Therapeutic focus – Interleukin modulators crowd pipeline for severe asthma

By mid-2014 the industry should have a good idea of whether attacks of a severe form of asthma can be prevented by suppressing immune response. Phase III trials of Teva’s Cinquil are expected to wrap up sometime this year, while GlaxoSmithKline’s mepolizumab should report mid- and late-stage data in the first half of next year. This will give researchers a sense of how well eosinophilic asthma can be controlled by modulating the action of interleukins.

Last week, Sanofi and Regeneron Pharmaceuticals reported positive phase II data from their antibody dupilumab, which when combined with an anti-inflammatory and bronchodilators significantly reduced the frequency of asthma attacks compared with placebo. The space is getting crowded, however – a scan of the pipeline shows at least 10 antibodies seeking to improve exacerbations, and small-molecule kinase inhibitors are also trying to elbow their way in (see table).

Wrong reaction

Somewhere around half of all asthma is believed to be of allergic origin related to inflammation caused by eosinophils – white blood cells that are responsible for fighting multicellular parasites and other infections, but which also play a role in allergic response. Dysfunctional allergic response leads to chronic inflammation of airways, and puts patients at higher risk of asthma attacks.

Patients can be identified by elevated eosinophil counts in their sputum, and indeed such elevations can begin developing weeks before an attack. Thus, patients with poorly controlled asthma could benefit from lowered eosinophil counts, offering the potential of a therapy that could treat the underlying disease processes rather than symptomatic control offered by corticosteroids and beta 2 adrenoreceptor agonists. It is estimated that some 38 million people in the USA will suffer from an eosinophilic asthma event in their lifetime.

The leading candidates in the space are antibodies that aim to bind to interleukins, which signal the maturation, recruitment and survival of eosinophils. However, another approach to blocking the signalling cascade is to bind to interleukin receptors, which is what the Sanofi and Regeneron antibody does, along with Aerovance’s recombinant protein Aerovant, now in phase II, which unlike the antibodies has been tested as an inhaled dry powder formulation.

Clinical-stage candidates for eosinophilic asthma
Product Generic name Pharmacology class Company Originator Trial ID
Phase III Bosatria mepolizumab Anti-interleukin-5 (IL-5) MAb GlaxoSmithKline SmithKline Beecham NCT01691521
Cinquil reslizumab Anti-IL-5 MAb Teva Pharmaceutical Industries Schering-Plough NCT01270464
Phase II AIN457 secukinumab Anti-IL-17 MAb Novartis Novartis NCT01478360
RG3637 lebrikizumab Anti-IL-13 MAb Roche Tanox First patient in PhIII Q3 2013
AMG 827 brodalumab Anti-IL-17 MAb AstraZeneca/Amgen Amgen NCT01199289
REGN668/ SAR231893 dupilumab Anti-interleukin-4 receptor (IL-4R) MAb Sanofi/Regeneron Pharmaceuticals Regeneron Pharmaceuticals NCT01312961
Benralizumab benralizumab Anti-IL-5 MAb AstraZeneca/Kyowa Hakko Kirin Kyowa Hakko Kogyo NCT01238861
ABT-308 - Anti-IL-13 MAb AbbVie Abbott Laboratories NCT00986037
QAX576 - Anti-IL-13 MAb Novartis Novartis NCT01479595
CAT-354 tralokinumab Anti-IL-13 MAb AstraZeneca Cambridge Antibody Technology NCT01402986
Aerovant IV pitrakinra IL-4 & IL-13 antagonist Aerovance Bayer NCT00801853
Aerovant pitrakinra IL-4 & IL-13 antagonist Aerovance Bayer -
R343 - Spleen tyrosine kinase (Syk) inhibitor Rigel Pharmaceuticals Rigel Pharmaceuticals NCT01591044
Phase I GSK2434735 - Anti-IL-13 MAb GlaxoSmithKline GlaxoSmithKline NCT01563042

Results soon

First up will probably be Teva’s Cinquil, a product picked up with Teva's acquisition of Cephalon in 2011 (Teva strives to meet growth targets with Cephalon buy, May 3, 2011). The monoclonal antibody has struggled to get any respect from analysts, who have yet to include it in their forecasts for the Israel-based group (Event – Teva looks to brand new success with Cinquil, December 3, 2012).

In phase II, the agent, infused intravenously, significantly improved lung function and reduced sputum eosinophils over 12 weeks compared with placebo, but just missed significance on improvements in asthma control questionnaire scores. 

GlaxoSmithKline’s Bosatria, which like Cinquil binds to IL-5, will be the next to read out phase III data, probably next year. Its phase III programme tests a subcutaneous and intravenous formulation, and will measure not only rates of exacerbations and lung function but also how well it reduces use of steroids and prevents exacerbations triggered by rhinovirus infections.

Expectations are growing for this candidate, with $229m in sales forecast for 2018, according to EvaluatePharma’s consensus. However, should it make it to market as predicted in 2016, it would mark a significant delay from original plans – the UK group had filed for European approval in hypereosinophilic syndrome and withdrew it after feedback from regulators.

A third candidate nearing late-stage trials is Roche’s lebrikizumab, or RG3637, an IL-13 antibody. This has two active phase II trials, but the Swiss company announced in October that it still needed to optimise manufacturing, and thus would be delaying pivotal work. Regulatory filing is not expected until after 2016.

Shotgun approach

Phase II has a mix of targets: IL-4, IL-5, IL-13 and IL-17. In addition to the Sanofi/Regeneron and Aerovance receptor targeting, Novartis has two agents in secukinumab and QAX576, targeting IL-17 and IL-13 respectively; AstraZeneca has three in AMG 827, benralizumab and CAT-354, which have emerged from partnerships with Amgen, Kyowa Hakko Kirin and Cambridge Antibody Technologies, and hitting IL-17, IL-5 and IL-13 respectively; and AbbVie’s ABT-354, focusing on IL-13. AMG 827 is also known as brodalumab, and is nearing a major phase III readout in psoriasis.

It is only in phase II that a different pathway is being targeted. Rigel Pharmaceuticals’ R343, a spleen tyrosine kinase (Syk) inhibitor, binds to mast cells and disrupts signalling from immunoglobulin E, a cascade that also plays a role in eosinophilic asthma.

Should the interleukin antibodies turn out less than promising in late-stage trials, it seems Rigel’s kinase inhibition approach could be the next opportunity to address the disease. Astra has gotten in on the ground floor here and locked up one of Rigel’s kinase inhibitors, a janus kinase that modulates the IL-13 pathway (Therapeutic focus - Astra and Rigel throw a JAK into the cytokine-targeting asthma box, June 21, 2012).

Even if the antibody approaches turn out effective, it may be that the tyrosine kinase products are preferable; as inhalation drugs, they would be attractive to a greater share of patients. As the interleukin-targeting antibodies begin to reach their pivotal readouts over the next couple of years, it will help clarify what sort of role the small molecule candidates might play.

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @JonEPVantage on Twitter

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