This year, the revolutionary peptic ulcer medication Losec turns 25. Professor Lars Fändriks shares with us how researchers at that era’s Faculty of Medicine contributed to one of the world’s biggest pharmaceutical triumphs, a story that began back in the 1950s.
In 1988, the proton pump inhibitor Losec was introduced. This was the beginning of the end of peptic ulcers as a widespread ailment, and Losec became one of Sweden’s all-time largest export triumphs. Behind Losec stood the small Astra-owned company Hässle AB based in Mölndal, just south of Gothenburg, and today, only a handful of people know that staff at Sahlgrenska and that era’s Faculty of Medicine played key roles in this almost matchless success story.
The collaboration between Hässle and Sahlgrenska from the late 1950s until Astra’s launch of Losec in 1988 is a classic case of medical research at its best, what is today known as translational research. The Losec project was based on a clinical problem area that served as the starting point for both basic research and targeted development. The project culminated in a unique medicine that reduced the suffering of peptic ulcer patients. At the same time, society saved significant amounts in the form reduced expenses from absenteeism due to illness and more workers employed in production.
So, just who did what in this consummate translational research process? The role of gastric acid in causing ulceration of the mucous membrane had long been known and the “no acid, no ulcer” principle was already being investigated in a number of places (more about this later in the article). However, developing and documenting new acid-inhibiting substances required enormous investments that could not be provided by public financing alone. The work was divided into university-based research for the basic knowledge while the company performed development expertise and provided capital required for productization. In short, academia and industry achieved a symbiosis. Astra’s owners made a large profit from the export revenue and the local region benefited greatly when the number of job opportunities in the pharmaceutical industry grew.
What about the researchers? Losec was the result of a two-decade-long process in which a crack squad with varying expertise cooperated and doggedly drove the project, overcoming all obstacles, both academic and industrial. This difficult collaborative process was quickly forgotten when the billions in profits began rolling in to Astra’s coffers in the early 1990s. Corporate management at the time described the research project as a well-directed development phase in an industrial business plan. Nothing could have been further from the truth. A number of the project’s former staff reacted to this conveniently altered version of the reality. This same management team had, in fact, been on the verge of canceling the Losec project on at least five occasions. The strongest reaction came from Hässle’s former research director, Ivan Östholm, who was acknowledged to have been a driving force within the Losec project. In a number of published books and articles, Östholm described his perspective for how the foundation for drugs from the Mölndal company (not just Losec) had been laid through close cooperation with researchers and clinicians at Sahlgrenska University Hospital and the Medicinareberget area, with its concentration of life scientists. According to Östholm, none of the researchers involved received extra compensation for their efforts.
Academia Laid the Groundwork for Industry
But we should begin the story from its beginning. How did Hässle, a pharmaceutical business from Hässleholm, end up in Mölndal in the first place? In the early 1950s, a number of young medical doctors from Lund University in southern Sweden were recruited to the newly established Faculty of Medicine at the University of Gothenburg. The university thus became Sweden’s fourth to offer a comprehensive medical program. One of the recruits from Lund was physiologist Björn Folkow. After having established his work in Gothenburg, Folkow met some acquaintances from what was then the Hässle company while on a trip to Lund. During a dinner at the historic Grand Hotel, the group discussed how Hässle could be developed. Folkow suggested to the Hässle employees that Gothenburg offered exceptionally good opportunities for conducting research with a clinical connection. At that time, drug stores often produced their own drugs, and industrially-manufactured pharmaceutical preparations were rarely produced based on clinical testing. The conversation over dinner at the Grand in Lund ultimately resulted in the company moving its operations in the mid-1950s, first to Gårda in Gothenburg, and later to Mölndal. Hässle’s newly-appointed research director, Ivan Östholm, immediately turned to Björn Folkow, who was able to conduct basal tests on intestinal absorption of the new preparation through the Department of Physiology. The idea that medications could have a scientifically documented effect was not a given in the 1950s. As such, Hässle AB’s collaboration with university-based researchers was an unusual method that would eventually prove
to be a major competitive advantage. Through Folkow, Östholm also made contact with associate professor of medicine Leif Hallberg and his research into iron absorption and deficiency. In the early 1960s, pharmacologist Arvid Carlsson and cardiologist Lars Werkö were also included in the project as important links between university-based research and Hässle AB. From then on, Hässle recruited a large number of newly-trained researchers from the Medicinareberget area of Gothenburg with its cluster-like concentration of life scientists and from Sahlgrenska. Many were allowed to continue their work at their parent departments, which allowed them to
keep pace with research development and also develop their own fundamental research projects. This community-based approach of industry and academia led to creative exchanges of knowledge. Clinical needs could be matched with innovative problem solving and a commercial mindset. The small research company Hässle provided the lion’s share of the Astra Group’s pharmaceutical flagships, including Aptin, Seloken, Plendil, and the enormously successful Losec. An important forum during this period was what was known as consultancy conferences, held by Hässle biannually. In 1966 a conference was held on peptic ulcer disease. Lars Olbe, a surgeon at Sahlgrenska, gave the closing address. His message was that the field of peptic ulcers was an area in need of modern drugs and one that Hässle should invest in.
