24 June 2021 UK-CTAP: record of decisions

UK-CTAP meeting, 24 June 2021.

Held via video teleconference.

Some information has been redacted for the reasons listed in ‘details’ for UK COVID-19 Therapeutics Advisory Panel: records of decisions.

1. Welcome and introductions

Chair welcomed the group, outlined the role and terms of reference for the group, no objections or observations were made.

The record of decisions from the UK-CTAP meetings held on 25 May 2021 and 10 June 2021 were agreed without amendment.

2. Conflicts of interest

Chair asked the subgroup members to raise any conflicts of interest.

Declarations

Frederick Hayden [redacted, General Data Protection Regulation]

Action

Recusal from voting on favipiravir intravenous (IV).

No other conflicts were recorded.

3. Subgroup advice

3.1 Early phase subgroup

Favipiravir IV

A member of the subgroup presented favipiravir IV noting the complexity of pharmacokinetic (PK) modelling of the compound based on the data from non-human primates and oral formulation data from healthy and diseased humans.

The group noted that there are different PK models of favipiravir, some of which suggests that the IV formulation could be beneficial.

In order to better understand the PK, (including intracellular and plasma concentrations) and the effective dosage of IV formulation, AGILE is considered to be the appropriate trial to study this drug.

The group noted that AGILE is planning to set up intracellular favipiravir ribofuranosyl-5′-triphosphate (RTP) assays in collaboration with [redacted for commercial sensitivity].

It is a broad-spectrum agent so resolving PK issues is important for COVID-19 as well as other viral diseases.

It was suggested that once the initial studies are complete, it will be beneficial to look at preclinical modelling of drug combinations amid potentially limited antiviral efficacy as single agent.

The group noted that after completion of phase 1 AGILE, favipiravir IV could have the potential to be included in phase 2b of RECOVERY trial instead of phase 2a of AGILE trial. This could be revisited after AGILE phase 1 readout.

Recommendation

The panel agreed on the advice of the sub-group and recommended favipiravir IV for study in the AGILE trial.

[Redacted for commercial sensitivity]

The subgroup is looking for a partner drug for [redacted for commercial sensitivity] which is a dihydroorotate dehydrogenase (DHODH) inhibitor with a slow onset of action and potential for redundancies in the pyrimidine pathway. Hence a combination with a suitable drug is suggested.

The subgroup and UK-CTAP secretariat reached out to Merck to initiate combination studies with molnupiravir but the company showed no interest.

The combination of [redacted for commercial sensitivity] with remdesivir and favipiravir would be of interest.

Recommendation

Subgroup to identify a suitable partner drug for [redacted for commercial sensitivity].

Subgroup to liaise with Queens University Belfast to perform preclinical studies on potential drug combinations with [redacted for commercial sensitivity].

The previous recommendation from the 25 May UK-CTAP record of decisions for [redacted for commercial sensitivity] in a human challenge trial is only applicable once a suitable combination is identified.

3.2 Antiviral subgroup

[Redacted for commercial sensitivity]

The subgroup chair raised significant concern of the drug’s safety profile. Side effects include severe gastrointestinal effects and the potential for QT prolongation.

The group acknowledged the preliminary clinical outcomes from two phase 2 trials and noted that the differences in the primary end point of both studies were not significant.

Pending full analysis of efficacy and safety data from [redacted for commercial sensitivity], subgroup could advise it for the phase 2 or phase 3 studies.

Recommendation

[Redacted for commercial sensitivity] is not recommended for the national trial platforms. The diligence team will monitor progress and outcomes for the international trials that are ongoing.

ACE2 inhibitor

The subgroup chair introduced [redacted for commercial sensitivity] which is a recombinant compound and is at an early stage of development. Apeiron has completed phase 2 studies.

[Comment redacted for commercial sensitivity]

The group noted that more data is needed to analyse the efficacy and safety profile of the compound and advised that it is not ready for phase 3.

The group is not interested in combination treatment.

More safety, PK and antiviral efficacy data are needed for [redacted for commercial sensitivity].

Recommendation

[Redacted for commercial sensitivity] is not currently prioritised for trial.

Antihistamine

It is suggested to be beneficial in the long COVID setting. It was an open study and there is uncertainty around the efficacy.

Recommendation

The antihistamines hydroxyzine, [redacted for commercial sensitivity], azelastine, cyproheptadine were not currently prioritised for any trial platforms.

