AZD4604
Preclinical pharmacology
AZD4604 is a potent and selective inhibitor of Janus kinase family member, JAK1, intended for inhaled add-on treatment of moderate to severe asthma, uncontrolled on standard of care. Due to the broad anti-inflammatory properties of JAK1 inhibition, AZD4604 is predicted to provide benefit to steroid sensitive and insensitive asthma endotypes, thereby offering a differentiation opportunity from existing biologics.
In a preclinical ovalbumin-challenge rat model of allergic asthma, lung and systemic delivered AZD4604 showed reduction of pSTAT3 and pSTAT5, indicating target engagement in the lung. Furthermore, AZD4604 administration suppressed late allergic response and airway inflammation to a similar level to that achieved with an ICS comparator, budesonide.
Safety and tolerability
The first-in-human study in with AZD4604 (xinafoate salt) in healthy volunteers is ongoing. Human safety and tolerability data is therefore not yet available. Safety and tolerability information from preclinical toxicology studies is summarised below:
Inhalation administration of AZD4604 xinafoate has been tolerated in toxicology studies in the rat (up to 6-months) and dog (up to 9-months). In the rat, reductions in respiratory rate and tidal volume have been observed, however these changes were not observed in the dog. Pathological changes consistent with irritation have been observed in the respiratory tract, but at dose levels greater than those to be used clinically. Infections were detected in several dogs at the highest dose level tested in the 9-month toxicology study, however no infections occurred at the lower dose levels, at which achieved systemic exposures were greater than those expected clinically.
Clinical pharmacology
The first-in-human study in healthy volunteers is ongoing. Drug-drug interaction risks with sensitive CYP1A2, CYP2B6 and CYP3A4/5 substrates cannot be excluded based on available preclinical data.
Suitable for and exclusions
AZD4604 xinafoate salt delivered by oral inhalation, is suitable for pre-clinical and Ph1 or Ph2 clinical investigations in adult male and female subjects (of non-child-bearing potential or with appropriate contraception), subject to the successful completion of the ongoing first-in-human study in healthy volunteers
Mechanism of Action
Janus kinase 1 inhibitor
Original Therapeutic Area
Respiratory and Immunology
CNS Penetrant
Low
Route of administration
Inhaled
Modality
Small Molecule
