October 9, 2019

Clinical trial in patients with severe pneumococcal pneumonia

Efficacy of CAL02, a novel broad-spectrum agent. Neutralising virulence effectors

 

Pathogens’ virulence effect are directly involved in the development of serious complications including multiple organ failure, or even death. An innovative agent, CAL02, has been developed to neutralise the multiple chemical messengers that are directly responsible for damaging organs, prompting inflammation, and hindering natural immune defence.

CAL02 is an intravenous formulation of liposomes mimicking microdomains that act as docking stations for a large range of bacterial virulence signals. It acts irrespective of the resistance profile of the infective pathogen, does not induce resistance and can be administered before pathogen identification.

In a double-blind, multicentre, randomised, placebo-controlled study, patients with severe community-acquired pneumococcal pneumonia that required ICU admission, CAL02: 4 and 16 mg/kg were compared to placebo, all given in addition to standard antibiotic treatment.

Marked and consistent differences in efficacy outcomes were observed between CAL02 high dose: 16 mg/kg and placebo:

 

CAL02 High-dose (n=10)
Placebo
(n=5)
Cured at early test of cure (day 8)
56%
20%
Cured at test of cure (between days 15–22)
100%
100%
Median time to cure (days)
8.0
10.0
All-cause mortality
10%
20%
Relative change in SOFA score from baseline to day 8
–64·7%
–29·2%
Relative change in APACHE II score from baseline to day 8
–60·4%
–22·1%
Relative change in PaO2/FiO2 from baseline to day 8
78·4%
58·5%
Median duration of invasive mechanical ventilation (days)
4·5
12·0
28-day ventilation-free days (days)
25·1
17·8
Median duration of intensive care unit stay (days)
5·0
12·0
Median duration of stay in hospital (days)
13·0
21·0

 

The time courses of C-reactive protein and procalcitonin between baseline and day 8 also showed a rapid decrease in the CAL02 group.

The safety profile of CAL02 (both doses) was similar to that of placebo. The most common adverse events were in line with the severity of the enrolled patients – at baseline: APACHE II: 21.5 (SD 4.9) and 58% of patients with septic shock – and included anaemia, atrial fibrillation, blood phosphorus decreased, cholestasis, constipation, hepatocellular injury, hyperglycaemia, hypernatremia, hypoglycaemia, hypokalaemia, hyponatraemia, hypotension, pleural effusion, renal failure, and thrombocytopenia.

 

STUDY STRENGTHS & LIMITATIONS

Strengths:

  • This is a study with prospectively and multiple pre-defined clinical and biomarker outcomes in a severe pneumonia population admitted in ICU and could pave the way for future, bigger trials. The results are encouraging.

Limitations:

  • A small sample size (total 19 patients).
  • Plasma pneumolysin determination could not be performed.

 

TAKE HOME MESSAGE
  • Despite best antibiotic treatments, pneumonia is still the top cause of worldwide mortality within infectious diseases.
  • CAL02 is a front runner in a new paradigm in the field of infectious diseases: a novel type of agent (very safe liposomes with a broad-spectrum activity) focusing on infection’s severity, in particular organ dysfunction.
  • CAL02 showed consistent superiority in all clinical, scores and biomarkers when compared to placebo in ICU-admitted patients with severe community-acquired pneumococcal pneumonia.

 

Article review for the ESICM Journal Review Club on behalf of the WG on Pneumonia provided by Jordi Rello, Professor of Medicine at the Universitat Autonoma de Barcelona and Head of the Critical Care Department at the Vall d’Hebron University Hospital in Barcelona, Spain.

Declaration of Interest by the author: Prof. Rello served in an advisory board for Combiaxin, Geneve, CH, five years ago.

#ERJC#ICU#ARF


REFERENCES

1) Laterre PF, Colin G, Dequin PF, Dugernier T, Boulain T, Azeredo da Silveira S, Lajaunias F, Perez A, François B. CAL02, a novel antitoxin liposomal agent in severe pneumococcal pneumonia: a first-in-human, double-blind, placebo-controlled, randomised trial (2019). Lancet Infect Dis. 19: 620-630. doi: 10.1016/S1473-3099(18)30805-3. Epub 2019 May 2

2) Pletz MW, Bauer M, Brakhage AA. One step closer to precision medicine for infectious diseases (2019). Lancet Infect Dis. 19: 564-565. doi: 10.1016/S1473-3099(19)30070-2. Epub 2019 May 2

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