IRL201104 (‘1104)

‘1104 is a first-in-class compound and is a peptide derived from the endogenous immuno-regulatory protein (mTB chaperonin 60.1). In models of lung inflammation, ‘1104 uniquely reduces the infiltration of three key cells involved in both allergic and non-allergic inflammation: eosinophils, neutrophils and lymphocytes.

Chaperonin 60.1 is a key immunomodulatory protein secreted by Mycobacterium tuberculosis, and is one of the strategies that mTB uses to ensure the bacteria can survive for decades within the human lung. This immune ‘resetting strategy’ by mTB modulates our own immune system by regulating the activity of key immune cells. Indeed, in patients with tuberculosis, or who have had the BCG vaccination, have been shown to be associated with a 5-fold reduction in the prevalence or risk of developing asthma or allergy.

A human clinical study has been conducted. Sixty two subjects have received at least one dose of IRL201104. The highest dose given is 8 mg with 4 healthy volunteers and 6 mild asthmatics receiving that dose as a single intravenous bolus. There were no SAEs, severe AEs or AEs that led to withdrawal. The numbers of adverse events were few, with no dose response  seen in terms of frequency or severity of adverse events reported. There were no safety concerns attributable to IRL201104 as assessed by vital signs, 12 lead ECG, ECG telemetry, laboratory (haematology, clinical chemistry, urinalysis) safety test and physical examination. Local tolerability was good. Overall tolerability of IRL201104 to date has been good (comparable to placebo), with no difference in safety profile between healthy volunteers and patients with mild asthma. The majority of subjects received a single dose  but one group was safely administered 3 x single IV injections on one day, two hours apart. Toxicology studies in rats and dogs have shown that 3 x IV injection at two hour intervals of a 0.5mg/kg dose on the same day and then once per day for 14 days thereafter is safe and well tolerated.

In a range of preclinical in vivo studies a single administration of ‘1104 prevented the infiltration of inflammatory cells into the lung. This effect is seen consistently using a variety of allergens, despite the compound being metabolised within a few hours (blood half-life, 10 minutes). ‘1104 was also shown to increase the expression of A20, a key regulator of the inflammatory response.

We have identified an exciting and unique receptor target for ‘1104 which has not been reported before in the inflammatory cascade. We continue to elucidate a greater understanding of the receptor target and the MoA, which will establish a platform to generate new molecules for new disease indications.

The company is working on new and exciting routes of administration before commencing Phase 2 studies.

Due the COVID-19 pandemic, IRL201104 is not an approved or marketed drug or vaccine, but may potentially be a therapeutic approach that could be used preventatively to slow down ICU admissions if used at the right time.  Immune Regulation are in touch with the relevant authorities concerning whether any investigational use of IRL201104 should be considered.

COVID-19 the overwhelming potential pathology with those at highest risk to COVID-19 infection is uncontrolled activation of the immune system to combat infection, particularly overactivation of neutrophils.  However, in the vulnerable, the action of these mediators lead to the destructive inflammation that can lead to overwhelming inflammation, leading to death.  This outcome could be a result of the inflammatory response itself, or through the inability to fight off other respiratory bacterial of viral infections.  Hence, a key element of timing, is to allow neutrophils to combat the virus,  but not to induce overwhelming inflammation.

IRL201104 has been shown to quickly and markedly reduce lung infiltration of neutrophils in mice following bronchial challenge with lipopolysaccharide stimulating acute neutrophil activation.  IRL1104 has a very short circulation exposure following IV administration and acts on neutrophil infiltration quickly but in a transient manner, which may mean that it would be able to provide a marked, but temporary, reduction in lung neutrophilia, potentially allowing the lung some respite from the high level of inflammation.