Current and emerging biologics for the treatment of hereditary angioedema

Perego, Francesca; Wu, Maddalena Alessandra; Valerieva, Anna; Caccia, Sonia; Suffritti, Chiara; Zanichelli, Andrea; Bergamaschini, Luigi; Cicardi, Marco

doi:10.1080/14712598.2019.1595581

Cited by 17 publications

(22 citation statements)

References 67 publications

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“…There are however still challenges to overcome before these therapeutics can be used in the clinic. Although the effects of plasma-derived and recombinant molecules are highly similar, with recombinant molecules easier to produce, a shortcoming of the recombinant regulators is that their half-life is often much shorter ( 171 , 185 ), which might hinder their clinical applications. In addition, the targeting or inhibiting of complement regulatory proteins in cancer is still in its infancy.…”

Section: Discussionmentioning

confidence: 99%

“…Hereditary angioedema is caused by a genetic C1-INH deficiency which can result in life-threatening edema from excessive bradykinin release ( 171 , 172 ). The plasma-derived C1-INH can prevent angioedema attacks completely, providing a safe treatment option with no significant side effects ( 171 , 173 ). Additionally, C1-INH has been recombinantly produced from the milk of transgenic New Zealand white rabbits ( 174 ).…”

Section: Future Potential Of Utilizing Complement Regulators In Theramentioning

confidence: 99%

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Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

Mourik

Jongerius

2020

Front. Immunol.

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The complement system is an important part of the innate immune system, providing a strong defense against pathogens and removing apoptotic cells and immune complexes. Due to its strength, it is important that healthy human cells are protected against damage induced by the complement system. To be protected from complement, each cell type relies on a specific combination of both soluble and membrane-bound regulators. Their importance is indicated by the amount of pathologies associated with abnormalities in these complement regulators. Here, we will discuss the current knowledge on complement regulatory protein polymorphisms and expression levels together with their link to disease. These diseases often result in red blood cell destruction or occur in the eye, kidney or brain, which are tissues known for aberrant complement activity or regulation. In addition, complement regulators have also been associated with different types of cancer, although their mechanisms here have not been elucidated yet. In most of these pathologies, treatments are limited and do not prevent the complement system from attacking host cells, but rather fight the consequences of the complement-mediated damage, using for example blood transfusions in anemic patients. Currently only few drugs targeting the complement system are used in the clinic. With further demand for therapeutics rising linked to the wide range of complement-mediated disease we should broaden our horizon towards treatments that can actually protect the host cells against complement. Here, we will discuss the latest insights on how complement regulators can benefit therapeutics. Such therapeutics are currently being developed extensively, and can be categorized into full-length complement regulators, engineered complement system regulators and antibodies targeting complement regulators. In conclusion, this review provides an overview of the complement regulatory proteins and their links to disease, together with their potential in the development of novel therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Future Potential Of Utilizing Complement Regulators In Theramentioning

confidence: 99%

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

Mourik

Jongerius

2020

Front. Immunol.

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“…Several drugs are under development for the treatment of C1-INH-HAE; most are for LTP, and only a few are for ondemand treatment [96,97].…”

Section: New Drugs Under Development For the Treatment Of C1-inh-haementioning

confidence: 99%

“…31(1): 1-16 © 2021 Esmon Publicidad doi: 10.18176/jiaci.0653 a decrease in bradykinin release. IONIS-PKKRx (IONIS Pharmaceuticals Inc) is a second-generation SC chimeric antisense single-stranded oligonucleotide designed to selectively bind and reduce the mRNA of prekallikrein in the liver [96,97]. A phase 1 clinical trial was completed (NCT03263507) with a dose-dependent reduction in prekallikrein and a good safety profile [100].…”

Section: New Drugs Under Development For the Treatment Of C1-inh-haementioning

confidence: 99%

Treatment of Hereditary Angioedema

Caballero

2021

J Investig Allergol Clin Immunol

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Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease. In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE. Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis. The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide. Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis. Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis. New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti–activated FXII action.

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“…KVD 900 [ https://www.clinical-trials.gov ] is a selective inhibitor of Pka, an oral treatment with a possible task in the treatment of acute attacks, and finally ATN-249, a novel oral plasma kallikrein inhibitor, that could be useful for prophylactic use in prevention of HAE attacks. Other ongoing animal experimental model are approaching HAE treatment based on new targets, like factor XIIa, prekallikrein and genetic therapy 25–28…”

Section: Current Therapeutic Landscapementioning

confidence: 99%

<p>Lanadelumab Injection Treatment For The Prevention Of Hereditary Angioedema (HAE): Design, Development And Place In Therapy</p>

Bova¹,

Valerieva²,

Wu³

et al. 2019

DDDT

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Despite the efficacy of the on-demand treatment for the control of acute attacks of Hereditary Angioedema due to C1-Inhibitor Deficiency (C1-INH-HAE), the number and severity of attacks and the impairment in the quality of life of the affected patients have led to the development of a new monoclonal antibody, lanadelumab, directly addressed to the blockage of bradykinin, the principal mediator of vasodilation during angioedema attacks. It is indicated for the prophylactic treatment, it is easy to administer, highly effective and with known limited side effects. The current review summarizes the development of the drug, its clinical background and its perspectives.

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Current and emerging biologics for the treatment of hereditary angioedema

Cited by 17 publications

References 67 publications

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

Therapeutic Lessons to be Learned From the Role of Complement Regulators as Double-Edged Sword in Health and Disease

Treatment of Hereditary Angioedema

<p>Lanadelumab Injection Treatment For The Prevention Of Hereditary Angioedema (HAE): Design, Development And Place In Therapy</p>

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