Pipeline

Antiviral subgroup chair updated the group that there have been number of discussions with antiviral taskforce (ATF) regarding oral agents that could potentially be used in community setting.

Antiviral subgroup chair also updated the group of two new proposals for community-based studies, which will be discussed in future subgroup meetings. One of them is for immunocompromised patients in community setting receiving monoclonal antibody treatment and the other receiving convalescent plasma.

4. RECOVERY ranking of recommendations

Chair informed the group that therapeutics taskforce (TTF) have asked UK-CTAP to rank the previously recommended drugs in RECOVERY and invited RECOVERY trial team to provide an update on infliximab.

4.1 Infliximab

The group noted that RECOVERY is withdrawing from trialling infliximab within the UK and internationally on the basis that:

infliximab is currently being investigated internationally by the World Health Organization’s Solidarity Trial, at the same dose in the same population. Solidarity aims to produce conclusive evidence
[comment redacted for commercial sensitivity].

Recommendation

The group endorsed the idea of withdrawing Infliximab from the RECOVERY trial, both within the UK and internationally.

4.2 Ranking of recommendations

The ranking recommended by UK-CTAP is:

phase 2

colony-stimulating factor 1 receptor (CSF1R) inhibitors
opaganib

phase 3

namilumab
C5 inhibitors

The panel noted that the RECOVERY team were already in the planning stages for sodium-glucose cotransporter-2 (SGLT2) inhibitors, and that there was broad international interest.

Recommendation

RECOVERY trial team to provide an update on the procurement of namilumab in the next UK-CTAP meeting.

5. Trials update

Chair invited a discussion on the possible candidates that could be fed into the trial pipeline.

The group noted that the pipeline of drugs is diminishing for antivirals and immune groups. So, the focus must change to investigate combination of drugs instead. The compounds that antiviral and immune groups are currently investigating are at early stages.

5.1 PRINCIPLE

The platform lead informed the group that favipiravir trial arm is currently recruiting patients.

Considering the amount of time it takes in preparation of a new drug into a trial, any recommendations from next month onwards will be introduced into the trial next year.

The group noted that PRINCIPLE trial receives drug recommendations from ATF and other routes such as TTF and UK-CTAP is not the only route.

Less than 200 patients were recruited in the colchicine trial arm. It was terminated due to a futility signal at the interim analysis. Colchicine side effects are entangled with COVID-19 and teasing them apart is not possible.

It was noted that protease inhibitors are not yet in phase 1 but could be ready to be included in trials for 2022.

The positive impact of vaccinations was discussed. It was noted that the interim data analysis suggests that the average time to recovery is shorter than it was before the vaccination. Also, the rate of hospitalisations in community trials is smaller compared to the end of last year. It could be due to the milder illness due to vaccination.

Recommendation

UK-CTAP secretariat will continue to look for drugs that can be trialled into PRINCIPLE.

5.2 Trial status report

It was noted that there is a pending recommendation for iota-caregeenan into prophylaxis trial arms.

The PROTECT-V and PROTECT-CH chief investigators (CIs) confirmed that they have capacity for an additional arm.

Niclosamide and ciclesonide were Prophylaxis Oversight Group (POG) recommendations, hence not included in this report as it covers UK-CTAP recommendations only.

It was also noted that metformin was recommended by UK-CTAP on 25 May. The Chief Medical Officer for England (CMO) has provisionally approved it but it is currently pending therapeutics taskforce due diligence.

It was suggested that additional data could be included in the report such as date of commencing contract negotiation with the supplier and draft documentation milestones.

Recommendation

UK-CTAP secretariat to follow-up on the recommendation for iota-caregeenan into prophylaxis trial arms.

UK-CTAP secretariat to follow-up on prednisolone as it has not been signed off by the CMO to go into the HEAL trial.

TTF to identify a suitable trial for pegylated interferon beta which was recommended by UK-CTAP in May 2021.

UK-CTAP secretariat to update the status report based on the update from trial leads.

6. Panel refresh

Chair referred to the ‘UK-CTAP subgroups reconfiguration’ paper and invited the subgroup leads and CIs to provide recommendations and suggest candidates for subgroup membership.

UK-CTAP thanked the subgroup members for their valuable contribution.

The panel made the following recommendations:

6.1 Antiviral subgroup

[Comment redacted, General Data Protection Regulation]

Action

UK-CTAP and CIs to make recommendations to the UK-CTAP secretariat for subgroup members with expertise in pharmacology, diagnostic virology, long COVID and other generalist and specialist areas that could be beneficial.