Latest developments in HAE

Dr Mauro Cancian spoke to the audience about the latest thinking in the treatment of HAE.

He started by reminding the audience of how far we’ve come in understanding the disease. Just 13 years ago, a modern, innovative classification of HAE was proposed. It called for just a few groups, whether hereditary or acquired, and whether caused by histamines (as for allergies) or by bradykinin in the case of HAE. Now, he said, there has been an enormous progression in diagnosis, making the classification very complex, sometimes even for experts, leading to an understanding of the genetics behind all forms of HAE. However, HAE with C1-inhibitor deficiency remains the most common form.

Dr Cancian dived straight into the first of his 5 topics.

1. Therapeutic targets and management strategies in HAE

Dr Cancian outlined how important it is to understand how a disease occurs to treat it effectively. He described the chain reaction that occurs in an HAE attack, when prekallikrein is activated, splitting bradykinin from high-molecular-weight kininogen and leading to gaps between endothelial cells in blood vessels, fluid leakage, and swelling.

All of that chain reaction, called the contact pathway, he said, was an opportunity to target a different level of the system.

When considering therapies and drugs for HAE, it is important to be aware of 4 key points. Dr Cancian explained these are:

• Target: Which part of the process that leads to an attack will you focus on
• Technology: How will you produce the medicine
• Administration: Will it be an injection, a tablet, or something else
• Indication: who will it be available for, and what will it aim to do (treat or prevent attacks, for example)

2. On-demand therapy

Turning to the existing treatment landscape, Dr Cancian listed the on-demand therapies, which he said remained the mainstay of treatment for all patients. These include plasma-derived C1-inhibitor, icatibant (which works on bradykinin), and kallikrein inhibitors such as sebetralstat.

3. Long-term prophylaxis

For short and long-term prophylaxis, plasma-derived C1-inhibitor was described, while for long-term prophylaxis alone, Dr Cancian listed donidalorsen, lanadelumab, berotralstat, and garadacimab. One special area of consideration is the potential for oral treatment, typified by berotralstat. Beyond this, the different medicines are administered at different timescales, which can be important to patients and the effective management of the disease.

4. Emerging treatments

Dr Cancian suggested new therapies for both on-demand and long-term prophylaxis were needed, as none of the available drugs work for every patient 100% of the time.

Looking at upcoming treatments, Dr Cancian mentioned deucrictibant as interesting, as it may work as both a preventive and a treatment for attacks. This could be achieved by changing the rate at which the medicine is absorbed into the body, either to provide long-term protection or to resolve an attack on demand.

Dr Cancian also described navenibart, which may only need to be taken infrequently to prevent attacks; ADX-324, which acts in an innovative way to prevent attacks; and NTLA-2002, which is a gene therapy currently being trialed. Gene therapy would unlikely be for every patient, Dr Cancian cautioned, but could work by silencing the faulty gene in people with HAE. It might represent a lifelong treatment.

5. Unmet needs and open questions

Finally, Dr Cancian turned to continuing challenges. He highlighted that in much of the world, there are few HAE-specific and effective treatment options to prevent or resolve attacks. Androgens (steroids) are still used, but while they may offer some effectiveness, they can lead to side effects, including high blood pressure, weight gain, and male hormone issues in women. Where necessary, androgens should be started at a very low dose.

Other issues included treating special populations, such as the very young and the elderly, especially those taking other medications at the same time. It will also be important to personalize the concepts of total control and the normalization of life, and to understand what this means in real life for different people.