE2 receptors[13].

Vaccines

There are multiple ways to develop a vaccine, with the main approaches being:

• Viral vaccines that expose the immune system to a weakened or inactivated version of the virus e.g. the measles or Polio vaccine.
• Viral vector vaccines that involve engineering an existing viral vector to express SARS-Cov-2 proteins. These can either be replicating, e.g. the new Ebola vaccine, or have certain genes inactivated to ensure they do not replicate in cells. The latter is commonly used in gene therapy
• Protein based vaccines where protein components of the SARS-CoV-2 virus are injected directly into the body, often with an adjuvant or as an artificially created viral like particle (“VLP”) e.g. HPV vaccine
• Nucleic acid vaccines where DNA or RNA is injected directly and taken up by cells which then express viral proteins to stimulate an immune response. These can be designed rapidly but so far, no nucleic acid vaccines have been licenced

Vaccine trials have been pushing ahead with Phase I trials underway or complete for at least 7 candidates as of the 18th May 2020[14]:

• Moderna, which developed an mRNA vaccine was the first to begin Phase I trials in on 16th March 2020. On the 18th May the company reported interim data from the Phase I trial. The vaccine was well tolerated and participants developed an antibody response to the virus at comparable or higher levels to that seen in the plasma from recovered patients. The antibodies from 8 immunised individuals were tested and found to neutralise the live virus in laboratory assays. Furthermore, Moderna indicated the vaccine successfully prevented viral replication in the lungs of mice. The company plans to start a Phase III trial in July. [15]
• CanSino Bio has completed its Phase I trial which launched in March 2020 and is undertaking a Phase II for its Adenovirus based vaccine. Data from the Phase I trial was published in the Lancet. Neutralising antibodies and T cell responses were detected in patients who received the vaccine, but it is too early to conclude whether it provided protection from the disease[16]
• SinoVac has launched a Phase I trial of its inactivated viral vaccine in mid April 2020. A pre-print study of a challenge experiment in rhesus macaque monkeys indicates the vaccine confers protection in non-human primates. Encouragingly the authors found no evidence of ADE.[17]
• Oxford University Jenner Institute and Vaccitech started a Phase I / II adaptive trial on 23rd April 2020 using a proprietary Chimpanzee Adenovirus vector vaccine. The group previously conducted Phase I trials on a Middle East Respiratory Syndrome (“MERS”) vaccine using the same vector with no adverse effects and reported reduced viral load and pneumonia in non-human primates[18], [19]. As of the 22nd May 2020 it was reported enrolment of the Phase II / III trial had begun[20]. The team has signed a partnership with AstraZeneca to support mass scale manufacture and distribution of its vaccine if approved[21].
  Pfizer and BioNTech dosed their first participants in Germany on the 23rd April 2020 with their mRNA based vaccine and a week later started testing the US
• Shenzen Geno Immune Medical Institute (cells infected with lentivirus), Inovio (DNA vaccine), Wuhan Institute of Biological Sciences (inactivated viral vaccine) have also all entered clinical trials
  Merck announced in late May it is investigating two vaccine candidates – one from the acquisition of Themis using a measles vector and the second through a partnership with IAVI using recombinant vesicular stomatitis virus (rVSV) that was the basis for Merck’s Ebola vaccine which received FDA approval. Novartis has agreed to manufacture a vaccine being developed by the Massachusetts Eye and Ear Hospital and the University of Pennsylvania[22].

After demonstrating safety at Phase I, the vaccines must demonstrate efficacy or evidence of providing protection against SARS-CoV-2. Trials are set up so that one group of trial patients receives the vaccines and the other group receives a placebo. The outcome is then measured as the number of patients that are infected with SARS-CoV-2 over the coming months. There is a risk as the current wave subsides and levels of the virus reduce in the community that trials may need to run for longer, with larger patient groups to show significant efficacy. Companies also need to be flexible and consider rapidly setting up trials in different countries as viral waves take off. Professor Sarah Gilbert, who is leading the team behind the Oxford University Jenner Institute / Vaccitech vaccine said they plan to have enough data for regulatory approval by September. GSK who are partnering with Sanofi has said it believes Q4 2021 is realistic.

We are tracking therapeutic and vaccine updates, along with other positive developments here.

The third part of this three-part blog series will be coming shortly. Watch this space!

Definitions

References

[1] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext
[2] https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19
[3] https://www.nejm.org/doi/full/10.1056/NEJMoa2007764?query=recirc_curatedRelated_article
[4] https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31042-4.pdf
[5] https://www.nejm.org/doi/full/10.1056/NEJMoa2012410
[6] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext
[7] https://www.sciencemag.org/news/2020/04/antimalarials-widely-used-against-covid-19-heighten-risk-cardiac-arrest-how-can-doctors
[8] https://www.npr.org/sections/coronavirus-live-updates/2020/05/25/861913688/who-halts-hydroxychloroquine-trial-over-safety-concerns?t=1590750077682
[9] https://www.ft.com/content/d31b9ce3-578f-41c3-853f-a0e7827ec79e
[10] https://www.forbes.com/sites/alexknapp/2020/05/02/large-scale-clinical-trials-of-mesoblasts-stem-cell-treatment-for-covid-19-coronavirus-set-to-begin-soon/#42447ec74086
[11] https://www.prnewswire.com/news-releases/covid-19-ards-patients-added-to-healios-one-bridge-study-301039906.html
[12] https://clinicaltrials.gov/ct2/show/NCT04288102
[13] https://www.clinicaltrialsarena.com/news/apeiron-biologics-phaseii-covid-19/
[14] https://blogs.sciencemag.org/pipeline/archives/2020/04/23/a-close-look-at-the-frontrunning-coronavirus-vaccines-as-of-april-23
[15] https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-interim-phase-1-data-its-mrna-vaccine
[16] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31208-3/fulltext
[17] https://science.sciencemag.org/content/early/2020/05/06/science.abc1932, https://medicalxpress.com/news/2020-04-chinese-biotech-firm-coronavirus-vaccine.html
[18] https://www.nytimes.com/2020/04/27/world/europe/coronavirus-vaccine-update-oxford.html
[19] https://www.biorxiv.org/content/10.1101/2020.05.13.093195v1.full.pdf
[20] https://www.fiercebiotech.com/biotech/astrazeneca-s-covid-19-vaccine-enters-phase-2-3-clinical-trial?mkt_tok=eyJpIjoiTVRrd1lUVm1NelkyWVRkaCIsInQiOiJabTlOQnM3RlgxVENcL1JRXC9tbUdHMHJVZDhPcGpqWDBqWTQrTGttU3RtMkpkaDZZeXZ0NzVzXC9PKzhLczZFaUx0Y2lqblZBM1wvZlZtOUhBeEpZQkZUdThJU2JYK0piM3dadmdnS3FcL2RORkN1R1JIVllcL1hUbW1LZk8xXC9naER5RFZUWnIyTlNQS1NnQUZXT2xrUXROc2hnPT0ifQ%3D%3D&mrkid=114702534
[21] https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-and-oxford-university-announce-landmark-agreement-for-covid-19-vaccine.html
[22] https://www.marketwatch.com/story/novartis-to-make-experimental-coronavirus-vaccine-2020-05-28

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