For Danny Cohn, internist and vascular medicine specialist, the disease hereditary angioedema (HAE) is one of his research lines. "The personal stories of my many patients have touched me. That is my motivation to improve the lives of these otherwise perfectly healthy people. And that now seems possible with a new drug," Cohn says. He explains that HAE is a rare hereditary disorder that occurs in 1 in 50,000 to 100,000 people. "These patients spontaneously develop external or internal swelling. Face, hands, feet and the pubic area are common sites, as well as the intestines, airways and throat. Internal attacks, in particular, are usually painful and disabling."
According to Cohn, the swellings can occur spontaneously but also due to certain triggers, such as hormone fluctuations and mild traumas resulting from, for example, horse riding, too-tight-fitting trousers or contact sports. "Stress is also a well-known trigger. It can ruin beautiful but exciting moments, such as birthdays, a school trip or a wedding day. The underlying cause is a deficiency of the C1-esterase inhibitor. This protein inhibits a process that is involved in the immune system and blood clotting. If this inhibitor does not work properly, localized leakages can occur in the blood vessel wall. This leads to fluid accumulation in the surrounding tissues."
There are various therapies to prevent or treat angioedema attacks. One of these therapies is twice-weekly infusions of plasma-derived C1-esterase inhibitor. However, such a frequent treatment is stressful for the patient and does not always offer sufficient protection. Another option is to enhance testosterone levels by taking supplements. This causes the body to produce slightly more C1-esterase inhibitor. Especially in young women, this male hormone can have unpleasant side effects. Finally, there is a drug that blocks a receptor in the blood vessels during an attack of swelling and thus inhibits the occurrence of leakage.
Switching off the protein
In recent years, Cohn and PhD candidate Lauré Fijen, from the international HAE expertise centre at Amsterdam UMC, have been focusing on an innovative and preventive approach to the disease. The protein prekallikrein is central to this approach. Cohn describes it as a signaling protein. "High prekallikrein levels are associated with angioedema. Normally, prekallikrein is suppressed by the C1-esterase inhibitor. HAE patients have low levels of the C1-esterase inhibitor, leading to high levels of prekallikrein.”
Cohn: "With the drug Donidalorsen, which we inject subcutaneously, we block the production of prekallikrein." Earlier, the Amsterdam researchers performed a phase I trial and pilot study, involving healthy persons and in two patients with severe HAE, to investigate whether this approach works. The results were promising. This led to a first publication in the New England Journal of Medicine (NEJM) in 2020.
Meanwhile, Cohn and Fijen, together with US colleagues, have completed a larger double-blind placebo-controlled phase 2 trial in 20 patients with severe HAE. The Amsterdam researchers designed the study. Six patients received a monthly injection of placebo and the others were given Donidalorsen. The results of this new study were published today by the researchers in NEJM, one of the most influential journals in medicine. Cohn is pleased with the outcome. "In the group that received Donidalorsen, the number of angioedema attacks decreased by 97 percent meaning that all but one patient were attack-free. Perhaps that one patient would benefit from a higher dose. We are investigating that now."
No serious side effects
Not only does the drug appear to work amazingly well, it also has no serious side effects. That is why the control group received their monthly injection of Donidalorsen immediately after the study. Furthermore, according to Cohn, the participants reported a huge improvement in quality of life. "They performed better, were less tired and in a better mood, ate better and were more free of shame and anxiety. How expensive the new therapy is remains to be seen, he continues. "First there will be a phase 3 study: a similar study, but then with 84 patients. Of course I am hopeful. It would be fantastic if HAE patients could gain total control over their disease with a completely normal quality of life."
Dutch text: John Ekkelboom