Rademikibart (CBP-201)

Rademikibart is an inhibitory human monoclonal antibody against the IL-4Rα, a common subunit for IL-4 and IL-13 receptors and a validated target for an FDA-approved therapy (Dupixent®). IL-4 and IL-13 are key Th2 cytokines with extensive overlapping functions, driving several inflammatory diseases.  Preclinical and clinical data demonstrated that dual inhibition of IL-4 and IL-13 dual is required to achieve desired efficacy in Th2-mediated diseases.

Rademikibart binds to a distinct and unique region in IL-4Rα in a manner that prevents the receptor from interacting with other receptor subunits that are required for activation of the signaling pathways that ultimately give rise to Th2-mediated diseases, including atopic dermatitis and asthma.

Our clinical development program is focused on differentiating rademikibart in three areas: the potential to show rapid onset and sustained improvements in clinical outcomes with a convenient dosing frequency.

Rademikibart has shown dose-dependent and differentiated pharmacokinetics and pharmacodynamics in early clinical trials and is currently being evaluated as potential treatment for atopic dermatitis and asthma in the following clinical trials:

Rademikibart is an inhibitory human monoclonal antibody against the IL-4Rα, a common subunit for IL-4 and IL-13 receptors and a validated target for an FDA-approved therapy (Dupixent®). IL-4 and IL-13 are key Th2 cytokines with extensive overlapping functions, driving several inflammatory diseases. Preclinical and clinical data demonstrated that dual inhibition of IL-4 and IL-13 dual is required to achieve desired efficacy in Th2-mediated diseases.

Rademikibart binds to a distinct and unique region in IL-4Rα in a manner that prevents the receptor from interacting with other receptor subunits that are required for activation of the signaling pathways that ultimately give rise to Th2-mediated diseases, including atopic dermatitis and asthma.

Our clinical development program is focused on differentiating rademikibart in three areas: the potential to show rapid onset and sustained improvements in clinical outcomes with a convenient dosing frequency.

Rademikibart has shown dose-dependent and differentiated pharmacokinetics and pharmacodynamics in early clinical trials and is currently being evaluated as potential treatment for atopic dermatitis and asthma in the following clinical trials:

Rademikibart blocks IL-4Rα, a common subunit for IL-4 and IL-13 receptors and a validated target for an FDA-approved therapy (dupilumab). Inhibition of IL-4 and IL-13 activity is important because the two cytokines have extensive overlapping functions. Preclinical and clinical data demonstrate that dual inhibition of IL-4 and IL-13 dual is required to achieve desired efficacy in Th2-mediated diseases. Rademikibart binds to IL-4Rα in a manner that prevents the receptor from interacting with other receptor subunits that are required for activation of the signaling pathways that ultimately give rise to Th2-mediated diseases, including atopic dermatitis and asthma.

Target Indications

Atopic dermatitis

Atopic dermatitis (AD), which has an estimated lifetime prevalence of up to 20% and is increasing globally, is the most commonly diagnosed chronic inflammatory skin disorder1 and is characterized by skin barrier disruption and immune dysregulation. It is estimated that 26.1 million people in the United States have AD2, of which 6.6 million have moderate-to-severe disease.3 Further, over 58% of adults with moderate-to-severe AD have disease that physicians consider to be inadequately controlled by approved therapeutic modalities, including topical anti-inflammatory agents and systemic agents.4

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Type 2 inflammatory asthma

Type 2 inflammation, which occurs in more than 80% of children and the majority of adults with asthma,5 is an important molecular mechanism that gives rise to asthma symptoms.5 Type 2 inflammation is mediated by type 2 helper T cells (Th2), which secrete inflammatory cytokines including IL-3, IL-4, L-5, IL-9 and IL-13.5

While corticosteroids have been a pillar of therapy for patients with type 2 inflammatory asthma, they are associated with multiple local and systemic side effects. Novel therapies that can inhibit aberrant Th2 activity with greater specificity will be critical for improving the care and outcomes of patients with type 2 inflammatory asthma.5

Pivotal China AD Trial: Reported interim Stage 1 results, currently in Stage 2 (maintenance)

The pivotal China trial evaluating rademikibart in 330 patients with moderate-to-severe AD reported its positive Stage 1 topline results in October 2022 and its positive Stage 2 topline results in November 2023.

Stage 1 of this pivotal trial compared a 2-week dosing regimen of rademikibart (Q2W) with placebo and met all its primary and secondary endpoints (more details here ). Stage 2 of the trial included Q2W and 4-week (Q4W) dosing treatment arms and showed that the clinical response (IGA 0/1 and EASI-75) achieved at Week 16 (end of Stage 1) with rademikibart treatment was maintained through Week 52 with both Q2W and Q4W dosing regimens. The data observed with Q4W rademikibart treatment substantially differentiate rademikibart from existing treatments, which are Q2W (more details here).

