Reviewing clinical considerations and guideline recommendations of C1 inhibitor prophylaxis for hereditary angioedema

Abstract Background Hereditary angioedema (HAE), a rare disease that is characterized by painful and recurring non‐allergic swelling episodes, is caused by the deficiency or dysfunction of C1 inhibitor (C1INH) protein. A comprehensive HAE management plan may require long‐term prophylaxis (LTP) in addition to on‐demand treatment to help “normalize” patients' lives so that they may fully engage in work, school, family, and leisure activities. Aim The main objective of this narrative review is to provide an overview of updated guideline recommendations specific to LTP of HAE and discuss clinical considerations and pharmacologic management options, with a focus on C1INH. Materials and Methods The authors reviewed relevant HAE literature for current recommendations regarding LTP and the role of C1NH. Results Acute HAE attacks are treated with on‐demand medication; however, there is a consensus that LTP should routinely be considered for risk reduction and prevention of future episodes. The 2017 World Allergy Organization/European Academy of Allergy and Clinical Immunology guidelines recommend that all patients with HAE be evaluated for LTP routinely and the 2020 HAE Association (HAEA) guidelines emphasize that the decision to use LTP should not be based on rigid criteria, but rather should be based on individual patient needs. Both guidelines recommend C1INH as first‐line/preferred therapy for LTP in a range of patient types including adults, children/adolescents, and pregnant/lactating patients. The HAEA also recommends the kallikrein inhibitor, lanadelumab, as a first‐line option for LTP. HAE pathway‐specific agents for LTP have not been associated with notable safety concerns. Discussion Plasma‐derived C1INH has been available for 40+ years in Europe and impacts multiple targets within the HAE pathway. C1INH has been used for on‐demand treatment and LTP. A subcutaneous formulation of plasma‐derived C1INH is approved for LTP and produces functional C1INH activity levels consistently above the threshold needed for protection from HAE attacks. Other pathway‐specific options for LTP include the plasma kallikrein inhibitors, lanadelumab‐flyo and berotralstat, approved for adults and pediatric patients aged ≥12 years. C1INH is approved for adults and pediatric patients aged ≥6 years. Conclusion Assessing the need for LTP is vital in the ongoing dialogue between clinicians and patients, as both disease‐related factors and patient preferences may change over time. Among available options for LTP, plasma‐derived C1INH is the broadly recommended first‐line option for LTP in patients with HAE, including pregnant/lactating women and pediatric patients (≥6 years).

pathway-specific options for LTP include the plasma kallikrein inhibitors, lanadelumab-flyo and berotralstat, approved for adults and pediatric patients aged ≥12 years. C1INH is approved for adults and pediatric patients aged ≥6 years.

Conclusion:
Assessing the need for LTP is vital in the ongoing dialogue between clinicians and patients, as both disease-related factors and patient preferences may change over time. Among available options for LTP, plasma-derived C1INH is the broadly recommended first-line option for LTP in patients with HAE, including pregnant/lactating women and pediatric patients (≥6 years).

K E Y W O R D S
bradykinin, C1 inhibitor, hereditary angioedema, kallikrein, long-term prophylaxis

S C H L Ü S S E L W Ö R T E R
bradykinin, C1-Inhibitor, hereditäres angioödem, kallikrein, langzeitprophylaxe

