How It Really Happened‐the Development of Inhaled Iloprost for Pulmonary Arterial Hypertension

In 1988, I had spent over 2 years at the Physiological Institute, working on the competition between skin‐ and muscle blood flow for cardiac output in man during exercise, when I started my residency in Internal Medicine. There I met Werner Seeger, who was a consultant and was directing the Intensive Care Unit at that time. He enrolled me in his research group, which focused on acute respiratory stress syndrome (ARDS), a condition characterised by a ventilation‐perfusion mismatch that results in competition for blood flow between well‐ and poorly ventilated lung areas, a topic I had previously explored in my scientific work. Werner's group had established the Multiple Inert Gas Elimination Technique (MIGET) and used it in a rabbit ARDS model regularly [1]. They had also published a clinical ARDS study, comparing the effects of prostacyclin, either applied as an infusion or as inhalation, showing that the inhaled drug was both pulmonary and intrapulmonary selective, which was beneficial for maintaining systemic arterial blood pressure and systemic oxygenation [2].

We hypothesized that pulmonary selectivity would be of utmost importance in severe pulmonary hypertension and published a perspective on this in a German journal. As a response, a PH patient came to us who had already visited many hospitals all over Germany, where she was offered different treatments, reaching from intravenous prostacyclin to heart‐lung transplantation—but she had refused all of these options. She was a charming woman in her early 50‐ies, running a successful business in the south of Germany, and suffered from the CREST syndrome with very severe Raynaud syndrome and PH with right heart failure, but no lung fibrosis in the high‐resolution CT. She was eager to undergo right heart catheterization and try inhaled NO, inhaled prostacyclin, and intravenous prostacyclin to see her individual responses.

After we had received approval from the ethics commission and her written informed consent, I did the right heart catheter in our ICU. Her pulmonary pressure was the highest I had ever seen, cardiac output was poor and during the investigation she had a severe Raynaud attack, up to her elbows. Inhaled NO had impressive pulmonary vasodilative effects and inhaled prostacyclin was even stronger and immediately stopped her Raynaud attack. The duration of the pulmonary hemodynamic effects was only 15 min, but she said this was a great experience. We had to find a pharmacological solution to avoid very frequent inhalations and the risk of a rebound pulmonary hypertensive crisis. Werner figured out that in Germany, a stable prostacyclin analog was available for infusion in Burger's syndrome, a very rare disease of the systemic arteries. The drug came in small ampoules and was manufactured and delivered by Schering, Berlin. We did another right heart catheterization in our patient and noticed hemodynamic effects comparable to inhaled prostacyclin, however, the effect duration was much longer. Our patient said she had not been so well on a single day in the last years and insisted on getting this drug on a regular basis. We provided her with an inhaler and with drug which she diligently used on our ward. We watched her very carefully for any adverse effects, however, she reported only beneficial effects. After an inhalation, the relief of dyspnea and the improvement of skin blood flow had a duration of 3–4 h. Therefore, we advised her to repeat the inhalations every 3 h, resulting in 6 inhalations per day. This regimen caused an impressive clinical recovery with no adverse effects [3]. She also tolerated the night pause very well.

We applied for compassionate treatment, and her insurance company agreed to pay for the medication. We did the same treatment approach in several other cases, but then we received an official letter from the Schering lawyers, making the argument that we were misusing their drug in a non‐approved indication, using a non‐approved way of application and that we should stop this immediately! Together with Werner, meanwhile, the Director of the Dep. Internal Medicine, I decided to ignore this letter, because our patients needed the medication. Some of them had been rescued from overt right heart failure by means of regular iloprost inhalations [4]. Two years later, Schering approached us again, now interested in a co‐operation. Finally, they sponsored two studies, a Phase II long‐term observational safety study and a pivotal Phase III double blind randomized controlled study (AIR), which was the basis for the approval of inhaled iloprost for PAH [5].

Inhaled iloprost is also recommended for pharmacologic testing of vasoresponsiveness as an alternative to inhaled NO. Inhaled iloprost was the basis for the development of combination therapy with sildenafil [6]. and for our development of inhaled treprostinil, including a novel ultrasound‐based treprostinil inhaler [7], which was successfully used in the INCREASE trial for PH patients associated with interstitial lung disease [8].

I profited from this drug development in many ways. I became a member of the AIR steering committee with Werner Seeger, Lewis Rubin, Gerald Simonneau, Nazzareno Galie, and Robert Naeije, developing the study protocol from scratch. I learned that even among the best experts, basic questions were unsolved, for example, what a normal pulmonary arterial pressure and resistance is, what is a normal wedge pressure, and when we would consider a disease as PAH and when as “secondary to” (now “associated with”) chronic lung or heart disease. These intense discussions were important impulses for my further research. My publications on inhaled iloprost facilitated my appointment as Prof. of Medicine and Director of the Div. Pulmonology at MedUniGraz, my corresponding authorship of the first German PH guidelines, and my success in funding applications.

I am very grateful to my mentor Werner Seeger, my colleagues and co‐workers and in particular to the very first iloprost patient, who was instrumental for all this development.

Ethics Statement

The author has nothing to report.

Conflicts of Interest

The author declares no conflicts of interest.

Guarantor

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Olschewski H, “How it Really Happened‐the Development of Inhaled Iloprost for Pulmonary Arterial Hypertension,” Pulmonary Circulation 15 (2025): 1‐2. 10.1002/pul2.70191.