Latest Developments in HAE Science and Therapies

This article is part of an extensive feature on the 2024 HAEi Regional Conference Americas, published in Global Perspectives #1 2024

Latest Developments in HAE Science and Therapies

Tony Castaldo introduced Prof. Marc Riedl, a world-class physician with amazing skills in patient care, to the audience. Prof. Riedl began his talk by addressing the conference theme of ‘Take Action.’ He told the audience that everyone does things every day to make their lives easier. However, big challenges remain. There’s no easy solution. It’s the same with HAE. Governments and health systems are not easy. “We can demonstrate that HAE has come a long way,” said Prof. Riedl, “The most difficult things are the ones worth doing, and we can achieve success by working together.”

Moving on to diagnosis, Prof. Riedl acknowledged that the blood tests for C1-inhibitor levels and functioning aren’t available everywhere. He mentioned the importance of measuring bradykinin, especially in those with HAE with normal C1, but said, “It’s tough to measure bradykinin; lots can go wrong as it’s very unstable.”

Prof. Riedl mentioned that across many ACARE centers, up to 25% of patients with HAE had normal lab results and normal C1 inhibitors. The pipeline for diagnostics is strong, and multiple people and groups are trying to bring more reliable bradykinin measures to the clinic.

Addressing the topics of HAE treatment and management, Prof. Riedl acknowledged the massive contributions of past physicians, especially Marco Cicardi and Michael Frank. Both dedicated their lives to improving the situation of the HAE community.

Prof. Riedl mentioned the importance of international guidelines in driving science forward. Guidelines recommend that every HAE patient has a rescue or on-demand treatment to deal with an attack when it happens and that every attack should be treated as early as possible. They also have recommendations for long-term prevention or prophylaxis. Prof. Riedl stated, “Prophylaxis may not be used by every patient with HAE, but increasingly, we’re seeing the benefits of just preventing swelling episodes. Why wait until you get sick?”

Moving onto the investigational therapies, Prof Riedl confirmed that the drugs he would discuss were not approved by any regulatory agency. There is a lot to discuss: “Our little condition of HAE—and I don’t mean that in a bad way—it is a rare condition, yet there is this long list of medicines that we are excited about.”

Prof. Riedl started his whirlwind tour of future medicines with a drug called garadacimab. This is a designer monoclonal antibody that targets FXII. It is a preventative medicine given subcutaneously once a month. Studies showed an 86% reduction in the mean or average attack rate per month compared to placebo. In the 6-month study, 61% of the patients on the treatment had no attacks during that time. The company will submit this data work to the FDA and other regulatory bodies. We should get a decision in the next six to 12 months.

The second drug was an RNA-based therapy called donidalorsen. This therapy has a very specific design; it works in the liver cells to return balance to the various proteins involved in HAE, hopefully preventing attacks. In a small phase two study, at about 4 months, we saw a 90% reduction in attacks.

The next treatment under investigation is an on-demand therapy. Sebeltralstat is an oral medicine that targets plasma kallikrein. Patients were asked to take a pill as soon as they knew they were having an attack. The people who got the medicine started to feel better within one to two hours. People who got a placebo took well over six hours before they reported feeling better. This data is being compiled to be submitted to the FDA and other agencies.

Another oral medicine is deucrictibant, which blocks that B2 receptor. This drug is interesting because it’s been developed to treat attacks, and to potentially prevent attacks. As a rescue treatment, it seems to work quickly and improve people’s symptoms, compared to placebo. 60% of the people who got placebo had to use their regular rescue medicine. In people taking deucrictibant at the highest dose, less than 10% needed to use a regular rescue medicine.  For the prevention of attacks, patients take the pill twice a day, every day. At the highest dose, there’s an 84% reduction in the monthly attack rate. We also saw a 92% reduction in the need for rescue medicine during the month people were on treatment compared to the placebo. These are smaller studies, and we need a larger study in phase three.

Prof. Riedl turned his attention to the two gene therapy programs. The first one uses CRISPR technology. In this, nanoparticles are infused into the person. These go into the liver, and effectively, ‘molecular scissors’ clip out the defective gene very specifically in the DNA. It’s only been tested in 10 patients to date, but it showed a 95% reduction in attacks. The second gene therapy Prof. Riedl outlined is AAV to deliver gene therapy. This takes a little piece of DNA and puts it in a virus that doesn’t cause human disease. This delivery service, he said, goes into the cells and unloads the DNA, so the gene and your cells integrate that and start to make whatever protein that gene codes for. This is an effort to produce more C1-inhibitor in the body by delivering gene therapy into the liver.

Other potential medicines include a monoclonal antibody called STAR-0215 and another RNA-targeted therapy ADV324.

“The HAE treatment landscape is incredible and exciting,” said Prof. Riedl, “But there’s a lot of questions, most importantly long-term safety. We need to see the results from long-term studies.” In conclusion, Prof. Riedl invoked Chat GPT to summarize the current challenges in HAE. In response, he encouraged people to seek out their experts, participate in advocacy in their local country, engage with HAEi, participate in clinical trials, and work with government legislators and health systems. “It can be scary,” Prof Riedl said, “But there is power in numbers. Everything we do now makes a huge difference for tomorrow.”