| INTRODUCTION
Hereditary angioedema (HAE) is caused by either a deficiency of C1 inhibitor (C1INH) protein (HAE Type I) or dysfunction of C1INH (HAE Type II). 1,2 Endogenous C1INH has a major role in regulating the complement and contact pathways, an important role in coagulation, and, under certain circumstances, impacts the fibrinolytic pathway. 2,3 In patients with HAE, deficiency in the levels and/or function of endogenous C1INH leads to production of excess bradykinin that underlies the recurrent episodes of swelling. 1,4 Most patients experience painful episodes of angioedema including recurrent skin swelling, recurrent abdominal pain episodes, and rarely occurring laryngeal edema. 5 Angioedema associated with HAE is considered to be non-allergic, since the underlying mechanism is bradykinin-mediated and distinct from the more familiar allergic, histamine-mediated angioedema.  Figure 2). 8 Direct replacement of naturally occurring C1INH with plasma-derived C1INH (hereafter referred to as C1INH) or recombinant C1INH impacts multiple targets within the HAE pathway ( Figure 1). 6,9,10 Other HAE pathway-based treatments target either plasma kallikrein or bradykinin specifically. 7 For treatment of acute attacks, it is recommended that all patients with HAE not only have on-demand treatment for two attacks, but also carry their ondemand treatment, whatever it may be, at all times. 11 In addition to having appropriate on-demand medication for acute attacks, there is a consensus that long-term prophylaxis (LTP) should be considered for risk reduction and prevention of future episodes. 12 Thus, for many patients, comprehensive management of HAE may be comprised of on-demand rescue medications as well as LTP. Of note, for patients who have an increased risk of HAE attacks associated with known triggers (e.g., invasive dental, medical, or surgical procedures and/or stressful life events), short-term prophylaxis (STP) with a single dose of C1INH (1-12 h prior to the stressor) or a short course of anabolic steroids (started 5-7 days before the event and continued for 2-5 days after) may be appropriate 13 ; however, the current review is focused on LTP.
This narrative review provides an overview of updated guideline recommendations specific to LTP of HAE and discusses pharmacologic management options, with a focus on C1INH as it is recommended as first-line treatment in children, adults, and specialized populations. In addition, clinical practice considerations regarding LTP will be shared. p < 0.001). The majority (90%) of patients in the C1INH(SC) 60 IU/kg group had a ≥ 50% reduction in HAE attacks. A prespecified post-hoc analysis of COMPACT found onset of attack prevention within 2 weeks of C1INH(SC) initiation. 26 Another post-hoc analysis of the COMPACT that focused on prespecified exploratory health-related quality of life (HRQoL) parameters found that C1INH(SC) improved F I G U R E 1 Mechanisms of action for therapies used in LTP of HAE. 6,7 Mechanisms of action for therapeutic agents in treating or preventing HAE. Multiple pathways are capable of complement activation and generating inflammatory mediators including complement anaphylatoxins C3a and, more important, C5a. Activation of the final complement cascade produces a membrane attack complex that produces cellular injury. Angioedema occurs after tissue injury from multiple causes. Tissue injury can activate contact activation (Hageman factor or factor XII) to generate kallikrein from prekallikrein, its precursor. Kallikrein in turn generates and activates plasmin from plasminogen, and plasmin can directly activate the C1 esterase complex to initiate complement activation. Under normal circumstances, C1INH functions to inhibit both complement activation and, to a lesser extent, modulate contact activation. In HAE-C1INH, because of quantitative or qualitative defective C1INH, the pathway proceeds unchecked, generating mediators that increase capillary permeability to produce angioedema. Therapeutic approaches for LTP of HAE include restoring C1INH levels with C1INH replacement or inhibiting kallikrein with lanadelumab or berotralstat. Attenuated androgens have been used as second-line options to increase liver synthesis of C1INH. The C1INH(SC) 60 IU/kg twice weekly group had a median timenormalized attack rate of 1 HAE attack per year. 28 Considering the COMPACT HRQoL analysis findings of improved anxiety and increased work productivity, together with the open-label extension findings of a safe and sustained effect, LTP with C1INH(SC) may allow patients to become free of HAE disease symptoms and enable them to regain an active and productive lifestyle. 27,28 The SC formulation filled a previously unmet need related to C1INH replacement: the pharmacodynamic profile of C1INH(SC) is characterized by steady state levels of functional C1INH activity above the ∼40% threshold required for adequate protection from HAE attacks-this is distinct from the IV formulation, which is characterized by more variable peaks and troughs, with the trough levels below the ∼40% threshold. 29,30 Pharmacodynamic data from the COMPACT study show that the mean C1INH functional activity increased from ∼30% at baseline (prior to initiation of LTP) to >65%

