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Hereditary Angioedema (HAE)

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Experimental Therapies

Currently, many drugs are being investigated for the treatment of hereditary angioedema (HAE), with developmental studies focusing on increased drug efficacy, tolerability, and ease of administration.

Garadacimab

Garadacimab (formerly CSL312) is a novel, recombinant, fully human monoclonal antibody that inhibits activated factor XII (FXII) a, a key initiator of the bradykinin-producing pathway. It is currently being investigated for the prophylactic treatment of patients with C1-esterase inhibitor-deficient HAE.1

A double-blind, placebo-controlled phase 2 study (NCT03712228) aimed to determine the efficacy and safety of garadacimab administered intravenously as a first dose and subcutaneously every 4 weeks over a 12-week period in 32 patients with HAE,1 and the results showed a significant reduction in the number of monthly attacks compared to placebo and a favorable safety profile.2

In May 2020, the US Food and Drug Administration (FDA) granted Orphan Drug designation to garadacimab as an investigational therapy for the prophylaxis of bradykinin-mediated angioedema, which includes both hereditary and non-hereditary angioedema.3

Small Interfering RNAs

Small interfering RNAs (siRNAs) are small RNA molecules (around 20-30 nucleotides long) that are designed to inhibit the intracellular translation of target messenger RNA (mRNA), thereby preventing protein production. ALN-F12 and ARC-F12 are siRNAs that are targeted against the FXII mRNA, blocking its translation into FXII protein and thereby limiting bradykinin generation. These siRNAs appear to be promising due to their long half-lives, so they do not require frequent dosing.4

ALN-F12

A single subcutaneous dose of ALN-F12 led to a potent reduction of plasma FXII in mice, rats, and cynomolgus monkeys. In 2 different models of bradykinin-driven vascular leakage, the administration of ALN-F12 resulted in a dose-dependent reduction of vascular permeability, demonstrating that the siRNA-mediated reduction of FXII can potentially mitigate excess bradykinin production.5

ARC-F12

ARC-F12 is a new siRNA therapy developed by Arrowhead Pharmaceuticals that is currently being investigated for the prophylactic treatment of HAE. The company reported significant reductions in serum FXII levels after a single subcutaneous injection of ARC-F12, and the bleeding risk did not increase in ARC-F12-treated mice.6

Donidalorsen

Donidalorsen (formerly IONIS-PKK-LRx) is an investigational second-generation antisense oligonucleotide developed by Ionis Pharmaceuticals using its advanced ligand-conjugated antisense (LICA) technology. It is designed to selectively reduce hepatic plasma prekallikrein mRNA synthesis, thereby reducing the production of prekallikrein protein, which plays a key role in the activation of inflammatory mediators associated with acute attacks of HAE.7 The phase 2 study (NCT04030598) results showed that donidalorsen significantly reduced the number of attacks suffered by patients with HAE compared to placebo, with a mean reduction of 97% in weeks 5 to 17. It also showed that the drug was well tolerated and had an adequate safety profile.8,9

NTLA-2002

NTLA-2002, developed by Intellia Therapeutics, is an investigational clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based therapy designed to inactivate the kallikrein B1 (KLKB1) gene that encodes for prekallikrein, the kallikrein precursor protein. It aims to prevent the long-term production of prekallikrein through a single intravenous dose of treatment, thereby preventing attacks in patients with HAE. An ongoing multinational phase 1/2 study is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2002 in adults with HAE.10

Plasma Kallikrein Inhibitors

Betrotralstat, a plasma kallikrein inhibitor, has already been approved for oral use for long-term prophylactic treatment of patients with HAE. Three oral plasma kallikrein inhibitors are currently being investigated – ATN-249, KVD824, and KVD900.4

ATN-249

ATN-249, developed by Attune Pharmaceuticals, is a potent, selective, and orally-administered plasma kallikrein inhibitor under investigation for the prophylactic treatment of patients with HAE. A randomized, double-blind, placebo-controlled, single-ascending dose phase 1 study of ATN-249 (ACTRN12618000430235) was conducted in 48 healthy male participants. The results of the study showed a dose-dependent inhibition of plasma kallikrein activity with a favorable safety profile.11,12

KVD900

KVD900, also known as sebetralstat, is being developed by KalVista Pharmaceuticals for on-demand therapy for patients with HAE. An ongoing phase 3 study (NCT05259917) is evaluating the safety and efficacy of KVD900 in adults and adolescents over the age of 12 years with HAE type 1 and 2.13,14

KVD824

KVD824 is an oral plasma kallikrein inhibitor designed for the prevention of HAE attacks. Due to its markedly longer half-life than that of KVD900, KVD824 is being developed for the prophylactic treatment of HAE. KVD824 has completed its first in-human study, in which 84 participants received at least 1 dose of KVD824. An ongoing randomized, double-blind, placebo-controlled phase 2 study (NCT05055258) is currently recruiting adult patients with HAE to evaluate the safety and efficacy of KVD824 for long-term prophylactic treatment.15,16

PHA121

PHA121 (PHA022121) is a novel, highly potent, selective, and orally administered drug that targets the bradykinin B2 receptor, which may prevent the binding of bradykinin to its receptor and thereby potentially prevent symptoms caused by excess bradykinin levels in patients with HAE.17,18 It is currently under clinical development by Pharvaris for use as both on-demand therapy and prophylactic treatment for HAE. In clinical studies, PHA121 has shown rapid and potent activity at multiple oral doses in a bradykinin-mediated challenge model with a favorable safety profile.19,20

