Sustained LDL-c reduction upon dose adjustment of PCSK9 inhibitor
Individualized low-density lipoprotein cholesterol reduction with alirocumab titration strategy in heterozygous familial hypercholesterolemia: Results from an open-label extension of the ODYSSEY LONG TERM trial
Introduction and methods
A recent EAS/ESC Consensus statement and a few guidelines state that treatment with PCSK9-directed antibodies should be considered for patients with heterozygous familial hypercholesterolemia (HeFH) at very high CV risk, with a family history of coronary artery disease at a very young age, or an LDL-c level far from goal despite being on other maximally tolerated lipid-lowering therapy [1-5].
The PCSK9 inhibitor alirocumab can be administered at doses of 75 or 150 mg every 2 weeks (Q2W). Both dosing regimens have demonstrated consistent LDL-c reductions of between 44% and 61% in the ODYSSEY clinical trial program [6-11]. In most studies, the reduction was not dependent on LDL-c levels at baseline [6-8,10].
The ODYSSEY LONG TERM trial assessed the long-term safety and efficacy of alirocumab 150 mg Q2W . For some patients, however, the lower dose may be sufficient to achieve their CV-risk-based LDL-c goals. HeFH patients receiving 150 mg Q2W in ODYSSEY LONG TERM could opt to enroll in the open-label extension (OLE) study, and receive alirocumab 75 mg Q2W at entry in ODYSSEY OLE. ODYSSEY OLE studied the effects of both approved doses of alirocumab in the same HeFH patient cohort, with relatively high LDL-c levels despite maximally tolerated statin therapy.
214 Patients enrolled in ODYSSEY OLE. From week 12, physicians were allowed to adjust the alirocumab dose from 75 to 150 Q2W and back, depending on their clinical judgment and the patient’s LDL-c level. Background statin and other lipid-lowering therapy were to be kept stable during OLE, if possible. The primary objective of ODYSSEY OLE was to assess long-term safety of alirocumab added to background therapy in HeFH, and the secondary objective was evaluation of long-term efficacy and immunogenicity.
- 185 Patients (86.4%) reported a treatment-emergent adverse effect (TEAE) during OLE.
- Four patients (1.9%) discontinued treatment due to TEAE (pregnancy, metastatic colon cancer, worsening myalgia in both legs and grade I transitional meningioma).
- Three deaths (1.4%) due to TEAEs occurred during OLE (sudden cardiac death, acute MI and metastatic colon cancer). None of these were considered related to the study treatment.
- Common TEAEs were viral upper respiratory tract infection (13.1%), influenza (10.3%) and bronchitis (8.9%) and local injection-site reactions were reported in 5.1% of patients.
- Mean LDL-c at OLE baseline (after 8-week washout) was 163.7 mg/dL (SD: 58.3), even though 71.5% of patients receiving high-intensity statins and 54.7% ezetimibe).
- Comparison of LDL-c reductions at week 8 in the LONG TERM parent study (on 150 mg Q2W) with at week 8 in OLE (on 75 mg Q2W) in the same patients, showed that mean LDL-c was 61.6 (SD: 42.9) mg/dL in LONG TERM (63.1% reduction from baseline) and 89.6 (SD: 54.9) mg/dL in OLE (47.3% reduction from OLE baseline).
- In OLE, alirocumab dose was increased from 75 to 150 mg Q2W in 51.9% (n=111) of patients, with a median time to dose increase of 14.1 weeks. In all but one case, this was due to high LDL-c values, and in one case due to high TG (LDL-c value unavailable).
- In 7 patients (6.3%) who had a dose increase, alirocumab was subsequently decreased back to 75 mg Q2W. In 5 patients, the reason for downtitration was low LDL-c, and in 1 patient it was due to an adverse event (memory loss of unknown etiology), and 1 for another reason.
- Those with dose increase to 150 mg Q2W showed a decrease of 55.4% at week 96 from OLE baseline (189.2 mg/dL to 84.7 mg/dL). Patients who were maintained on 75 mg Q2W, showed 46.8% reduction at week 96 (135.6 mg/dL to 69.7 mg/dL).
- Five patients (2.4%) showed a positive alirocumab antidrug antibody (ADA) response, two of whom already showed a positive ADA response during the parent study. One patient had a persistent ADA response during OLE.
- In those who had a negative ADA status during the parent study, ADA titers measured during OLE were low, No consistent pattern between ADA status and efficacy of LDL-c lowering was observed.
- No neutralizing ADAs were observed during OLE in the overall population.
Both the 75 mg and the 150 mg Q2W doses of alirocumab yielded substantial LDL-c reductions over the treatment duration of up to four years. The difference in percentage reduction in LDL-c between the two doses of alirocumab (15.8%) is as expected based on simulation models used for design of the ODYSSEY phase 3 clinical trial program, and consistent with what was seen in double-blind trials. Both patients who remained on 75 mg Q2W and those with a dose increase to 150 mg Q2W showed a sustained reduction in LDL-c. These findings allow for an individualized approach to LDL-c lowering with PCSK9 inhibition in patients with HeFH.