Investigational HDL Mimetic modifies HDL-c level but does not affect coronary disease progression
Impact of Infusion of an ApoA-I HDL Mimetic on Regression of Coronary Atherosclerosis in Acute Coronary Syndrome Patients: The MILANO-PILOT Study
News - Nov. 15, 2016Presented at the AHA Scientific Sessions 2016 by: Stephen Nicholls, MBBS Ph.D., University of Adelaide; Royal Adelaide Hospital; South Australian Health and Medical Res Institute, Australia
Infusions with the investigational MDCO-216, which is an HDL-mimetic containing apoA-IMilano, failed to induce a clinical benefit with regard to coronary disease progression in the MILANO-PILOT Study. These finding have led the Medicine’s Company to decide to discontinue further development of this agent.
While epidemiological studies suggest that HDL protect against cardiovascular disease, raising HDL-c with pharmacotherapy has not led to reduction of CV events in clinical trials. A small early IVUS study suggested that infusing HDL containing apoA-IMilano promoted plaque regression.
Initially it was difficult to produce large quantities for clinical use. Recent efforts have, however, enabled adequate production to enable further development of this novel agent.
The MILANO-PILOT Trial (MDCO-216 Infusions Leading to changes in Atherosclerosis: a Novel therapy in development to improve cardiovascular Outcomes - Proof of concept IVUS, Lipids and Other surrogate biomarkers) Trial is a phase 2, double-blind, placebo-controlled trial. 120 patients with a recent acute coronary syndrome were randomised at 28 sites in 5 countries to receive five 20 mg/kg weekly infusions of MDCO-216 or placebo, in addition to contemporary therapy for post-ACS. Patient enrolment was completed in September, 2016 and an interim analysis was conducted. Patients have a mean age of 61.3 years, 19% had diabetes and 47% were treated with a statin at presentation.
HDL-c was significantly reduced (-7.8%) in those treated with MDCO-216, and increased in placebo-treated patients (+8.0%, P<0.001). Apolipoprotein A-I was also decreased in the MDCO-216 group (-5.3%), as compared with an increase of 5.6% in the control group (P<0.001). No significant changes between treatment groups were seen in LDL-c, free cholesterol, triglycerides, apolipoprotein B and hsCRP levels.
The primary efficacy parameter was the nominal change in PAV from baseline to end of study. Median change in PAV was -0.8% (95%CI: -2.3 to 0.2, P<0.001) in the placebo group and -0.5% (-1.8 to 0.5, P=0.11) in the MDCO-216 group and no significant difference was seen between treatments (P=0.10).
Secondary efficacy parameters included the nominal change in normalised total atheroma volume, across the entire vessel length. No significant change in TAV across the entire vessel length (P=0.77) was seen between groups (-6.9 mm3 (-17.5 to 2.2, P<0.01) with placebo vs. -4.7 mm3 (-13.7 to 1.7, P<0.01) with MDCO-216, nor within the 10-mm segment containing the greatest plaque burden (-2.4 mm3 (-4.6 to 1.3, P=0.04) with placebo vs. -2.4 mm3 (-7.0 to 0.7, P=0.01). 67.2% of patients receiving placebo demonstrated regression, as compared with 55.8% on MDCO-216, and 32.8% and 44.2% in the respective groups showed progression (P=0.21).
In an exploratory analysis, a potential effect of prior statin use was explored. In those who had not received a statin in the past, the median change in PAV was -0.4% with placebo and -0.9% with MDCO-216. In patients with prior statin use, the response in those on placebo was -1.9% and in those receiving MDCO-216 it was -0.1%.
When looking at percent change in HDL-c at different time points after infusion, an initial increase is seen on day 1 with MDCO-216, after which a decrease is seen, from -3% at day 8 to -9 at day 29. With placebo, decreases of -5% and -1% on days 1 and 8 were seen, and increases of about 3%, 2% and 4% on days 15, 22 and 29 respectively.
No significant differences were seen between treatment groups in the occurrence of adverse clinical events, except for adverse events of special interest such as acute renal failure, infusion reaction, thrombo-embolic event, non-infectious hepatitis, or liver abnormalities requiring investigation (4.7% with placebo and 15.5% with MDCO-216, P=0.05).
