Novartis has lifted the lid on data from its failed cardiovascular outcomes trial, reporting a total absence of efficacy that could intensify questions about upcoming readouts from Amgen and Eli Lilly.
The Swiss drugmaker reported the failure of the phase 3 Lp(a)Horizon trial in September. At the time, Novartis revealed that pelacarsen, its Ionis-partnered antisense oligonucleotide, lowered Lp(a) levels but failed to cut the risk of a heart attack, stroke or other major cardiovascular event (MACE). Lacking data to understand the failure, analysts held out hope that rival drugs from Amgen and Lilly may succeed.
Those hopes took a hit Saturday when data published in The New England Journal of Medicine showed pelacarsen failed to even numerically improve on placebo. At a median follow-up of 4.7 years, 12.3% of patients on pelacarsen experienced a MACE, compared to 12.1% of their peers on placebo.
Limiting the analysis to patients with higher baseline levels of Lp(a) failed to change the dynamic. Among people with baseline Lp(a) of at least 90 mg/dL, the MACE rate was 12.3% in the pelacarsen and placebo arms. The trial enrolled patients with baseline Lp(a) of at least 70 mg/dL.
Pelacarsen failed to prevent cardiovascular events despite having the expected effect on Lp(a). Levels of the lipoprotein dropped from 236 nmol/L at baseline to 64.4 nmol/L after 12 months on the study drug. Lp(a) levels were 233.4 nmol/L after 12 months on placebo. The Lp(a) reduction on pelacarsen is in line with the 72% decline reported in phase 2.
Amgen and Lilly have linked their siRNA candidates, olpasiran and lepodisiran, respectively, to deeper Lp(a) reductions than pelacarsen achieved. Analysts were looking to the pelacarsen data for signs that lowering Lp(a) more would drive better outcomes. BMO Capital Markets analysts observed in a Nov. 3 note that a minor separation on Novartis’ primary endpoint could make a meaningful difference.
Pelacarsen failed to achieve a minor separation over placebo. Similarly, BMO analysts named any signal on pelacarsen in patients with higher baseline Lp(a) as a trend that would likely be positive for olpasiran and lepodisiran. However, pelacarsen was equally ineffective in the high-Lp(a) subgroup as in the overall population.
Olpasiran and lepodisiran could still succeed where pelacarsen failed. Amgen and Lilly set higher Lp(a) thresholds for enrollment, 200 nmol/L and 175 nmol/L, respectively, compared to about 149 nmol/L in the pelacarsen trial. People with high Lp(a) levels may benefit more from the drugs. Yet baseline Lp(a) in the pelacarsen trial suggests the populations may be more similar than the enrollment criteria suggest.
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