RESEARCH UPDATE BULLETIN January 2014

Transcription

1 RESEARCH UPDATE BULLETIN January 2014 Exclusive to COPD Therapy Trends clients, Impact Assessments are dynamic analyst bulletins evaluating the impact of events over the next 12 months. Impact Assessments convey views of key opinion leaders delivered within days of a significant event happening, providing a continuous updated report. What s new? GlaxoSmithKline s Anoro receives US approval for COPD In December 2013, GlaxoSmithKline s Anoro, a once-daily fixeddose combination of umeclidinium and vilanterol, was approved in the US for the long-term maintenance treatment of COPD. 1 GlaxoSmithKline developed umeclidinium, a long-acting muscarinic antagonist (LAMA) and licensed vilanterol, a long-acting beta agonist (LABA) from Theravance. Anoro is the first LABA/LAMA combination to be approved by the US Food and Drug Administration (FDA). Novartis, Almirall/Forest, AstraZeneca and Boehringer Ingelheim are also developing LAMA/LABA fixed-dose combinations for the US market. This is a wonderful development because you get a better result with a LABA/LAMA combination than with the LAMA alone. The combination is superior in efficacy to either component separately, so why not give the patient the benefit of the doubt in terms of achieving a greater improvement in lung function? It should translate into a greater improvement in shortness of breath, exercise tolerance, and reduction in exacerbations and need for rescue medication use. Opinion leaders highlighted that Anoro may improve adherence, as the product is more convenient than administrating a LAMA and LABA in two inhalers. ISSUE 1 CONTENTS GlaxoSmithKline s Anoro receives US approval for COPD The FDA only approved the lower dose strength of umeclidinium Anoro lacks an exacerbation claim Where will Anoro be positioned in guideline recommendations? Anoro has a boxed warning that LABAs increase the risk of asthma-related death Anoro represent a very significant advance because anything that improves adherence is clinically worthwhile. Having it in the same device will be convenient and probably will improve adherence. US Key Opinion Leader 1 GlaxoSmithKline. ANORO ELLIPTA approved as first once-daily dual bronchodilator for the treatment of COPD in the US. 18th December All Contents Copyright January 2014

2 The FDA only approved the lower dose strength of umeclidinium GlaxoSmithKline had sought approval of two dose strengths in the US: umeclidinium 62.5mg/vilanterol 25mcg and umeclidinium 125mg/vilanterol 25mcg; only the lower dose was approved. Opinion leaders believed that the failure to gain approval of the higher umeclidinium dose probably does not matter and that Anoro works fine at the lower approved dose. The FDA is a conservative organisation when it comes to safety. If you look at the umeclidinium dose response studies, the highest dose of 500mcg was associated with more side effects, but there wasn't much difference between 250mcg and 125mcg. The dose response with respect to efficacy of LAMAs is relatively flat and since you get quite a robust response even at lower doses, the FDA preferred to go with the lower dose even though there wasn't much of a safety difference. It doesn t surprise me that the FDA takes a conservative approach with respect to the dosing. The drug works fine at that dose. It's a reasonable bronchodilator. An application was made to the European Medicines Agency (EMA) in January 2013 with the same two dose strengths used in the US application. Although the FDA did not approve the higher dose, the EMA may do so given that the regulator approved higher doses of GlaxoSmithKline s Seretide/Advair and Novartis s Arcapta/Onbrez than the FDA. Anoro lacks an exacerbation claim The Anoro Phase III programme did not include exacerbation endpoints (US approval was granted based on the primary endpoint of trough FEV 1). Ongoing pivotal trials with LAMA/LABAs developed by Boehringer Ingelheim, Almirall/Forest and AstraZeneca also do not include exacerbation endpoints (only the EU filing of Novartis s LABA/LAMA, Ultibro, included exacerbation data from the SPARK trial. 2 ) An opinion leader believed head-to-head trials of LABA/LAMAs are required to demonstrate non-inferiority (and ideally superiority) to ICS/LABAs, particularly in terms of exacerbation reduction. LABA/LAMA combinations have to be compared with ICS/LABA combinations with respect mainly to reduction in exacerbations, because it's the inhaled corticosteroid component of the ICS/LABA combination that is advocated for the prevention of exacerbation. GlaxoSmithKline s ICS/LABA products, Breo and Seretide/Advair, have both been granted a US label claim for reduction of exacerbations. GlaxoSmithKline may position Anoro, at least initially, as the treatment of choice in COPD patients with moderate disease (where an exacerbation claim is not required in most patients) and Breo as the preferred treatment in COPD patients with severe or very severe COPD. Opinion leaders firmly believed GlaxoSmithKline should conduct exacerbation trials with Anoro. 2 Wedzicha JA et al. Analysis of Chronic Obstructive Pulmonary Disease Exacerbations with the Dual Bronchodilator QVA149 Compared with Glycopyrronium and Tiotropium (SPARK): a Randomized, Double-blind, Parallel-group Study. Lancet Respir Med 2013 All Contents Copyright January 2014

