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Real World Superiority Data May Not Be Enough To Boost GSK’s Breo In COPD – The Pink Sheet

Precision for Value’s Dan Renick offers his perspective on GSK’s Breo in The Pink Sheet.

The Pink Sheet

May 30, 2016

Real World Superiority Data May Not Be Enough To Boost GSK’s Breo In COPD

By Emily Hayes

Executive Summary

Breo Ellipta is associated with a lower rate of exacerbations in real world Salford study, but some analysts question whether it’s too late to turn performance around in a highly competitive, highly price-conscious market.

GlaxoSmithKline PLC‘s Salford Lung Study of its Relvar/Breo Ellipta inhaler in chronic obstructive pulmonary disease breaks new ground as a prospective, randomized, controlled trial in everyday health care practice started prior to launch, though analysts question the commercial impact.

The Phase IIIb Salford Lung Study was designed as a real world safety and efficacy study of the once-daily product, which combines the inhaled corticosteroid fluticasone furoate with the long-acting beta agonist vilanterol. The study was performed in Salford, near Manchester, UK.

“It’s a bit like a study in the wild rather than the zoo. It’s not rigidly controlled, it’s naturalistic.” – GSK’s Sue Collier

An important difference between this trial and other studies of real world outcomes is that it had a prospective randomized design. The study was also large, with 2,802 participants with similar baseline characteristics randomized 1:1 to Breo Ellipta with a long-acting muscarinic agonist (LAMA) or standard of care/physician’s choice, which could include monotherapy, dual therapy or triple therapy (inhaled corticosteroid (ICS), LABA and LAMA).

Another unique aspect was that the study was started in 2012, prior to approval in the US in May 2013 and the EU in November of that year (““Real-World” Breo Study: A Q&A With GSK’s David Leather” — “The Pink Sheet” DAILY, Nov. 27, 2013). At the time, the company was looking for ways to demonstrate value in a more constrained health care world in a way that a traditional study designed to control for bias and be “scientifically correct” could not.

The company said that it has a long track record of generating real world evidence to inform development across all therapeutic areas, including observational studies, but this study is a first in being a real world RCT done prior to launch. Sue Collier, head of medical operations for the study, said that the company is considering its application in other therapeutic areas.

The primary endpoint in the trial was exacerbation rates measured over one year directly using electronic health records from the National Health Service.

In a top-line release May 24, GSK reported that there was a significant 8.41% lower rate of exacerbations between Breo and the standard of care (p=0.025). Adverse event rates – severe and overall – were similar.

The data are very reassuring about the product’s effectiveness, commented Collier, who is also a general practitioner, in an interview.

In randomized controlled trials, the patient population is ideal but not always typical of the broad spectrum of patients prescribed a drug in the real world, the exec said. In an RCT, investigators dictate how a therapy is used, typically against placebo or a single comparator drug, and patients are brought in for frequent reviews. Also, patients are often filling out questionnaires regularly.

“All of those things have an impact on how the patients behave, because they are being observed closely,” Collier said.

Typically, the endpoints are hard, such as blood pressure and lung function, and may not measure things that matter to patients, such as how they feel and how often they need to go to the hospital and utilize health care resources, the exec said.

Feedback from health providers and physicians indicate there is demand for more studies reflective of real world situations and increasingly there is demand for proof that health care is being delivered in the most cost-effective way, Collier said.

Studies done to look at these issues are more typically observational, which carries a bias, Collier said. With the Salford Lung Study, the company sought to keep the scientific robustness of an RCT with a real world study. “We were trying to blend the best of both worlds,” she explained.

There were very few exclusion criteria – COPD patients typically have a range of comorbidities – and doctors had their choice of treatment. Electronic medical records were monitored directly to assess a wide range of factors, including filling scripts, primary care office visits, hospitalization rates and well-being as measured on a quality-of-life questionnaire. However, the questionnaires were done infrequently to avoid influencing behavior.