Lars Olbe—The Surgeon Who Eliminated Peptic Ulcer Surgery
Lars Olbe’s dissertation in pharmacology from Karolinska Institutet examined the regulation of gastric acid production. In 1965 he began working as a surgeon at Sahlgrenska in Gothenburg, and as an associate professorship in experimental surgery, he began applying his theoretical knowledge clinically. Ivan Östholm took an interest in this, and tried to recruit Olbe to work for Hässle with the aim of finding a drug to combat peptic ulcers. Olbe was initially completely uninterested in the offer. He didn’t want to be governed by industry’s requirements to meet goals and targets. It was only when Hässle guaranteed that he would be given free hands to conduct his research that he agreed to help the company set up its own gastric research lab. This is when Sahlgrenska’s Gastlab was established, at which Olbe used surgery as a platform for human physiology research conducted under the motto: “Why study rats and mice when you can study humans?”. At Gastlab, Olbe and his colleagues demonstrated how gastric acid secretion is regulated in humans, but also that gastric surgery at times caused severely disabling side effects, which heightened the need for a new pharmaceutical strategy. It was also Gastlab that performed the first human trials of omeprazole, the substance that would later come to be called Losec. A host of Sahlgrenska surgeons defended dissertations on peptic ulcer surgery and the effect of omeprazole. As such, Olbe laid the foundation for the Losec project and served as Hässle’s clinical and theoretical mainstay. He stubbornly defended the project when Astra’s management tried to abandon development on several occasions. In true Hässle fashion, the project was evaluated by the industry-academic consultancy group (see image), where it was thumbs up, and sometimes thumbs down. There was also resistance within the Astra Group, and the project certainly did not have the same level of support within the Faculty of Medicine as the Hässle collaboration on cardiovascular research. Omeprazole was 22 years in development and, ultimately, became a mega-success commercially. It was probably also the greatest medical paradigm shift that researchers at the University of Gothenburg have ever been involved in. Losec could cure chronic peptic ulcers and alleviate gastric acid-related symptoms, which served to change the structure of health care. Surgery requiring hospitalization became unnecessary and primary care took over effective treatment. It might seem paradoxical that a surgeon more or less eliminated his own job in exchange by helping develop medication that patients could take instead. Olbe passed away in 2008, although Gastlab continues its work at Sahlgrenska (see below).
Losec Revolutionized the Treatment of Gastric Acid-Related Illnesses
Up until the 1980s, chronic peptic ulcers were a very common ailment. It was estimated that around ten percent of the population suffered from peptic ulcers at some point in their lives. It was known that the stomach’s production of hydrochloric acid played a decisive role, especially in duodenal ulcers. It was also known that peptic ulcers healed if the stomach’s hydrochloric acid production was curbed, in line with the “no acid, no ulcer” principle, but the medications of the day were either acid neutralizers (antacids) with a short-lived effect or anticholinergic (atropine-like) drugs that were non-specific and marred by many side-effects. With no effective medications, peptic ulcer surgery was very common in the country’s surgical clinics. Most effective treatment was simply to surgically remove parts of the stomach or perform a vagotomy, that is, to cut the gastric secretion-stimulating vagus nerves. Peptic ulcers were a chronic and painful condition, but they could also result from surgical interventions. This is why it was so important to find better treatments. At the late 1970s, histamine-2 receptor blockers (e.g., cimetidine and ranitidine with commercial names like Tagamet and Zantac) were introduced. These offered better gastric acid suppression, though they still had quite a few side effects. Losec represented a new class of pharmaceuticals, proton pump inhibitors, and it reduced gastric acid production very effectively while having very few side effects. From the early 1990s, Losec became the first-line of treatment for gastric ulcers, and the need for surgery and other medicines decreased immediately. Even so, the root cause of ulcers was still unknown.
