Safety Aspects and Rational Use of Lanadelumab Injections in the Treatment of Hereditary Angioedema (HAE): Clinical Insights

Abstract

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of skin/mucosal swelling, and/or attacks of severe abdominal pain when it affects the gastrointestinal tract. The disease might be unexpectedly fatal when the upper airways are compromised. HAE clinical presentation, disease course and prognosis are associated with significant disease burden and severely impaired quality of life. Lanadelumab is a breakthrough therapy for the prevention of attacks in HAE type 1 and 2 patients. This revolutionary approach to administer a single subcutaneous injection (once every two to four weeks) and achieve complete disease control has dramatically improved patient care resulting in significant change in the life of affected families. Current data support the drug's tolerability in adult and adolescent patients without notable safety concerns in both clinical research and real-world settings. Rational use of prophylactic treatments of HAE searches for a socio-economic balance, taking into account the life-long course of the disease, the public health funds who pay the monetary price, and the patients who might need to receive the therapy for a period longer than investigated during the development program. In this review, we address the current evidence on lanadelumab's tolerability, highlighting aspects of the drug's rationale use in clinical practice. Further studies need to investigate whether this therapy might be appropriate in other forms of angioedema, such as idiopathic primary angioedema and HAE with normal C1 inhibitor. Future efforts must focus to improve modern drugs' accessibility in more countries. Although modern prophylactic options lessen the risk of fatal laryngeal attacks, patients must be equipped with reliable on-demand therapies and be trained how to use them as such a risk cannot be fully diminished with potentially life-threatening attacks occurring even in subjects with successful and stable long-term prophylaxis. Notwithstanding, further studies are needed to identify early responders from non-responders and develop therapies for the latter.

Keywords: C1 inhibitor; bradykinin; drug safety; hereditary angioedema; kallikrein; lanadelumab.

Figure 1

Kallikrein-kinin system (and place of intervention with lanadelumab). Angioedema occurs after tissue injury from multiple causes. Tissue injury can activate contact activation (Hageman factor or Factor 12) to generate kallikrein from its precursor prekallikrein. Under normal circumstances, C1-INH functions to inhibit both complement activation and to modulate the contact activation. In HAE‐C1-INH, due to defective C1-INH, the pathway remains uncontrolled, generating bradykinin from the high-molecular weight kininogen (HMWK). Bradykinin binds to the bradykinin B2R on the endothelial cells resulting in increased vascular permeability and angioedema.

Figure 2

Mechanism of action of lanadelumab. One of the therapeutic approaches for long-term prophylaxis of HAE includes inhibiting kallikrein with lanadelumab. Lanadelumab is a first-in-class fully human IgG1 monoclonal antibody made in recombinant Chinese Hamster Ovary cells that binds plasma kallikrein with high affinity and selectivity and thus preventing the cleavage of high-molecular weight (HMWK) to release vasoactive bradykinin.