Croatia’s Participation at the 1st Global Angioedema Forum

Croatia’s Participation at the 1^st Global Angioedema Forum

Sudjelovanje Hrvatske na 1. Globalnom forumu za istraživanje i liječenje angioedema

With the relatively recent approval of lanadelumab (Tahkzyro) and berotralstat (Orladeyo), drugs for long-term prophylaxis (LTP) of hereditary angioedema (HAE) attacks, that came into force in May 2024 in Croatia, many of us, both doctors and patients alike, experienced a new kind of hope in relation to the treatment of this rare and debilitating disease. The timing of this new hope, fuelling fresh motivation in HAE management, aligned perfectly with the organisation of the first Global Angioedema Forum (GAF). Organised by the Angioedema Centres of Reference and Excellence (ACARE) network, a combined initiative of the Global Allergy and Asthma European Network (GA2LEN) and HAE International (HAEi) (1, 2), GAF was held alongside the Global Leadership Workshop (GLW) in Copenhagen, Denmark, from 3rd to 6th October 2024. It hosted 750 attendees from 90 countries (1), and a handful of us from Croatia had the fortunate opportunity to attend it: doctors who attended GAF, and patients from the national HAEi patient organisation who attended GLW. GA2LEN and HAEi are both non-profit organisations or networks, the former being the network of clinical and research facilities for allergy and asthma, and the latter being the network of HAE patient associations worldwide, while ACARE works to encourage clinical care and research for HAE. (2)

Some allergy and clinical immunology specialists and rheumatologists from Croatia were in attendance as well, taking full advantage of the extensive programme offered by GAF: Prim. Marko Barešić and Boris Karanović from the University Hospital Centre (UHC) Zagreb, Prof. Jasminka Milas-Ahić from the UHC Osijek, Prof. Dijana Perković and Marijana Matijaš from the UHC Split, Daniel Šimac from the UHC Rijeka, Željka Kardum from the Zadar General Hospital (GH), and Prim. Ljerka Čulav, otorhinolaryngologist from the GH of the Šibenik-Knin County. This group also presented a poster with the following authors: Prof. Srđan Novak from the UHC Rijeka, Ana Marija Masle from the UHC Osijek, Prof. Branimir Anić from the UHC Zagreb, who were unable to attend. The poster was entitled Clinical characteristics and the burden of disease of the Croatian adult patients with HAE – nationwide survey analysis, and it was based on the study led by Prim. Barešić. (3, 4) Other experts in attendance were paediatricians Prof. Irena Ivković Jureković from the Children’s Hospital Zagreb and Renata Vrsalović from the UHC Sisters of Mercy, as well as the president of the HAEi Croatia organization, Mihaela Šogorić with other supporting members. The abstract and the poster presented results of a nationwide survey of HAE patients, and the findings showed that this disease was mainly predominant in the female population and among family members (67% and 78%), that most patients have HAE type 1 (51% patients with type 1, 12% with type 2, 37%: other types), and that danazol was used as LTP in the majority of cases (72%). (3, 4) Patients’ greatest fears included child inheriting HAE (51%), followed by social life issues (39%), job security (31%), and death anxiety (31%). (3, 4) This research provides a great snapshot of the current status of HAE patients and their management in Croatia prior to the introduction of lanadelumab and berotralstat, and it will be interesting to see how these results will change down the road with the availability of these new drugs. Perhaps the results will show an increase in satisfaction and a decrease in anxiety. Both the abstract and the poster are available for online viewing (see References).

