Date: 2017-02-23
Type of
information: Publication of results in a medical journal
phase: 1b
Announcement: publication of results in The New English Journal of Medicine
Company: Dyax (USA - MA), now Shire (UK - USA)
Product: DX-2930 - lanadelumab
Action
mechanism: monoclonal antibody. DX-2930 is a novel, fully human monoclonal antibody inhibitor of plasma kallikrein (pKal) and is being developed by Dyax as a subcutaneous injection for the prevention of HAE attacks. Uncontrolled pKal activity leads to excessive generation of bradykinin, a vasodilator thought to be responsible for the localized swelling, inflammation and pain characteristically associated with HAE.
Disease: prevention of hereditary angioedema (HAE) attacks
Therapeutic
area: Rare diseases - Genetic diseases - Hematological diseases
Country: Italy, Jordan, USA
Trial
details:
- The multicenter, randomized, double-blind, placebo-controlled, multiple-ascending dose study enrolled a total of 37 patients randomized to receive lanadelumab or placebo across four different dosing groups of 30, 100, 300, or 400 mg. Each subject received two doses of lanadelumab or placebo, separated by 14 days, and was followed for 120 days post-dose. The primary objective of the study was to assess the safety and tolerability of multiple subcutaneous administrations of lanadelumab at different dose levels in HAE patients. Secondary and tertiary objectives included characterization of the pharmacokinetics and pharmacodynamics of lanadelumab, evaluation of immunogenicity, and assessments of HAE attack frequency and use of acute attack therapy. (NCT02093923)
Latest
news:
- • On February 23, 2017, Shire announced the publication of results from the Phase 1b study of lanadelumab (SHP643; formerly DX-2930) in the February 23, 2017 issue of the New England Journal of Medicine (NEJM). "In this Phase 1b study, no serious adverse events or discontinuations due to adverse events were observed at all doses studied. Pre-specified efficacy analyses in patients with at least 2 attacks in the 3 months prior to enrolment demonstrated that from day 8 to day 50, the administration of two doses of lanadelumab (300 or 400 mg) 14 days apart, reduced the rate of attacks by 100% and 88% respectively, when compared with placebo. In addition, all subjects were attack-free in the 300 mg group and 82% were attack-free in the 400 mg group, compared to 27% in the placebo group," said Dr. Aleena Banerji, Associate Professor, Massachusetts General Hospital, Boston.
- There were no serious adverse events or discontinuations due to adverse events reported in patients treated with lanadelumab. A total of 29% of the patients who received lanadelumab and 38% of those who received placebo had an adverse event that was considered by trial investigators, who were unaware of the trial-group assignments, to be treatment-related. The most common treatment-related adverse events were injection site pain (25% lanadelumab, 23% placebo) and headache (8% lanadelumab, 15% placebo).
- In HAE patients, the pharmacokinetic profile of lanadelumab is linear, dose-dependent, and exhibits a half-life of approximately 14 days, typical of a human monoclonal antibody. The pharmacodynamic profile of lanadelumab was assessed by plasma levels of cleaved high molecular weight kininogen (cHMWK). Pharmacodynamic results confirm plasma kallikrein inhibition in a dose and time-dependent manner, and suggest doses of 300 mg or greater have the potential to normalize cHMWK levels based on levels of cHMWK approaching that observed in healthy subjects.
- A pivotal Phase 3 trial evaluating the safety and efficacy of lanadelumab as a long-acting prophylactic treatment for HAE is currently underway.
- • On March 31, 2015, Dyax announced positive safety, pharmacokinetic, biomarker, and efficacy results from the Phase 1b clinical study of DX-2930. The ongoing Phase 1b study is a multi-center, randomized, double-blind, placebo-controlled, multiple-ascending dose study designed to assess the safety, tolerability and pharmacokinetics of DX-2930 in HAE patients. An analysis of HAE attack rate was also conducted following a pre-specified statistical analysis plan. A total of 37 subjects were randomized to active drug or placebo in a 2:1 ratio across 4 dosing groups of 30, 100, 300, or 400 mg. Each subject received two doses of DX-2930 or placebo, separated by 14 days, and was followed for 15 weeks after the second dose. DX-2930 was well tolerated at all dose levels. There were no deaths or subject discontinuations due to an adverse event. There were no serious adverse events in subjects treated with DX-2930 and no evidence of dose-limiting toxicity. There was no safety signal in treatment-emergent adverse events, clinical laboratory results, vital signs, or electrocardiograms. Subcutaneous injection was well tolerated.
- Pharmacokinetic results demonstrated that DX-2930 has linear, dose-dependent exposure and a mean elimination half-life of approximately 14 days across all dose groups studied. Pharmacodynamic results from two different exploratory biomarker assays confirmed ex vivo plasma kallikrein inhibition in a dose- and time-dependent manner.
- Primary proof-of-concept efficacy analyses were based on subjects in the 300 mg, 400 mg, and placebo dose groups who reported having at least 2 attacks in the 3 months prior to study entry. During the pre-specified, primary efficacy interval of 6 weeks (from days 8 to 50; corresponding to peak drug level), the HAE attack rate (adjusted for baseline attacks) was 0 in the 300 mg group and 0.045 attacks per week in the 400 mg group, compared to 0.37 attacks per week in the placebo group. This resulted in a 100% reduction for the 300 mg dose group as compared to placebo (P < 0.0001), and an 88% reduction for the 400 mg dose group as compared to placebo (P=0.005). During this primary efficacy interval, 100% of subjects in the 300 mg group (P=0.026) and 82% of subjects in the 400 mg group (P=0.030) were attack-free compared with 27% of subjects in the placebo group. The study will be complete when all subjects in the 400 mg dose group finish the final safety assessments on study day 120.
- • On November 3, 2014, Dyax announced the expansion of its ongoing Phase 1b clinical trial evaluating DX-2930 to include additional patients and dosing cohorts. The ongoing Phase 1b clinical trial is a multi-center, randomized, double-blind, placebo-controlled, multiple ascending dose study designed to assess the safety, tolerability and pharmacokinetics of DX-2930 in HAE patients. As of October 31, 2014 , 21 subjects were enrolled and completed dosing in three ascending dose cohorts (30 mg, 100 mg and 300 mg) of DX-2930 or placebo. Subjects in each cohort were randomized to active drug or placebo in a 2:1 ratio. Each study subject received two doses of study drug or placebo separated by 14 days and will undergo 15 weeks of follow-up after the second dose. In light of faster than anticipated enrollment rates, Dyax has decided to take the opportunity to further characterize DX-2930 by adding two additional cohorts. Subjects will continue to be randomized to active drug or placebo in a 2:1 ratio and the dosing regimen will remain unchanged. Active drug-treated subjects in the fourth cohort will receive 400 mg of DX-2930. The dose level of the fifth cohort will be decided based upon a review of interim data. Addition of the new dosing cohorts is in accordance with the provisions included in the original protocol which allows enrollment into additional dose groups and/or additional patients at any dose group. Total enrollment can be increased to as many as 36 patients and data from additional patients will be used to expand the DX-2930 safety database and provide potentially informative pharmacodynamic data. The company expects to report data from this study in early 2015, followed by a Phase 2 study which is also currently planned to begin in 2015.
Is
general: Yes
