6 Feb 2021 Episode 108 part 2 immuno-modulatory treatment

Sat, 02/06/2021 - 20:13

Episode 108 Part 2 on Immunomodulatory treatments

Dear colleagues,

This episode contains a rather complex story on immunomodulation that may not be easy to digest for everyone.  To avoid frustration, I will first discuss some papers of general interest

  1. A report in The Guardian of 4 Feb, indicating that there is a serious underestimation of COVID cases and deaths in Sub-Saharan Africa.
  2. A Comment in Lancet on the resurgence of the infection in Manaus, “the capital of the Brazilian Amazon”, which was hit so hard by the first wave that it had reached the theoretical level of 70 % seroprevalence, supposedly sufficient for “herd immunity”.  Obviously, waning immunity 6 months later, but certainly also the appearance of the P1 variant, with multiple mutations may be responsible for that resurgence.


  1. News on the Chinese inactivated vaccines
  • A phase 1 and 2 study in Lancet on 3 Feb with Coronavac (by Sinovac) in older adults showing good safety and induction of neutralizing antibodies also in subjects > 70 yrs.
  • A press release by Chinese media today 6 Feb that this vaccine is now approved, based on phase III studies, showing: As of December 16, 2020, data from Brazil's Phase III clinical trial showed that the vaccine has a protective efficacy of 100.00% for hospitalized, severe and dead cases, and 83.70% for COVID-19 cases with obvious symptoms and requiring medical intervention. The protective effect of all COVID-19 cases including mild cases that do not require medical intervention is 50.65%. According to data from Turkey's Phase III clinical trial, the protective efficacy of the vaccine is 91.25%.


  1. British variant could be 35 % more deadly:
  • Is that effect more pronounced in old age?
  • Were co-morbidities taken into account?
  • Was the overwhelming of the health system partly responsible?


  1. Heterologous prime-boost? A logical step in the optimization of the existing vaccines is to use DNA vector, mRNA and protein vaccines in combination:
  • Oxford will launch a phase 2 trial with the Astra-Zeneca DNA chimp Adeno vector as prime, followed 4 or 12 weeks later with the Pfizer mRNA boost. The purpose is not to test vaccine efficacy, but rather investigate whether the strength and quality of (neutralizing) antibody and T cell (CD4+ T helper type 1 and CD8 + T cytotoxic) responses improve
  • Other ideas is to “mix” with the Russian Sputnik V (Adeno 5 and 26) and with Novavax S protein vaccines.   


  1. The first signs of real world effectiveness in Israeli elderly and British health care workers vaccinated with Pfizer (see attachment): clearly there is hope, but we haven’t won the battle yet….  


In this second part, I will focus on immunomodulatory treatments that are more targeted than the broadly immune-suppressive corticosteroids.  These target pro-inflammatory cytokines such as IL-6 and IL-1 or transducer molecules such as Janus-like kinases (JAK) and signal transducer and activator of transcription proteins (STATs) that are indeed the transducers of signals from various membrane receptors towards intracellular pathways. These antibodies and molecules are in clinical use in some serious auto-immune inflammatory diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).

As an introduction, two reviews to set the stage: Giulio Cavalli in Front Pharmacol (Ep 108-11) and  Seok Kim (Ep 108-12).  See summarizing slides 2 and 3.  

Par 1 Anti-IL6

  1. Early review on effects Toculizimab (TCZ) = humanized anti-IL6 receptor monoclonal antibody (mAb) in case-control and uncontrolled studies, published until August 4th 2020by Kaye (Ep 108-13). 
  • Slide 4 reiterates how IL-6 could be pathogenic in SARS-CoV-2 infection: by increasing various aspects of viral infiltration as well as host inflammation, coagulation, hypertension on  one hand and reducing viral clearance as well as many aspects of immune defense.
  • Slide 5 illustrates how TCZ could block the IL-6 receptor and hence prevent the “cytokine storm”.
  • Slide 6 and 7 show that a significant reduction in mortality was observed in 9/16 case-control studies, with an overall decrease in mortality by more than 50 %.
  • Uncontrolled studies showed the same beneficial trend.
  • The major feared side effect was secondary infections, which indeed occurred in up to 1/3 of the patients, but this figure was similar in the “standard of care” patients.
  • Several variables varied between studies that could impact the mortality rate results. These include SOC, observation time, TCZ administration, treatment date, baseline clinical characteristics, geographic location and resources and mean/median age. Study design was also an important varying factor that may change results as 9 of the 16 studies matched cases with controls and 13 studies were retrospective as opposed to prospective cohort.


