The rapid evolution of healthcare presents many challenges to drug developers; as many lucrative disease markets become mature, competing against a crowded field becomes ever more difficult. Additionally, as many healthcare problems are solved, the challenges that remain unanswered become progressively more difficult, forcing developers to tackle ever more challenging scientific problems, in some cases on top off grappling with changing guidelines and treatment algorithms. Chronic obstructive pulmonary disease (COPD) is well-treated compared with many other diseases, with multiple therapies in each of several available drug classes, and the trends in this market highlight many of the hurdles manufacturers in other markets may face in the future.
For a given therapy to achieve regulatory approval, placebo-controlled trials remain the gold standard. However, as the COPD market becomes increasingly crowded, comparisons to placebo are insufficient for a therapy to secure reimbursement, especially in European markets where regulators frequently require comparisons to a standard of care in order to grant market access and favorable reimbursement status. Such requirements are forcing manufacturers to include various comparator therapies in their clinical trial packages, but with rapid changes in the guidelines for COPD, it can be difficult for companies to stay abreast of the newest developments.
DRG’s extensive primary market research, incorporating both physician- and payer-based insights, reveals that both groups of stakeholders select therapies based on comparisons to the standard of care for COPD. However, the rapid evolution of the COPD market has made it difficult for manufacturers to select comparisons at the beginning of a trial that will still be relevant by the time the trial is completed, especially for those running long-term clinical trials to evaluate exacerbation frequency. That is, a trial may begin where the investigatory drug is compared against the existing standard of care, for example, long-acting beta2-agonist / inhaled corticosteroid fixed-dose combinations (LABA/ICS FDCs), but by the time it is completed and analyzed the guidelines for treatment have changed to support an alternative, such as long-acting beta2-agonist / long-acting muscarinic antagonist (LABA/LAMA) therapy, instead. Additional fluctuations in the definition of disease severity and debate around asthma/COPD overlap introduce additional complications.
The clinical development of GlaxoSmithKline’s respiratory portfolio illustrates how manufacturers have struggled to or succeeded in reaction to the changing definitions and guidelines for COPD. They will be the first respiratory manufacturer to successfully bring a triple therapy (LABA/LAMA/ICS) to market in the United States and have carefully built a portfolio that includes a LAMA monotherapy, a LABA/ICS, a LABA/LAMA, and the triple FDC all delivered in the same inhaler, performing overlapping clinical trials that supported multiple therapies in the portfolio. Development of Incruse, their LAMA monotherapy, and Anoro, the LABA/LAMA FDC, had substantial overlap in their clinical trials and regulatory submission, with multiple studies including both mono-components as trial arms, along with the FDC. Two of these trials also included tiotropium as an active comparator, excluding placebo entirely, although other trials included in the regulatory submission package were placebo-controlled. Direct comparisons were influential on the uptake of Anoro, and with comparisons to the market-leading Spiriva and Advair featuring prominently on its website, this example illustrates that if a therapy can compare itself favorably to the long-term market leaders, it can succeed in the market (anoro.com, accessed November 30, 2017).
However, the picture is somewhat more complicated for both Breo, the LABA/ICS in GlaxoSmithKline’s Ellipta portfolio, and for Trelegy, the recently approved triple therapy. Breo underwent an extensive clinical trial designed to compare it to usual care; results from the Salford Lung Study began to be released at the ERS conference in 2016. Instead of using a placebo control, this study compared patients receiving Breo against patients prescribed any other COPD therapy. Despite achieving the primary endpoints, interviewed pulmonologists remain skeptical of the results, indicating that the comparators in this study do not represent a true standard of care. Notably, the Salford study was done post-marketing, as the necessary placebo controlled trials were performed prior to securing regulatory approval.
While the Salford study was taking place, debate over the use of ICS continued, and results from the FLAME study were released; this study demonstrated that Ultibro, a LABA/LAMA FDC, had a superior ability to reduce exacerbations compared to Advair/Seretide, a LABA/ICS FDC. These results were incorporated into the GOLD international guidelines in early 2017, and ICS-containing therapies were removed from the preferred treatment algorithm for a majority of COPD patients. This move threatens uptake of both Breo and Trelegy, and makes their strategy of comparison to other ICS-containing therapies less influential. GlaxoSmithKline responded with the IMPACT study, which demonstrated that Trelegy delivered a 25% reduction in exacerbations when compared with Anoro, showing that ICS therapy does deliver benefits when added on to a dual bronchodilator. This comparison was frequently cited by key thought leaders as the biggest missing piece of information to support use of triple therapy and is likely to be influential in uptake of the triple FDC.
With Trelegy successfully securing approval in the United States, and EMA approval secured but with country-specific reimbursement negotiations ongoing, what lessons can emerging therapies learn from the clinical strategy pursued by GlaxoSmithKline? First, although therapies must be evaluated against placebo, demonstrating superiority to existing therapies is critical to secure robust uptake. However, with the rapid evolution of guidelines, it may benefit developers to test against a suite of therapies rather than selecting just one, in order to hedge their bets should evidence emerge that motivates a change to the guidelines. If successful, comparisons against multiple competitors will also help emerging therapies stand out in this increasingly crowded market. Second, the COPD market has shifted to emphasize end points like exacerbation frequency that can deliver cost benefits for payers. Using exacerbation frequency or mortality as a primary end point can be risky, but if longer-term clinical trials are planned to measure bronchodilation or exercise endurance, including these metrics as co-primary or secondary end points could help build a competitive data package to use for marketing the drug. The eventual uptake of GlaxoSmithKline’s triple therapy, especially compared with other emerging triple FDCs, will illustrate the success of these strategies, and DRG will continue to follow these developments with interest.