Allergen Delivery Inhibitors

Description:

A developable candidate drug that displays in vivo efficacy in animal models with a good duration of action when delivered to the airways.

Background

Asthma remains a condition with significant unmet needs. Exacerbations of the disease result in intense breathlessness, frequently requiring hospitalisation, and are potentially fatal. There will be 400 million sufferers by 2025. House dust mites (HDMs) are globally prevalent and potently allergenic. As the most common indoor cause of allergy, they are of major clinical significance because they are pervasive and persistent triggers of asthma attacks.

The Wellcome Trust funded a collaboration between St George’s, University of London, and the University of Manchester which has identified potential asthma / allergy treatments (Allergen Delivery Inhibitors, or ADIs) that uniquely work as root cause interventions by inhibiting the cysteine peptidase activity of group 1 HDM allergens. This family of cysteine peptidases are serodominant initiator allergens which make significant contributions to the development, maintenance and escalation of allergic responses to themselves and unrelated allergens.

With the first selective agents aimed at this target family, and a strong associated IP portfolio, it is believed that this approach provides a major advance either as monotherapy or in combination with established medicines.

Technology Overview

The Allergen Delivery Inhibitor (ADI) Programme provides an alternative therapeutic solution.

A developable candidate drug (CD1) that displays in vivo efficacy in animal models with a good duration of action when delivered to the airways has been identified. CD1 is supported by several developable back-ups and a further, mechanistically distinct, chemical series.

These novel inhibitors of HDM cysteine peptidase allergens have low nanoMolar inhibition constant (nM Ki) values and exhibit good selectivity over off-target peptidases, receptors and other enzymes. Their molecular and physicochemical properties have been optimised for inhaled delivery from a range of devices, including dry powder inhalers and pressurised metered-dose inhalers. Low oral bioavailability and rapid systemic clearance further de-risk their safety profile. The ADI candidate drug (CD1), designed for inhalation, is ready for IND enabling studies.

Publications

Benefits

ADIs show excellent efficacy in models when delivered to the airways. Their pharmacokinetic profiles have been designed for compatibility with delivery by inhalation and provide protection that is suggestive of once- or twice-daily dosing in humans. In addition to actions against established allergy, compounds from the programme significantly inhibit the development of allergen-specific immunoglobin E (IgE) -mediated sensitisation, which is indicative of a unique potential for prophylactic action.

Applications

Clinical development will fast follow pharma’s narrow spectrum injectable biological therapies for the severest types of asthma.

An important difference with the pharma approach is that the university will use already existing affordable clinical tests to one-time identify ADI responders. This will avoid the need for development of a new companion diagnostic or complex treatment algorithms for regular patient visits, saving significant cost, complexity and time for healthcare professionals.

The team at St George’s, University of London, which has outstanding experience with respiratory product development and inhalation, has designed the physiochemical properties of ADIs to take advantage of the multiple benefits of dry powder inhalation delivery. A route familiar to many millions of patients around the world and the basis of significant recent investment by pharmaceutical companies. Inhalation devices available from numerous suppliers can be used within the proposed clinical development programme. Ultimately, they believe the expected clinical benefits and the dry powder properties of the ADIs will create a powerful opportunity for partnership(s) with the respiratory franchise of major pharmaceutical companies. ADIs will allow these companies to extend the use of their inhalers and more importantly alter the course of disease and transform asthma for patients.

Opportunity

Overall, success for ADIs in the launch indication will pioneer several product offerings of unprecedented disease modifying potential for patients. Firstly, to address the specific unmet need for better control in moderate to severe asthmatics and reduce the number of exacerbations which patients experience. Secondly, there is potential synergy with the injectable biologicals, targeted at severe asthma, where the biologicals will likely be coming off patent when ADIs become new drugs. ADIs offer a lifecycle extension for these biologicals. Thirdly, the opportunity for ADIs to reduce the use of steroids by developing steroid tapering combination products which will focus on milder asthma disease types and ultimately all age groups. Reduction in use of steroids should improve both patient compliance and reduce anxiety for parents with diagnosed children and improve public health.