The drug market for chronic obstructive pulmonary disease has been dominated for years by two maintenance products: GlaxoSmithKline PLC’s long-acting beta2 agonist (LABA)/corticosteroid combination Advair (salmeterol/fluticasone propionate) and Boehringer Ingelheim GMBH/Pfizer Inc.’s long-acting muscarinic antagonist (LAMA) Spiriva (tiotropium). Advair has been available for COPD for 10 years and Spiriva for nine, and the two have held court over the market for most of that time.

Now the market is about to become more fragmented by new entries, mainly new single-agent LABAs and LAMAs and the first fixed-dose combinations of the two. LABA/LAMA combinations could eventually become the new standard of care.

But new drugs will need to be differentiated from legacy brands on efficacy and hold up on safety if they are to be well received by payers and find their way into patients’ hands. Clinical data for new drugs so far has demonstrated largely incremental efficacy benefits and dosing advantages over current standard of care. In a market where patients and payers are already sensitive to the cost of treatment, modest efficacy improvements may not be enough to accelerate launches.

Growing Demand For Outcomes Data

The market for COPD is large though, and because patients with the disease progress even on treatment, the unmet medical need remains high. Recent advances have centered around dosing and convenience –once-daily versus twice-a-day or fixed-dose combinations – but these won’t be enough to convince payers to accept higher prices. They want to see data on how dosing advantage impacts compliance, and even on the impact of modest improvements in surrogate endpoints like forced expiratory volume in 1 second (FEV1) – a standard endpoint used by FDA to evaluate efficacy in clinical trials – affects clinical outcomes.

Drug makers that can demonstrate value on endpoints like reduced exacerbations, reduced hospitalizations or overall reductions in cost of care, will stand out in the competitive market and have a good chance of becoming blockbuster brands. Advair and Spiriva both carry indications for maintenance treatment to improve airflow but also for reducing exacerbations.

Sean Karbowicz, the director of clinical evaluation and policy at the pharmacy benefit manager RegenceRx, agreed. Many new products for COPD are coming to the market with data showing improvements in FEV1, but without supportive evidence showing how the drugs benefit disease progression and other broader health outcomes, he said.

“Just because a product is more convenient to take, how does that translate to those more important outcomes,” he said. “Let’s see the dots get connected and find out how those changes in the formulation of the products leads to people getting better.” New drugs need to reach or surpass the bar set by the existing gold standards if they are to achieve broad acceptance by payers, he said.

Payers are also concerned about the lack of generics. FDA is creating a high bar for generics in the respiratory area, which is an obvious advantage to innovator companies. Generic versions of today’s leading medicines for COPD, including LABAs and LAMAs, are not available in the U.S.

The agency is concerned about establishing bioequivalence for inhaled respiratory drugs and, despite assertions that it is interested in doing so, it has not yet released guidance to industry outlining those requirements. The situation could change, and certainly, generics makers have their eye on the respiratory space and are already working to develop bioequivalent LABAs and LAMAs.

A Crowded Market With Clear Leaders

The global market for COPD was nearly $9 billion in 2011 and is expected to grow at a steady annual rate of 4% between 2011 and 2021, when sales will reach almost $13.4 billion, according to the market research firm Decision Resources. The leading LABA/corticosteroid combination in the market is Advair and the leading LAMA is Spiriva. Advair is dosed twice-a-day and Spirvia is once daily. The individual components of Advair are also marketed as Serevent (salmeterol) and Flovent (fluticasone).

In the U.S., in 2012, Advair held a 72.3% share of the $6.79 billion ICS/LABA market, which encompasses both COPD and asthma, while AstraZeneca PLC’s Symbicort (budesonide/formoterol) held 19.2%, according to IMS Health. Of the $4.28 billion anti-cholinergic market, Sprivia held a 64.6% share, followed by Boehringer’s Combivent (ipratropium/albuterol), which held a 26% share, IMS data show.

A variety of short-acting beta agonists, including generic albuterol, which are dosed every four to six hours or as needed, and corticosteroids, are also prescribed for COPD. The first phosphodiesterase inhibitor was approved for COPD in 2011, Forest Laboratories Inc.’s Daliresp (rofumilast).

Physicians largely base their prescription choices on treatment guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Patients with mild COPD generally start pharmacologic treatment with short-acting bronchodilators. As a patient’s disease progresses with more symptoms and increased risk of exacerbations, they step up to a LABA, a LABA/corticosteroid combination or a LAMA. The most severe patients might consider triple therapy with a LABA, corticosteroid and LAMA, or treatment with Daliresp.

