The New England Journal of Medicine has just published the results from the Phase 1b study of lanadelumab (SHP643; formerly DX-2930) from Shire plc.
Lanadelumab is a subcutaneously administered, human monoclonal antibody that specifically binds and inhibits plasma kallikrein, and it is being investigated for the prevention of angioedema attacks in patients with HAE.
“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.
“The overall results of this study are encouraging; it should be noted that while the duration of treatment was relatively short and only a small number of patients were investigated, the results supported further Phase 3 investigations, which are currently ongoing,” added Dr. Paula Busse, Associate Professor, Mount Sinai Hospital, New York.
“Despite improvements in the management of HAE in recent years, there is still a need for long-acting prophylactic treatment options. At Shire we are proud of our history in HAE and ongoing commitment to the clinical development of lanadelumab, an investigational prophylactic therapy for this rare genetic disease,” said Philip J. Vickers, Ph.D., Global Head of Research and Development at Shire.
A pivotal Phase 3 trial evaluating the safety and efficacy of lanadelumab as a long-acting prophylactic treatment for HAE is currently underway.
With the clinical development of lanadelumab, Shire is building on its legacy in HAE and as the world leader in rare diseases.
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.
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.