Hereditary Angioedema Symposium PDF

Hereditary Angioedema Dr Michael D Tarzi Senior Lecturer&Consultant Immunologist Brighton&Sussex Medical School&UHSussex NHS Foundation Trust Disclosures Principle investigator for RAPIDE and CHAPTER1 at UHS Paid speaker for Takeda&CSL-Behring Conference funding from Biocryst&Takeda Hereditary angio...

Hereditary Angioedema Dr Michael D Tarzi Senior Lecturer&Consultant Immunologist Brighton&Sussex Medical School&UHSussex NHS Foundation Trust Disclosures Principle investigator for RAPIDE and CHAPTER1 at UHS Paid speaker for Takeda&CSL-Behring Conference funding from Biocryst&Takeda Hereditary angioedema (HAE) Autosomal dominant genetic deficiency of C1 inhibitor protein Cardinal features: – Recurrent attacks of subcutaneous swelling Any body site Predilection for hands, feet, face and genitals – Recurrent attacks of submucosal swelling Abdominal viscera: severe abdominal pain Laryngeal: airway compromise Photographs supplied by HAE UK with patient consent for distribution Photographs supplied by HAE UK with patient consent for distribution Photographs supplied by HAE UK with patient consent for distribution Mayo Clinic Proceedings 1988 Mayo Clinic Proceedings 1988 General Features of C1 inhibitor deficiency Around 1 in 25 000 to 1 in 100 000 Worldwide distribution Symptoms often delayed to pre-teenage or teenage years Wide spectrum of severity Attacks generally untriggered, however – Trauma, surgery, infection and dental work increase risk – Women often oestrogen-sensitive (avoid combined pill, may worsen during pregnancy or with HRT) – ACE inhibitor likely to worsen symptoms Considerable associated anxiety and reduced function in many patients Genetics C1 inhibitor protein encoded in 8 exons on C11 Large number of disease-causing mutations described with autosomal dominant transmission Type 1 HAE – Deletions/ missense mutations in C1 inhibitor gene – Low C1 inhibitor protein levels Type 2 HAE – Point mutations at active site – Normal/ high levels dysfunctional protein Very rare familial forms of hereditary angioedema with normal C1 inhibitor described – a result of mutations in other members of the pathway Also an ‘acquired’ form of the condition (AAE), often associated with paraprotein Bradykinin is the major mediator of swelling in C1 inhibitor deficiency KALLIKREIN (CONTACT) COAGULATION Negative surface exposed by trauma or unknown precipitants fXII fXIIa XI Prekallikrein XIa fXIIa Kallikrein Etc fXIIa and KK autoactivate one another Kinins Kinases Bradykinin Pathway inhibited by C1 inhibitor INACTIVATED Bradykinin is the major mediator of swelling in C1 inhibitor deficiency KALLIKREIN (CONTACT) COAGULATION Negative surface exposed by trauma or unknown precipitants fXII fXIIa XI Prekallikrein XIa fXIIa Kallikrein Etc fXIIa and KK autoactivate one another Kinins Kinases Bradykinin Pathway inhibited by C1 inhibitor ACE-inhibitors inhibit INACTIVATED On-demand treatments: general principles All patients should have their own supplies at home Almost all patients can self-administer medication Treat all abdominal attacks, any actual or threatened airway attacks and any swelling above the shoulder Other attacks generally treated, at patient discretion ED attendance should be exception On-demand options Option Features C1 inhibitor concentrate: Cinryze Plasma-derived Fixed dosing 1000 units with option to repeat dose Slow intravenous injection Plasma-derived Dosed at 20 units/ kg Option for 500 unit vial or 1500 unit in 3ml Slow intravenous injection Recombinant Dose at 50 units/ kg Slow intravenous injection Pre-filled syringe for subcut injection Option to repeat Can be uncomfortable; injection site reactions Cheaper generics C1 inhibitor concentrate: Berinert C1 inhibitor concentrate: Ruconest Icatibant Prophylaxis: general principles The range of available drugs expanding Move away from attenuated androgens Worldwide push to increase use with the aim of abolishing attacks, but high cost and commissioning policies are a barrier How do we decide who qualifies? – – – – – Number of attacks? Severity/ location of attacks? Impact of attacks? Quality of life? Response to acute treatments? Regular C1 inhibitor concentrate injections KALLIKREIN (CONTACT) Negative surface exposed by trauma or unknown precipitants Prekallikrein fXIIa fXIIa and KK autoactivate one another Kallikrein Kinins Bradykinin Cinryze licensed product for prophylaxis Starting dose around 1000 units every 3 or 4 days, but dose escalation often needed Short half-life, high cost and intravenous formulation limit use; pregnancy is the most common indication Subcutaneous prophylaxis with Berinert 1500 units in 3ml highly effective, but not marketed or routinely commissioned for this indication in the UK Lanadelumab Monoclonal antibody against activated kallikrein KALLIKREIN (CONTACT) Negative surface exposed by trauma or unknown precipitants Prekallikrein fXIIa fXIIa and KK autoactivate one another Subcutaneous injection every 2 weeks, with option to reduce to monthly if patient attack-free 90% reduction in attack frequency vs placebo Kallikrein Around 60% of patients become attack-free Strict commissioning criteria limit use Kinins Bradykinin KALLIKREIN (CONTACT) Negative surface exposed by trauma or unknown precipitants Berotralstat Small molecule inhibitor of pre-kallikrein Only licensed oral prophylaxis option Once-daily capsule Gastro-intestinal side-effects in some patients 40% reduction in attack frequency vs placebo Take several weeks to reach full effect Commissioning requirements less strict compared to C1 inhibitor/ lanadelumab Prekallikrein fXIIa fXIIa and KK autoactivate one another Kallikrein Kinins Bradykinin Donidalorsen Anti-sense inhibitor of pre-kalikrein In phase 3 KALLIKREIN (CONTACT) Negative surface exposed by trauma or unknown precipitants Garadasamab FXIIa inhibitor Seeking approval Some emerging drug treatments Gene therapy also in development Prekallikrein fXIIa fXIIa and KK autoactivate one another Kallikrein Kinins Bradykinin Deucrictibant Oral BK inhibitor Sustained release for prophylaxis, short-acting for treatment Phase 3 commences 2024 Case study 55 year old, HAE 1 Fairly well-controlled with stanozolol Berinert on-demand for acute attacks Stanozolol no longer available; switched to danazol but seemed less effective and subsequent supply issues Met commissioning requirements for intravenous prophylaxis 1500 units twice weekly – completely asymptomatic