In addition to Daliresp, two new products recently came onto the market – Forest’s Tudorza (aclidinium), a twice-daily LAMA approved in the U.S. in 2012, and Novartis AG’s ArcaptaNeohaler (indacaterol), a once-daily LABA approved in 2011 Also see "Novartis Finally Wins Arcapta Approval, Having Lost Battle On Desired Dose" - Pink Sheet, 5 July, 2011.. Sales of all three drugs have been modest thus far, but both Forest and Novartis are eying the longer-term prize, the development of their respective products in combination. [Editor’s note: This story was updated to reflect that Tudorza is a LAMA, not a LABA as originally stated]

Tudorza generated sales of $10.8 million in Forest’s fiscal fourth quarter ended March 31, the drug’s first full quarter on the market. Daliresp generated sales of $78 million in Forest’s fiscal 2012. Arcapta generated sales of $134 million in 2012 and $48 million in the first quarter of 2013. Sales of Advair, in contrast, were $7.72 billion (£5.05 billion) in 2012, though that includes prescriptions for both COPD and asthma.

The Fixed-Dose Combo Race

Forest, with its partner Almirall SA, released positive top-line data from two Phase III trials studying Tudorza with the LABA formoterol and expects to file the combination with regulators in the U.S. and Europe in the fourth quarter. Novartis has completed Phase III studies testing indacaterol with the investigational LAMA glycopyronium in Europe and is running a separate program in the U.S., incorporating a lower dose and twice-daily dosing to address concerns FDA has about safety of the drug class. Novartis expects to file its combination by the end of 2014 in the U.S.

Both will likely be beaten to the market by GSK, however, which has several respiratory drugs nearing the regulatory finish line. Breo Ellipta (fluticasone furoate/vilanterol inhalation powder), a once-daily LABA/ICS combination intended as a next-generation of Advair and developed with partner Innoviva Inc., has a PDUFA date of May 12. Anoro Ellipta, a once-daily combination of vilanterol and the LAMA umeclidinium, has also been filed and has a Dec. 18 PDUFA date. Breo received a positive endorsement from FDA’s Pulmonary-Allergy Drugs Advisory Committee April 17, a strong indicator it will receive FDA approval ([A#00130422010]).

And that’s not all. Boehringer has its own once-daily LABA Striverdi Respimat (olodaterol) pending at FDA, a product it is studying in combination with Spiriva in Phase III trials. Striverdi received a positive endorsement from FDA’s advisory committee in January, though the committee was uncertain about how to address exercise tolerability claims Boehringer is hoping to have included in the label Also see "Boehringer’s Novel Exercise Claims In COPD May Spur FDA Action To Clarify Requirements" - Pink Sheet, 4 February, 2013.. FDA action was expected to come by the end of March, but hasn’t and Boehringer hasn’t publicly said when it expects a decision.

The Future Of COPD Drugs

Drug Manufacturer

Drug Name

Mechanism Of Action

Development/Regulatory Status

Boehringer Ingelheim

Striverdi Respimat (olodaterol)

Once-daily LABA

Pending at FDA (PDUFA date undisclosed)

Olodaterol/tiotropium

Once-daily LABA/LAMA

Phase III

Forest Laboratories

Aclidinium/formoterol

Twice-daily LAMA/LABA

Regulatory filing targeted for fourth quarter 2013

GlaxoSmithKline

Breo Ellipta (vilanterol/fluticasone)

Once-daily LABA/ corticosteroid

Pending at FDA (May 12 PDUFA date)

Anoro Ellipta (vilanterol/umeclidinium)

Once-daily LABA/LAMA

Pending at FDA (Dec. 18 PDUFA date)

Umeclidinium

LAMA monotherapy

Pending at FDA (likely 2014 action date)

GSK961081

Bifunctional muscarinic antagonist-beta2 agonist (MABA)

Phase II

Novartis

Indacaterol/ glycopyronium

Once- or twice-daily LABA/LAMA

U.S. Phase III trial ongoing, filing targeted for 2014

Source: “The Pink Sheet” story archives; company reports

These activities could mean big changes for the COPD drug market. “I think LABA/LAMA combinations will be the new standard of care,” said Novartis Global Head-Primary Care Development David Morris. “As we look at the efficacy that is seen from bronchodilation as well as symptomatic benefit, improvement in exacerbations, we are seeing that the LABA/LAMA combination is really delivering substantial added benefit over either of the monotherapies, even at higher doses.”

