Respiratory Leader Boehringer Ingelheim Ups The Ante In “Real-World” Trial Design — And Pushes The Envelope In Treating Lung Disorders.
Tunde Otulana, M.D., heads Boehringer Ingelheim’s clinical development and medical affairs group. He is a former FDA reviewer who studied, learned, and finally got the chance to apply his knowledge of clinical trials when he stepped over into industry in 1997. As a pulmonologist who previously worked for about seven years in the FDA’s pulmonary division, Otulana subsequently led related R&D efforts at several companies before coming to BI in 2011. He now plays a key role in the U.S. in preserving the company’s position as a pioneer and leader in respiratory therapy, mainly in chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
BI belongs to a small handful of pharmas, such as its fellow German company Schering AG, that popularized the first metered-dose inhalers for respiratory patients — devices that became so familiar they appeared as props in a host of movies and TV shows. Until the mid-1970s, the company’s largest products on the market were respiratory, but by then its R&D and product lines had branched into the cardiovascular and gastrointestinal areas. Eventually it got into antivirals, and more recently, launched its first cancer drug. In R&D, the company now lists four key research areas in addition to respiratory: cardio-metabolic, central nervous system, immunology/inflammation, and oncology.
Still a private, family-owned company, BI started nearly 130 years ago producing chemical acids and subsequently alkalines, then in the 1920s began to introduce some early medicinal products with the active substances isolated or synthesized from natural sources. One of BI’s first respiratory medicines was an “antitussive,” or cough suppressant launched in the 1930s, ensuring its claim on an area that proved rewarding over time as the company developed better active ingredients and delivery forms, culminating in inhalers. Now the company is striving to raise the bar again with new products that improve the condition of patients with respiratory diseases beyond what they have attained with their established treatments.
Such an ambitious strategy for clinical development requires a corresponding change in how the company qualifies patients, sets endpoints, and evaluates the data in trials of the pipeline candidates. Rather than testing its new COPD drugs against placebo in treatment-naïve patients, BI is studying their effects when added to the “background” of existing treatments the trial subjects are undergoing. Obviously, the “benefit over background” strategy represents a high-stakes play, informed by the company’s confidence that clinical outcomes will clearly show additional benefits in sharp contrast to the background. BI has dubbed its innovative study design the “real-world clinical trial.”
Contrasts In Efficacy
“It is not inaccurate to say that we have been very innovative in the way we do our studies,” says Otulana. “We tend to do studies that will answer questions that will address specific issues with our drug or with the disease in general.”
As examples, Otulana cites two Phase 3 trials — UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium), a 6,000-patient study, and TIOSPIR (Tiotropium Safety and Performance in Respimat), a 17,000-patient study — conducted a few years ago in COPD patients. Both trials looked at the disease progression, based on measuring patients’ lung function, not only to win regulatory approvals but also to increase the company’s understanding of the disease and the ways tiotropium impedes its progress. Importantly, he says, the trials enrolled patients who continued on their other meds.
“In the past, many new-drug studies required patients to go off the background treatment. We would divide patients into two treatment arms and then randomize them to receive new drugs or a placebo. The benefit of the old method is it reveals the effect of your drug very clearly if it makes a difference, and you can amplify your drug’s effect because patients are not taking any other medications that may crowd out the added benefit. But that is not the real world, where physicians want something they can add to existing treatments for even potentially more benefit.”
BI is now developing a new class of COPD agents, the long-acting beta-agonists (LABAs) — such as olodaterol, which it found could be added to its older product Spiriva (tiotropium) for greater symptom control. So now it is also developing a fixed-dose combination of olodaterol and tiotropium for COPD. Again, the new products are tested against background treatments.
“If a patient is receiving various drugs to treat COPD, we will let them continue those drugs in our trial as long as the drugs are not in conflict with the new drug we are introducing,” says Otulana. “It cannot be of the same class as the new drug, for instance, because that will make the data incomplete. We have chosen the ‘real-world’ design because we believe our studies should be as close as possible to what physicians actually do. We believe our studies reflect the real-world environment and that the data that we provide to physicians will actually mimic what happens when the drug becomes available and they use it in their patients. It’s a very innovative design, and we’ve been very pleased with the data we have collected, and I believe the data has also been appreciated by the physicians who looked at it.”
Although the main, if not only, examples of the new trial design are with respiratory drugs, Otulana claims no credit on behalf of his unit for originating the design in the company as a whole. “The real-world trial ties in with the BI way of doing things,” he says. “We are constantly seeking new ways we can tailor our research to meet the needs of treatment in actual practice. Physicians want data that shows how to use our new drugs in real patients, not theoretical patients. It is the way BI looks at its drug development overall.”