  1.  A meta-analysis on randomized controlled trials (RCT) and cohort studies with TCZ was done by Tleyjeh in Nov (Ep 108-14)
  • Slide 8 shows that no significant reduction in short-term mortality was observed with TCZ  in 5 RCT, but a slight reduction in need for mechanical ventilation. Overall there was no increased risk for infection, not other side effect (slide 9)
  • The risk of short term mortality upon TCZ treatment was in cohort studies was heterogeneous, but overall showed a reduction (slide 10).

Their overall conclusion is: Cumulative moderate-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized COVID-19 patients. While RCTs showed that tocilizumab did not reduce short-term mortality, low-certainty evidence from cohort studies suggests an association between tocilizumab and lower mortality. We did not observe a higher risk of infections or adverse events


  1. Della Torre et al tested another Sarilumab, another IL-6 receptor blocking mAb in a small open label study of 28 severely ill patients and 28 matched controls (Ep 108-15).  The results were not very encouraging, as there was no significantly better clinical improvement, nor survival in the treated patients, but probably a faster recovery in a subset with minor lung consolidation at baseline (slide 11).


  1. A retrospective multicenter study in Spain by Ruiz-Antoran (Ep 108-16) investigated the potential additive effect of TCZ and steroids on mortality in a cohort of almost 500 patients.  As can be seen in Table 1, the patients groups were originally not matched, but an a posteriori approach was used to make them comparable: the inverse probability of the treatment weights(IPTW).  
  • As shown in slide 12, TCZ was clearly associated with lower mortality, but this effect was most pronounced when steroids were associated.
  • A subgroup analysis (slide 13) indicated that the TCZ effect was more pronounced to patients  with risk factors such as > 65 yrs, cardiovascular disease, hypertension, lymphopenia.  Remarkably, also receiving hydroxychloroquine, but not interferon beta was associated with a favorable effect of TCZ


  1. REMAP-CAP (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia) is a very large international protocol to compare the effects of the IL-6 antagonists TCZ and Sarilumab, IL-1 receptor antagonist, anakinra; and interferon beta-1a with controls.  In this study corticosteroids were given to > 80 % of all patients, who were critically ill and received respiratory support in intensive care.  The preprint in medRxiv of 7 Jan 2021 (Ep 108-17) is called a “preliminary report”. It marks a decision of the DSMB that TCZ is efficacious, implying that further randomization to control arm is stopped.
  • Both TCZ and Sarilumab ecreased in-hospital mortality compared with standard care:  28% v 35.8%,  adjusted odds ratio for survival 1.64 (slide 14-15).
  • Both also reduced progression to intubation, cardiovascular support and reduced the duration of stay in ICU (slide 14-16).
  • No increased side effects.


This large multinational RCT seemed to provide a final judgement on the usefulness of IL-6 receptor blockade in critically ill COVID-19 patients


  1. A few days later on Jan 11 2021, however, a smaller Brazilian RCT (Ep 108-18) showed evidence that TCZ was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality (slide 17).


  1. In a comment in the same journal (BMJ) on 27 Jan, McCreary discusses the different outcomes in various trials , without providing a final explanation (Ep 108-19).  His conclusion: 
  • The totality of randomized data evaluating tocilizumab neither overwhelmingly support nor convincingly refute routine use.
  • The harm reported by Veiga and colleagues is an outlier in a small trial. On balance of evidence, tocilizumab is unlikely to be life threatening.
  • The mortality benefit reported by REMAP-CAP is also a statistical outlier, but it is more robust because of the larger population and is consistent with signals of benefit in the sickest patients in COVACTA and EMPACTA.
  • The results of the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial are eagerly awaited to further inform tocilizumab’s role in the management of critically ill patients with covid-19.


Par 2 Blockage of IL-1:


  1. A small study by Katia et al (Ep 108-20) used a single 300 mg subcutaneous administration of the anti-IL1beta Canakinumab in 17 mild to severe COVID patients, requiring oxygen but no intensive care in an open label trial, compared with 17 comparable patients on standard care. In the Canakinumab group, there was a reduction in some inflammatory markers (e.g. CRP) , but more importantly an increase in the P/F ratio (= arterial oxygen partial pressure (PaO2 in mmHg) divided by fractional inspired oxygen (FiO2)) by 60 % and a reduced need for oxygen supply (slide 18). Clearly, the Canakinumab group recovered faster on day 3 = T1), but not any more on day 7 (T2).   Not very convincing….


