First published 3/6/23 - currently in progress
Summary:
ESPR CLEAR outcomes data from NEXLETOL trial reported over the weekend at ACC.23 (on 3/4/23)
The data was positive but the market did not react well (-20% upon report)
This news was covered by many news outlets and definitely gave NEXLETOL more coverage
See our table for how Nexletol Outcomes data compared to other LDL lowering products
Final CLEAR Outcomes Data Reported
Huge news from ESPR over the weekend for NEXLETOL CLEAR Outcomes trial! Many news outlets even covered this story, leading to more awareness for ESPR and Nexletol/Nexlizet. An article and 2 editorials were posted in NEJM. ACC.23 also greatly increased the activity of the patient website and awareness of NEXLETOL, with patient website activity +1426% since ACC. However, the stock was down 20% and it seems the news failed to impress investors.
This Outcomes trial included 14,000 patients with or at risk for cardiovascular disease. See our previous post for more info about the previous results from NEXLETOL trials and Outcomes data from other LDL-C lowering approved products HERE. Learn more about subscribing HERE. Also see Table 1 (below) for a summary of this previous data and to see how NEXLETOL compared.
Regulatory filings are expected with the FDA and EMA in the first half of this year. There is a high likelihood for sNDA after regulatory filings and a label expansion based on this data. Overall the press was positive about this readout - especially because the primary endpoint was met, but the investors did not seem to react well. ESPR was down 23% on data which seems like a market negative over-reaction.
While data showed superior cardiovascular outcomes compares to other oral non-statin treatments and had broader outcome benefits than PCSK9 inhibitors, the therapy is not as good at lowering cholesterol as statins or PCSK9 inhibitors. Also only a small portion of patients are statin intolerant, and is it difficult to determine. Additionally, 25.2% of patients treated with Nexletol experiences serious treatment emergent adverse events compared to the 24.9% of patients treated with a placebo.
Data Results
This trial focused on MACE-3 (secondary endpoint) and MACE-4 (primary endpoint) events, and Nexletol reduced the risk of these events by 15% and 13% respectively. Compared to the placebo, Nexletol also reduced the risk of heart attack and coronary revascularization by 23% and 19% respectively. Nexletol looks as though it is able to reduce heart attacks.
See Table 1 for a comparison of this data with other LDL-C lowering products. While this data looks promising, this trial also included drop-ins* in the trial, which makes it harder to interpret the full effectiveness of NEXLETOL compared to statins or PCSK9s. This is more relevant in the real world, though, and there is still statistical significance for the primary and secondary endpoints.
9.4% of patients treated with Nexletol received any type of LMT (4% treated with statins and 2.8% treated with PCSK9 inhibitors) and over 15% of patients treated with placebo received LMT.
It will be interesting to see how ESPR stock reacts when NOVARTIS reports outcomes data on RNA drug LEQVIO. LEQVIO uses an RNA mechanism to breakdown mRNA for PCSK9. LEQVIO is in many ongoing trials (ORION program) including the ORION-4 Outcomes trial. Previous LEQVIO trials included the Phase 3 ORION-5 trial in HoFH, the ORION-10 and ORION-11 trials in patients with atherosclerotic cardiovascular disease or disease risk equivalent, and the ORION-3 trial (an open label study in ASCVD). ORION-4 Outcomes trial data likely will not be reported until 2026.
*Drop-ins are when a patient started taking another therapy to lower LDLs during the trial, which ESPR felt was ethically required, and is similar to real world.
Table 1. Final CLEAR Outcomes Data compared to other LDL-lowering products
Next Steps
Next steps for ESPR now include regulatory filings in the first half of 2023 and expanding the sales force team in preparation for label changes in Q4 2023.
ESPR expects to receive $300M in milestone payments from collaborative partners upon inclusion of cardiovascular risk reduction data in European label and up to $140M in other regulatory milestones.
See the full slidedeck from ESPR here for even more info on this data and comparisons to statins and PCSK9 antibodies.
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