“It’s a bit like a study in the wild, rather than the zoo. It’s not rigidly controlled, it’s naturalistic,” Collier said.

Investigators collected massive amounts of data in the process. “Every time they go to the hospital, we know about it. Every time they go to see their GP, we know about it,” she said.

The plan is to publish other findings later this year, perhaps at the European Respiratory Society International Congress in September.

Commercial Impact Unclear

Breo could use some good news. As the successor to GSK’s twice-daily ICS/LABA Advair/Seretide (fluticasone/salmeterol), it has faced challenges in the market. The company had sought to differentiate Breo based on efficacy in addition to dosing convenience – easier use theoretically minimizes errors and improves outcomes. But in the SUMMIT study, Breo failed to show a mortality benefit against placebo for reducing exacerbations and the product has struggled to get a foothold commercially (“GSK’s Breo Fails To Reach Peak In SUMMIT Survival Study” — “The Pink Sheet” DAILY, Sep. 9, 2015).

Generics of Seretide are available in Europe and taking a bite out of sales. Advair generics are expected to launch in the US in 2017. Sales for GSK’s respiratory franchise dropped by 2% to £1,148m ($1,681m) in the first quarter, including £111m for Breo Ellipta.

Interviews with payers suggest that pricing is an important differentiator and plans will be imposing restrictions against branded drugs and offering incentives for patients to use generics when Advair goes off patent in the US, according to a May 12 Datamonitor report on reimbursement for COPD by analyst Astrid Kurniawan.

Payers have indicated that the minimum benefit expected for reduction in the rate of moderate-to-severe exacerbations in studies is 20% to 30%. Compared to that, an 8% reduction looks “modest,” Kurniawan commented.

Collier said that a 20% reduction might be expected in a traditional trial against a placebo or a medication that doesn’t impact exacerbations.

However, in the Salford study, patients could be given any medication that a doctor thought was appropriate, and stepped up or stepped down accordingly. At the start of the study, 86% were already on ICS treatment and 52% were on triple therapy with an ICS, LABA and LAMA.

“To see a benefit of over 8% in patients who were already fairly maximally treated is impressive,” Collier said.

The company is running a similar study in asthma and invested £80m in the two indications.

“More data are needed to understand the potential economic impact – the effect on the total cost of care – and therefore the value with payers”, according to Dan Renick, president of Precision for Value, a company that helps pharma and life sciences companies demonstrate the value and outcome of their products.

For example, it would be good to know the rate of hospitalizations and whether there is a bigger reduction in the rate of exacerbations in certain patient groups, which could allow tailoring of therapies based on need, he said.

Datamonitor’s Kurniawan notes that the Salford study had a great design, but it’s still questionable whether it will help Breo Ellipta at this stage as the study doesn’t address the issues that have been problematic for the drug in the market, such as dosing, and the real world data may not be enough to sway payers. Furthermore, Kurniawan notes that ICS treatment is becoming marginalized with the rise of LABA/LAMA combinations.

Positive results for Novartis AG‘s Ultibro Breezehaler, which combines the LABA indacaterol with the LAMA glycopyrronium, against Advair/Seretide in the FLAME study were recently released at the American Thoracic Society meeting and could accelerate this trend away from steroids, she said (“FLAME Shoots LABA/LAMA Combos Up To First Choice In COPD” — “The Pink Sheet,” May 23, 2016).

There may also be questions about application of the GSK trial beyond the geographic area where the study was conducted. Collier said that she expects the data may be generalizable to other parts of the UK as well as Europe and the US because ethnic variations are not an issue for the disease and treatment is similar. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines are used worldwide.

Such a study could be done anywhere electronic medical records are available in an integrated health system, as long as general practitioners and pharmacies are willing to participate. About 80 GP practices and 130 pharmacies took part in the Salford study and there was a “huge training effort” for these professionals, who had never done research before, Collier said.

