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Background
NewAmsterdam Pharma (NASDAQ: NAMS) is a clinical-stage biopharmaceutical company focused on developing novel therapies for cardiovascular and metabolic diseases. The company’s lead drug candidate is Obicetrapib, a cholesteryl ester transfer protein (CETP) inhibitor. The company’s management team has significant expertise in lipidemia from the perspective of actively treating physicians, clinical trialists, and drug development.
NAMS Pipeline overview (NAMS Pipeline overview)
Obicetrapib, a potential blockbuster CETP inhibitor
NAMS – oral obicetrapib as CETPi clinical profile (NAMS – oral obicetrapib as CETPi clinical profile)
Obicetrapib has shown a drastically different clinical profile compared to previous CETP inhibitors, with LDL-C and apoB reduction approaching levels seen with PCSK9 inhibitors. The company has designed appropriate Phase III clinical trials to evaluate Obicetrapib as a potent, safe, and oral LDL-C (and apoB) lowering agent. The ongoing Phase III trials, BROOKLYN and BROADWAY, are designed to confirm the LDL-C benefit already reported in Phase II studies, with results from both expected in 2024. If the data are positive, we expect approval as early as 2026 (after the phase 3 CVOT PREVAIL trial, which will provide more clarity around the outcomes).
We believe Obicetrapib has a good chance of achieving significant LDL-C and apoB lowering, ultimately translating into clinically meaningful cardiovascular outcomes and risk reduction in the ongoing Phase III trials. We believe continued demonstration of LDL-C reductions of 45-50% in the ongoing Phase IIb ROSE2 trial in 2023 and Phase III BROADWAY and BROOKLYN trials in 2024 will increase investor confidence in the differentiated profile of Obicetrapib and drive share price appreciation.
| Endpoint | ApoB | HDL-C | Lp[A] |
|---|---|---|---|
| Definition | Apolipoprotein B | High-density lipoprotein cholesterol | Lipoprotein[A] |
| Function | Measure of non-HDL cholesterol particles | Measure of “good” cholesterol | Measure of genetically determined cardiovascular risk |
| Importance for FDA approval | High ApoB levels are associated with an increased risk of cardiovascular events, and reduction in ApoB is a recognized surrogate endpoint for cardiovascular risk reduction | Increasing HDL-C is not sufficient on its own to improve cardiovascular outcomes and has not been established as a surrogate endpoint for cardiovascular risk reduction | Lp[A] is an independent risk factor for cardiovascular disease and is used as a biomarker for genetic risk of cardiovascular events |
| Importance for patient care | High ApoB levels are an important marker of cardiovascular risk and can be used to guide treatment decisions, such as the use of lipid-lowering therapy | HDL-C levels may be used to inform treatment decisions, but not in isolation from other factors such as LDL-C levels and cardiovascular risk factors | Elevated Lp[A] levels are associated with an increased risk of cardiovascular disease, and may be used to guide treatment decisions in high-risk patients, including the consideration of therapies such as PCSK9 inhibitors and anti-sense oligonucleotides |
Competitive dynamics in cardiovascular disease therapeutics
Cholesteryl ester transfer protein (CETP) inhibitors are a class of drugs designed to prevent the transfer of cholesteryl esters from high-density lipoprotein [HDL] particles to other lipoprotein particles, such as low-density lipoprotein [LDL]. By inhibiting this transfer, CETP inhibitors increase HDL cholesterol (HDL-C) levels, which has long been considered a promising target for reducing cardiovascular risk.