Rademikibart continued to be well tolerated over 52 weeks of treatment.

Connect recently announced it entered into a partnership for rademikibart development and commercialization in Greater China with Simcere Pharmaceuticals (more details here). Based on the received positive feedback from China’s Center for Drug Evaluation (CDE) earlier in 2023, Simcere will be taking the lead on the NDA submission for rademikibart in AD with the Chinese CDE in the first quarter of 2024 and may receive potential NDA approval in China as early as 2025.

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

Chronic rhinosinusitis (CRS), which is characterized by chronic inflammation of the nasal mucosa and paranasal sinuses, is a common condition with an estimated prevalence of 8-11%.6 Approximately 25-30% of individuals with CRS develop nasal polyps, which are growths that occur in the nasal passages and sinuses and are frequently associated with asthma, allergic rhinitis and chronic rhinosinusitis.7 As nasal polyps increase in size and/or number, they can interfere with normal breathing and may also lead to a loss of sense of smell.7 In some cases, nasal polyps may need to be removed surgically.7 Patients with CRS with nasal polyps (CRSwNP) have significant morbidity and decreased quality of life.7 Despite the availability of an injectable biologic for nasal polyps due to chronic rhinosinusitis, many patients continue to have unmet medical need.7

Mechanism of Action

rademikibart blocks IL-4Rα, a common subunit for IL-4Rα and IL-13 receptors and a validated target for an FDA-approved therapy (dupilumab). Inhibition of IL-4 and IL-13 activity is important because the two cytokines have extensive overlapping functions. Preclinical and clinical data demonstrate that dual inhibition of IL-4 and IL-13 dual is required to achieve desired efficacy in Th2-mediated diseases. rademikibart binds to IL-4Rα in a manner that prevents the receptor from interacting with other receptor subunits that are required for activation of the signaling pathways that ultimately give rise to Th2-mediated diseases, including atopic dermatitis and asthma.

Phase 1b Clinical Data in Patients with Moderate-to-Severe Atopic Dermatitis

In a Phase 1b clinical study of CBP-201 in adult patients with moderate-to-severe AD, we observed that multiple doses of CBP-201 were well tolerated. At week four, 88% and 100% of patients receiving CBP-201 150 mg (n=8) or 300 mg (n=7), respectively, achieved a 50% reduction in the Eczema Area and Severity Index score, or EASI-50, and 50.0% and 42.9% and of patients receiving CBP-201 150 mg or 300 mg, respectively, achieved clear/almost clear skin (Investigator Global Assessment 0,1). Additionally, skin lesion improvements were rapid, as evidenced as early as Week 1 after dosing, and were correlated with a rapid reduction in pruritus intensity and frequency. Dermatology Quality of Life Index scores showed improvements at Week 1, and these early and rapid improvement continued to increase through Week 4.

Global Phase 2b Clinical Data in Adult Patients with Moderate-to-Severe Atopic Dermatitis (Completed)

Data from a global Phase 2b clinical trial in adult patients with moderate-to-severe AD found that all three doses of rademikibart evaluated (300mg Q2W, 150mg Q2W or 300mg Q4W) met the primary endpoint of eczema area and severity index (EASI) percent reduction from baseline at Week 16 and were statistically superior to placebo. For EASI secondary endpoints, all three rademikibart arms showed statistically significant improvements in the proportion of patients achieving at least a 50% or 75% reduction in EASI score from baseline at Week 16, compared with placebo (EASI-50 or EASI-75, respectively). The Phase 2b study also achieved key secondary endpoints of Investigator’s Global Assessment (IGA) score of 0 or 1 (clear or almost clear) and a reduction of >2 points from baseline at Week 16, and change from baseline to Week 16 in weekly average Peak Pruritus-Numerical Rating Scale (PP-NRS).

Rademikibart was also observed to have a favorable safety profile, with a similar incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and TEAEs leading to study drug discontinuation reported for rademikibart treatment and placebo groups. Finally, there was a low reported incidence of injection site reactions (1.8%), conjunctivitis (3.5%), and herpes infections (0.6%) in patients receiving rademikibart.

Based on the results of the global Phase 2b trial, we are confident about the potential for a highly competitive efficacy and safety profile for rademikibart coupled with a more convenient and differentiated Q4W dosing schedule.

Current Development Status

Based on the positive data from the completed global Phase 2b and China pivotal AD trials, we are looking for potential global and regional partners to advance rademikibart into a global Phase 3 AD program and bring us a step closer to delivering a differentiated therapeutic program with improved efficacy and dosing convenience.

Pivotal China-only AD Trial: Reported interim Stage 1 results, currently in Stage 2 (maintenance)

rademikibart is also in an ongoing trial in moderate-to-severe AD in China in which it reported positive topline results meeting all primary and secondary endpoints.