Gene Therapy

Gene therapy with an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of the normal human C1-esterase inhibitor (ie, the SERPING1 gene) resulted in sustained and adequate plasma levels of C1 inhibitor for at least 24 weeks in a murine model of HAE.21

Preclinical studies with AAV vector-based gene therapies for HAE are being conducted by Biomarin (BMN331) and REGENXBIO and aim to develop a potential one-time treatment with such gene therapies.22,23

References

  1. A study to investigate CSL312 in subjects with hereditary angioedema (HAE). ClinicalTrials.gov. October 19, 2018. Updated June 10, 2022. Accessed June 30, 2022.
  2. Craig T, Magerl M, Levy DS, et al. Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2022;399(10328):945-955. doi:10.1016/S0140-6736(21)02225-X
  3. CSL Behring presents results for garadacimab as preventive treatment in hereditary angioedema. News release. CSL Behring; June 8, 2020.
  4. Fijen LM, Bork K, Cohn DM. Current and Prospective Targets of Pharmacologic Treatment of Hereditary Angioedema Types 1 and 2. Clin Rev Allergy Immunol. 2021;61(1):66-76. doi:10.1007/s12016-021-08832-x
  5. Liu J, Qin J, Borodovsky A, et al. An investigational RNAi therapeutic targeting factor XII (ALN-F12) for the treatment of hereditary angioedema. RNA. 2019;25(2):255-263. doi:10.1261/rna.068916.118
  6. Arrowhead Pharmaceuticals presents new data on ARC-F12 and ARC-LPA using DPCsqTM subcutaneous RNAi delivery vehicle. News release. Arrowhead Pharmaceuticals, Inc; November 14, 2016.
  7. Ionis reports positive topline phase 2 study results of its novel antisense treatment for hereditary angioedema. News release. Ionis Pharmaceuticals, Inc; March 29, 2021.
  8. Fijen LM, Riedl MA, Bordone L, et al. Inhibition of prekallikrein for hereditary angioedema. N Engl J Med. 2022;386(11):1026-1033. doi:10.1056/NEJMoa2109329
  9. A study to assess the clinical efficacy of IONIS-PKK-LRx in participants with hereditary angioedema. ClinicalTrials.gov. July 24, 2019. Updated May 14, 2021. Accessed June 30, 2022.
  10. NTLA-2002 in adults with hereditary angioedema (HAE) (NTLA-2002). ClinicalTrials.gov. November 15, 2021. Updated May 4, 2022. Accessed June 30, 2022.
  11. Busse P, Kaplan A. Specific targeting of plasma kallikrein for treatment of hereditary angioedema: a revolutionary decade. J Allergy Clin Immunol Pract. 2022;10(3):716-722. doi:10.1016/j.jaip.2021.11.011
  12. Kalfus I, Offman E, McDonald A. Pharmacokinetics and safety of ATN-249, a novel oral plasma kallikrein inhibitor for hereditary angioedema. Poster presented at: Western Society of Allergy, Asthma, and Immunology (WSAAI) 2019 Annual Scientific Session; January 20-24, 2019; Wailea, HI.
  13. Sebetralstat for HAE. KalVista Pharmaceuticals. Accessed June 30, 2022.
  14. A phase III, crossover trial evaluating the efficacy and safety of KVD900 for on-demand treatment of angioedema attacks in adolescent and adult patients with hereditary angioedema (HAE). ClinicalTrials.gov. March 2, 2022. Updated June 21, 2022. Accessed June 30, 2022.
  15. A trial to evaluate the efficacy and safety of different doses of KVD824 for prophylactic treatment of HAE type I or II (KVD824-201). ClinicalTrials.gov. September 24, 2021. Updated May 17, 2022. Accessed June 30, 2022.
  16. KVD824 for HAE. KalVista Pharmaceuticals. Accessed June 30, 2022.
  17. Pipeline & platform: B2-receptor-mediated diseases. Pharvaris. Accessed June 30, 2022.
  18. Derendorf H, Lesage AS, Crabbé R, et al. Bradykinin challenge provides surrogate endpoints for hereditary angioedema treatment using bradykinin-B2-receptor antagonists. Poster presented at: American College of Asthma, Allergy and Immunology (ACAAI) 2020 Annual Scientific Meeting; November 13-15, 2020; Virtual.
  19. Dose-ranging study of oral PHA-022121 for acute treatment of angioedema attacks in patients with hereditary angioedema (RAPIDe-1). ClinicalTrials.gov. November 5, 2020. Updated February 28, 2022. Accessed June 30, 2022.
  20. Dose-ranging study of oral PHA-022121 for prophylaxis against angioedema attacks in patients with hereditary angioedema type I or type II (HAE CHAPTER-1). ClinicalTrials.gov. September 17, 2021. Updated June 30, 2022. Accessed June 30, 2022.
  21. Qiu T, Chiuchiolo MJ, Whaley AS, et al. Gene therapy for C1 esterase inhibitor deficiency in a murine model of hereditary angioedema. Allergy. 2019;74(6):1081-1089. doi:10.1111/all.13582
  22. Pipeline: BMN 331 for hereditary angioedema (HAE). BioMarin. Accessed June 30, 2022.
  23. REGENXBIO expands pipeline using NAV vectors to deliver therapeutic antibodies for the treatment of hereditary angioedema and neurodegenerative diseases. News release. REGENXBIO Inc; July 24, 2019.

Reviewed by Kyle Habet, MD, on 6/30/2022.

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