Copenhagen, Denmark – September 15, 2023 – In a significant pivot for its cardiovascular pipeline, global pharmaceutical giant Novo Nordisk has announced the premature termination of two pivotal Phase III clinical trials investigating its novel inflammation-targeting therapy, ziltivekimab. The decision, stemming from a recommendation by an independent data monitoring committee, signals a strategic re-evaluation of the drug’s potential in chronic heart failure management. While this marks a considerable setback, the company has reaffirmed its commitment to exploring ziltivekimab’s utility as an acute treatment for post-heart attack patients, with hopes pinned on the ongoing ARTEMIS trial.
The halted trials, known as HERMES (NCT05636176) and ATHENA (NCT06200207), were designed to assess the efficacy of ziltivekimab in patients suffering from heart failure and concurrent inflammation. Novo Nordisk communicated this decision to trial investigators on September 4th, with the news first being reported by Endpoints on September 7th. Both studies were evaluating ziltivekimab head-to-head against a placebo.
This abrupt halt follows a series of disappointing results for ziltivekimab, most notably the failure of the Phase III ZEUS trial (NCT05021835) in July to meet its primary endpoint. The ZEUS trial aimed to evaluate the drug’s ability to reduce the risk of major adverse cardiovascular events (MACE) in patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and inflammation. The cumulative data from these trials, as reviewed by the data monitoring committee, led to the conclusion that further pursuit of ziltivekimab in the current chronic heart failure indications was unlikely to yield a different outcome.
A Strategic Re-evaluation: From Chronic Management to Acute Intervention
The termination of the HERMES and ATHENA trials represents a significant strategic shift for Novo Nordisk’s ziltivekimab development program. The HERMES trial was specifically designed to assess ziltivekimab’s impact on the time to the first occurrence of heart failure-related endpoints, including cardiovascular death and hospitalizations or urgent physician visits due to heart failure. The ATHENA trial, meanwhile, focused on a broader spectrum of heart failure-specific factors, including improvements in patient quality of life. The early cessation of these studies suggests that the accumulated data did not demonstrate a compelling benefit in these critical areas, prompting the data monitoring committee to recommend discontinuation.
Novo Nordisk’s rationale for halting the trials was clearly articulated in a statement to Clinical Trials Arena. The company stated that the decision was based on the recommendation of the data monitoring committee, which, after a comprehensive review of all available data, concluded that the HERMES and ATHENA trials were unlikely to achieve their intended objectives. This conclusion was heavily influenced by the preceding failure of the ZEUS trial.
The ZEUS trial’s outcome was particularly impactful, as it represented a crucial late-stage evaluation of ziltivekimab’s potential to mitigate cardiovascular risk in a complex patient population. Its failure to demonstrate a reduction in MACE in patients with ASCVD, CKD, and inflammation cast a long shadow over the drug’s broader cardiovascular development trajectory. The data monitoring committee’s assessment appears to have extrapolated this lack of efficacy to the chronic heart failure settings being investigated in HERMES and ATHENA, leading to the difficult decision to terminate these studies.
Chronology of Setbacks and Shifting Horizons
The journey of ziltivekimab through late-stage clinical development has been marked by a series of critical milestones and, more recently, significant setbacks. Understanding the timeline of these events provides crucial context for Novo Nordisk’s current strategic adjustments.
-
2020: Novo Nordisk acquired the rights to ziltivekimab, a novel, once-monthly subcutaneous injectable therapy targeting inflammation, through a substantial $725 million upfront takeover of the Massachusetts-based biotechnology firm Corvidia Therapeutics. This acquisition signaled the company’s strategic intent to build a robust pipeline in cardiovascular and metabolic diseases, with a particular focus on addressing unmet needs through innovative mechanisms of action.
-
July 2023: The Phase III ZEUS trial, a cornerstone of ziltivekimab’s development for cardiovascular risk reduction in patients with ASCVD, CKD, and inflammation, failed to meet its primary endpoint. This outcome was a significant blow, as it suggested the drug’s ability to prevent major cardiovascular events in this high-risk population was not as anticipated.
-
September 4, 2023: Novo Nordisk officially informed investigators of the decision to terminate the HERMES and ATHENA Phase III trials. This decision was based on the recommendation of an independent data monitoring committee, which reviewed the totality of data and concluded that the trials were unlikely to achieve their goals, particularly in light of the ZEUS trial’s outcome.
-
September 7, 2023: The news of the trial terminations was first reported by Endpoints, bringing wider attention to Novo Nordisk’s challenges with ziltivekimab in its chronic heart failure indications.
Despite these setbacks, Novo Nordisk has been quick to emphasize that the ARTEMIS trial, a Phase III study evaluating ziltivekimab as an acute treatment in the post-heart attack setting, will proceed as planned. This trial represents a critical remaining avenue for ziltivekimab’s success, with a data readout anticipated in the first half of 2027. This pivot underscores the company’s strategy to explore different therapeutic windows and patient populations where ziltivekimab’s anti-inflammatory properties might still offer a significant benefit.
