Building the inhaled product pipeline
Skyepharma has industry-leading expertise and technology in developing and manufacturing inhalers for the treatment of asthma and COPD, which combined, addresses a c $29bn global market. One only need look to its existing partner base to see the myriad of mid to large global pharmaceutical players that are reliant on Skyepharma’s technology.
Professor Dave Singh of the University Hospital of South Manchester, an eminent pulmonologist, outlined the more recent advances in the understanding of COPD pathophysiology. As a reminder, COPD is a chronic respiratory disorder linked to cigarette smoking and characterised by reduced lung function and severe shortness of breath, with worsening exacerbations triggered by viruses, bacteria and pollution; one in 10 hospitalised patients do not survive upon that admission. Treatment is more symptomatic, and under GOLD guidelines varies depending on classification of COPD and the patient’s severity. The mainstay of treatment is LAMA/LABA/SABA/SAMA. More severe patients also receive inhaled corticosteroid (ICS); the addition of an ICS to LABA leads to a 14% reduction in the mean number of exacerbations than LABA alone, compared to a 25% reduction compared to placebo (Exhibit 1).
Exhibit 1: Effect of inhaled corticosteroids
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Source: Calverley et al. NEJM 2007
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Part of the reason for this mediocre overall 14% reduction is due to corticosteroid resistance in COPD, linked to downregulation of Histone Deacetylase 2 (HDAC2, a protein coding gene). Corticosteroids use HDAC2 to switch off activated inflammatory genes. Exhibit 2 highlights the pathway to ICS resistance mediated by HDAC2 downregulation.
Furthermore, the current treatment paradigm does not differentiate between the different endotypes of COPD. An endotype is defined as a subtype of a clinical condition defined by a distinct pathophysiological mechanism. Combining the latter points lead us to the crux of SKP-2075, through the potential optimum combination of ICS and low-dose theophylline in a metered dose inhaler.
Exhibit 2: Corticosteroid resistance in COPD: HDAC2 downregulation
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Source: Ito et al. NEJM 2005
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What can be done to address corticosteroid resistance as a direct result of HDAC2 downregulation?
A drug with proven efficacy in COPD is theophylline, which is often given orally and intravenously in the acute setting to aid control of an exacerbation. However, systemically administered theophylline is associated with intolerable side effects, which can limit its use in the chronic setting at the current high oral dose indication. Theophylline works to alter the P13K signalling pathway, which in turn affects HDAC2 and increases its expression. By administering theophylline by the inhaler route, a lower dose of drug can be delivered directly to the diseased lung tissue and bypassing the side effects associated with high-dose systemic administration. In summary, combining ICS with low-dose theophylline should theoretically elicit a higher immunomodulatory response than ICS alone.
Is there a subtype of COPD that can be identified as more responsive to ICS?
An endotype of COPD is COPD/smoking asthma, where the underlying pathology resembles asthma with an influx of a particular inflammatory cell type; the eosinophils. In fact, post-hoc clinical trial analysis has shown that inhaled corticosteroids have greater utility in patients with high sputum eosinophils or high blood eosinophils.
A GSK-funded post hoc analysis of data from two phase III studies published by Pascoe et al (Lancet Respir Med 2015) highlighted the short-term benefits of inhaled corticosteroids for patients with COPD are greater in patients with evidence of eosinophilic airway inflammation. Across all doses of inhaled corticosteroids, fluticasone furoate and vilanterol reduced exacerbations by 29% compared with vilanterol alone (mean 0.91 vs 1.28 exacerbations per patient per year; p<0.0001) in patients with eosinophil counts of 2% or higher; whereas exacerbations were reduced by just 10% (0.79 vs 0.89; p=0.2827) in patients with eosinophil counts lower than 2%.
Effectively, this is an example of personalised medicine, where a specific marker can be identified to tailor treatment accordingly. In summary, ICS has great utility in COPD/smoking asthma patients with a high blood eosinophil level. Note that this is an easy and cheap blood test.
