NEW YORK—Attune Pharmaceuticals, a biotechnology company focused on the discovery and development of novel oral small-molecule therapeutics for treatment of rare diseases, recently announced preclinical data results for ATN-249, a novel orally administered plasma kallikrein inhibitor for the treatment of hereditary angioedema (HAE). The data was presented in a poster presentation at the 2017 American Academy of Allergy, Asthma & Immunology Annual Meeting (AAAAI 2017), and highlighted a profile which suggests high potency with a wide therapeutic window and the potential for once-daily dosing of ATN-249.
“We are pleased with the performance of ATN-249, in particular the relative activity against C1-INH, the standard of care in the relevant preclinical 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 1 in 2017.”
When asked how ATN-249 differs from other drugs in its class, McDonald responds, “Kalbitor (ecallantide) is an approved injectable product that is also an inhibitor of plasma kallikrein.” As for ATN-249’s working mechanism and its similarity or dissimilarity to other HAE drugs, McDonald says, “ATN-249’s mechanism is similar to other drugs for the treatment of HAE in that they all inhibit the production of bradykinin.”
HAE is a rare, potentially life-threatening disease characterized by acute skin and mucosal edema. It is caused by an autosomal dominant mutation of the SERPING1 or F12 genes, resulting in diminished C1 inhibitor levels and/or function. Dysregulation of the contact-kallikrein pathway mediated by dysfunctional C1 inhibitor causes upregulation of bradykinin production, leading to increased vascular permeability, recurrent abdominal pain and mucosal swelling, which can be fatal with laryngeal involvement. Current treatments are limited by route of administration and adverse events, since all HAE drugs are administered intravenously or subcutaneously, and may be associated with drug-specific adverse effects.
The poster presented at AAAAI 2017 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.
According to the study, ATN-249 was over 2,000-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. ATN-249 demonstrated about tenfold greater plasma kallikrein inhibition relative to C1-INH in both biochemical inhibition and contact activation assays. A single oral dose of ATN-249 at 15 mg/kg provided 24-hour exposure 30-fold greater than EC50. 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 preclinical safety profile, Phase 1 clinical studies of ATN-249 are expected to start in the middle of 2017 to evaluate ATN-249’s safety, tolerability and pharmacokinetic profile in healthy volunteers.
When DDNews asked if Attune has any other drugs or projects in the pipeline, McDonald simply says, “Attune is also working in the area of complement mediated diseases.” According to Attune’s website, “Attune Pharmaceuticals has discovered novel small-molecule inhibitors of a key component of the complement system. The complement system is an important part of the innate immune system and is comprised of a group of serum proteins that are activated through sequential protease based steps. There are three major pathways of complement activation: the classical, the alternative and the lectin.”
“In certain diseases, activation of the complement system results in pathogenesis,” Attune’s website continues. “For example, in HAE, patients are deficient in C1-INH (C1-inhibitor). The absence of this key inhibitor results in hyperactivation of the classical complement pathway. When activated, high molecular weight kininogen is cleaved by plasma kallikrein, releasing high levels of bradykinin, which causes edema. Attune Pharmaceuticals is advancing oral-small molecule inhibitors of plasma kallikrein, which will restore normal levels of bradykinin, potentially preventing or reducing the frequency of HAE attacks.”