However, clinical trials of earlier CETP inhibitors, such as torcetrapib and dalcetrapib, were unsuccessful, as they failed to demonstrate significant clinical benefit despite raising HDL-C levels.
| CETP Inhibitor | Key Endpoint[S] | Outcome | Safety |
|---|---|---|---|
| Torcetrapib | Reduction in LDL-c, increase in HDL-c | Increased risk of mortality, no benefit in CVD outcomes | Increased blood pressure, increased incidence of cardiovascular events and death |
| Dalcetrapib | Reduction in major adverse cardiac events [MACE] | No significant benefit in MACE reduction, increased risk of heart failure | No significant safety concerns |
| Anacetrapib | Reduction in LDL-c, increase in HDL-c | No significant benefit in CVD outcomes | No significant safety concerns |
Note: LDL-c = low-density lipoprotein cholesterol HDL-c = high-density lipoprotein cholesterol MACE = major adverse cardiac events
Obicetrapib, a CETP inhibitor developed by NewAmsterdam Pharma, has demonstrated a unique mechanism of action that differentiates it from previous CETP inhibitors. Unlike earlier CETP inhibitors, obicetrapib has been shown to significantly reduce LDL cholesterol (LDL-C) levels while also increasing HDL-C levels. In contrast, statins primarily reduce LDL-C levels, while PCSK9 inhibitors, such as Repatha and Praluent, reduce LDL-C levels by targeting the degradation of LDL receptors. Anti-Lp[A] therapies, on the other hand, aim to reduce lipoprotein[A] (Lp[A] levels, which are genetically determined and considered an independent risk factor for cardiovascular disease.
The LDL-C reduction achieved by obicetrapib is comparable to that seen with PCSK9 inhibitors, with a 45-50% reduction reported in Phase II trials. Obicetrapib has also been shown to reduce apolipoprotein B (apoB), a key component of LDL particles that has been identified as a more accurate predictor of cardiovascular risk than LDL-C levels alone. In Phase II trials, obicetrapib reduced apoB levels by approximately 30%, which was also comparable to the reduction seen with Proprotein convertase subtilisin/kexin type 9 inhibitors.
Current post-statin LDL-lowering products (Current post-statin LDL-lowering products)
One important distinction between obicetrapib and Proprotein convertase subtilisin/kexin type 9 inhibitors is the route of administration. Proprotein convertase subtilisin/kexin type 9 inhibitors are delivered via subcutaneous injections every two to four weeks, while obicetrapib is an oral medication that can be taken once daily. Additionally, the commercial launch of PCSK9 inhibitors has been slow due in part to their high cost, which has been a barrier to access for many patients. Obicetrapib, on the other hand, has the potential to be priced significantly lower than PCSK9 inhibitors, which could make it a more accessible option for patients and a more attractive product for payers.
On the anti-Lp[A] therapies end, they have shown promise in reducing Lp[A] levels; however, the leading late-stage therapies have yet to demonstrate significant clinical benefit in large-scale clinical trials. In contrast, obicetrapib has shown robust LDL-C and apoB reductions, which are supported by strong evidence linking these biomarkers to cardiovascular outcomes. In the ongoing Phase III trials, obicetrapib will be evaluated for its ability to reduce major adverse cardiovascular events [MACE]which will provide critical evidence of its clinical benefit.
Risks
While investing in NewAmsterdam Pharma presents an attractive opportunity, it is not without risks. These include the possibility of unfavorable clinical trial outcomes, regulatory challenges, and competition from comparable products developed by other companies. Additionally, the slow adoption and lower-than-expected uptake of recently introduced LDL-C lowering therapies could affect the commercial launch of obicetrapib. Therefore, successful pricing negotiations and gaining formulary access will be vital factors that could determine the commercial viability of obicetrapib. As an investor, one should keep in mind the potential risks and closely monitor the progress of NewAmsterdam Pharma’s pipeline as well as the overall market dynamics.
Conclusion
NewAmsterdam Pharma’s obicetrapib represents a potential breakthrough in the treatment of cardiovascular and metabolic diseases. The drug has shown a significant ability to lower LDL-C and apoB levels, with reductions comparable to those seen with PCSK9 inhibitors. The management team has taken appropriate measures to demonstrate this differentiated clinical profile with appropriately designed Phase III clinical trials. Continued strong results in these trials would increase not only investor confidence in the drug but also have the potential to drive substantial share price appreciation. Overall, NewAmsterdam Pharma’s position in the market, innovative pipeline, and strong management team make it an attractive investment opportunity for those seeking exposure to the pharmaceutical industry.
