Attune Pharmaceuticals, a biotechnology company focused on the discovery and development of novel oral small molecule therapeutics for the treatment of rare diseases, has announced the first preclinical data results for ATN-249, a novel orally administered plasma kallikrein inhibitor for the treatment of HAE. The data was presented in a late-breaking poster presentation at the 2017 American Academy of Allergy, Asthma & Immunology Annual Meeting (AAAAI) and highlighted a profile which suggests high potency with a wide therapeutic window and the potential for once daily dosing of ATN-249.
Studies demonstrated ATN-249 was highly selective and potent at plasma kallikrein inhibition in both biochemical inhibition and contact activation assays. “We are pleased with the performance of ATN-249, in particular, the relative activity against C1-INH, the standard of care in the relevant pre-clinical assays for kallikrein inhibition,” said Dr. Andrew McDonald, CEO of Attune Pharmaceuticals, “The data we have seen to date indicates that this lead drug candidate may be a potent, safe, orally-administered plasma kallikrein inhibitor for treatment of HAE and we intend to start Phase I in 2017.”
The poster outlined the results of several well-established preclinical assays. The studies included evaluation of selectivity by biochemical inhibition on plasma kallikrein relative to other serine proteases, potency by biochemical inhibition and contact activation assays in human plasma, and pharmacokinetic exposure in monkeys after a single oral administration of ATN-249.
- SELECTIVITY: ATN-249 was >2000-fold more selective at inhibiting plasma kallikrein versus other closely related serine proteases, including tissue kallikrein 5, plasmin, Factor Xa, Factor VIIa, thrombin, and tissue plasminogen activator (tPA)
- POTENCY: ATN-249 demonstrated ~10-fold greater plasma kallikrein inhibition relative to C1-INH in both biochemical inhibition and contact activation assays — an ex-vivo assay that closely represents clinical pharmacologyo In biochemical inhibition, ATN-249 had an IC50 of 2.7nM versus 25.4nM for C1-INH
o In contact activation assays, ATN-249 had an EC50 of 8.2nM versus 92.4nM for C1-INH
- PHARMACOKINETICS: A single oral dose of ATN-249 at 15mg/kg provided 24- hour exposure 30-fold greater than EC50
- SAFETY: No adverse events were observed at the highest dose (300mg/kg) when evaluated in 14-day non-GLP rat and monkey toxicology studies; safety evaluation in 28-day GLP studies are ongoing.
Based on the positive performance and excellent pre-clinical safety profile, Phase 1 clinical studies of ATN-249 are expected to start in the middle of this year to evaluate ATN-249’s safety, tolerability and pharmacokinetic profile in healthy volunteers.
Attune Pharmaceuticals is a pre-clinical stage biotechnology focused on the discovery and development of novel oral once-daily small molecule therapeutics for the treatment of rare diseases. Attune Pharmaceuticals is currently developing 2 programs in rare diseases: HAE and complement-mediated diseases. Attune Pharmaceuticals has identified ATN-249 as a lead candidate to treat HAE and will begin clinical testing in 2017.
(Source: Attune Pharmaceuticals)