At both dose levels, NTLA-2001 was generally well tolerated. Two of 12 patients reported transient infusion reactions, which was the only observed treatment-related adverse event. One patient in the 0.7 mg/kg dose NYHA Class III cohort experienced a Grade 3 infusion-related reaction, which resolved without clinical consequence. Per the study protocol, this group was subsequently expanded from three to six patients to further characterize safety at this dose level. No additional patients in the 0.7 mg/kg dose NYHA Class III cohort reported a treatment-related adverse event. No clinically significant liver findings were observed at either dose level.
The Phase 1 study, run by the Company as the program’s development and commercialization lead as part of a multi-target collaboration with Regeneron, is evaluating NTLA-2001 in patients with either ATTR-CM or hereditary ATTR amyloidosis with polyneuropathy (“ATTRv-PN”). A protocol amendment has been submitted to evaluate a fixed dose corresponding to 0.7 mg/kg in the dose-expansion portion, with enrollment across both arms expected to be completed by the end of 2022, subject to regulatory feedback.
Interim Clinical Data of NTLA-2002
On September 16, 2022, at the 2022 Bradykinin Symposium, the Company presented positive interim results from an ongoing Phase 1/2 clinical study of our second in vivo genome editing candidate, NTLA-2002, which is being developed as a single-dose treatment for hereditary angioedema (“HAE”). The interim data presented are from the initial six adult patients with HAE treated in the ongoing dose-escalation study with a data cut-off date of July 27, 2022. Single doses of 25 mg (n=3) and 75 mg (n=3) of NTLA-2002 were administered via intravenous infusion, and changes from baseline values of plasma kallikrein protein were measured for each patient. Administration of NTLA-2002 led to dose-dependent reductions in plasma kallikrein and achieved maximal reductions by week eight, with mean reductions of 65% and 92% in the 25 mg and 75 mg dose cohorts, respectively. Furthermore, these reductions have been sustained through at least 16 weeks in the 25 mg cohort and 8 weeks in the 75 mg cohort for which complete cohort biomarker data were available.
In addition to plasma kallikrein levels, HAE attack rates are also being measured in the study, with the first analysis occurring at the end of the pre-specified 16-week primary observation period. To date, all three patients in the 25 mg dose cohort have reached the end of this initial observation period. Patients in this group had a baseline HAE attack rate ranging from 1.1 to 7.2 attacks per month, as confirmed by the investigator. Treatment with a single dose of 25 mg of NTLA-2002 resulted in a mean reduction in HAE attacks of 91% throughout the 16-week observation period. Additionally, two of the three patients have not had a single HAE attack since treatment, and all three patients have been attack free since week 10 (follow-up through weeks 24 - 32). Patients in the 75 mg cohort have not completed the primary 16-week observation period, and attack rate data for this cohort will be presented at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting, November 10 –14 in Louisville, Kentucky.
Prophylaxis medications are permitted in the Phase 1 part of the study. Two of the three patients in the 25 mg cohort were actively receiving prophylaxis therapy prior to administration of NTLA-2002. For these two patients, the study protocol permitted investigators to withdraw the patient’s prophylaxis therapy after completion of the 16-week primary observation period. This treatment approach was implemented for the two applicable patients in this cohort, and neither patient has had an HAE attack since discontinuing their prophylaxis therapy through the latest follow-up.
At both dose levels, NTLA-2002 was generally well tolerated, and the majority of adverse events were mild in severity. The most frequent adverse events were infusion-related reactions, which were mostly Grade 1 and resolved within one day. There have been no dose-limiting toxicities, no serious adverse events and no adverse events of Grade 3 or higher observed to date. No clinically significant laboratory abnormalities were observed, including any significant elevation in liver enzymes.
Based on the interim data presented in September 2022, the Company selected a third dose of 50 mg to be evaluated in the ongoing dose-escalation portion of the Phase 1/2 study. Dosing at this level has recently been completed and the Company expects to select up to two doses to further evaluate in the Phase 2, placebo-controlled dose expansion portion of the study, which is expected to begin in the first half of 2023. The Company anticipates expanding country and site participation, including U.S. clinical sites, as part of the Phase 2 study.