Why is SKP-2075 suitable?
Therefore, it is clear from the hypothesis outlined above how SKP-2075, which is an inhaled fixed dose combination ICS plus low-dose theophylline to enhance the anti-inflammatory potential of ICS, represents a new approach for the treatment of COPD/smoking asthma characterized by eosinophilia.
SKP-2075 a star of the show
Skyepharma acquired global rights and related intellectual property (including granted patents and patent applications) to a novel inhaled therapy platform from Pulmagen Therapeutics in 2014. SKP-2075 (a single capsule dry powder inhaler, comprising the ICS fluticasone propionate in combination with low-dose theophylline) is the first product developed through this technology since the acquisition. While good progress is being made in formulating the product and the start of non-clinical studies, the company has outlined a clinical trial programme designed to offer a relatively quick development pathway for Europe, with a comprehensive Phase II data dossier to maximise the economic returns for the partnering process. Specifically, the updated development programme is as follows:
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Start a Phase I tolerability study in healthy volunteers, and initiate a dose-ranging trial of theophylline in Phase II.
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Preparations are underway for a Phase II study of a size large enough to produce meaningful statistically significant clinical data (refinement of statistical sizing to >500). The company estimates this to start in 2016 (treatment duration 12 weeks) and complete in 2017, so headline data could read-out in H217. The target population are patients with features of asthma and COPD that are anticipated to benefit from ICS in the light of hypothesised mode of action of low-dose theophylline.
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Aim to partner following proof-of-concept Phase II data, with the partner funding the larger-scale study programmes that would be required for approvals.
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Potential combination opportunities with LABA, LAMA and LABA/LAMA.
The investment required to formulate a suitable inhaled dosage form and complete the Phase II POC trial is estimated at around £18m through to the end of 2017 (£14m previously disclosed, plus a further £2m per annum in 2016 and 2017 announced at the CMD for the additional studies), and will be funded from internal cash generation including additional revenues from flutiform. Under the terms of the deal with Pulmagen, there is no upfront or fixed fee, with Pulmagen receiving launch milestones (in specified but undisclosed markets), and a share of Skyepharma’s licensing income from any eventual deal. The proportion of this share will reflect the amount of work that has had to be performed in developing SKP-2075.
If the potentiating effect of low-dose theophylline on ICS therapy is confirmed in larger and more robust trials, it could find a useful role in treating all stages of COPD, with a possible role as an integral part of the widening range of inhaled combinations being employed. From a commercial perspective, such combination products would benefit not only from additional patent protection, but would also offer greater differentiation in an increasingly complex and crowded therapeutic segment. Despite the attraction of this therapy platform, we currently do not include any explicit forecasts for SKP-2075 in our DCF model.
SKP-2076 to broaden the respiratory offering
Skyepharma has started feasibility work on its triple ICS/LABA/LAMA combination product for the treatment of asthma patients who are not adequately controlled on currently available combination ICS/LABA products. The rationale follows emerging data that the addition of a LAMA may confer higher bronchodilator efficacy and reduction in exacerbations over ICS/LABA combinations alone. The UniTinA- asthma programme presented at ERS 2014 showed that the addition of Boehringer Ingelheim’s Spiriva (LAMA) to ICS/LABA maintenance therapy reduced the risk of a severe asthma exacerbation by 21% (Kerstjens et al, NEJM 2012). Skyepharma joins a limited number of pharmaceutical players developing a triple combination inhaler for asthma, including Novartis and Boehringer; however, given the relative size of the asthma market (£9.7bn in 2014) there is room for multiple players developing a triple therapy. ICS/LABA will likely remain the mainstay of therapy.
Skyepharma has identified the following characteristics to target while it makes good progress with initial formulation: one device with known chemical entities, aiming for twice-daily dosing and a rapid onset of action.
The next step is to move SKP-2076 into GMP scale manufacturing in 2016. Furthermore, the company is engaged in partnering discussions to license and further fund development post the initial formulation stage.