| Bradykinin inhibition
(approximating the lower limit of the normal range of ∼70%) in the 60 IU/kg twice-weekly group; this increase of C1INH functional activity to well above the ∼40% threshold for protective effect was sustained in the extension period of up to 88 additional weeks ( Figure 3). 28 These results were consistent with data from an earlier phase 2 study of C1INH, which showed dose-dependent increases in trough plasma levels of functional C1INH activity to be above the threshold for a protective therapeutic effect. 30 Of interest, a posthoc analysis of COMPACT found that, among patients who were using the IV formulation of C1INH as routine prophylaxis pre-study, switching to the SC formulation of C1INH produced a clinically meaningful ∼50% mean reduction in HAE attacks. 32 Another important point is that available data support that rescue medications remain effective in patients on LTP for HAE. For example, in the COMPACT phase 3 study, use of C1INH(SC) for LTP did not diminish the effect of on-demand treatments, such as C1INH(IV), icatibant, or ecallantide (i.e., most patients needed just 1 dose of rescue medication). 25,28

| Plasma kallikrein inhibition
C1INH inhibits multiple targets in the contact system, including plasma kallikrein. The first drug specifically targeting plasma kallikrein, the SC kallikrein inhibitor ecallantide (KALBITOR ® ; Takeda Dyax Corp), was developed for on-demand treatment and approved in the US, though not yet in the EU. 33 More recently, 2 plasma kallikrein inhibitors have been developed for LTP. F I G U R E 2 Long-term HAE prophylaxis and medications reported as used "most frequently". 8 Proportion of physicians reporting HAE LTP and medications used "most frequently." Over the past decade, reported use of pathway-specific options has increased, while use of anabolic steroids has decreased. The figure is reproduced with permission from Riedl et al. 8 39,40 Another plasma kallikrein inhibitor, berotralstat (ORLADEYO™; BioCryst Pharmaceuticals, Inc.) was approved as prophylaxis to prevent attacks of HAE in adults and pediatric patients aged ≥12 years. 41,42 The efficacy of berotralstat was demonstrated in the 24-week randomized phase 3 APeX-2 study (NCT03485911) of patients with type 1 or 2 HAE who experienced ≥2 investigatorconfirmed HAE attacks requiring treatment or causing functional impairment in the first 56 days of the prospective run-in period.
Berotralstat 150 mg once daily significantly reduced attacks relative to placebo: 1.31 attacks per month versus 2.35 attacks per month (p < 0.001). 43 APeX-2 was designed as a 3 part study, and the results of Part 2, which evaluated an additional 24 weeks of blinded berotralstat treatment without a control group, were recently reported. 44 Mean attack rates among patients receiving berotralstat 150 mg/day declined by 67% from baseline to week 48; reductions in attack rates either continued or declined further from Part 1 to Part 2 of the study, with no new safety signals. Part 3 of Apex-2, a long-term openlabel extension phase, is ongoing.

| GUIDELINES REGARDING LTP OF HAE
A comprehensive and effective HAE management plan is intended to help "normalize" a patient's life as much as possible, so that they can fully engage in work, school, family, and leisure activities. 13 Although on-demand treatment is effective, for many patients it may be inadequate. Novel therapies for LTP are now available (Table 1)  recommends that all patients with HAE be evaluated for LTP routinely. 11 The recently released HAE Association (HAEA) guidelines note that the decision to use LTP should not be based on rigid criteria, but rather should be based on an individual patient's needs. 13 Factors related to disease burden as well as the patient's quality of life and treatment preference should be evaluated. 13,45 Key decision factors when considering LTP are noted in Table 2.
Both the WAO/EAACI and HAEA guidelines recommend C1INH as first-line therapy for LTP. Dosage and/or treatment interval for LTP should be adapted, as needed, to minimize disease burden. 13,45 The HAEA also recommends the kallikrein inhibitor, lanadelumab, as a first-line option for LTP. 13 HAE pathway-specific treatments for LTP are discussed in detail above.
Androgens are a second-line option for LTP that may be used in special circumstances (e.g., if the recommended first-line pathwaybased options are unavailable, or if a patient not willing/able to use recommended injectable treatment). 13 As noted previously, with the increased use of pathway-specific treatments, particularly C1INH, use of androgens for HAE has declined substantially in the past decade. 8 Use of androgens for LTP is limited by poor tolerability; moreover, these agents are not recommended in children and are contraindicated during pregnancy. [45][46][47] F I G U R E 3 Improvement in functional C1INH levels with C1INH(SC) (phase 3 COMPACT and OLE). 28 Pharmacodynamic findings over the course of the COMPACT study and OLE. Mean (dots) and SD (vertical lines) of C1INH functional activity; gray boxed area indicates the extended study period. This figure is reproduced, with slight alterations (as described in the following sentences), from J Allergy Clin Immunl Pract, 7 (6) Table 3. 13,45 Notably, C1INH is recommended as first-line therapy for LTP for each of these patient populations. The WAO/EAACI and HAEA recommendations are consistent with pediatric-specific guidelines, which consider C1INH to be a preferable and safe option for LTP in children. 6,48

