Novartis has been a bit annoyed lately. At the beginning of September, Novartis' two heavyweight pipelines successively failed Phase III clinical trials.

On September 8th, del desiran, an antibody oligonucleotide conjugate (AOC) drug used to treat myotonic dystrophy type 1 (DM1), failed to meet the standards in the Phase III HARBOR study.

A few days ago, on September 4th, Pelacarsen, who had been highly anticipated by the entire cardiovascular field, failed to deliver ideal results in the Phase III Lp (a) HORIZON Large Cardiovascular Outcome Study.

Research has shown that pelacarsen can reduce Lp (a) levels in patients, but it did not reach the primary endpoint: compared to placebo, the drug did not significantly reduce the risk of cardiovascular events.

This result raises a question that can shake the underlying logic of the Lp (a) field: can the reduction of Lp (a) be translated into cardiovascular clinical benefits?

01. Golden target

Lp (a) is a special plasma lipoprotein formed by the disulfide bond between low-density lipoprotein (LDL) - like particles and apolipoprotein (a), encoded by the LPA gene on human chromosome 6. This gene evolved from the replication of the plasminogen gene millions of years ago and is mainly present in higher primates, especially humans.

This also determines one of the most unique properties of Lp (a). The concentration of Lp (a) is highly controlled by genetic factors and is less affected by lifestyle factors such as gender, age, weight, and exercise. Statins are also difficult to reduce Lp (a).

For populations with high baseline Lp (a), this means an almost unsolvable clinical dilemma. Risk is inherent, but in the past few decades, there have been almost no specialized treatments for it in clinical practice. Hundreds of millions of people worldwide have elevated Lp (a), which is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD).

The scientific community's understanding of this target has also gone through a long cycle.

In 1963, Lp (a) was accidentally discovered. For decades thereafter, it remained a "puzzle" in the field of cardiovascular disease. The academic community has observed a correlation between it and cardiovascular disease, but has long been unable to distinguish whether the two are simply related or have a causal relationship.

Until around 2009, Mendelian randomization studies confirmed a causal relationship between elevated Lp (a) and myocardial infarction, rather than a simple correlation. Based on this conclusion, Lp (a) has officially demonstrated the enormous value of a new generation of cardiovascular drug targets.

After the value of the target was confirmed, BD trading quickly heated up. In 2016, Anjin acquired the OLPasiran equity from Arrowhead with a down payment of $35 million and a potential total transaction value of $670 million, marking the beginning of the Lp (a) trading boom.

In the following years, multiple MNCs entered the market one after another: Novartis introduced Pelacarsen from Ionis, and Eli Lilly introduced Lepodisiran from Dicerna.
Lp (a) has thus become one of the most anticipated targets in the cardiovascular drug race. To this day, Novartis Pelacarsen, Amgen OLPasiran, and Eli Lilly Lepodisiran remain the core assets of the first tier of the Lp (a) track.

02. An unexpected failure

Pelacarsen is an antisense oligonucleotide (ASO) drug targeting LPA mRNA, which utilizes N-acetylglucosamine (GalNAc) to achieve liver cell targeting and inhibit Lp (a) synthesis from the source.

Its Phase II data once gave the market strong confidence. Under the highest dosing regimen, the average reduction in Lp (a) in patients is about 80%.

The core question to be answered in the Phase III outcome trial is not whether the drug can reduce Lp (a), but whether this decrease can translate into cardiovascular risk benefits.

In the phase III HORIZON study, 8323 patients with Lp (a) ≥ 70mg/dL and confirmed cardiovascular disease were included. The higher risk subgroups with Lp (a) ≥ 90mg/dL were preset for analysis to evaluate the impact of pelacarsen on the composite endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and emergency coronary revascularization requiring hospitalization). All participants received standard treatments such as lipid-lowering and blood pressure lowering as recommended by current guidelines.

But the results did not meet expectations. Although pelacarsen did indeed reduce Lp (a), the improvement in biomarkers did not translate into a significant decrease in the overall risk of cardiovascular events in the study population.

A senior executive of Lp (a) R&D company, who declined to be named, suggested in an interview with Yiyi Jun that the failure of Pelacarsen should be objectively viewed, as it does not mean that the Lp (a) target itself has been declared a failure.

In the short term, the industry's attention will focus on the Phase III data of Anjin and Eli Lilly siRNA pipelines. The ASO mechanisms of the two drugs and pelacarsen are different, and theoretically, deeper and more sustained reductions in Lp (a) can be achieved. Is residual Lp (a) the key reason for the failure of this experiment, as ASO reduces the depth of Lp (a) worse than siRNA? ”

Pelacarsen belongs to ASO, while Anjin and Eli Lilly both choose siRNA route, and their mechanisms are significantly different. SiRNA mainly binds to target mRNA in the cytoplasm and relies on RISC complexes to degrade the target; ASO intervenes in mRNA through mechanisms such as RNase H. In theory, siRNA can achieve stronger and longer lasting inhibition of Lp (a).

