Episode 295: Follow-up on real world studies on single antivirals and on animal experiments with combined treatment.
As a reminder, see Episode 286 with a first evaluation of clinical trials and real world studies with the polymerase inhibitors Remdesivir (RDS) and Molnupiravir (MOL) as well as the protease inhibitor Paxlovid (PAX). Provisionally all 3 drugs can be used in outpatients at risk. RDS is also approved for non-critical hospitalized patients. It is essential that these antivirals y are used within days of symptoms onset.
Conclusions on RDS were:
- RDS seems somewhat less effective in preventing disease progression, especially in outpatients (Piccicacco HR = 0.4) than in the Gottlieb RCT (HR = 0.13)
- Early application is crucial. If applied early, maybe additive effect of interferon beta 2 IV
- RDS may not be effective in critically ill (high flow oxygen or mechanical ventilation): maybe inflammation dominates the pathogenesis at that point and antivirals less useful?
- Resistant mutations may occur in chronically infected immunocompromised patients.
Conclusions on PAX:
- PAX effective in outpatients, but maybe less than in the randomized trials
- Care should be taken to avoid potential drug-drug interactions due to Ritonavir.
- There are multiple possible pathways to resistance and a large number of mutations has been associated with PAX use, but provisionally the clinical significance is not clear.
Conclusions for MOL:
- MOL is in general less active than either PAX or RDS
REBOUND of viral load and/or symptoms occurs in a minority of patients, but it is presently hard to say whether it occurs more frequently in PAX or MOL treated vs untreated subjects. Figures vary and studies were not properly controlled. It is, however, clear that rebound occurs more in subjects with underlying conditions.
The official guidelines from the European Medical Agency are summarized
In the following paragraphs, I will review new data from “real world” studies as well as from some trials on Remdesivir, Molnupiravir and Paxlovid in outpatients and hospitalized ones. A new paper on rebound will be discussed as well as two animal model studies on combination therapy with Molnupiravir and Paxlovid. Finally, I will focus on remaining opportunities for mAbs against the BA.2.75.2 and BQ.1.1 variants.
Par 1 REMDESIVIR in outpatients
Ep 295-1: Jittamala medRxiv 19 0ct 2022 compares effect of RDS and Casivirimab/ Imdevimab (= Regeneron cocktail Ronapreve) in mildly symptomatic low risk patients during delta and omicron waves.
Acceleration of viral clearance as compared to no-treatment:
- Remdesivir 42% (95%CI 18 to 73%) (n=67).
- Casirivimab/imdevimab 58% (95%CI: 10 to 120) in Delta (n=13), and 20% (95%CI: 3 to 43) in Omicron variant (n=61), with 8% in BA.1 (95%CI: -21 to 59) and 23% (95%CI:3 to 49) in BA.2 and BA.5 Omicron subvariants.
The latter data of Ronapreve effectiveness Delta >> BA.2 >> BA.1 are consistent with the ex vivo data in Ep 270-1 Bruel Nat Med.
Neutralization of Delta and Omicron BA.1 and BA.2 by sera of immunocompromised individuals receiving Ronapreve and/or Evusheld as a pre-exposure prophylaxis
Par 2 MOLNUPIRAVIR in outpatients
Ep 295-2: Butler SSRN 4 Oct: PANORAMIC trial during omicron
Par 3 PAXLOVID in outpatients
Ep 295-3: Aggarwal medRxiv 15 Sept 2022Real world effectiveness of Paxlovid in outpatients during BA.2/BA2.12.1 wave in Colorado: retrospective observational with propensity score matching
Clearly, Paxlovid showed expected therapeutic effect, independent of age, immune-competence and vaccination, but the effect was restricted to people with 2+ comorbidities.
There was no evidence of rebound (requiring emergency dept) within 28 days.
Ep 295-4: Lewnard medRxiv Oct 2022 finds an even higher effectiveness in a large matched cohort study amongst over 4000 treated and over 20,000 untreated SARS-CoV-2 outpatients in California during the first half of 2022.
Ep 295-5: Xiaofeng Zhou medRxiv Sept 2022: Very similar data in a US-wide cohort after propensity score matching
Ep 295-6: Schwartz KL medRxiv 5 Nov 2022 Similar data in well-matched cohort in Ontario Canada
Par 4 REBOUND?
Ep 295-7: Jay A. Pandit medRxiv 15 Nov 2022 Paxlovid rebound study
Prospective study in COVID patients eligible for Paxlovid who choose to take or not take the medicine.
- Viral rebound incidence was 14.2% in the Paxlovid group (n=127) and 9.3% in the control group (n=43).
- COVID-19 symptom rebound incidence: the Paxlovid group (18.9%) vs the control group (7.0%).
- There were no notable differences in viral rebound by age, gender, pre-existing conditions, or major symptom groups during the acute phase or at the 1-month interval.
- Rebound after clearance of test positivity or symptom resolution is higher than previously reported.
- A similar rate of rebound in both in the Paxlovid and control groups.
- In both treatment and control groups the rebound symptoms are milder than symptoms of the original COVID-19 infection
Par 5 HOSPITALIZED PATIENTS
Ep 295-8: Alstutz SSRN 11 Oct 2022 Systematic review of 9 eligible RCT in hospitalized patients confirms that reduced mortality is only seen in non-ventilated patients.
There was no evidence for a credible subgroup effect with respect to age, presence of comorbidities, time to start of Remdesivir after symptom onset, C-reactive protein level, enrollment period, or presence of anti-SARS-CoV-2 antibodies.