| CONSIDERATIONS FOR CLINICAL PRACTICE
Allergists and other healthcare providers have an ongoing commitment to discuss management options with their HAE patients, reassess regularly, and make adjustments. 49  A periodic review of the nature and frequency of attacks, triggers, and treatments provides the opportunity to identify and address any needed changes to the management plan for HAE. 49 The updated HAE guidelines emphasize the importance of an ongoing dialogue regarding LTP. Routinely asking patients about LTP, rather than assuming that an existing HAE management plan remains adequate, enables healthcare providers to stay current with their patient's potentially changing needs.
Likewise, this type of proactive engagement encourages the patient to reevaluate their own lifestyle and goals in relation to their disease and ask questions about new therapies. [50][51][52] Due to both the variability in the disease and changes in the patient's circumstances and/or preferences, the threshold for/barriers to LTP may change over time. An ongoing and iterative shared "3D" decision-making model for provider-patient collaboration in HAE has been proposed, with the 3D's being "discover" (i.e., explore patient's needs/ preferences, establish goals, acknowledge available options), "discuss" (i.e., discuss reasonable alternatives aligned to the patient's needs/preferences), and "decide" (i.e., make shared decisions based on mutual understanding and accurate information). 50  A.

Consideration of LTP
Recommend that all patients (adult and pediatric) be evaluated for LTP at every visit; disease burden and patient preference should be taken into consideration (grade of evidence: D; strength of recommendation: Strong, 100% agreement).
LTP may be indicated during pregnancy, especially in patients who experience an increase in the frequency of HAE attacks. When C1INH concentrate is not available for LTP, antifibrinolytics are preferred over androgens because of their better safety profile; however, efficacy is questionable and data supporting use are not available.
Androgens are not recommended in children and adolescents prior to Tanner Stage V; however, long-term use has been reported, and in some cases the benefits may outweigh the risks; administration of androgens requires careful safety monitoring.
Pregnant/lactating patients C1INH concentrate is considered a safe and effective treatment option.
Antifibrinolytics may be considered if C1INH concentrate is unavailable, but efficacy is not proven.
Androgens are contraindicated, as these drugs cross the placenta (adverse effects include masculinization of the female fetus, placental insufficiency, and fetal growth retardation).
Breastfeeding should be discontinued before androgens are introduced; terminating lactation itself may reduce attack frequency.

Consideration of LTP
The decision on when to use LTP cannot be made on rigid criteria but should reflect the needs of the individual patient (level of evidence: High for HAE C1INH; low for HAE-nl-C1INH; strength of recommendation: Strong).

| CONCLUSIONS
Assessment of a patient's need for LTP is an important part of the ongoing dialogue between providers and patients living with HAE, as both disease-related factors and patient preferences may change over time. LTP can be an instrumental part of an HAE management plan that enables patients to feel "normalized," and therefore be fully engaged in their work/school, family, and leisure activities, rather than limited by the constraints of uncontrolled disease. Plasmaderived C1INH is the broadly recommended first-line option for LTP in patients with HAE, including pregnant and/or lactating women, and pediatric patients aged as young as 6 years.

ACKNOWLEDGMENTS
Funding for writing and editorial support was provided by CSL Behring; CSL had no role in the development of manuscript content.
Writing and editorial assistance was provided by Kulvinder Katie Singh, PharmD, Churchill Communications (Maplewood, NJ).