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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 7  |  Issue : 1  |  Page : 12-14

Ligelizumab: A promising option on the horizon for the management of chronic spontaneous urticaria


1 Department of Dermatology, Dr. DY Patil Medical College, Nerul, Navi Mumbai, Maharashtra, India
2 Department of Pharmacology, Dr. DY Patil Medical College, Nerul, Navi Mumbai, Maharashtra, India
3 Shree Skin Centre, Nerul, Navi Mumbai, Maharashtra, India

Date of Submission09-Jun-2020
Date of Acceptance19-May-2021
Date of Web Publication25-Jun-2021

Correspondence Address:
Anant D Patil
Department of Pharmacology, Dr. DY Patil Medical College, Nerul, Navi Mumbai - 400 706, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_33_20

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  Abstract 


Chronic spontaneous urticaria may pose challenges for the treatment in some patients. Different options for the management of chronic urticaria include second-generation antihistamines, leukotriene receptor antagonists, omalizumab (anti-IgE antibody), and immunosuppressants. Omalizumab, a monoclonal antibody, is a valuable option for patients not responding to up-dosing (up to 4 times) of second-generation antihistamine. However, in about one-fourth of the patients, omalizumab may not be effective in controlling symptoms. Considering this, there is a need to identify the drugs for effective treatment. Ligelizumab is a novel anti-IgE monoclonal antibody with higher affinity to IgE than omalizumab. In phase 2b clinical trial, it is found to be effective and well tolerated in patients with chronic spontaneous urticaria. When approved, it may be beneficial for patients who cannot receive or have suboptimal efficacy with omalizumab.

Keywords: Ligelizumab, management, urticaria


How to cite this article:
Godse K, Patil AD, Godse G. Ligelizumab: A promising option on the horizon for the management of chronic spontaneous urticaria. Indian J Drugs Dermatol 2021;7:12-4

How to cite this URL:
Godse K, Patil AD, Godse G. Ligelizumab: A promising option on the horizon for the management of chronic spontaneous urticaria. Indian J Drugs Dermatol [serial online] 2021 [cited 2021 Nov 27];7:12-4. Available from: https://www.ijdd.in/text.asp?2021/7/1/12/319356




  Introduction Top


Chronic spontaneous urticaria is a dermatological condition characterized by severe pruritus and impaired functions resulting in impairment of quality of life.[1],[2],[3] It can pose challenges for the treatment in some patients.[3] Untreated or undertreated patients are at risk of sleep difficulty and psychiatric problems such as depression and anxiety.[2] Options for the treatment of chronic urticaria include second-generation antihistamines, drugs-blocking leukotriene receptors, monoclonal antibody (omalizumab), and immunosuppressive agents.[1] Second-generation antihistamines are the mainstay of treatment in chronic urticaria. In patients not responding to normal dose, up-dosing of nonsedating second-generation antihistamine up to four fold is recommended.

Omalizumab is used for the treatment of chronic spontaneous urticaria in patients not showing effective response to antihistamines.[4] Omalizumab is a monoclonal antibody which targets plasma IgE and useful option for the treatment of IgE-related diseases such as chronic urticaria.[5] It is useful agent for the patients not responding to up-dosing with nonsedating second-generation antihistamines. In about one-fourth of the patients, symptoms are not controlled by omalizumab.[3] Considering this, there is a need to identify the newer drugs which can target different pathways offering distinct profile than available options.

Obviously, the expectations from newer drugs will be higher. For the patients, they should provide long-lasting remission and convenient for administration and should not be costly.[6] Ligelizumab is one such promising drug currently evaluated in clinical trials. Currently, it is under investigation, hence not available in the markets worldwide or in India.

In the following section, pharmacology and currently available evidence of ligelizumab in chronic spontaneous urticaria are discussed.


