16 January Episode 224 Drugs part 3 Tocilizumab Baricitinib and Sotrovimab

Dear colleagues,

In the present episode, I will continue the discussion on drugs, based on two statements from WHO with recommendations to include Tocilizumab, Baricinitib and Sotrovimab.   As you will see,

• Tocilizumab, an injectable monoclonal, and Baricitinib, an oral small molecule, are mainly meant to cope with the hyper-inflammation and therefore are not really dependent on the viral strain.  The question is rather whether they are complementary to systemic corticosteroids
• Sotrovimab is a monoclonal directed against the Spike and here the question should be asked about potency towards omicron and sensitivity to resistance induction.

TOCILIZUMAB

Tocilizumab (TCZ) is a humanized monoclonal antibody that , via the binding to soluble and membrane interleukin (IL)-6 receptors, produces inhibition of the proinflammatory signals .

It is commonly used in an intravenous form in several types of inflammatory arthritis, in Castleman’s syndrome, and in cytokine release syndrome secondary to chimeric antigen receptor T cell therapies.

Since increased IL-6 is increased in severe COVID, it has been extensively tested.

Ep 224-3: Maraolo in J Clin Med performed a meta-analysis of clinicals trials, after a strict selection.  They find a significant effect on 28 days mortality of -16 % .  However, it was restricted to open label studies (not clear in double blind studies) and in severe patients (not moderate)

Ep 224-4: Mahmood Moosazadeh in J Med Virol risk of death after Tocilizumab (TCZ) alone or combined with corticosteroids as compared with control conditions.  They include only 5 studies, but with over 3300 patients.  As can be seen, there is quite some heterogeneity, but finally the authors conclude that:

Risk of death     = 0.74 (CI 0.36–1.50) in patients treated with TCZ + corticoids versus TCZ

= 0.48 (95% CI: 0.31–0.74) in patients treated with TCZ + corticoid vs control

So the combined effect of TCZ + corticoids vs controls is significant, but not the difference between TCZ alone and TCZ + corticoids.  

BARICITINIB

Baricitinib is an oral inhibitor of JAK 1 and 2, which was originally approved for rheumatoid arthritis.. JAK inhibitors (JAK i’s) can prevent the dysregulated production of proinflammatory cytokines primarily involved in cellular survival, proliferation, differentiation, and immigration; proving to be clinically useful in immune, inflammatory, and hematopoietic diseases. Baricitinib has thus been evaluated in treatment of COVID-19 with the rationale of suppressing the hyperinflammatory state of cytokine release syndrome (CRS) or hypercytokinemia (cytokine storm) associated with COVID-19

NIH guidelines include baricitinib as an add on treatment option to corticosteroids and/or remdesivir for hospitalized patients requiring high flow oxygen or noninvasive / invasive ventilation or ECMO (extracorporal membrane oxygenation).

Ep 224-5: Review on available evidence medRxiv Dec 2021

ACTT-1 baricitinib + remdesivir (SARS-CoV-2 polymerase inhibitor) significant improvement over standard of care

• in median time of recovery to control group subjects (6 days vs 8 days, rate ratio 1.21; 95% CI, 1.06 to 1.39),
• mortality rate 5.1%  vs 7.8% in control (hazard ratio 0.65; 95% CI, 0.39 to 1.09)

Marconin et al: oral baricitinib 4 mg vs standard of care:

• Mortality rate: 8.1 vs 13.1 %
• Requirement for high flow oxygen or for non-invasive ventilation: 7.5 vs 12.9 %

Both studies had low risk of bias.

Ep 224-6: Wesley Ely medRxiv Nov 2021 COV-BARRIER trial  investigates additional effect of Baricinib in critically ill patient on mechanical ventilation or extracorporeal membrane oxygenation (ECMO) and compared with standard of care (including corticosteroids): Clear beneficial effects:

• Mortality after 28 days and 60 days: 39 vs 58 % ( and 45  vs 62 % (p 0.03)
• Shorter hospital stay: 23 vs 26 days  (p 0.05)
• No difference in rates of infections, blood clots, and adverse cardiovascular events

SOTROVIMAB (or VIR S309)

Omicron

In the following papers, the in vitro neutralizing activity of Sotrovimab and  other mAbs is compared against Wuhan strain (B1) and omicron. In one case also against Delta.   