The only study (preprint) that I could find with comparative data
Ep 295-9: Carlos C Wong medRxiv May 2022: Comparison of Molnupiravir, Paxlovid and no antiviral during omicron BA.2 in Hong Kong in hospitalized patients, not requiring oxygen (retrospective, but with propensity score matching)
Paxlovid and MOL have a similar beneficial effect (about 50 %) on need for oxygen; disease progression and mortality. Both compounds also similarly shortened the time to achieve lower viral burden.
PAR 6 COMBINATION MOL + Nirmatrelvir
Ep 295-10 : Ju Jeong Antivral Reasearch Oct 2022 : Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice: also clear effects on clinical score and viral loads
Ep 295-11: Kyle Rosenke bioRxiv 5 Sept 2022. Molnupiravir and Nirmatrelvir in Rhesus macaques
Combined treatment resulted in
- milder disease progression,
- stronger reduction of virus shedding from mucosal tissues of the upper and lower respiratory tract,
- reduced lung pathology
PAR 7 MONOCLONAL ANTIBODIES UPDATE
With every new variant the profile of mAbs that is still active or not changes. Sometimes mAbs that were useless against a previous VOC become active again. We will focus on the variants BQ.1 and BA.2.75, because they are now becoming more important.
Ep 295-12 = Ep 289-14: Yunlong Cao in bioRxiv 23 Sept 2022 shows that 3 commercial Ab cocktails have lost activity against both BA.2.75.2 and BQ.1.1
- Ronapreve combination (REGN 10987 + 10933 or Casivirimab + Imdevimab),
- Evusheld (COV2-2130 + 2196 or Cilgavimab + Tixagevimab)
- and the BRI Bioscienes cocktail (BRII-196 + BRII-198)
Bebtelovimab (LyCOV1404) remains active against BA.2.75.2, but not against BQ.1.1.
Sotrovimab (S-309) loses some activity against BA.2.75.2, but becomes inactive against BQ.1.1
The Singlomics mAb SA55 remains fully active against both.
Ep 295-13: Daniel Sheward in bioRxiv 19 Sept 2022 investigates the sensitivity of BA.2.75.2 to mAbs
Clearly, Evusheld and Ronapreve are inactive (in line with Cao). Also the Eli Lilly Cocktail (LY-CoV016 or Etesevimab + LY-CoV555 or Bamlanivimab) is inactive.
Bebtelovimab remains fully active and Sotrovimab loses only about 4 times.
Interestingly, the S2K146 mAb remains very active.
Ep 295-15: Youn-Yun Park describes this mAb S2K146 in a Science paper of Jan 2022: It broadly neutralizes viruses belonging to SARS-CoV– and SARS-CoV-2–related sarbecovirus clades, which use angiotensin-converting enzyme 2 (ACE2), including SARS-COV, SARS-CoV-2 and related animal viruses with zoonotic potential.
Ep 295-15: Delphine Planas bioRxiv 17 Nov 2022 Resistance of Omicron subvariants BA.2.75.2, BA.4.6 and BQ.1.1 to neutralizing antibodies.
Nice overview of mutations
BA.2.75.2 remains only sensitive to Bebtelovimab, which is in line with Sheward and PlanaS.
However data of BA.2.75.2 on sensitivity to Sotrovimab are contradictory: Cao and Sheward found remaining sensitivity of BA.2.75.2 (852 resp 442 ng/ml), while Planas found a much higher EC50 (almost 20,000 ng/ml)
BQ.1.1 has a > 10 X reduced sensitivity to Sotrovimab, while Cao found a much higher EC50 of 5581 ng/ml
Ep 295-16: Monograph on Sotrovimab p. 10
Based on noncompartmental analysis, mean peak plasma concentration following a single 1-hour IV infusion is 137 mcg/mL and mean concentration on day 29 is 34 mcg/mL.
Clearly, this concentration is about 40 times higher than the in vitro EC50 value by Planas, but only 6 times according to Cao.
- Molnupiravir had limited advantage in omicron-infected outpatients, according to the PANORAMIC study (Ep 295-2), but according to Wong it had a similar beneficial effect as Remdesivir in hospitalized patients, infected with BA.2 and not requiring oxygen (Ep 295-9).
- The beneficial effect of Paxlovid in non-hospitalized high risk and of Remdesivir in severely ill, but not critical patients, has been confirmed in several studies.
- Rebound of viral load after treatment stop is possible, but not much more than in untreated subjects and it remains without severe consequences.
- A combination treatment with Molnupiravir and Paxlovid was show to be beneficial in both a mouse and a non-human primate model. I could not find human studies in this regard.
- The mAb cocktails Ronapreve, Evusheld, BRII and Eli Lilly have lost activity against the new variants BA.2.75.2 and BQ.1.1.. While BA.2.75.2 remains sensitive to Bebtelovimab, BQ.1.1 is clearly resistant to this mAb. The data on sensitivity to Sotrovimab are contradictory:
- For BA.2.75.2: Cao and Sheward find some remaining sensitivity, while Planas shows almost complete resistance
- For BQ.1.1 Planas finds a reasonable sensitivity (764 ng/ml), while Cao finds almost complete resistance (> 5500 ng/ml)
- Some new mAbs (SA55 and S2K146) may have a broader spectrum, but independent evaluation is needed. Clearly, standardization of in vitro testing would also be helpful to avoid discrepant results….
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