Comparative data between drugs in the therapeutic area is limited, though a few head-to-head studies have been completed in blinded or open-label settings. Data on Breo has been mixed. Treatment improved lung function compared to placebo and a steroid alone in several trials, but failed to demonstrate a statistically significant difference in some trials at certain doses and failed to demonstrate superiority to Advair in either COPD or asthma in two non-pivotal studies Also see "Relovair Data Raises Respiratory Stakes For GSK And Theravance" - Pink Sheet, 16 January, 2012..

The Novartis LABA/LAMA combination has demonstrated notable efficacy in clinical studies, including demonstrating superiority to Advair in one trial, but the studies conducted in Europe were at higher doses than the study Novartis is running for the U.S. filing to address the concerns of FDA Also see "Novartis Once-Daily COPD Combo Safe, Effective And Ready For Filing – Everywhere But In The U.S." - Pink Sheet, 10 September, 2012..

Cost Is A Factor In Treatment Choice

Physicians say treatment choices in COPD frequently come down to cost. COPD patients are generally older, on fixed incomes and often run up against the notorious donut hole in Medicare Part D drug coverage. Many of the newer products aren’t securing a top tier reimbursement position from insurers, they say.

“The majority of patients vote with their wallets,” said James Donohue, MD, a pulmonary disease specialist and professor of medicine at the University of North Carolina, Chapel Hill. “The affordability issue in this geriatric disease is very difficult, and we end up with a lot of patients, regardless of these great products, taking Brovana or Perforomist by nebulizer with budesonide because that is free for the patient,” he said. Nebulized LABAs, including Brovana (arformoterol) and Perforomist (formoterol) are reimbursed under Medicare Part B. Nebulizers convert liquid medicines into a mist that can be inhaled.

Donohue said scripts he writes for Arcapta often go unfilled because of high copays. Indeed, many insurers are giving new COPD drugs like Daliresp, Arcapta and Tudorza a non-preferred position on formulary.

RegenceRx hasn’t given any of the three medicines a preferred formulary position because of the uncertain clinical value. “Newer drugs like Daliresp, Tudorza and Arcapta are some good examples of drugs that have that shorter track record, and typically those products are not going to be embraced or preferred as front-line therapies,” Karbowicz said.

Prime Therapeutics said it also has not included those drugs on formulary. Prime Chief Clinical Officer David Lassen said the PBM is taking particular care as more drugs become available to make sure drugs approved for COPD aren’t used inappropriately for asthma. The company is taking steps to implement new programs at the point of sale at the pharmacy to confirm the appropriate diagnosis, he said.

Jill Ohar, MD, a pulmonologist at Wake University School of Medicine questioned the incremental benefit offered by newer drugs. “When you look at what is the value for this marginal improvement over the last generation of the drug, especially when every day of my life I hear patients who cannot afford their drugs, then I wonder if maybe the most improvement available to patients would be generics,” she said.

The costs of the medicines generally run between $200 and $300 for a 30-day supply. The wholesale acquisition cost of Advair Diskus at the dose approved for COPD is $259.87, according to GSK. It’s not clear how drug manufacturers plan to price newer once-daily products and fixed-dose combinations, but the expectation is that new drugs would be priced higher than the legacy brands. GSK has declined say publicly how it is thinking about pricing for Breo.

Drug makers say they are working to collect a broad array of data to present a compelling value case to payers. GSK appears to be taking the most serious stab. For example, in March 2012 GSK announced plans to initiate the Salford Lung Study in the U.K., enrolling 4,000 patients with COPD and 5,000 patients with asthma to study Breo in a “limited intervention” setting. The study is being conducted with North West e-Health, University of Manchester and NHS. About half of the patients in the one-year trial will receive Breo and the other half their existing background regimens, and the study will rely on electronic health records to evaluate different endpoints like patient symptoms, exacerbations, and contact with health care providers due to respiratory issues or other issues, while mainly keeping patients out of the usual well-controlled clinical trial environment.

GSK is also conducting a 16,000-patient outcomes study called SUMMIT, studying Breo’s ability to improve survival in patients with COPD and a history of or risk from cardiovascular disease compared to placebo. The trial will also evaluate decline in lung function and cardiovascular endpoints including death, heart attacks and strokes.

Boehringer’s Tunde Otulana, MD, VP-clinical development and medical affairs pointed to the unmet medical need in COPD as justification for new medicines. “There may be issues with market access and things, but the reality on the ground is there is still a lot of work that needs to be done to reduce the morbidity and mortality in COPD,” he said.

COPD Market Snapshot: New Products, Limited Differentiation

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