Curtis Rambaran’s Insights from Zerlasiran P-II Study for Patients with Elevated Lipoprotein (a) at High-Risk ASCVD Events

Shots:

Curtis gave a brief introduction about Zerlasiran. He also talked about the study design and the results from the P-II trial (ALPACAR-360) under which Zerlasiran is being evaluated
He also highlighted how Zerlasiran can differ from other therapies that are in development to treat elevated lipoprotein (a) at high risk of atherosclerotic cardiovascular disease (ASCVD) events
The interview shows how Silence Therapeutics is developing a new generation of medicines by harnessing RNAi to target pathology of diseases with significant unmet need

Smriti: Tell us a little more about zerlasiran, its MoA, RoA, formulations, etc.

Curtis Rambaran: The plasma concentration of lipoprotein(a) is primarily genetically determined (approximately 70 to ≥90%), and its expression is controlled by the apolipoprotein(a) gene (LPA). Zerlasiran is a small interfering RNA (siRNA) that precisely targets LPA gene expression.

Zerlasiran works by harnessing the body’s natural mechanism of RNA interference (RNAi) to break down LPA mRNA effectively ‘silencing’ the LPA gene to reduce Lp(a) production. Zerlasiran specifically targets LPA activity in the liver, which is the principal source of Lp(a) in the body.

Zerlasiran is formulated and administered as a subcutaneous (sc) injection. While Silence has not yet determined the optimum dosing frequency for zerlasiran, we reported substantial maximal median Lp(a) reductions (up to 98%) in our APOLLO single dose study last year with meaningful effects still observed after 150 days. We are currently evaluating zerlasiran in the APOLLO multiple dose study and ALPACAR-360 phase 2 study.

Smriti: Shed some light on the study design of the P-II trial (ALPACAR-360) evaluating zerlasiran. When can we expect the results of the study?

Curtis Rambaran: ALPACAR-360 is a randomized, double-blind, placebo-controlled parallel arm phase 2 clinical study to investigate the efficacy, safety, and tolerability of zerlasiran in adults with elevated Lp(a), defined as ≥ 125 nmol/L, who are at high risk of atherosclerotic cardiovascular disease (ASCVD) events. The primary endpoint of the trial is the time averaged change in Lp(a) from baseline to week 36

We randomized the first patient into the ALPACAR-360 study in January 2023 and announced complete enrollment on May 1^st, 2023 – 8 months ahead of schedule. This reflects strong execution from the Silence team, enthusiasm around Lp(a) in the global cardiovascular community as well as the significant market opportunity. Silence expects to report topline data from the study in mid-2024.

Smriti: Please elaborate on your results obtained from the P-I (APOLLO) single-dose study. When can we expect the data from the multiple-dose portion of the APOLLO program?

Curtis Rambaran: The phase 1 APOLLO trial evaluated zerlasiran in healthy individuals with elevated Lp(a).

In the single-dose portion of the study, participants received 30 mg, 100 mg, 300 mg or 600 mg doses of zerlasiran. A single sc injection of zerlasiran reduced median maximal Lp(a) by 46-98% compared with pretreatment baseline, and participants who received the highest doses (300 mg and 600 mg) saw median maximal Lp(a) reductions of 96% and 98% from baseline, respectively. At these highest doses, median Lp(a) reductions of 71-81% from baseline persisted at 150 days post-injection.

Zerlasiran was considered safe and was well-tolerated, no clinically important safety concerns were observed, and the most common side effect was temporary soreness at the injection site.

On the recommendation of the independent safety review committee, Silence extended the study period to 365 days to further assess the duration of action of zerlasiran in the single-dose cohorts receiving 300 mg and 600 mg doses. At day 365, some participants still exhibited substantial reductions of Lp(a) to approximately 50% of baseline, with no new drug-related safety findings in either dose group.

Silence has completed dosing in the multiple-dose portion of the phase 1 APOLLO study and is on-track to report topline data from this portion of the study in the fourth quarter of 2023.

Smriti: How does zerlasiran differ from other drugs available (in direct dyslipidemia molecules) or in development for patients with elevated lipoprotein(a) at high risk of atherosclerotic cardiovascular disease events?

Curtis Rambaran: There are no approved therapies for reducing Lp(a). Approved therapies for dyslipidemia, such as statins, reduce low-density lipoprotein cholesterol (LDL-C) but they have no effect on Lp(a).

There are several Lp(a)-reducing therapies in clinical development. We believe the siRNA approach is ideal because it can achieve great efficacy with potentially an infrequent dosing schedule – we saw up to 98% Lp(a) reductions after a single dose in the zerlasiran APOLLO study – the effects are long lasting, and the safety/tolerability profile appears benign.

High Lp(a) is a major untreated CVD risk factor impacting up to 20% of the world’s population. While we see opportunities to further differentiate zerlasiran through clinical development, we also believe given the vast size of this global market there will be a need for multiple therapies like the LDL-lowering market.

Smriti: Would the Silence team be assessing zerlasiran in other rare CVD indications in the future?

Curtis Rambaran: The zerlasiran profile certainly opens the door for us to consider other CVD indications. We are currently focused on advancing zerlasiran in adults with high Lp(a) who are at high risk of ASCVD events, which represents a substantial global opportunity and high unmet need in CVD.

Smriti: How does Silence plan to educate HCPs about Lp(a) and how it can be diagnosed?

Curtis Rambaran: Elevated Lp(a) can be diagnosed by a blood test, similar to the way high LDL-C is diagnosed. However, Lp(a) testing is not routinely conducted by HCPs, primarily because, to date, no Lp(a)-reducing drug therapy has been available. That situation is now changing and many professional cardiovascular organizations are recommending testing at least once in an adult’s lifetime, especially if there is a family history of premature ASCVD or personal history of ASCVD.

With this in mind, Silence plans to collaborate with industry partners, third party organizations and key opinion leaders to ensure education on Lp(a) is a priority.

Smriti: What are your coming year plans in terms of collaborations & licensing agreements etc.?

Curtis Rambaran: Silence is actively seeking a partner to help advance and commercialize zerlasiran.

Image source: Canva

About the Author:

Curtis Rambaran

Curtis Rambaran is the VP and Head of the Clinical Science group at Silence Therapeutics. Curtis joined the Respiratory Translational Medicine team at GlaxoSmithKline (GSK) in 2009 developing first in human and experimental medicine studies for novel oral and inhaled assets. He then moved on to the Cardiovascular Therapy Area to work on several outcome studies (CVOTs) with novel MOA including Darapladib and Losmapimod. He received his medical degree from the University of the West Indies, followed by residency training in Yorkshire, UK, then completed a Welcome Trust Cardiology Research Fellowship at King’s College London, with subsequent specialty training in Cardiovascular Medicine and Clinical Pharmacology at Guy’s & St Thomas’ Hospital London.