Supporting Data and the Role of the Data Monitoring Committee
The decision to halt clinical trials is never taken lightly. In the case of ziltivekimab’s HERMES and ATHENA studies, the recommendation came from an independent data monitoring committee (DMC). DMCs are crucial oversight bodies in clinical trials, comprising independent experts who periodically review unblinded safety and efficacy data. Their primary role is to protect the welfare of trial participants and ensure the scientific integrity of the study.
The DMC’s recommendation for early termination is typically based on a clear indication that a trial is unlikely to demonstrate a statistically significant benefit, or that continuing the trial would expose participants to unnecessary risks without a reasonable prospect of a positive outcome. In this instance, the committee’s assessment was informed by a comprehensive review of the data accumulated thus far in both HERMES and ATHENA.
While the specific details of the data reviewed by the DMC are proprietary, their conclusion strongly suggests that the observed trends in efficacy were not sufficiently promising to warrant continuing the extensive and resource-intensive late-stage trials. The fact that both trials were halted based on a unified recommendation from the DMC indicates a consistent pattern of insufficient efficacy across the investigated chronic heart failure endpoints.
The HERMES trial, with its focus on primary cardiovascular endpoints and heart failure hospitalizations, and the ATHENA trial, with its broader assessment of quality of life and other heart failure-specific metrics, were both designed to capture potential benefits of ziltivekimab. The DMC’s conclusion that these benefits were unlikely to materialize implies that the drug’s mechanism of action, while potentially beneficial in other contexts, did not translate into significant improvements in these specific chronic heart failure outcomes within the parameters of these trials.
Official Responses and Future Outlook
Novo Nordisk has maintained a transparent approach in communicating these developments. In a statement provided to Clinical Trials Arena, the company reiterated its commitment to its ongoing research and development efforts.
"Novo Nordisk has decided to discontinue the HERMES and ATHENA Phase III trials evaluating ziltivekimab in patients with heart failure and inflammation," a spokesperson stated. "This decision was made based on the recommendation of the independent data monitoring committee, which concluded that the trials are unlikely to meet their objectives. We are grateful to the patients and investigators who have participated in these studies."
The company also clarified the immediate next steps for participants in the halted trials: "All patients will be followed through to their three-months follow-up visit as already planned." This ensures that participants receive appropriate care and that valuable data from the completed study periods are collected.
Looking ahead, the focus for ziltivekimab has definitively shifted to the ARTEMIS trial. "We remain committed to exploring the potential of ziltivekimab as an acute treatment in the post-heart attack setting through the ongoing Phase III ARTEMIS trial," the spokesperson added. This trial represents Novo Nordisk’s remaining significant investment in the drug’s cardiovascular development, aiming to ascertain its utility in a more acute phase of cardiovascular disease. The anticipated data readout from ARTEMIS in the first half of 2027 will be a critical determinant of ziltivekimab’s future prospects.
Implications and the Broader Landscape of Cardiovascular Drug Development
The premature termination of the HERMES and ATHENA trials carries significant implications for Novo Nordisk and the broader field of cardiovascular drug development. For Novo Nordisk, it represents a substantial financial and strategic setback, necessitating a re-evaluation of its R&D priorities and pipeline. The substantial investment made in acquiring Corvidia Therapeutics and subsequently advancing ziltivekimab through late-stage trials highlights the high stakes involved in developing novel cardiovascular therapies.
The failure of ziltivekimab in these chronic heart failure indications also underscores the immense challenges inherent in treating complex cardiovascular diseases. Heart failure, in particular, is a multifactorial condition influenced by a myriad of genetic, environmental, and lifestyle factors. Developing therapies that can effectively modify disease progression and improve patient outcomes in the long term remains a formidable scientific and clinical hurdle.
Furthermore, the decision to halt these trials may prompt a broader reassessment of the role of inflammation-targeting therapies in cardiovascular disease. While inflammation is increasingly recognized as a key driver of atherosclerosis and cardiovascular events, translating this understanding into effective therapeutic interventions has proven complex. The IL-6 pathway, targeted by ziltivekimab, has shown promise in various inflammatory conditions, but its precise impact on chronic heart failure requires further elucidation.
The continued focus on the ARTEMIS trial suggests that Novo Nordisk believes ziltivekimab may still hold promise in an acute setting. This could be due to different pathophysiological mechanisms at play post-myocardial infarction, where rapid inflammatory responses might be more amenable to therapeutic intervention. The success of ARTEMIS would be crucial for salvaging the ziltivekimab program and demonstrating its value in a specific niche within cardiovascular medicine.
Ultimately, the ziltivekimab saga serves as a potent reminder of the inherent risks and uncertainties in pharmaceutical R&D. While disappointing outcomes can occur, the ability of companies to adapt, learn from failures, and strategically pivot their research efforts is critical for continued innovation. The pharmaceutical industry will be closely watching the results of the ARTEMIS trial to see if ziltivekimab can ultimately fulfill its therapeutic potential in a different clinical context.
About the Author
