Imsidolimab, previously known as ANB019, is an antibody that inhibits the function of the interleukin-36-receptor, or IL-36R, which we are initially developing as a potential first-in-class therapy for patients suffering from generalized pustular psoriasis (GPP), EGFRi-mediated skin toxicity, ichthyosis, hidradenitis suppurativa and acne.
GPP is a chronic, life-threatening, rare disease with no currently approved therapies. GPP is a systemic inflammatory disease characterized by the development of widespread pustules marked by exacerbations. In severe cases, GPP patients can die from cardio-pulmonary failure, exhaustion and/or infection subsequent to occurrences of pustular flares. Patients with GPP suffer without robust therapeutic options because currently approved psoriasis management therapies have not demonstrated clear efficacy in the treatment of this condition. In addition, these therapies, including high-dose cyclosporine, methotrexate and retinoids, are often tapered or discontinued due to toxicity. Studies have shown that GPP is associated with uncontrolled signaling through the IL-36R, which in some patients can be mediated by genetic mutations. We estimate GPP affects approximately 3,000 patients in the United States.
We have completed a double-blind, placebo-controlled healthy volunteer Phase 1 trial of imsidolimab, where 36 subjects were administered a single subcutaneous or intravenous dose of imsidolimab ranging between 10 mg and 750 mg, 18 subjects were administered multiple ascending doses of imsidolimab intravenously ranging between 40 mg and 300 mg weekly for four consecutive weeks and 18 subjects were dosed with placebo. Imsidolimab was well-tolerated by all subjects and no dose-limiting toxicities were observed. The most frequent treatment-emergent adverse events observed in the single ascending dose cohorts were upper respiratory tract infections in 10 of 36 (28%) subjects dosed with imsidolimab versus six of 12 (50%) subjects dosed with placebo, and headache in 10 of 36 (28%) subjects dosed with imsidolimab versus 3 of 12 (25%) subjects dosed with placebo. In the multiple ascending dose cohorts, the most frequent treatment-emerging adverse events observed were headache in 7 of 18 (39%) subjects dosed with imsidolimab versus 1 of 6 (17%) subjects dosed with placebo. No serious adverse events were reported among any subjects in the trial. The in vivo half-life of imsidolimab was approximately 28 days for both subcutaneous and intravenous routes of administration, with bioavailability of approximately 90%. A single dose of imsidolimab at certain dose levels was able to completely suppress IL-36 cytokine function for 85 days, as measured by IL-36 cytokine-mediated release of IL-8 using an ex vivo pharmacodynamic assay. We presented data from this Phase 1 trial at the 2018 European Academy of Allergy and Clinical Immunology (EAACI) Congress on May 28th 2018, (click here to download).
We are concluding a single arm, open-label Phase 2 trial of imsidolimab in 8 patients with generalized pustular psoriasis, or GPP, also known as the GALLOP trial. Patients were screened among 12 sites located in the United States and Europe. Patients were washed out of prior therapy and no concomitant therapy was permitted during the trial. Key inclusion criteria include active ongoing GPP disease with a minimum mJDA-SI score of 7 and at least 10% body surface area covered by active pustules and erythema, while key exclusion criteria included concomitant dermatological conditions or infection. Patients were treated with a 750mg intravenous induction dose of imsidolimab at Day 1, followed by monthly 100mg subcutaneous doses on Days 29, 57 and 85 during the 16-week study. The primary endpoint of this trial was clinical response on the CGI scale on Day 29 and Day 113 without rescue therapy. Baseline clinical assessments were conducted for each patient on Day 1 prior to imsidolimab dosing.
An interim analysis was conducted after the patients completed 29 days of imsidolimab monotherapy, where 6 or the 8 patients achieved the primary endpoint of disease improvement at Day 29. Two of 8 patients were considered to have not met the primary endpoint because they dropped out of the trial prior to day 29. Rescue therapy was not required by any patients while enrolled in the trial.
The mean baseline value on the modified Japanese Dermatology Association severity index total score (mJDA-SI) was 9 (Table 1), body surface area covered by erythema and pustules was 24% and the serum C-reactive protein (CRP) was 56 mg/L. Patients were on average 51 years of age, 50% female and diagnosed with GPP for 4.3 years. The patients demonstrated rapid and sustained modified Japanese Dermatology Association (mJDA) improvement, with a reduction of 29% at Day 8 and 54% at Day 29 on average. Erythema with skin pustules, which clinically defines GPP, decreased by 60% on Day 8 and 94% on Day 29. Anti-drug antibodies were not detected as of day 29 in any patient.