In parallel with the Salford Lung Study, Glaxo performed the COPD-CPRD Hawthorne Effect Study in Salford (CHESS), which will assess the generalizability of results from Salford to other communities in the UK and whether all the training and education of the health care practitioners in Salford improved the standard of care in the community. Results are expected later this year.

Real World Momentum

Whether or not the Salford study has any commercial impact remains to be seen, but the study itself is part of an important trend as drug sponsors try to win over payers with alternate evidence to demonstrate the full value of their drugs (see sidebar). Respiratory diseases, with their chronic nature, broad populations and numerous therapeutic options, have been a target for payers to crack down, and thus an area where manufacturers are experimenting with providing different types of data.

GSK Leads Way With Real World Data, But Others Follow

The firm’s hands-off pragmatic trial in the UK paves the way for real world studies in other disease areas where there are many products and arguably little differentiation to sway payers on market access.

The real world impact shown by Salford is part of that, but GSK is not done. One thing still unknown about the Salford results is how the difference in exacerbations affected hospitalization rates; that data could become available later this year along with a more in-depth assessment. Clearer evidence about outcomes could have more of an effect on Breo’s reimbursement and performance.

“Breo’s main challenge was that it entered into a saturated market experiencing downward pricing pressures as a result of generic entry in the ICS/LABA class. Its once-daily formulation isn’t really viewed as an advantage worthy of better pricing or reimbursement,” Kurniawan said in an interview.

“In the EU, Breo is reimbursed nationally for COPD, but regionally, the product has struggled,” she noted, with some local formularies excluding the drug. In the US, the product was initially excluded from coverage by CVS Health Corp.‘s pharmacy benefit manager CVS/caremark and Express Scripts Holding Co., which hurt the launch. By 2016, the product secured branded preferred tier status from three payers – Cigna Corp., Humana Inc. and, for the first time, Aetna Inc.

“Breo now has the same formulary placement as Advair within Aetna’s three-tier open formulary,” Kurniawan said. “These changes are expected to moderately increase the uptake of Breo and are a favorable sign that the payers are now satisfied with the rebate agreement set for the once-daily drug.”

“In my opinion, payers are looking to capitalize upon the patent expiration of Advair and using lower-priced generics to manage inhaler spending. That is their priority at the moment, and unfortunately, while these results demonstrate that Breo can be effective in real world settings, the success of Breo will come down to the price that GSK can negotiate with payers,” Kurniawan commented.

Key opinion leaders advising payers in Europe expressed mixed views on the value of real world data. Some told Datamonitor that real world practice is rarely assessed in a scientific way – studies are biased and therefore have a limited role, though they may be considered in price negotiations. Others said that real world data are useful, but the results need to be tied to financial impact, and usually this type of data isn’t available at the time regulators are making decisions.

The limited results available right now don’t look significant enough to change reimbursement policy in the UK, let alone the rest of the Europe and the US, said Kurniawan.

More Competition Coming

Furthermore, the role of the entire ICS/LABA class is diminishing in COPD, the analyst noted.

The LABA/LAMA class had already been viewed as superior to LABA/ICS for non-exacerbating COPD and the new results from FLAME establish its superiority in exacerbating COPD, Datamonitor notes. Primary care doctors have been faithful to Advair, regardless of the past results, but payers may be persuaded to implement education programs about the superiority of LABA/LAMA if there is a change in guidelines.

On top of that, Breo will also be competing with triple combination inhalers currently in development, the analyst noted. GSK, Chiesi Farmaceutici SPA and AstraZeneca PLC have triple combinations in Phase III. When these launch, patients taking an ICS/LABA with a LAMA therapy will most likely switch to triple inhalers, Kurniawan said.

“I am not convinced that the results from the Salford study will do much to address its existing predicaments,” the analyst said.

Precision Medicine Group is an integrated team of experts in fields from advanced lab sciences to translational informatics and regulatory affairs, payer insights to marketing communications. Together, we help our pharmaceutical and life-sciences clients conquer product development and commercialization challenges in a rapidly evolving environment.