Key: in the quoted literature, various names are used for therapeutic mAbs:

SOTROVIMAB, also called VIR S309 or VIR 7831; while  VIR 7832 is a “sister mAb”

REGENERON combination = Casirivimab (REGN10933)  + Imdevismab (REGN10987)  

ELY-LILY combination = Bamlanvimab (LY-CoV555) + Etesevimab (Ly-CoV016)

ASTRA-ZENECA combination EVUSHELD =   Tixagevimab (AZD8895 or COV2-2196)

and Cilgavimab (AZD1061 or COV2-2130)

Ep 224-7: According to Hofman: the Regeneron and Lily cocktail are inactive against omicron, because of multiple mutations in their binding site while Sotrovimab and soluble ACE-2 are still active. Nevertheless there are 2 mutations that slightly  affect  Sotrovimab’s activity (N440K and G339D).

Ep 224-8: Similar observation by Cameroni et al in Nature Dec 2021:

• Sotrovimab (and it’s “sister” VIR-7832loses only 2-3 fold potency against both pseudovirus and live virus.
• The Astra-Zeneca mAbs COV-2196 (Tixagevimab) and COV2-2130 (Cilgavimab) are both almost inactive, but the combination  has still activity in the migrogram/ml range
• REGENERON and LILLY single mAbs and cocktails are essentially inactive

Ep 224-9: And by Van Blargan in Res Square: similar IC50 of S 309 for Wuhan and Omicron strain…

Van Blargan also finds almost unaltered activity of Sotrovimab against omicron as compared to Wuhan and essentially no activity of Regeneron and Lilly mAbs or cocktail against omicron. In their assay, however, the COV2-2130 (Cilgavimab) loses 10 X and COV2-2196 (Tixagevimab) loses 100 times, while the AstraZeneca cocktail of both loses also 10 times.

Ep 224-10: Similar finding by Ikemura medRxiv 14 Dec: Sotrovimab and soluble ACE2 keep their potency, but Regeneron almost completely loses activity (1000 times less).

Effectiveness and risk on resistance development of SOTROVIMAB during DELTA wave

Ep 224-11:

Among 3,069 non-hospitalized mild/moderate patients, mAb treatment (Casirivimab and Imdevimab or sotrovimab) was associated with reduced risk of hospitalization or death by 28 days compared to no treatment (risk ratio=0.40, 95% CI: 0.28–0.57).  Sotrovimab seems a bit less convincing, but criteria for non-inferiority were not met.

Note: there are no clear in/ex-clusion criteria, but according to Table 2, many patients had risk factors such as obesitas  (> 50%); age > 65 ys ( 30 %), respiratory condition (22 %) and/or immunosuppression (15 %), diabetes (10 %) etc…

Ep 224-12: Out of an original series of 100 patients, treated with Sotrovimab for Delta infection, Rocket describes 8 patients with serious co-morbidities (see Table 1 p 15) who maintained high viral load, hence failed to control the virus and required hospitalisation.  In 4 of those, a mutation in the 340 position was found from E (glutamic acid) to Alanine, Lysine (K) or Valine. In addition an E337L mutation was present in one of the patients.     

This indicates that individuals may remain infectious after acquiring mutations and therefore can transmit resistant virus. This may result in reduced efficacy of sotrovimab and potentially of other immunotherapies,including vaccination, in sotrovimab-naïve individuals

Acquisition of mutations in the Sotrovimab target epitope at S protein amino acid positions 335-361 was reported during COMET-ICE.

Phenotypic characterization of these mutations demonstrated that high-level Sotrovimab resistance (100 to 295-fold reduction in neutralization) was conferred by E340K/A/V, while a 192 to 304-fold reduction was also noted with the appearance of mutation P337L/K/R.

CONCLUSIONS

1. Both Tocilizumab and Baricitinib have proven to reduce mortality in severely ill COVID patients  and there is some evidence that they have an additional effect to corticoids.
2. Amongst the presently commercially available mAbs,  Sotrovimab is clearly most active against omicron.  Experience with Delta virus shows that in immune compromised patients, who are not able to clear the infection under Soptrovimab therapy, resistant viruses with particular mutations in Spike 335-361 can emerge.

Best wishes,

Guido