Stage one of the China trial compared a 2-week dosing arm (Q2W) with placebo. Stage 2, which is currently ongoing, includes 2-week and 4-week (Q4W) dosing arms. We expect this second stage will provide more insight into the potential for an extended Q4W dosing regimen, which would substantially differentiate rademikibart from existing treatments, which are Q2W.

The China trial is the largest trial, to date, of this class of drug in China (n=255). China’s Center for Drug Evaluation (CDE) has indicated that depending on the results, it could review rademikibart for approval based on this trial. Accordingly, there is the potential for Connect to file an NDA with the Chinese CDE in 2024 and receive potential NDA approval in China as early as 2025.

Phase 2b trial for rademikibart for the treatment of patients with moderate-to-severe asthma with type 2 inflammation (Completed)

This Phase 2b trial was a global, multicenter, randomized, double-blind, placebo-controlled study conducted in 79 sites in the United States, Poland, Hungary, China and South Korea with 322 patients randomized 1:1:1 to rademikibart 150 mg every two weeks (Q2W) with a loading dose of 600 mg (n=106), rademikibart 300 mg Q2W with a loading dose of 600 mg (n=108) and placebo (n=108). Two-thirds of the randomized patients were treated in the United States.

Topline results from the trial were announced in December 2023 showing that the trial met its primary endpoint absolute change from baseline in pre-bronchodilator (BD) forced expiratory volume over one second (FEV1) showing that at Week 12, lung function significantly improved over placebo with both rademikibart doses. The significant improvements seen compared to placebo with both rademikibart 150 mg and 300 mg started as early as Week 1 (p < 0.001 for both) and were sustained through 24 weeks of treatment (p = 0.001 and p < 0.001, respectively). A predefined exploratory analysis showed further improvement in lung function was achieved in patients with eosinophil levels of ≥ 300 cells/µl (more details here).

The Company plans to schedule an End of Phase 2 (EoP2) meeting with the U.S. Food and Drug Administration to discuss rademikibart’s Phase 3 regulatory path. Additionally, the Company plans to submit detailed results from this study for presentation at a future medical congress.

Posters & Publications

WCD 2023 Primary Poster_19June2023
Presented at the World Congress of Dermatology, July 3-8, 2023

WCD 2023 EASI and Safety Poster_19June2023
Presented at the World Congress of Dermatology, July 3-8, 2023

WCD 2023 Investigator Reported Outcomes Poster_19June2023
Presented at the World Congress of Dermatology, July 3-8, 2023

WCD 2023 Patient Reported Outcomes_19June2023
Presented at the World Congress of Dermatology, July 3-8, 2023

CBP-201 Efficacy by IGA severity_RAD abstract_27March2023
Presented at the Revolutionizing Atopic Dermatitis (RAD) Conference, April 30, 2023

2023 RAD Poster – CBP-201 Severity – 18Apr2023
Presented at the Revolutionizing Atopic Dermatitis (RAD) Conference, April 30, 2023

CBP-201 CN002 Pivotal_AAD 2023
Presented at the American Academy of Dermatology Annual Meeting, March 17-21, 2023

AAD2023 Late Breaker 11Mar2023
Presented at the American Academy of Dermatology Annual Meeting, March 17-21, 2023

CBP-201 BodyRegion_AAD 2023 Abstract
Presented at the American Academy of Dermatology Annual Meeting, March 17-21, 2023

EASI body region_AAD 2023 Presentation_17Mar2023
Presented at the American Academy of Dermatology Annual Meeting, March 17-21, 2023

CBP-201 investigator rated over time EADV 2022 Abstract
Presented at the 31st European Academy of Dermatology and Venereology Congress (EADV), September 7-10, 2022

Investigator Rated EADV 2022 Poster
Presented at the 31st European Academy of Dermatology and Venereology Congress (EADV), September 7-10, 2022

CBP-201 PRO over time EADV 2022 Abstract
Presented at the 31st European Academy of Dermatology and Venereology Congress (EADV), September 7-10, 2022

PRO-EADV 2022 Poster
Presented at the 31st European Academy of Dermatology and Venereology Congress (EADV), September 7-10, 2022

  1. Weidninger S, Beck LA, Bieber T, et al. Atopic dermatitis. Nature Reviews Disease Primers. 2018;4:1
  2. National Eczema Association. Atopic Dermatitis: What is atopic dermatitis? Available at: https://nationaleczema.org/eczema/types-of-eczema/atopic-dermatitis/
  3. Asthma and Allergy Association of America. Atopic dermatitis in America: Study overview. Available at: https://www.aafa.org/media/2209/Atopic-Dermatitis-in-America-Study-Overview.pdf
  4. 2014 Adelphi US AD Disease Specific Programme
  5. Holgate ST, Wenzel S, Postma DS, et al. Asthma. Nature Reviews Disease Primers. 2015;1:15025.