  Ligelizumab Top


Pharmacodynamics

There are structural and mechanistic differences between ligelizumab and omalizumab.[7] Ligelizumab is a second-generation novel anti-IgE monoclonal antibody.[4],[5] It is IgG1 anti-IgE monoclonal antibody.[8],[9] Activity against free serum IgE is the most important mechanism for therapeutic anti-IgE antibodies, their binding affinity for IgE plays an important role in the determination of clinical efficacy.[7] It has high affinity to the Cε3 domain of IgE.[7],[8],[10] Ligelizumab is a monoclonal antibody with higher affinity to IgE than omalizumab.[3],[7]

The binding epitopes in the IgE Cε3 domain are different for ligelizumab and omalizumab with some overlap. They are suggested to have differences in ability to inhibit IgE interactions with FcεRI and CD23. The resultant inhibition profile of two agents is qualitatively different.[7]

Ligelizumab causes inhibition of IgE binding without displacement of IgE bound to receptor.[11] Compared to omalizumab, ligelizumab has reported to cause 6–9 times higher suppression of allergen-induced skin prick tests.[8] It may have more potency than omalizumab in the treatment of chronic spontaneous urticaria.[8]


  Pharmacokinetics Top


In patients with chronic spontaneous urticaria, ligelizumab administered subcutaneously every month for 5 months has reported to have dose-response relationship with symptoms.[3]

A randomized trial[10] evaluated pharmacokinetics of ligelizumab in atopic participants. In this study, 2–4 doses of ligelizumab 0.2–4 mg/kg were administered by subcutaneous route every 2 weeks. Of the 110 patients, 96 completed the study. The results showed exposure and half-life dependent on dose and serum IgE levels. The mean Cmax with ligelizumab 0.2 mg/kg, 0.6 mg/kg, 2 mg/kg, and 4 mg/kg ligelizumab was 1.86, 6, 20.7, and 22.1 mcg/mL, respectively. In participants with IgE level more than 700 IU/mL, receiving ligelizumab 2 mg/kg, the mean Cmax was 16.8 mcg/mL. The mean half-life of ligelizumab 0.2 mg/kg, 0.6 mg/kg, 2 mg/kg, and 4 mg/kg ligelizumab was 14.6, 23.2, 25.9, and 26.2 days, respectively. The mean half-life in participants with IgE more than 700 IU/mL receiving 2 mg/kg ligelizumab was 13.0 days.


  Evidence of Ligelizumab in the Management of Chronic Spontaneous Urticaria Top


Dose response relationship with ligelizumab

In a phase 2b study, Maurer et al.[12] evaluated the effects of ligelizumab in 382 patients with moderate-to-severe chronic spontaneous urticaria. The enrolled patients received subcutaneous injection of ligelizumab 24 mg, 72 mg, or 240 mg, omalizumab 300 mg, or placebo. The treatment was given every 4 weeks for a total of 20 weeks. Patients in one group were given only one injection of 120 mg ligelizumab. Patients were monitored with weekly activity scores for disease symptoms. The primary endpoint of complete control of hives at 12 weeks was observed in 30%, 51%, and 42% of the patients receiving 24 mg, 72 mg, and 240 mg ligelizumab, respectively. There was a dose response relationship with ligelizumab. A total of 26% patients receiving omalizumab achieved the primary objective at 12 weeks and none with placebo. At week 12, complete symptom control was seen in 30%, 44%, and 40% patients receiving 24 mg, 72 mg, and 240 mg ligelizumab, respectively. It was seen in 26% of the patients receiving omalizumab and none in placebo group. Ligelizumab treatment was associated with rapid and sustained symptom control in these patients.[12]


  Open Label-extension Study Top


Posttreatment follow study showed prolonged symptom control with ligelizumab. In an extension study, at week 52, 61.1% of patients achieved 7-day Urticaria Activity Score 7 <6. After the end of treatment, patients maintained well-controlled disease activity was median of 28.0 week. Longer-term treatment with ligelizumab 240 mg achieved more prolonged symptom control than the core study.[13] The abstract of this extension study is published;[13] however, full report is yet to become available. In coming time, more evidence will add valuable information about the safety and efficacy of ligelizumab.


  Tolerability Top


Ligelizumab administration can be associated with reactions at the site of injection. These are most common side effects with ligelizumab.[3] In a phase 2b dose finding study, higher number of adverse event related to treatment was reported in patients receiving 72 and 240 mg ligelizumab. These adverse events were mainly mild-to-moderate reactions at the site of injection. Such reactions were reported by 4% and 7% of the patients receiving 72 mg and 240 mg of ligelizumab, respectively. Similarly, mild erythema at the site of injection was seen in 2% and 6% patients receiving 72 mg and 240 mg of ligelizumab, respectively. The incidence of serious adverse events in patients receiving 24 mg, 72 mg, and 240 mg ligelizumab was 7%, 2%, and 2%, respectively, whereas 4% of patients receiving omalizumab and 9% receiving placebo had serious adverse events. There were no cases of anaphylaxis in this study.[12] In a study among patients with mild allergic asthma were ligelizumab 24, 72, or 240 mg administered every 2 weeks for 10 weeks was well tolerated.[9] The results from phase 3 trials will provide more insights about efficacy and safety of ligelizumab.