  1. In a small prospective 33 cases - 15 controls open label study by Generali (Ep 108-21),  using 150 mg Canakinumab on day 0 and day 7, several favorable observations were made:
  • A significantly better improvement of P/F ration and radiographic (CT) image (slide 19).
  • A faster clinical improvement and higher survival rate (slide 20)
  • A concomitant improvement in some inflammatory markers: decrease of neutrophils, increase of lymphocytes; more decrease of CRP, fibrinogen and IL-6 (slide 21)


  1. The IL-1 receptor antagonist Anakinra was evaluated in CORIMMO a  multicentre, open-label, Bayesian randomised clinical trial, with 116 COVID patients with mild-to-moderate pneumonia (Ep 108-22). Anakinra was given intravenously at 200 mg 2 times a day (total 400 mg) on days 1–3, then at 100 mg twice a day (total 200 mg) on day 4, and 100 mg once on day 5. It failed to improve any outcome parameter.  The authors suggest that it may be tried in severe COVID.


  1. A small group of 10 pt severe COVID-19 pneumonia and moderate hyperinflammation., who received Anakinra after either methylprednisolone (MP) alone or MP + TCZ had a better survival (in retrospect) than those patients (adjusted for age and disease severity, who did not receive Anakinra (Ep 108-23 and slide 22).  Clearly this evidence is rather weak.  


  1. In a small prospective cohort study with 21 Anakinra-treated versus 39 control critically ill patient, Anakinra showed some effect on inflammatory parameters, but not on clinical improvement (Ep 108-24).


Par 3 JAK inhibitor: Baricitinib

Baricitinib is a selective inhibitor of Janus kinase signal transduction (JAK),

  • modulates the biologic activity of a broad array of inflammatory cytokines.
  •  also inhibiting the signal transduction of type 1 and type 3 interfer­ons, which are important early in the antiviral host response.

Thus, the drug has a formidable toxicity profile including serious infections, viral reactivation (ie, zoster) and venous thrombotic complications

  1. The highest profile data are in a NEJM paper of 5 Jan 2021, where the combination with Remdesivir (RDV)is studied in a large (> 1000pt)  RCT (Ep 108-25). The effect of the combined Baricitinib + RDV  vs single RDV was modest:
  • A 1-day shortening of recovery time– median 7 days (95% confidence interval [CI] 6–8) vs 8 days (95% CI 7–9).
  • The 28-day mortality rate was 5.1% in the combined treatment vs 7.8% in the control group (hazard ratio [HR] 0.65, 95% CI 0.39– 1.09).
  • The effect size was greatest for those requiring noninvasive ventilation or high-flow oxygen and lowest for those who did not need oxygen, suggesting that stage and timing of treatment may be critical.


  1. In an observational cohort study of 112 pt total, comparing the combination of glucocorticosteroids (GC) + baricitinib with GC only by Rodriguez-Garcia et al (Ep 108-26),  a clear-cut improvement of the respiratory function, associated with a decrease in d-dimers was shown (slides 24-25).  Obviously the set-up (observational cohort) is a weak point.


  1.  Calabrese on 25 Jan (Ep 108-27) , based on recent NIH guidelines, advices caution:
  • In the rare circumstances where corticosteroids cannot be used, the Panel recommends using baricitinib in combination with remdesivir for the treatment of COVID-19 in hospitalized, nonintubated patients who require oxygen supplementation.
  • The Panel recommends against the use of bar­icitinib in the absence of remdesivir, except in a clinical trial.
  • There are insufficient data for the Panel to recommend either for or against the use of bar­icitinib in combination with corticosteroids for the treatment of COVID-19. Since both agents are potent immunosuppressants, there is potential for an additive risk of infection.”


Par 4 Anti-TNF therapy


On this topic, I found only case reports, apparently no clinical trial has yet been published



Difficult to make general conclusions out of these heterogenous data.  As some of the papers suggest, the choice of patients might be crucial: there was a tendency that beneficial effects were more pronounced in critically ill patients.  It might also be important to select based on the level and the pattern of systemic hyperinflammation. In some of the papers there was limited evaluation of this aspect, but it was not done in a systematic nor standardized way.


Therefore, it would be useful to preserve plasma and cells from these patients before the start and at predefined times after initiation of therapy.  This material then could be used for extensive, standardized measurements of cytokines and other inflammatory markers in the serum as well as transcriptomic RNA patterns in the PBMC.  Using a bio-informatic approach inflammatory/transcriptomic as well as clinical correlates of treatment failure of success could be identified.  Based on those data algorithms could be built to help clinicians take the decision on whether and which immunomodulatory treatment could be useful  for an individual patient with a particular profile.