3 Anoro needs to be compared with an ICS/LABA. GlaxoSmithKline needs to conduct trials in which exacerbations are the primary endpoint and show efficacy in terms of significantly reducing exacerbations compared to either component alone. Is it important for GlaxoSmithKline to do a trial? The answer is absolutely. It is really important that there be fewer exacerbations with Anoro. As of December 2013, no Anoro studies were identified in clinicaltrials.gov that include exacerbation endpoints. Novartis is conducting a head-to-head study with glycopyrronium/indacaterol and fluticasone/salmeterol (study number NCT ) which is recruiting patients with a history of COPD exacerbations. This trial, which is expected to be completed in 2015, will likely be the first to determine which therapy (LABA/LAMA or ICS/LABA) is more effective in reducing exacerbations. My prediction is that LAMA/LABAs will be shown to be superior to ICS/LABAs because tiotropium has already been shown to be equivalent to Advair in terms of reducing exacerbations. Since LABA/LAMAs are superior to the LAMA alone in terms of improving the lung function, LABA/LAMAs may prove to be at least as efficacious and possibly more efficacious than ICS/LABAs in terms of reducing exacerbations, a key aim in the management of COPD. Where will Anoro be positioned in guideline recommendations? The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 3 guidelines categorise COPD patients into four groups, A to D. For Group B patients, a long-acting bronchodilator (LABA or LAMA) is recommended as initial therapy; in Group B patients with severe breathlessness, combination treatment with a LABA and LAMA can be considered. The recommended first line therapies for Group C and D patients are ICS/LABA or a LAMA, with some evidence supporting the use of triple therapy (ICS/LABA and LAMA) in Group D patients. An alternative treatment option in group C and D patients is dual treatment with a LAMA and LABA, based on evidence that both reduce the risk of exacerbations and although good long-term studies are lacking, according to GOLD. LABA/LAMAs are recommended as a second choice by the GOLD guidelines. There's not that much evidence, so we need to expand the evidence base. We also have to look at the long-term safety, because both LABAs and LAMAs have potential effects on the heart. Most pulmonologists like starting a LAMA first. Most people will still be symptomatic and so a dual combination is reasonable and you could make the case that it would be reasonable from the beginning. 3 Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for Diagnosis, Management, and Prevention of COPD. All Contents Copyright January 2014

4 Additional studies with Anoro may be required to determine positioning in the GOLD guidelines. In particular, this may require data in Group B patients that demonstrates the advantages of Anoro over either component given alone. GOLD may recommend Anoro as an alternative treatment option in Group C and D patients, although for GOLD to recommend Anoro as a first-choice therapy, evidence of non-inferiority (and ideally superiority) versus ICS/LABAs in terms of reduction in exacerbations may be required. Further data may also be required that compare Anoro with triple therapy of ICS/LABA plus free-dose LAMA. It would be worthwhile to determine whether Anoro should be a first choice in Group B patients. For Group C and D, there is not much doubt it should be a first choice, but more evidence may be needed. Another question is whether there is any advantage of triple therapy over Anoro in patients with severe or very severe COPD with a history of exacerbations. It would be an interesting study to compare Anoro with LABA/ICS plus LAMA. The uptake of Anoro could be accelerated if it is shown the product reduces healthcare utilisation, as this would support favourable formulary decisions. The pricing of Anoro relative to products such as Advair and Spiriva will also likely influence uptake. In the US, managed care organisations are primarily interested in reducing cost. If it could be shown that Anoro saves money they'd be more likely to include the combination in their formulary. I d prefer to initiate therapy with a LABA/LAMA in any symptomatic COPD patient as you have the advantage of additive effects with regard to lung function. But that's going to be largely driven by what the insurance companies allow. I suspect that where Anoro will fit in the treatment paradigm will depend most importantly on the cost. A prescription for Advair or Spiriva might be $300 a month. If it's sold at a 20 percent premium to that it's not going to be very popular. If it's sold at a discount to that it might be very popular. The uptake of Anoro as initial maintenance therapy may be highest in COPD patients with moderate disease, especially those patients who have persistent symptoms with either LABA or LAMA monotherapy and require a second bronchodilator. This introduces a drug sequencing issue when an ICS is indicated. No free-dose ICS are approved for COPD in the US. Off-label free-dose ICS could be added to Anoro, although to treat within label recommendation, patients would need to be switched to an ICS/LABA (Breo, Seretide/Advair, or Symbicort) plus free-dose LAMA. If patients do not do well on Anoro, you either add on a free-dose ICS, which is neither recommended nor approved as monotherapy for the treatment of COPD, or you stop Anoro and switch to a LABA/ICS and add on a free-dose LAMA such as tiotropium or aclidinium. It's a really complicated question. I don't think anybody really knows the answer to that question. Triple combinations will eventually facilitate this kind of step up. All Contents Copyright January 2014

5 Anoro has a boxed warning that LABAs increase the risk of asthma-related death The FDA requires that all products containing a LABA include a boxed warning following results from the Salmeterol Multi-center Asthma Research Trial (SMART), which showed an increase in asthma-related deaths in patients receiving salmeterol. A consequence of the boxed warning is that physicians may be cautious about prescribing Anoro (without an ICS) in COPD patients who they suspect may have asthma, as this is contraindicated. This suggests ICS/LABAs may remain the preferred initial maintenance therapy in some COPD patients, although one opinion leader believed the boxed warning would not discourage Anoro prescribing very much. The boxed warning is meant to scare physicians. Physicians do pay attention to it as we live in a very litigious society. There is a theoretical concern that if 20 percent of patients with COPD also have an asthma component, would they be at similar risk? There often is diagnostic confusion as to whether patients have asthma or COPD or, if they have COPD, have an asthmatic component. I think physicians would feel more comfortable prescribing a LABA in combination with an inhaled corticosteroid as a first line therapy, because physicians are concerned about the safety of LABA monotherapy. I don't think it's going to discourage use very much. The boxed warning already exists on all LABA containing products and they're widely used. All Contents Copyright January 2014