Symptoms As Causes
BI has products on the shelf and in development for other respiratory conditions, but COPD remains its largest market area, with about 26 million patients in the United States alone, according to Otulana Decades ago, when BI pioneered treatments for the disease, launching the anticholinergic Atrovent (ipratropium bromide) in 1975, it had few potential competitors. Later, it was the first company to develop a combination of short-acting bronchodilators, Combivent (ipratropium bromide and salbutamol) to boost airway- opening capacity over single-entity inhalers. The long-acting bronchodilator Spiriva, first launched in 2002, is now the world’s most prescribed drug for COPD.
“Fifty years ago, many respiratory diseases were treated with oral medications, so the introduction of inhalers was a significant milestone,” says Otulana. “The benefit of inhalation is it delivers the drugs directly to the site of action in the lung, minimizing drug exposure to the rest of the body and allowing a smaller dosage. Another milestone was the development of inhalers with longeracting medications so that patients use the inhaler just once a day.” He also notes a third milestone for BI: the transition from propellant-induced inhalers to its Respimat device, which uses a propellantfree technology. Respimat is the platform for Combivent and the company’s future inhaled drugs.
Such apparent maturity as a market leader brings up the question: If current treatments for COPD are so effective that physicians will continue using them even when new treatments come on line, why should BI or any company develop new ones? What possible benefit could it add to the short- and long-term symptom relief already available, short of curing the disease? The answers turn out to be rather interesting. Sometimes, prevention of some symptoms can really be worth thousands of cures.
Because COPD is the result of permanent damage to the lungs, actual treatments for its root causes, which would reverse the damage, lie many years in the future at best. Thus, current COPD drugs on the market and in the pipeline all address the extremely serious symptoms of the disease. Those symptoms — mainly chronic cough with mucous, restricted breathing, and hypoxia — can actually cause further damage, making the overall condition even worse, as Otulana explains.
Tunde Otulana, M.D., Head of Boehringer Ingelheim’s Clinical, Development and Medical Affairs Group
“Part of the manifestation of COPD is ‘exacerbations,’ dramatic crises in breathing when patients have acute worsening of their disease. A COPD exacerbation is a major setback for patients when one develops, and it does in half of all patients. Exacerbations often lead to emergency room visits or hospitalization, and patients who experience them have an increased likelihood of mortality or worsening morbidity. By reducing exacerbations, we hope to improve the overall symptomatology for patients in the short and the long term, and that’s why we’re continuing to develop new drugs in the respiratory area.”
In addition to its COPD pipeline, BI is developing a number of other drugs in other respiratory conditions such as asthma and sometimes much rarer respiratory conditions, such as idiopathic pulmonary fibrosis (IPF) — a “natural step for a leader in the respiratory field,” as Otulana describes it. In asthma, another condition in which exacerbations occur, the company first looked for and found a candidate among its existing COPD drugs: Spiriva. It is currently conducting a Phase 3 trial and has released some positive data from the trial, indicating tiotropium “improved lung function and was well tolerated in patients with asthma who remain symptomatic while receiving maintenance ICS [inhaled corticosteroid] treatment.”
BI has completed Phase 3 trials of a new compound, nintedanib, in IPF — a rare, progressive, and rapidly fatal disease, considered an orphan condition in the United States with around 130,000 patients who have no FDA-approved treatments. According to Otulana, about 50 percent of IPF patients die within three to five years of diagnosis. The trial results show nintedanib “slows disease progression by reducing annual decline in lung function by approximately 50 percent,” according to data published in May, and BI has since filed for market authorization of nintedamib with the European Medicines Agency (EMA).
In what might appear as an unusual turn in therapeutic targeting, BI’s research has also led it into cancer. It launched its first oncology drug, Gilotrif (afatinib) in the United States last December with an indication for lung cancer patients with 13 specific mutations. Without giving away much about how the company singled out afatinib and identified the mutation-based patient set, Otulana implies the long-term commitment and planning needed for such efforts is a unique advantage of the company’s private family ownership.
“The family has certain guiding principles for where they want us to focus our development, and since its beginning in 1885, the company’s focus has always been long term. We are patient enough to look at the needs and do clinical trials until we get to a point where we feel we can make a difference. We don’t want to go into the cancer space just to have a drug on the market. We have developed a strategy for what we’re going to do, we’ve identified the areas with unmet needs, and we’ve come out with a drug that will specifically target these populations.”
New rules, product-approval requirements, and data preferences by the regulatory authorities, as well as pricing and other restrictions by payers and providers — Otulana says BI has to pay attention to all those factors, just as other companies do. “But the actual development of our products is under our control. BI has a long heritage of focusing development on areas where we can bring the most benefit to patients and carrying out development with a long-term view.”
Respiratory diseases are notoriously tough conditions to treat, and despite all of the advances in inhaled medicines to open and protect air passages for breathing, patients routinely continue to suffer serious, intractable symptoms. Otulana and his company see plenty of room to add new drugs, and thus new relief, over the background of existing treatments. Such is BI’s simple but real-world strategy for remaining “the leader in respiratory.”