Imsidolimab was generally well-tolerated and most treatment-emergent adverse events were mild to moderate in severity and resolved without sequelae. No infusion or injection site reactions were observed. One patient dropped out of the trial due to a diagnosis of Staphylococcal aureus bacteremia in the first week, which was a serious adverse event deemed to be possibly drug-related. Because the patient was symptomatic prior to dosing and had a prior medical history of bacteremia, a common comorbidity of GPP, the Company does not believe this event is likely attributable to imsidolimab. Another patient dropped out of the study on Day 22 due to investigator reported inadequate efficacy. One patient contracted COVID-19 during the course of the trial, which was mild, unrelated to imsidolimab, and did not lead to study discontinuation.
Genotypic testing indicated homozygous wild-type IL-36RN, CARD14 and AP1S3 alleles for all 8 patients. We believe this suggests that imsidolimab is broadly applicable to pustular diseases irrespective of genetic drivers.
The Company plans to report full data from the GALLOP trial at a medical conference in 2021 In July 2020, the U.S. Food and Drug Administration granted orphan drug designation for imsidolimab for the treatment of patients with GPP. The Company has received FDA feedback on an orphan disease registration plan for imsidolimab in the treatment of GPP and anticipates initiation of a registration-enabling Phase 3 trial in mid-2021 after subsequent protocol alignment with the FDA following complete 16-week data from the GALLOP Phase 2 trial.
|Endpoint||Baseline||Day 8 Relative to Baseline||Day 29 Relative to Baseline|
|Improvement on CGI||N/A||7 of 8 patients||6 of 8 patients|
|Erythema with Skin Pustules
(% body surface area)
The Company has initiated a worldwide patient registry, called RADIANCE, of patients diagnosed with GPP, which is anticipated to improve understanding of the patient journey and support future clinical trial enrollment.
Treatment of solid tumors with inhibitors of epidermal growth factor (EGFRi) and MAPK/ERK kinase (MEKi) is frequently limited by the occurrence of skin toxicities. Recent translational data has suggested that these skin toxicities are mediated by excess IL-36 signaling, leading to IL-8-mediated cutaneous neutrophilia and acneiform rash. Based on existing claims data, approximately 60,000 patients are prescribed EGFRi and/or MEKi treatments annually, and the vast majority of these patients experience dermatological toxicity, which in some cases leads to dose reduction and/or discontinuation of treatment. Current standard-of-care treatments are generally ineffective in patients with the most severe grades of EGFRi and/or MEKi mediated acneiform rash.
The Company has initiated a 45-patient, placebo-controlled Phase 2 trial, called EMERGE, of imsidolimab for treatment of EGFRi/MEKi-mediated skin toxicity where interim top-line data in anticipated at the end of 2021.
Ichthyosis is a family of rare, inherited, dermatological disorders characterized by dry, scaling and thickened skin. Recent human translational studies have suggested that the underlying skin inflammation responsible for ichthyosis is mediated by dysregulated IL-36 signaling, and we believe that imsidolimab treatment may be efficacious in treatment of this condition. Approximately 6,000 patients in the United States are affected with moderate-to-severe levels of ichthyosis and no approved therapies are available for this disease.
INSPIRE, a 30-patient, placebo-controlled Phase 2 trial of imsidolimab for treatment of IL-36 associated ichthyosis subtypes has been initiated and top-line data in anticipated in 2022.
Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory skin disease characterized by painful nodules in intertriginous areas that can progress to abscesses, sinus tracks and scarring. Current treatment options for HS, including antibiotics, corticosteroids and anti-TNF therapy, have variable efficacy in moderate-to-severe patients, which often leads to surgery for removal of HS nodules. Human translational studies have demonstrated elevated IL-36 cytokine expression in HS skin biopsies and we believe treatment of moderate-to-severe HS with imsidolimab may lead to therapeutic benefit for this patient population. Moderate-to-severe HS affects approximately 150,000 adults in the United States. We intend to initiate a Phase 2 trial of imsidolimab in HS, called HARP, in Q2 2021.
Acne is the most common skin disorder in the United States, with approximately 7 million patients diagnosed with moderate-to-severe disease. Moderate-to-severe acne typically presents with painful papules, pustules, nodules, cysts and scarring. A key contributing factor to the pathogenesis of acne is the immune response to p. acnes, which is associated with upregulated IL-36 cytokine activity, localized inflammation and neutrophil infiltration of the skin. Existing therapies, including isotretinoin and systemic antibiotics, provide variable efficacy for moderate-to-severe acne patients and have practical limitations to their use given potential for clinically meaningful side effects. The Company anticipates initiating a Phase 2 trial of imsidolimab, called ACORN, for the treatment of moderate-to-severe acne in Q2 2021.
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