  Expected Place in Therapy Top


Ligelizumab is currently not approved for marketing worldwide or in India. However, considering its pharmacology and benefits in early clinical trials, it is expected to be valuable option in the available armamentarium for the management of chronic spontaneous urticaria. Ligelizumab may be beneficial for patients with chronic spontaneous urticaria who cannot receive or have suboptimal response to omalizumab.


  Conclusion Top


Ligelizumab is an attractive treatment option for the management of chronic spontaneous urticaria. At this moment, there is limited evidence about efficacy and safety of ligelizumab. Currently available evidence suggests that ligelizumab is effective and well tolerated in patients with chronic spontaneous urticaria.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Johal KJ, Saini SS. Current and emerging treatments for chronic spontaneous urticaria. Ann Allergy Asthma Immunol 2020;125:380-7.  Back to cited text no. 1
    
2.
Deza G, Ricketti PA, Giménez-Arnau AM, Casale TB. Emerging biomarkers and therapeutic pipelines for chronic spontaneous urticaria. J Allergy Clin Immunol Pract 2018;6:1108-17.  Back to cited text no. 2
    
3.
Wedi B. Ligelizumab for the treatment of chronic spontaneous urticaria. Expert Opin Biol Ther 2020;20:853-61.  Back to cited text no. 3
    
4.
Kolkhir P, Altrichter S, Munoz M, Hawro T, Maurer M. New treatments for chronic urticaria. Ann Allergy Asthma Immunol 2020;124:2-12.  Back to cited text no. 4
    
5.
Vigl B, Salhat N, Parth M, Pankevych H, Mairhofer A, Bartl S, et al. Quantitative in vitro and in vivo models to assess human IgE B cell receptor crosslinking by IgE and EMPD IgE targeting antibodies. J Immunol Methods 2017;449:28-36.  Back to cited text no. 5
    
6.
Kocatürk E, Zuberbier T. New biologics in the treatment of urticaria. Curr Opin Allergy Clin Immunol 2018;18:425-31.  Back to cited text no. 6
    
7.
Gasser P, Tarchevskaya SS, Guntern P, Brigger D, Ruppli R, Zbären N, et al. The mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab. Nat Commun 2020;11:165.  Back to cited text no. 7
    
8.
Kocaturk E, Maurer M, Metz M, Grattan C. Looking forward to new targeted treatments for chronic spontaneous urticaria. Clin Transl Allergy 2017;7:1.  Back to cited text no. 8
    
9.
Gauvreau GM, Arm JP, Boulet LP, Leigh R, Cockcroft DW, Davis BE, et al. Efficacy and safety of multiple doses of QGE031 (ligelizumab) versus omalizumab and placebo in inhibiting allergen-induced early asthmatic responses. J Allergy Clin Immunol 2016;138:1051-9.  Back to cited text no. 9
    
10.
Arm JP, Bottoli I, Skerjanec A, Floch D, Groenewegen A, Maahs S, et al. Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy 2014;44:1371-85.  Back to cited text no. 10
    
11.
Jensen RK, Jabs F, Miehe M, Mølgaard B, Pfützner W, Möbs C, et al. Structure of intact IgE and the mechanism of ligelizumab revealed by electron microscopy. Allergy 2020;75:1956-65.  Back to cited text no. 11
    
12.
Maurer M, Giménez-Arnau AM, Sussman G, Metz M, Baker DR, Bauer A, et al. Ligelizumab for chronic spontaneous urticaria. N Engl J Med 2019;381:1321-32.  Back to cited text no. 12
    
13.
Soong W, Bernstein J, Sussman G, Lanier B, Sitz K, Maurer M, et al. Long-term treatment with ligelizumab achieves prolonged symptom control during the posttreatment follow-up. J Allergy Clin Immunol 2020;145:AB1-352.  Back to cited text no. 13
    




 

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Abstract
Ligelizumab
Pharmacokinetics
Evidence of Lige...
Open Label-exten...
Tolerability
Expected Place i...
Conclusion
Introduction
References

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