Meet the Expert: Sorena Kiani on hereditary angioedema

17th August 2022

Hospital Healthcare Europe had the pleasure of speaking with Sorena Kiani, MBPhD FRCP FRCPath, Consultant Immunologist at Barts Health NHS Trust, about the burden of the rare disease hereditary angioedema, and recent clinical and real-world data presented at EAACI 2022.

Sorena Kiani is a consultant immunologist at Barts Health NHS Trust, where they have the largest cohort of patients with angioedema in the UK. The trust has performed all the UK clinical trials on hereditary angioedema (HAE) so far.

He did a combined medical and immunology research degree, qualifying with an MBPhD from University College London, and did his postgraduate training in general medicine rotating in London hospitals, followed by specialisation in clinical immunology at King’s College Hospital.

What is the pathophysiology of HAE?

HAE is a chronic, rare genetic disorder characterised by unpredictable severe, painful swelling attacks affecting skin or mucosa which can be life-threatening.

These swelling attacks occur because HAE affects how the immune system controls vascular permeability. HAE is caused by a deficiency or dysfunction in the gene encoding the protein C1-esterase inhibitor (C1-INH), which plays a central role in regulation of parts of the immune system. People living with HAE therefore have abnormal levels of functional C1-INH in their bloodstream, intermittently causing increased levels of the mediator bradykinin. Bradykinin promotes swelling by increasing the leakage of fluid through blood vessel walls to body tissues.

What are the hallmarks of the condition, and how important is patient screening and prompt or differential diagnosis? 

The hallmark of HAE is frequent and unpredictable swelling attacks, which can occur in the face, extremities, genitals, abdomen and airways.¹ The median age of onset of HAE is 12 years old² and as a rare, genetic disease (affecting an estimated one in 50,000 individuals worldwide³), only children of people living with HAE are routinely tested for HAE.

It is estimated that about 20% of patients with HAE do not have any family members who have HAE. These patients are thought to be the first people in their line of inheritance to have the genetic abnormality. This is called a de novo mutation. For these patients, HAE is not always diagnosed from the start and can be mistaken for acute allergic reactions and/or anaphylaxis.⁴ As this is a rare disease, the abdominal attacks of swelling and excruciating pain can be mistaken by emergency services for appendicitis and result in unnecessary emergency surgery. To avoid misdiagnosis at emergency services, patients often bring a letter explaining their HAE diagnosis, allowing them to receive appropriate care. 

If HAE attacks are untreated, the swelling can be potentially life-threatening, particularly if it takes place in the airways. Therefore, a prompt diagnosis of HAE is vital; it allows for the swift and efficient treatment of a painful and potentially deadly attack.

Could you tell us about the burden of HAE on the patient and some of the interventions that are used to address these? 

The frequency of HAE attacks is varied in different patients. As attacks can last anywhere between several hours to days and can be extremely painful, patients might be unable to attend work, school, or continue with normal social activities.⁵ As a result of this, patients have to make significant lifestyle changes with regards to their career choices and relationships. Due to the impact of HAE on their own lives some patients carry significant guilt about the potential of passing the disease on to their children or might even reconsider having biological children.^6,7 Individuals with HAE can be traumatised by the experiences of their family members with HAE, as some might have passed away following asphyxiation because of a pharyngeal or laryngeal HAE attack. Up to 49.9% of HAE patients experience mild to severe anxiety and 24% experience depression.⁷

A few decades ago, there were limited options for safe prophylaxis and poor access to medications used for acute treatment. There have been great strides made in treatment options in the last 30 years. At the 2022 European Academy of Allergy & Clinical Immunology (EAACI) Congress, we saw data from both clinical trials and real-world-evidence including data from the open-label randomised Phase III APeX-2 trial⁸ showing that patients over 12 years of age with HAE receiving the oral prophylactic berotralstat experienced fewer attacks that required treatment with injectable on-demand medication and used less on-demand medication (doses/month) to treat attacks from baseline.⁸ This effect was observed and continued to improve throughout the 96-week trial.⁸ 

What are the factors that need to be considered in the decision-making process for each patient and optimising adherence and outcomes?

When choosing a treatment regimen for patients, it is vital that healthcare professionals consider the patient’s lifestyle, preferences and requirements. The shared decision-making process between a healthcare professional and their patient is an opportunity to discuss the factual information on available treatments, treatment goals and suitability to the patient’s lifestyle. 

What are the mainstays of treatment?

International consensus guidelines⁹ recommend that patients are assessed at every visit for their eligibility for long-term prophylaxis to prevent attacks, alongside a choice of acute/on-demand treatment for use when a HAE attack occurs. The mainstays of an effective acute or prophylactic treatment includes factors such as ease of administration, speed of resolution of swellings or the degree to which attacks are prevented with minimal side effects. 

Please tell us about some of the novel developments in management (and how you see their impact and place in therapy) 

In the last 10-20 years, novel therapeutics targeting the vascular permeability pathway (kinin-kallikrein system) have provided efficient treatment options to prevent HAE attacks and to treat acute attacks. Of note, international consensus guidelines recommend three first-line treatments for the prevention of HAE attacks, providing patients with a greater variety of treatment options. These prophylactic treatments can allow patients greater time between attacks, and in some cases reducing severity of their attacks. 

With greater time between attacks, patients are allowed to live a more normal life which does not always revolve around their attacks. They feel more empowered to attend important events and milestones such as family weddings, to work full-time, and travel abroad safely, and generally enjoy their lives without constant fear of an HAE attack. If pharmaceutical companies remain committed to the HAE community, and continue supporting studies prioritising real-world outcomes, there is an even greater opportunity on the horizon to improve the lives of people living with HAE.