The Phase II data also confirms this difference. The highest Lp (a) of pelacarsen decreased by about 80%; According to the Phase II data of Amgen Olapasiran, Lp (a) can be reduced by over 95%, and after nearly a year of discontinuation, Lp (a) still maintains a decrease of 40% -50%. The results of the Phase II clinical trial of Lepodisiran from Eli Lilly and Company showed that a single highest dose administration resulted in an 88.5% reduction in Lp (a) levels; After two doses, from day 30 to day 360, the decrease in Lp (a) can reach 94.8%. By comparison, siRNA significantly outperforms ASO in reducing Lp (a). If the failure of pelacarsen is indeed caused by residual Lp (a) levels, then the siRNA route with deeper reduction and longer lasting efficacy theoretically has a higher probability of success. This is also the reason why Anjin and Lilly Phase III trials have become the core observation targets in the entire industry.

According to clinical trial registration information, the Anjin OCEAN (a) - Futures study has enrolled over 7000 cases and is expected to be completed by 2028; Lilly ACCLAIM Lp (a) is currently being promoted among approximately 17300 subjects and is expected to be completed by 2029.

In addition, the baseline risk characteristics and sample size of the enrolled population are also key variables that determine the success or failure of the outcome trial, "the executive added.

Comparing three Phase III trial designs horizontally, there are significant differences in the inclusion thresholds of the three: olpasiran requires Lp (a) ≥ 200 nmol/L, while the inclusion line for leptospiran is ≥ 175 nmol/L; Pelacarsen is ≥ 70 mg/dL.

A low baseline for enrollment means that even if the percentage decrease appears significant, the absolute decrease in Lp (a) levels may not be sufficient to drive clinical benefits.

At the same time, the experiments conducted by Anjin and Lilly deliberately targeted populations with higher concentrations of Lp (a) and more concentrated event risks. Anjin requires subjects to have a history of myocardial infarction/coronary revascularization, combined with at least one additional risk factor; Lilly has included both the secondary prevention population with a history of cardiovascular events and the primary prevention population over 55 years old who have no previous events but have high-risk factors. At the same time, the inclusion threshold has been raised to 175 nmol/L or above, and the trial scale has been expanded to over 17000 people.

Novartis HORIZON is included in the secondary prevention population, requiring a history of myocardial infarction or stroke and meeting the condition of Lp (a) ≥ 70 mg/dL, with more lenient requirements for baseline risk stratification.

Some patients with Lp (a) exceeding the standard but with a moderate risk of events were included in the trial to dilute the overall event density, making it difficult for the treatment group to achieve statistical differences within a limited follow-up period.

Of course, the above is only a deduction based on the experimental plan, and the complete conclusion still needs to be studied by disclosing the original data.
03. Oral administration of small molecules: the rising third pole

In addition to the two small nucleic acid routes of ASO and siRNA, the Lp (a) track is emerging as a third technological path - oral small molecules.

Compared to small nucleic acid drugs administered by injection, oral administration of small molecules has obvious advantages: convenient administration and better patient compliance. For a potential target that covers hundreds of millions of people with chronic diseases, the delivery method itself is enough to reshape the commercial ceiling of a drug.

Hengrui Pharmaceutical HRS-5346 is the fastest progressing oral small molecule Lp (a) inhibitor in China, approved for clinical use in May 2024 and entering phase II in February 2025.

On March 25, 2025, Hengrui Pharmaceutical and Merck reached an exclusive licensing agreement, granting Merck the global development, production, and commercialization rights of HRS-5346 outside of Greater China. Hengrui Pharmaceutical received a down payment of 200 million US dollars, with a maximum milestone payment of 1.77 billion US dollars plus sales commission, and a total transaction amount of approximately 19.7 US dollars.

Shiyao Group adopts a "small molecule+small nucleic acid" dual line layout: siRNA pipeline SYH2068 will enter phase I clinical trials in June 2025; In October 2024, Shiyao Group granted global rights to AstraZeneca for the preclinical Lp (a) small molecule inhibitor YS2302018, with a total transaction value of approximately $2.02 billion.

The mechanism of action of YS2302018 is to block the assembly of Apo (a) and ApoB-100 to form Lp (a). AstraZeneca is betting on this asset, perhaps not just focusing on its single drug value, but also on the imaginative space for future "oral PCSK9+oral Lp (a)" combined lipid-lowering. If two types of oral medications can demonstrate clinical benefits, cardiovascular lipid-lowering therapy may break away from the traditional framework dominated by statins.