GAF’s programme was truly comprehensive, and it presented the latest information in the field of angioedema with a particular focus on HAE, but two main areas of discussion prevailed: new developments in the field of pathophysiology and diagnosis, including newer genes for HAE with normal C1-inhibitor (nC1-INH), and treatments that are still in development, including potential cures with gene therapy. (1) The information presented on pathophysiology and detrimental genes can be best summarised in the work by Reshef et al., which was also specifically presented: the DANCE consensus on defining, naming, and classifying angioedema. (1, 5) In short, the consensus divides angioedema into 5 main groups: mast cell-mediated (formerly IgE-mediated), causing classic allergies; bradykinin-mediated, which includes HAE due to C1-inhibitor (C1-INH) deficiency or dysfunction (type 1 and 2), kallikrein-kinin pathway mutations (HAE nC1-INH), and acquired (autoimmune); vascular endothelium dysfunction (also HAE nC1-INH); drug-induced, namely angiotensin-converting enzyme (ACE) inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs), among others; and lastly, unknown. (5) Other common angioedema-causing drugs are tissue-type plasminogen activators, dipeptidyl peptidase IV inhibitors, and neprilysin inhibitors. (5) Disease-causing gene mutations which have been discovered include FXII (factor XII), which is currently the most common, PLG (plasminogen), KNG1 (kininogen-1), for bradykinin-mediated; ANGPT1 (angiopoietin-1), MYOF (myoferlin), and most recently discovered, HS3ST6 (heparan sulphate-glucosamine 3-O-sulfotransferase 6), for vascular endothelium dysfunction. (5) With the discovery of more genes and pathological mutations, pathophysiology of HAE nC1-INH becomes clearer, helping us to diagnose the disease more accurately, and hopefully, treat it more effectively.

On the note of treatment, several new drugs are currently in development, most of which are in phase 2 or 3 of the clinical trials. This was covered at length during GAF, and is concisely presented in an article by Smith et Riedl. (1, 6) Icatibant, which is a currently available drug and an on-demand subcutaneous treatment against bradykinin receptors is seeing an update with deucrictibant, and phase 2 of the clinical trials is completed. Deucrictibant is an oral, on-demand treatment, and it will possibly be used as a prophylactic medicine. (6) Berotralstat may soon be joined by sebetralstat, an upgraded kallikrein inhibitor, and phase 3 of the clinical trials is completed. (6) Garadacimab, which is a treatment targeting factor XIIa, and STAR-0215, which is a treatment targeting kallikrein, are monoclonal antibodies in development to be used as a prophylactic medicine. Phase 3 of the clinical trials for the aforementioned drugs is done and phase 1b/2 is still ongoing. (6) There are a couple of promising RNA-based treatments that could be used as prophylactic medicine, such as donidalorsen (currently in phase 3 of the clinical trials) and ADX-324 (currently in phase 1 of the clinical trials). Both of the aforementioned drugs are targeting prekallikrein. (6) Furthermore, possibly one of the most exciting treatments that are currently being studied are gene therapy and genome editing, particularly NTLA-2002, which is currently in phase 2 of the clinical trials and is designed to inactivate prekallikrein via CRISPR/Cas9 biotechnology (Clustered Regularly Interspaced Palindromic Repeats; CRISPR-associated protein 9). The aforementioned biotechnology has been shown to be safe and effective for treatment. (6) BMN 331, adeno-associated virus (AAV) 5, and OTL-105, autologous haematopoietic stem cell (HSC) gene therapies targeting C1-INH are still in the early stages of development (phase 1/2 and preclinical phase). (6) It is certainly thrilling to think of the fact that so many new treatments are currently in development, which gives us more treatment options, with both oral and parenteral methods of administration, and especially in the case of drug inefficiency.

Although the number of doctors specializing in HAE treatment is small, and the same (fortunately) goes for the number of patients suffering from HAE, we are certainly not forgotten. This is especially true when it comes to the professional networks and patient organisations that have been established over the years, and all the research and discoveries being made, from pathological gene mutations, to new curative treatments. And, with the first Global Angioedema Forum behind us, it is an exciting time for both doctors and patients, and it is a great feeling to be able to be a part of this whole process.

Daniel Victor Šimac, dr. med.

Daniel Victor Šimac