Removing the gastric acid with Losec allowed the ulcers to heal quickly but when the patient stopped the medicine, the ulcers redeveloped. In the late 1980s, there was growing awareness of a curved bacteria in the mucous membrane of gastric ulcer patients. This was eventually given the name Helicobacter pylori and was shown to play an equally important role in the occurrence of gastric ulcers as gastric acid. H. pylori had developed special qualities that made it possible to survive the stomach’s acidic environment and colonize the mucous membrane. Since this gastric ulcer bacterium had found a special niche, it was particularly difficult to treat with conventional antibiotics. Once again, the proton pump inhibitor Losec proved critical for successful treatment. Intensive treatment with a combination proton pump inhibitor and at least two antibiotics cleared 9 of 10 patients of their H. pylori. Not only did the ulcers heal quickly, they did not return. It became possible to cure peptic ulcer disease and surgery, such as vagotomy, became completely unnecessary.
Another very common gastric acid disorder is acid reflux from the stomach into the esophagus that can cause a burning sensation (chest burn/heartburn) and sometimes chest pain that can be difficult to distinguish from symptoms of heart disease. These symptoms are found in as much as 15-20% of the population. By effectively reducing the acid that irritated the mucous membrane, Losec was amazingly good at relieving symptoms for patients who experienced inflammation of the esophageal mucous membrane. Fundoplication was the previous established surgical treatment. This involved the re-creation of a mechanical valve between the stomach and esophagus to prevent reflux. The surgery also came to be replaced to a great degree by proton pump inhibitors.
Proton Pump Inhibitors – A New Class of Drugs
The active chemical ingredient in Losec (and its successor Nexium) is called omeprazole. With several unique characteristics, it gave rise to an entirely new class of drugs, proton pump inhibitors, with the suffix “-zole.” Today there are a number of omeprazole-related medicines based on the same basic pharmacological principle. Several extraordinary scientific discoveries helped Losec have a huge impact. Perhaps most important was that the drug was developed at the same time as the molecular physiology of gastric acids was being determined. It turns out that omeprazole only becomes active in gastric parietal cells, i.e., in the cellular source of hydrochloric acid production. The channel system for the parietal cells is an acidic environment which allows the omeprazole to locally convert into the active substance that can block the proton pump itself (K+/H+ ATPase), which is the key enzyme in acid production. No other medicine had previously been able to achieve so specific and so local mechanism of action and this is what made it so effective. Blocking of proton pump virtually stopped all production of gastric hydrochloric acid. Risk of side effects is minimal since it is an inactive prodrug that only activates when in the right spot, that is, inside the parietal cells. Omeprazole’s sensitivity to acid also makes it sensitive to chemical effects in the gastrointestinal tract before it is absorbed into the bloodstream. Losec was so successful, in part, because of the substance’s advanced packaging, which allowed it to be swallowed and then released only after passing the stomach.
What happened after 1988?
After ulcer surgery was eliminated from operating rooms, it was replaced by other types of surgery. This includes metabolic surgery, originally developed to help reduce weight and also known as bariatric surgery or weight loss surgery. Gastric bypass surgery is a type of gastrointestinal surgery that is not only effective in the long term against obesity and overweight, but dramatically improves the other components of metabolic syndromes: hypertension, dyslipidaemia, and type 2 diabetes. The situation is similar to the ulcer problem of 40 years ago; compared with the available medical treatment, surgery offers far more effective, but the mechanisms involved are unknown. For this reason, today’s Gastlab continues to use surgery as a research platform for finding mechanisms that may be suitable targets for drugs and that hopefully can replace some surgical procedures in the future.
Professor of Interactive Physiology and Pharmacology
Department of Gastrosurgical Research and Education/Gastlab-Sahlgrenska
Institute of Clinical Sciences
Lars Fändriks’ experiences and personal communication with Björn Folkow, Lars Olbe, and several other relevant individuals.
Ivan Östholm: Drug Discovery: a pharmacist’s story, Swedish Pharmaceutical Press, 1995.