Lilly Muvallaplalin is also rapidly advancing, and its Phase III cardiovascular outcome study has been launched in 2025, with plans to enroll over 10000 patients. An earlier Phase II KRAKEN study showed that at 12 weeks, treatment with muvalapelin can reduce Lp (a) levels by up to 70% using traditional blood testing methods; According to the new complete Lp (a) particle detection method, Lp (a) levels can be reduced by up to 85.5%.

It should be noted that muvalin works by blocking the assembly of Lp (a) particles, and free apo (a) remains and is cleared. The decrease in concentration measured by different detection methods varies greatly, and it is not suitable to directly benchmark the decrease with nucleic acid drugs.  

04. Finding the next golden target for cardiovascular disease

The reason why Lp (a) attracts a large number of multinational pharmaceutical companies to invest heavily is due to the huge unmet clinical needs in the cardiovascular field.
According to WHO data, cardiovascular disease remains the leading cause of death worldwide. In 2022, approximately 19.8 million people worldwide died from cardiovascular disease (CVD), accounting for 32% of all deaths that year.

Statins lay the foundation for modern lipid-lowering therapy, while PCSK9 inhibitors further expand the space for downregulation of LDL-C. Two types of drugs have pushed LDL-C management to new heights, significantly reducing the risk of cardiovascular events.

But the clinical reality is that even if LDL-C control is up to standard, a large number of patients still have residual cardiovascular risks; Elevated Lp (a) is a key genetic risk factor independent of LDL-C, and traditional lipid-lowering drugs are almost unable to intervene.

A target with a large patient base, blank clinical methods, and solid genetic evidence will naturally become a battleground for pharmaceutical companies. Compared to the core value of the previous generation of lipid-lowering targets, Lp (a) precisely hits the clinical pain point of residual risk. This is also the underlying logic behind Anjin, Novartis, and Eli Lilly's willingness to invest billions or even billions of dollars in this target.

But the development of new cardiovascular drugs is itself one of the most difficult tracks in drug research and development.

The first difficulty comes from the scale threshold of the Phase III trial. To demonstrate that drugs can reduce cardiovascular events, large-scale, long-term hard endpoint studies must be conducted. Novartis HORIZON enrolled over 8300 people, while Lilly ACCLAIM Lp (a) plans to enroll 17300 cases. Such high clinical investment is unaffordable for the vast majority of small and medium-sized biotech companies, and the cardiovascular heavyweight pipeline that has entered the critical outcome validation stage is basically in the hands of large pharmaceutical companies.

The second challenge is to strive for incremental benefits on top of mature standard treatments.

Currently, cardiovascular patients generally accept lipid-lowering, antihypertensive, antiplatelet, anticoagulant, as well as increasingly sophisticated management of heart failure and metabolic diseases. The new drug is not aimed at the untreated population, but at patients who still have residual risks after multiple interventions. The new drug needs to prove that it can further reduce the risk of events on the basis of the existing plan already being effective. This goal is extremely difficult to achieve.

Recently, negative results for cardiovascular stage III have been concentrated, and Pelacarsen is not an isolated case.

Last November, BMS and Johnson&Johnson announced the termination of the LIBREXIA ACS study on the FXIa inhibitor Milvexian. The independent data monitoring committee determined that the drug was difficult to achieve the primary efficacy endpoint; On July 9th of this year, AstraZeneca and Ionis announced that the CARDIO TTResponse study using Eplontersen for ATTR-CM did not reach the primary endpoint; On July 31st, Novo Nordisk disclosed the ZEUS study of IL-6 monoclonal antibody Ziltivkimab, with a MACE hazard ratio of 0.99 (95% CI 0.88-1.11) and almost no risk reduction observed. Subsequently, Novo Nordisk decided to terminate the Phase III studies HERMES and ATHENA of Ziltivekimab in advance.

These failures span across multiple targets such as TTR, FXIa, IL-6, Lp (a), and cannot be simply attributed to any one type of technological route. But this series of failures collectively point to a reality: the difficulty of developing new cardiovascular drugs has far exceeded any previous period.
 

- Write at the end -

The development of new cardiovascular drugs is entering a "high threshold validation period".

In the past, finding a good target and developing a drug that could alter biomarkers was enough to excite the market; Now, this is just an admission ticket
This is not a dilemma for a single company, but a new normal that the entire field must face. Who can truly achieve incremental benefits in the 'residual risk' is qualified to define the next decade.

Reference material:
1. Novartis, AstraZeneca, and Novo Nordisk have suffered consecutive setbacks, why do cardiovascular drugs always fall in phase III; Dingxiangyuan Insight Database
2 Novartis announces Lp(a)HORIZON Phase III topline results for pelacarsen in patients with elevated Lp(a) and established cardiovascular disease (CVD)； Novartis
3 Novartis Lp(a) drug fails to lower cardiovascular risk in closely watched ph. 3 trial； Fierce Pharma
4. After nearly billions of dollars were smashed, has the new king of the billion dollar "golden target" emerged; Arterial network