The long battle against pulmonary fibrosis

Boehringer Ingelheim has developed one of the first medicines for people with fibrotic pulmonary diseases, including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD). Their scientists adopted a unique research approach: They sought to identify commonalities across different groups of diseases. The goal was to develop a novel medicine that would be effective against a wide range of diseases.

The breakthrough is fresh in the mind of Dr. Craig Conoscenti. “We all looked at each other. It was an incredible feeling,” he remembers. Conoscenti and his colleagues were not only excited because they had taken a step forward: There was something else in the air. “Suddenly,” says Conoscenti, “there was hope.” That was in 2007 and nintedanib, a drug in development for patients with idiopathic pulmonary fibrosis (IPF), had just passed the second phase of clinical testing. For Boehringer Ingelheim’s research teams in Ingelheim, Germany, and Ridgefield, Connecticut, USA, one thing was now clear: A potential medicine for people with this rare, chronic lung disease might actually exist. Before this discovery, the disease had brought a swift death for those affected within a few years of diagnosis.

Very little was known about IPF in the early nineties. “There wasn’t even a standardized name for the disease, let alone a standardized treatment,” says Conoscenti. Having worked as a pulmonologist since 1985, he took an early interest in interstitial lung diseases early in his career. Patients living with IPF face progressive loss of lung function due to the formation of scar tissue in their lungs. The reason for this is unknown. “At the time, nothing could be done for these patients other than trying out various non-approved medicines, none of which helped over the long term.” While he was already working as a pulmonologist, Conoscenti’s father, who was one of the first registered respiratory therapists in the US, died of IPF. This was another reason for Conoscenti to push ahead and continue to work on IPF in a clinical setting and eventually join Boehringer Ingelheim to be part of the team to discover a treatment for this devastating disease.

There wasn’t even a standardized name for the disease, let alone a standardized treatment.

Dr. Craig Conoscenti

A holistic therapeutic approach

Boehringer Ingelheim had been working on the first therapeutic approaches even before the turn of the millennium. “This was remarkable,” explains Conoscenti, “mainly because hardly anyone else was interested in this small group of patients.” IPF is a rare, debilitating and fatal lung disease, which affects approximately three million people worldwide. Still, IPF is the most common form of pulmonary fibrosis. Early on, Boehringer Ingelheim noted the potential for a number of diseases beyond IPF – namely, whether it could aid in finding a therapy for the more than 200 other interstitial lung diseases.

“Boehringer Ingelheim has continuously expanded this holistic therapeutic approach over the years,” says Dr. Jay Fine, Global Head of Immunology and Respiratory Diseases Research. Fine has been working on new lung disease treatments for more than a decade, including the last five years at Boehringer Ingelheim. “Our focus is always on how we can develop potential medicines for multiple diseases or populations and therefore help the most patients,” says Fine. At first, it is often unclear how many diseases a novel medicine can treat. Nonetheless, Fine’s team looks for common pathways between individual diseases to uncover unique “disease clusters” for each new therapy. This increases the scope and value of an individual medicine enormously.

Dr. Jay Fine

He is the Global Head of Immunology and Respiratory Diseases Research at Boehringer Ingelheim.

With this goal in mind, the research team around Conoscenti continued studies on IPF, pulmonary fibrosis, and other related interstitial lung diseases. There were setbacks along the way: An initially promising combination of medications did not work as they had hoped. But the working group ultimately developed nintedanib. This medicine inhibits processes that occur in fibrosis, thus slowing the formation of scar tissue and the progression of the disease. IPF remains incurable, but nintedanib reduces the degree of lung function lost each year by roughly half. After its breakthrough in the middle 2000s, nintedanib was approved as OFEV® for US patients for the first time in 2014. Since then it has been approved in more than 70 countries and has offered hope to many IPF patients.

Fine is convinced: “Nintedanib serves as a foundation for our research on fibrosis.” The research team has identified a number of parallels between IPF and other illnesses in its cluster, such as systemic sclerosis-associated interstitial lung disease (SSc-ILD), a rare, incurable autoimmune disease in which scar tissue forms in the skin and numerous internal organs including the lungs. The affected patients are typically younger than IPF patients and are often middle-aged women. The progression of the disease, however, is similar for both patient groups. Boehringer Ingelheim tested the effect of nintedanib on SSc-ILD patients in a large-scale clinical study. The study, called SENSCIS, found that the medicine was able to slow the loss of lung function by 44 percent within one year. In early September 2019, the FDA, the US regulatory authority, approved nintedanib as the first medication for treating SSc-ILD. Boehringer Ingelheim also received positive opinion by the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) in SSc-ILD in February 2020. In March 2020, the FDA also approved nintedanib to treat people with a chronic (long lasting) interstitial lung disesase in which lung fibrosis continues to worsen (progress).

We focus on three principles: Target, Repair, and Prevent.

Dr. Jay Fine

“FIRST-IN-CLASS” MEDICINES

For Fine, “first-in-class” medicines like these give meaning to his team’s research; they hope to discover new, unique mechanisms of action for treating disease. “Our vision is to transform the treatment of inflammatory and fibrotic diseases by pioneering a patient insight-driven translational approach,” says Fine. His team pursues this vision on the basis of three principles: Target, Repair, and Prevent. Inflammatory illnesses are often triggered by an over-expressed immune system, which attacks the body’s own tissues, leading to impaired function of the affected organs and a loss of quality of life. For this reason, Fine’s team first targets mechanisms that are central to driving tissue injury. They then investigate the best approaches to selectively block these responses or to repair the tissue itself. If the fibrotic process has already begun, the goal is to obstruct it as much as possible to prevent disease progression.

This holistic research approach has also proven itself with other forms of inflammatory and fibrotic disorders. For example, the research team has developed an investigational medicine called spesolimab which blocks a mechanism called the interleukin (IL)-36 receptor. Spesolimab is believed to have potential to target and prevent a range of inflammatory and fibrotic diseases, and has recently shown promise in patients with pustular psoriasis. “While still early in its development, spesolimab has the potential to improve the lives of many people affected by this cluster of diseases,” Fine explains. He knows how a research breakthrough feels – the moment it becomes clear: We did it; we helped people. “This,” says Fine, “is why we do this job.”