Many clinical trials have also prioritised the evaluation of ‘real-world outcomes’ to measure the impact of HAE treatments, ensuring that novel treatments are tailored to patient preferences. In the UK, we have the Early Access to Medicines Scheme (EAMS). This gave the UK HAE network an opportunity to perform a survey and evaluate real-world outcomes for 54 patients across 12 UK centres who were initiated on the treatment Orladeyo (berotralstat) before its commercialisation.

The data from this independent real-world study was presented at EAACI in July 2022.¹⁰ Through participation in the EAMS, HAE specialist centres such as Barts Health NHS Trust have been able to generate valuable real-world evidence, and allow patients with significant unmet needs to gain early access to innovative treatments,¹⁰ which is another great step towards standardising care across the global HAE community. 

References

1. NHS Commissioning Board. Clinical Commissioning Policy: Treatment of Acute Attacks in Hereditary Angiodema (Adult). 2013. Reference: NHSCB/B09/P/b
2. Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol 2012;130(3):692–7.
3. Longhurst H, Bork K. Hereditary angioedema: an update on causes, manifestations and treatment. Br J Hosp Med 2019;80(7):391–8.
4. Henao M, Kraschnewski J. Diagnosis and screening of patients with hereditary angioedema in primary care. Ther Clin Risk Manag 2016;12:701–11.
5. Bygum A et al. Disease Severity, Activity, Impact, and Control and How to Assess Them in Patients with Hereditary Angioedema. Proc 2014;35:47–53.
6. Caballero T et al. The humanistic burden of hereditary angioedema: results from the Burden of Illness Study in Europe. Allergy Asthma Proc 2014;35(1):47–53.
7. Devercelli G et al. Patient-Reported Burden of Hereditary Angioedema: Findings from a US Patient Survey. Presented at the 2018 American Academy of Allergy, Asthma and Immunology (AAAAI)/World Allergy Organization (WAO) Joint Congress. 2–5 March 2018, Orlando, FL.
8. Geng B et al. Improvement in Quality of Life and Hereditary Angioedema (HAE) Attack Rates Observed in Patients Treated with Long-term Berotralstat in the APeX-2 Study. Abstract presented at the European Academy of Allergy and Clinical Immunology (EAACI) Hybrid Congress in Prague, Czech Republic, 1–3 July 2022.
9. Maurer M et al. The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update. World Allergy Organization Journal 2022;15.3: 100627.
10. Ahuja M et al.  Berotralstat for the prophylaxis of hereditary angioedema – a national survey of patient outcomes in the UK. Poster presented at the European Academy of Allergy and Clinical Immunology (EAACI) Hybrid Congress in Prague, Czech Republic,
    1–3 July 2022.

Berotralstat approved for recurrent attacks of hereditary angioedema

17th September 2021

NICE has recommended the use of berotralstat as a treatment option for recurrent attacks of hereditary angioedema in those 12 years and older.

Hereditary angioedema (HAE) is a rare, inherited disorder that presents with unpredictable, recurrent attacks of oedema, leading to a rapid swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. The condition affects around 1 in 50,000 of the population in the UK, which equates to around 1,500 people and the condition often first presents between the ages of 5 and 11 years.

The underlying cause of HAE is a mutation of the SERPING1 gene which codes for a protein, C1 esterase inhibitor (CI IHB), which regulates inflammatory pathways. This mutation can result in either low levels of C1 IHB, which is the most common presentation (type 1), accounting for around 85% of cases, or normal levels of C1 IHB, but with a reduced function (type 2). There is also a third, much rarer type characterised by normal C1 IHB levels but other mutations which also give rise to elevated levels of bradykinin. Irrespective of the underlying cause, reduced functioning of C1 IHB leads to an increased production of the vasoactive peptide, bradykinin which mediates vasodilation in subcutaneous or submucosal tissues.

The aim of treatment is to either reverse or prevent attacks with a view to improving patient’s quality of life. Treatments have been based on prophylactic use of C1 IHB concentrates, some of which have been developed as injectables for self-administration. In contrast, berotralstat, is an oral, once daily inhibitor of plasma kallikrein which is hydrolysed to release bradykinin.

NICE Approval

The NICE approval was based on the findings of the randomised phase 3 trial, APex-2, a double-blind, parallel-group study in which patients were randomised 1:1:1, to receive once-daily berotralstat in a dose of 110 mg, 150 mg or placebo. In APex-2, the primary efficacy end point was defined as the rate of investigator-confirmed HAE attacks during the 24-week treatment period. The study found that use of berotralstat led to a significant reduction in attack rate at both 110 mg (1.65 attacks per month, p = .024) and 150 mg (1.31 attacks per month, p < .001) relative to placebo (2.35 attacks per month). An extension of APex-2 was published in June 2021 in which patients originally assigned to placebo were randomised to either 110 mg or 150 mg of berotralstat and followed for 48 weeks. At the study end, mean attack rates for the 150mg group declined from a baseline of 3.06 attacks/month to 1.06 at week 48. Similarly, for the 110mg group, attack rates reduced from a baseline of 2.97 to 1.35 at week 48.

NICE has declared berotralstat is an innovative prophylactic treatment for recurrent attacks of hereditary angioedema and recommended that the drug can be used under the following circumstances.

In people 12 years and older, only if:
• they have at least 2 attacks per month and
• it is stopped if the number of attacks per month does not reduce by at
least 50% after 3 months.

Source: NICE. Berotralstat for preventing recurrent attacks of
hereditary angioedema, September 2021.