20 March 2021 Episode 121 Present treatment strategies and perspectives on new therapeutics

Sat, 03/20/2021 - 21:07

Dear colleagues,

Based on two nice science journalists reviews (Ep 121-1 and Ep 121-13), I will provide an update on present treatment guidelines and the research perspectives

  1. Present strategies (Ep 121-1)
    1. Ep 121-2: Principle trial shows that the combination of azithromycin + doxycyclin offers no benefit to COVID outpatients.
    2. Ep 121-3:  RECOVERY randomized > 10,000 hospitalized COVID patients to either usual care or + high titer (>1/100) neutralizing convalescent plasmaNo differences were seen in any subgroup with regard to progression to invasive mechanical ventilation, 28 day discharge or 28 day-mortality.
    3. Ep 121-4: the Regeneron monoclonal antibody cocktail (Casirivimab plus Imdevimab) administered once in freshly diagnosed outpatients reduced nasopharyngeal viral load over 1 week in a dose-dependent fashion.
    4. Ep 121-5: the Eli Lily single monoclonal (Bamlanivimab)could also lower viral load at day 11, but not as clearly dose-dependently.  There was also some clinical benefit.
    5. Ep 121-6 We know in the meantime that this Eli Lily monoclonal is sensitive to recent mutation (E484K) more than the Regeneron cocktail.  
    6. Ep 121-7: based on these data the statement of NIH on Feb 11 was still very doubtful: There are currently insufficient data to recommend either for or against the use of bamlanivimab or the casirivimab plus imdevimab combination for the treatment of outpatients with mild to moderate COVID-19
    7. Ep 121-8:  Eli lily proposed a new combination of bamlanivimab and etesevimab, cutting hospitalization and death by 87%, while also VIR Biotechnology proposed an antibody with a similar effect (85%).  
    8. Ep 121-9: NIH is now more enthusiast and states on March 10th: The Panel recommends the use of bamlanivimab 700 mg plus etesevimab 1,400 mg for the treatment of outpatients with mild to moderate COVID-19 who are at high risk of clinical progression
    9. While REMDESIVIR, a polymerase inhibitor,  is recommended by NIH, it is not recommended by WHO, because it showed no benefit in the SOLIDARITY trial.
    10. Ep 121-10 and Ep 121-11 Low dose preventive anticoagulation upon COVID hospital admission is standard of care.  However, in patients with severe Covid-19, high dose therapeutic anticoagulation did not improve hospital survival or days free of organ support compared to usual care pharmacological thromboprophylaxis. Therefore ICU patients were no longer enrolled, but then came the more favorable results in non-ICU patients, in whom a full dose anticoagulant therapy  reduced the need for organ support… So, you really have to choose your patients right….  
    11. Ep 121-12 Similarly, but in the opposite direction: RECOVERY showed that dexamethasone had a dramatic survival benefit in patients on mechanical ventilation (29 % vs 41 %), while for patients on oxygen only the difference was less dramatic 23 vs 26 % mortality and for those who did not need oxygen, dexamethasone seemed to increase mortality (18 vs 14 v%).
    12. Ep 121-13: Based on the results, I discussed in Ep 108, Tociluzimab (anti-IL6) in combination with dexamethasone is recommended for COVID patients with rapid respiratory decompensation.  However, for patients with conventional oxygen supplementation, either Remdesivir and/or dexamethasone is recommended.

 

  1. Perspectives on new therapeutics (Ep 121-14)
    1. ENTRY inhibitors: (Ep 121-15,-16,-17)  all bind firmly to the receptor-binding domain of Spike with pico- or nanomolar activity in vitro. CTC-445.2d (121-15) protected hamsters partly from SARS-CoV-2 disease and completely from death after prophylactic intranasal treatment with 560 µg (which is rather  high).
    2. Protease inhibitors:
      • The HIV protease inhibitor (Lopinavir-Ritonavir) was inactive in RECOVERY trial. Status of the HCV inhibitor Boceprevir unclear: in vitro active
      • Ep 121-18: GC376 is a specific inhibitor of 3CL protease.  It was used in lethally SARS-CoV-2 infected mice, at 100 mg/kg/day from day 1 to day 10 and cured the mice.
      • PF07034818 from Pfizer is an NSP5 (Mpro) inhibitor, developed for SARS-CoV-1, can reduce SARS-CoV-2 viral load in mice.   A promising lead?
    3. Polymerase inhibitors: besides “repurposing” favipiravir, ribavirin, triazvirin and galdesivir, there is a promising molnupiravir MK-4482/EIDD-2801
      • Ep 121-19: Sheehan shows that it is orally bioavailable and active against several Coronaviruses in mice.
      • Ep 121-20: Wahl shows potent activity against SARS-CoV-2 in lung tissue and in mice, both prophylactically and therapeutically
      • Ep 121-21: Cox shows that molnupiravir treatment of infected ferrets can block transmission
      • Ep 121-22: Painter reports on phase 1 in humans, with favorable pharmacokinetics and tolerability.
    4. Miscellaneous: camostat-mesylate a TMPRSS2 inhibitor will enter phase 2/3.  Similarly furin inhibitors could be considered.

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