Over 200 COVID-19 trials nearing completion should provide a busy summer of data readouts

A breakdown of COVID-19 trials by therapeutic mechanism, size, phase, comparator

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Less than three months after COVID-19 reached pandemic status, and five since the virus was sequenced, drug development has reached the point where hundreds of clinical trials will soon read out. With a pile of repurposed agents, a handful of novel vaccines and the first SARS-CoV-2 neutralizing mAb on deck, the winnowing of mechanisms and modalities may soon begin.

A look at the compounds and therapeutic mechanisms in these studies hints at the biological questions that could be start to be answered in the near term, while an assessment of trial sizes, comparators and phases can help separate impending signal from noise.

All these parameters are searchable in BioCentury’s COVID-19 Clinical Trial Dashboard, an open-access tool that currently includes COVID-19 trials in ClinicalTrials.gov and the Chinese database www.chictr.org.cn, with completion dates before Sept. 1, as well as a growing number of studies for which the company has projected an interim readout between now and then. The dashboard is updated weekly.


Figure: COVID-19 Clinical Trial Dashboard

At least 232 clinical trials of therapeutics and vaccines for COVID-19 are slated to end or yield interim results between June 1 and Aug. 31, meaning drug developers and health professionals should enter the fall with a clearer picture of when and which countermeasure strategies hold promise.


Figure: Clinical trial end dates

 
Novel agents

Novel vaccines and therapies tailored to SARS-CoV-2 have started to join repurposed agents in the clinic.

The two front-runner companies with vaccines, Moderna Inc. (NASDAQ:MRNA) and CanSino Biologics Inc. (HKEX6185), have already released early results demonstrating their respective vaccines induced virus neutralizing antibodies in healthy volunteers. Preliminary data could be available from as many as eight more vaccines by the end of summer (see “Comparing Timelines of COVID-19 Vaccines”).

The most advanced neutralizing mAb against the SARS-CoV-2 spike protein, Ly-CoV555 from Eli Lilly and Co. (NYSE:LLY) and AbCellera Biologics Inc., started clinical testing this week, with the first data expected by the end of the month (see “Phase I Start Marks Two Firsts”).

Virus neutralizing mAbs stand out for their potential in both prophylactic and treatment settings. At least three other companies plan to bring virus neutralizing mAbs into the clinic this summer: Lilly, which is partnered with Shanghai Junshi Biosciences Co. Ltd. (HKEX:1877); Vir Biotechnology Inc. (NASDAQ:VIR) and partner GlaxoSmithKline plc (LSE:GSK; NYSE:GSK); and Regeneron Pharmaceuticals Inc. (NASDAQ:REGN).


Figure: Compound overlap

 
Repurposed agents

Most of the trials with near-term end dates are testing repurposed agents.

Hydroxychloroquine is the standout by far, accounting for at least 61 trials with the drug being tested as monotherapy or part of a combination.

Evidence is already mounting that it lacks efficacy in COVID-19; it’s reasonable to assume that by the end of the summer there will be enough data to either rescind the Emergency Use Authorization, as France has already done, or advance it to full approval. (see “Failing in Master Protocol” and “Fails Another Trial”).

Other agents in the top ten that have provided little benefit in trials to date include the antiviral combination lopinavir/ritonavir, which did not speed time to clinical improvement in a 199-patient study in China, and favipiravir, which did not improve clinical recovery rate at day 7 compared with the influenza therapy Arbidol umifenovir in a 240-patient trial in China.

The one non-repurposed therapy in the top ten is mesenchymal stem cell (MSC) treatment; the cells are being tested in a dozen studies slated to end this summer. MSCs are chiefly being employed for their anti-inflammatory properties to prevent or correct the excess inflammation thought to contribute to acute respiratory distress syndrome (ARDS) in severe COVID-19 patients.

Immunosuppressants, most of which are repurposed, are leading the therapeutic classes, beating out antiparasitics such as hydroxychloroquine and ivermectin, and antivirals.


Figure: Class breakdown

 

IL-6 inhibition, via agents such as tocilizumab, is a leading approach for reining in inflammation. Tocilizumab is in 11 trials with primary completion dates this summer.

Early results from IL-1 inhibitors have been mixed. In late April, Regeneron’s Kevzara sarilumab showed no notable benefit in clinical outcomes in severe COVID-19 patients, and an IDMC recommended that only “critical” patients continue enrollment in an ongoing Phase III study.

By contrast, Actemra tocilizumab from the Genentech Inc. unit of Roche (SIX:ROG; OTCQX:RHHBY) led to a significant reduction on the composite primary endpoint of need for ventilation or death at day 14 vs. placebo in the Phase II CORIMUNO-TOCI trial (see “Anti-IL-6 Data in COVID-19”).


Figure: Trial sizes skew small

 

Trial harmonization needed

While Phase I and Phase I/II trials represent less than 15% of upcoming readouts, the sizes of trials across all stages skew small, with about 46% of trials enrolling under 100 patients.

Furthermore, only 42% of the trials are placebo-controlled and half have no blinding, suggesting their results will be difficult to interpret.


Figure: Trial designs

 

The high proportion of small, unblinded trials underscores the need for trial coordination and harmonization through master protocols. At least nine master protocols have been designed for COVID-19 therapeutics and one for vaccines.

The U.K. has been leading the way in terms of funneling patients, therapies and trial sites into master protocol trials and setting them up for success, and has launched a master protocol designed to test combination therapies (see “U.K. Sets Bar”; “REMAP-CAP Master Protocol”).

The timeline below shows 180 of the trials with completion dates or readout dates by Aug. 31; it excludes Phase I studies and convalescent plasma trials.


Figure: Timeline of COVID-19 trials with end dates by Aug. 31

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