Thus, it can be concluded that the five MDCO-216 infusions were well-tolerated and decreased HDL-c levels post-infusion as expected, but did not produce a significant effect on coronary disease progression, as measured by IVUS. The findings from this pilot study do not provide the evidence required to proceed with further development.
- Our reporting is based on the information provided during the AHA congress –
Infusions with the investigational MDCO-216, which is an HDL-mimetic containing apoA-IMilano, failed to induce a clinical benefit with regard to coronary disease progression in the MILANO-PILOT Study. These finding have led the Medicine’s Company to decide to discontinue further development of this agent.
While epidemiological studies suggest that HDL protect against cardiovascular disease, raising HDL-c with pharmacotherapy has not led to reduction of CV events in clinical trials. A small early IVUS study suggested that infusing HDL containing apoA-IMilano promoted plaque regression.
Initially it was difficult to produce large quantities for clinical use. Recent efforts have, however, enabled adequate production to enable further development of this novel agent.
The MILANO-PILOT Trial (MDCO-216 Infusions Leading to changes in Atherosclerosis: a Novel therapy in development to improve cardiovascular Outcomes - Proof of concept IVUS, Lipids and Other surrogate biomarkers) Trial is a phase 2, double-blind, placebo-controlled trial. 120 patients with a recent acute coronary syndrome were randomised at 28 sites in 5 countries to receive five 20 mg/kg weekly infusions of MDCO-216 or placebo, in addition to contemporary therapy for post-ACS. Patient enrolment was completed in September, 2016 and an interim analysis was conducted. Patients have a mean age of 61.3 years, 19% had diabetes and 47% were treated with a statin at presentation.
HDL-c was significantly reduced (-7.8%) in those treated with MDCO-216, and increased in placebo-treated patients (+8.0%, P<0.001). Apolipoprotein A-I was also decreased in the MDCO-216 group (-5.3%), as compared with an increase of 5.6% in the control group (P<0.001). No significant changes between treatment groups were seen in LDL-c, free cholesterol, triglycerides, apolipoprotein B and hsCRP levels.
The primary efficacy parameter was the nominal change in PAV from baseline to end of study. Median change in PAV was -0.8% (95%CI: -2.3 to 0.2, P<0.001) in the placebo group and -0.5% (-1.8 to 0.5, P=0.11) in the MDCO-216 group and no significant difference was seen between treatments (P=0.10).
Secondary efficacy parameters included the nominal change in normalised total atheroma volume, across the entire vessel length. No significant change in TAV across the entire vessel length (P=0.77) was seen between groups (-6.9 mm3 (-17.5 to 2.2, P<0.01) with placebo vs. -4.7 mm3 (-13.7 to 1.7, P<0.01) with MDCO-216, nor within the 10-mm segment containing the greatest plaque burden (-2.4 mm3 (-4.6 to 1.3, P=0.04) with placebo vs. -2.4 mm3 (-7.0 to 0.7, P=0.01). 67.2% of patients receiving placebo demonstrated regression, as compared with 55.8% on MDCO-216, and 32.8% and 44.2% in the respective groups showed progression (P=0.21).
In an exploratory analysis, a potential effect of prior statin use was explored. In those who had not received a statin in the past, the median change in PAV was -0.4% with placebo and -0.9% with MDCO-216. In patients with prior statin use, the response in those on placebo was -1.9% and in those receiving MDCO-216 it was -0.1%.
When looking at percent change in HDL-c at different time points after infusion, an initial increase is seen on day 1 with MDCO-216, after which a decrease is seen, from -3% at day 8 to -9 at day 29. With placebo, decreases of -5% and -1% on days 1 and 8 were seen, and increases of about 3%, 2% and 4% on days 15, 22 and 29 respectively.
No significant differences were seen between treatment groups in the occurrence of adverse clinical events, except for adverse events of special interest such as acute renal failure, infusion reaction, thrombo-embolic event, non-infectious hepatitis, or liver abnormalities requiring investigation (4.7% with placebo and 15.5% with MDCO-216, P=0.05).
Thus, it can be concluded that the five MDCO-216 infusions were well-tolerated and decreased HDL-c levels post-infusion as expected, but did not produce a significant effect on coronary disease progression, as measured by IVUS. The findings from this pilot study do not provide the evidence required to proceed with further development.
- Our reporting is based on the information provided during the AHA congress –
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