UK-CTAP meeting, 10 December 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, thanking them for their continued commitment as UK-CTAP recommissioned (UK-CTAP 2.0).
2. Conflicts of interest
Declarations
Frederick Hayden
[Redacted, General Data Protection Regulation]
Action
As there is no financial or personal benefit, no action required.
Charlotte Summers
[Redacted, General Data Protection Regulation]
Action
Chair to manage conflict as appropriate to topics discussed.
Michael Jacobs
[Redacted, General Data Protection Regulation]
Action
Chair to manage conflict as appropriate to topics discussed.
No other conflicts were recorded.
3. Terms of reference
The panel proposed the following changes:
- correct the omission of Dr Sir Michael Jacobs in membership
- delete the requirement to meet monthly at minimum, in favour of ad hoc meetings [to meet operational demand].
4. RECOVERY+ update
RECOVERY+ investigators invited questions arising from the RECOVERY+ update paper ahead of presenting the case for inclusion of sotrovimab and molnupiravir.
The board were reassured that C5 inhibitors remain in the pipeline for an autoimmune arm of RECOVERY+.
4.1 Sotrovimab
Charlotte Summers recused decision making.
The panel heard that assays have suggested that [redacted for commercial sensitivity] would not maintain efficacy against the omicron variant of COVID-19, furthermore that the pivot between the transition from delta to omicron as the dominant variant was likely to occur within the next two weeks.
The panel heard that GSK had provided data to demonstrate that sotrovimab is effective against omicron and previous COVID-19 variants.
The panel saw summary data from the National Institutes of Health ACTIV3 trial, noting that whilst it was stopped it had passed the futility threshold.
The panel noted that independent analysis of the preclinical data suggested that this was based on IC50 levels at a 500mg dose, but that there was substantial divergence at IC90 by day 28.
The panel noted that the community dose was 500mg but substantially higher doses had shown no safety issues. The panel recommended a higher dose of 1,000mg should be considered to address the high variability in pharmacokinetic (PK) between individuals.
The panel questioned whether high-titre convalescent plasma (HCVP) may be a more effective intervention if monoclonal antibodies were only effective for three months before variants render them ineffective.
The panel satisfied itself that the case for HCVP did not negate the need to find an answer on sotrovimab to face potential COVID-19 waves in late December and early January.
The panel expressed the strongly held view that stringent monitoring for resistant variants should be in place.
The panel were reassured that the trial would ensure that surveillance for resistance would be at least as rigorous as in the post-authorisation community setting. They heard the trial would collect sequencing antibody and antigen data at days zero, three, and five.
Recommendation
UK-CTAP 2.0 makes the following recommendations into RECOVERY in a factorial design:
- sotorivimab at a higher dose of 1g
- molnupiravir for longer than five days (duration to be decided).
These recommendations are contingent on a supply being secured that does not compromise community use, and with careful monitoring for the possible emergence of resistant strains.
4.2 Molnupiravir
The panel heard that molnupiravir has been authorised for community treatment subsequent to a trial of 1,400 participants showed a 30% reduction of hospitalisation.
The panel noted that study of hospitalised patients had not given definitive answers on efficacy, with only 75 patients receiving the proposed twice daily dose.
The panel agreed there remained a reasonable question to answer regarding molnupiravir in hospitalised patients, noting the RECOVERY+ proposal of a factorial design.
The panel proposed that the dosing regimen should be extended beyond the five day window used in community treatment, they offered a suggested duration of 10 days.
The panel expressed a strong view that combinations are a critical factor in moving forward with COVID-19 therapeutics, noting that the AGILE trial team had done some initial thinking on the trialling of combinations.
The panel noted it would be important to understand how molnupiravir might interact with remdesivir as standard of care.
The panel heard that triple therapy (molnupiravir, remdesivir and sotrovimab) had not been ruled out.
The panel noted stock issues and expressed the opinion that the trial should not compromise community treatment.
The panel reiterated the strongly held view that stringent monitoring for resistant variants should be in place.
The panel were reassured that the trial would ensure monitoring for resistance would be rigorous and that the collect sequencing, antibody and antigen data at days zero, three, and five, would be extended to match the treatment course.
Recommendation
UK-CTAP 2.0 makes the following recommendations into RECOVERY in a factorial design:
- sotorivimab at a higher dose of 1g
- molnupiravir for longer than five days (duration to be decided).
These recommendations are contingent on a supply being secured that does not compromise community use, and with careful monitoring for the possible emergence of resistant strains.
5. Outstanding actions
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.
5.1 [Redacted for commercial sensitivity]
The panel considered whether combinations needed to demonstrate efficacy as monotherapies before combination or whether a synergistic effect may drive inclusion of an otherwise ineffective compound.
The panel agreed further PK data was required on [redacted for commercial sensitivity] before inclusion could be considered.
The panel asked the secretariat for an update on intravenous (IV) favirpiravir trial in AGILE.
Recommendation
The panel did not prioritise [redacted for commercial sensitivity].
5.2 Fluvoxamine
The panel noted that there was no new compelling evidence to prioritise fluvoxamine as a treatment.
The panel heard that emerging evidence suggested any effect would be small and that the opportunity cost too high when compared to high dose dexamethasone.
The panel noted with interest that Health Data Research UK (HDR UK) was analysing data to generate a hypothesis on the necessary trial power to demonstrate an effect.
Recommendation
The panel did not prioritise fluvoxamine for trial.
5.3 Dornase alpha
The panel heard that the COVASE trial had delivered its primary endpoint in a reduction of c-reactive protein. It also heard that there were positive trends in the secondary endpoints in terms of hospital stay duration.
The panel agreed that neutrophil extracellular traps (NET) clearance was an interesting method of action and the reduction in hospital stay duration was potentially exciting. However, the sample size was not big enough to give confidence to recommend to a large phase 3 trial.
The panel asked the secretariat to look for similar studies on dornase alpha that had significantly higher participant numbers.
Recommendation
The panel did not prioritise dornase alpha for trial.
6. Pipeline
The panel heard that the UK-CTAP 1.0 portal remain closed and that four main sources of information would drive the UK-CTAP 2.0 order of business:
- therapeutics taskforce generated proposals
- trial readouts
- data connectivity with HDR UK
- combination assays.
Chair noted that UK-CTAP 2.0 was not resourced to triage the large volumes of proposed compounds that UK-CTAP 1.0 had sourced.
The panel agreed that submissions made to the RECOVERY+ principal investigators could be forwarded to the UK-CTAP secretariat for consideration.
7. Close
No other business was raised and the chair closed the meeting.
Attendees
Scientific experts
- Patrick Chinnery (Chair)
- Munir Pirmohamed
- Moira Whyte
- Duncan Richards
- Charlotte Summers
- Frederick Hayden
- Michael Jacobs
- Ian Hall
Observers
- 2 trial investigators
- 1 Department of Health and Social Care representative
- 3 secretariat members