Novel PCSK9 inhibitor yields safe and effective LDL-c lowering
LIB003, a new anti-PCSK9 therapeutic, progresses to phase 3 trial
Presented at EAS 2019 in Maastricht, The Netherlands, by Evan Stein (LIB Therapeutics and Metabolic & Atherosclerosis Research Center, Cincinnati, USA).
Introduction and methods
Monoclonal antibodies directed against PCSK9 have been demonstrated to be highly effective in lowering LDL-c (>50%), and in large outcomes studies they have been demonstrated to lower CV events in patients at high CV risk. PCSK9 antibodies are well tolerated. PCSK9 antibodies generally need to be given every two or four weeks.
Other novel agents are in development, with the aim of extending the dosing interval, for the convenience of patients. One of these novel agents is LIB003, a recombinant fusion protein of a PCSK9-binding domain (adnectin) and human serum albumin (HAS). Binding of adnectin to PCSK9 prevents the interaction between PCSK9 and the LDL receptor. Linkage of HAS to the adnectin increases the half-life of 12 to 15 days.
In a phase I study in patients with elevated LDL-c on diet or statin therapy, single doses of LIB003 of 150 mg to 600 mg (in small volumes of about 0.6 to 2 mL) were well tolerated, and showed sustained LDL-c reductions.
This phase 2 dose-ranging double-blind study evaluated the safety, tolerability and LDL-c lowering efficacy of LIB003 in patients with LDL-c levels greater than 80 mg/dL (about 2.0 mmol/L) on maximally tolerated statin therapy. These patients were randomly allocated to treatment with LIB003 150mg, 300mg and 350 mg or placebo given subcutaneously every 4 weeks for 12 weeks. The two co-primary endpoints were the placebo-corrected percent change from baseline in LDL cholesterol at week 12, and the mean of weeks 10 and 12. 81 Patients were enrolled and 79 completed the trial.
- The dose of 300 mg (in 1.2 mL) given every 4 weeks, yielded 77.3% (SE: 6.6) LDL-c reduction at 12 weeks, compared with placebo. 150 mg yielded 33.5% (SE: 6.5), and 350 mg provided -70.1 (SE: 6.5) reduction.
- When looking at the average of weeks 10 and 12, 300 mg gave 76.1% (SE: 4.99) LDL-c reduction at 12 weeks, compared with placebo. 150 mg yielded 48.0% (SE: 4.87), and 350 mg provided -70.3 (SE: 4.93) reduction.
- Treatment was well tolerated: the incidence of adverse events compared with placebo did not differ between treatment groups. Any treatment emergent adverse event (TEAE) was seen in 50.0% of those on placebo, 42.9% of those on 150 mg, 57.9% on 300 mg and 61.9% of those receiving 350 mg.
- Severe TEAE were seen in 1 person in the placebo, 150 mg and 300 mg groups, and in three persons receiving 350 mg LIB003.
- Apolipoprotein B was lowered by almost 60% with 300 mg LIB003, lipoprotein(a) by almost 30% and HDL-c was increased by a little over 10%.
A new agent directed against PCSK9 was highly effective in lowering LDL-c in a phase 2 trial, when administered every 4 weeks, during 12 weeks, in patients with elevated LDL-c on maximally tolerated statin. At a dose of 300 mg, 77% reduction in LDL-c was seen at the end of the 12-week study. Monthly LIB003 doses of 150, 300 and 350 mg for 12 weeks were well tolerated. The higher dose of 350 mg did not produce further LDL-c reduction as compared with the 300 mg dose, suggesting maximal suppression of PCSK9 is achieved with the 300 mg dose. The 150 mg dose achieved similar LDL-c reductions to 300 mg, but did not maintain maximal LDL-c reductions for the full 4 weeks between doses.
In a press release, lead investigator Dr Evan Stein notes: ‘When compared with the PCSK9 monoclonal antibodies, LIB003offers greater efficacy in a smaller injection volume. The reasons for this are due to 1) its formulation with the adnectin molecule, which is only 11 KD, but with high potency in binding PCSK9, and 2) its fusion with the albumin component, only 66 KD, which increases its half-life to 12 to 15 days. As a result, the total size of the molecule is about half that of a PCSK9 monoclonal antibody, and as it is highly soluble, more drug can be given in a smaller volume. This means that LIB003 can be dosed in small volumes (about 1ml) and still achieve maximal and stable LDL cholesterol reduction when given once a month. The drug is also stable at room temperature for more than 6 months, making it easier for patients to store and take their medication with them when they go away for business or leisure.’
Our reporting is based on the information provided at the EAS 2019 congress