Trials That Missed the Mark in 2024
Understanding why some clinical trials fail, or "flop," is just as important as celebrating their successes, as these outcomes offer invaluable insights into the complexities of drug development. From challenges related to drug efficacy and unforeseen side effects to operational and regulatory obstacles, failed trials expose the hurdles faced in bringing new therapies to market. These failures can profoundly impact the market, influencing drug development timelines, investor confidence, regulatory decisions, and market dynamics. A high-profile trial failure can lead to significant drops in stock prices, alter investor sentiment, and even cause delays in regulatory approvals or force strategic shifts in therapeutic focus. In this report, we will examine a few of the top clinical trial failures in 2024 and explore their ripple effects on the market.
1. PHOENIX
One of the year's most significant clinical failures, Amylyx Pharmaceuticals’ disappointing post-approval trial results for Relyvrio shocked the ALS community and raised concerns about the industry’s R&D pipeline. Approved in 2022 based on positive Phase 2 results, Relyvrio was promised to be withdrawn if it failed the post-approval trial. After releasing the late-stage results (PHOENIX), Amylyx announced it would cease sales of Relyvrio—its only approved product—and cut its workforce by 70%. The ALS space has faced numerous setbacks, but about 100 companies remain active, with the ALS Association noting there are "more than 50 potential treatments" in development.
2. LIFT-AD
Athira Pharma has announced topline results from the Phase II/III LIFT-AD trial of its leading Alzheimer’s therapy, fosgonimeton. The findings indicate that the study did not meet its primary or key secondary endpoints. This news severely affected Athira’s stock, which plummeted nearly 72% in premarket trading on September 4, 2024.
3. EVOLUTION clinical trials
Bruton tyrosine kinase (BTK) inhibitors have proven their effectiveness in oncology, with drugs like Genentech’s Rituxan achieving blockbuster status. The potential for this class of drugs to either slow the progression of multiple sclerosis or provide a cure has spurred significant R&D activity and led to major deals, such as Sanofi’s $3.7 billion acquisition of Principia Biopharma in 2020. However, in December, hopes were dashed when Merck KGaA announced that its BTK inhibitor, evobrutinib, failed in two Phase 3 trials (evolutionRMS 1 and evolutionRMS 2). These studies compared the treatment to Sanofi’s Aubagio and showed no significant difference in reducing relapsing-remitting MS. Despite these setbacks, the results may not spell the end for other BTK inhibitor candidates from Sanofi, Roche, and Novartis that are currently in Phase 3 trials for MS. Scientists observed that Merck KGaA's results focused on the drug's effectiveness in relapsing MS, rather than its impact on slowing disease progression. Since BTK inhibitors are believed to be more effective at crossing the blood-brain barrier compared to other MS treatments, some researchers remain optimistic that future data from the company may reveal the drug's potential to successfully slow the disease.
evolutionRMS 1
evolutionRMS 2
4. CLARION-CKD
Novo Nordisk announced it will incur a DKr5.7 billion ($816 million) loss after its acquired drug ocedurenone failed in a Phase III trial. The CLARION-CKD trial (NCT04968184) did not meet its primary endpoint in patients with uncontrolled hypertension and moderate to severe (stage 3b/4) chronic kidney disease (CKD). Novo acquired the drug from KBP Biosciences last year in a $1.3 billion deal, while KBP was already conducting the Phase III study. Following the trial results, Novo expects to report an impairment loss of $816 million related to ocedurenone in Q2 2024. The trial included a prespecified interim analysis by an independent data monitoring committee after 12 weeks, which revealed that it had not met its primary endpoint of change in systolic blood pressure (SBP), prompting Novo to terminate the study.
5. CYCLONE 3
In addition to the diabetes and obesity medications Mounjaro and Zepbound, Eli Lilly's first-quarter growth was primarily driven by the SGLT2 inhibitor Jardiance and the CDK4/6 cancer drug Verzenio. However, both medications faced setbacks in late-stage clinical trials. Lilly has decided to discontinue the phase 3 CYCLONE-3 trial, which was evaluating Verzenio in combination with Johnson & Johnson’s antiandrogen therapy Zytiga and the corticosteroid prednisone for metastatic hormone-sensitive prostate cancer (mHSPC). This decision followed an interim analysis indicating that the Verzenio combination was unlikely to outperform Zytiga and prednisone alone in delaying disease progression or mortality. Additionally, the CYCLONE-3 trial's failure compounds a previous setback for Verzenio in the phase 3 CYCLONE-2 study earlier this year, which focused on metastatic castration-resistant prostate cancer (mCRPC). As a result of the disappointing outcomes in prostate cancer trials, Lilly recorded an impairment charge of approximately $75 million in the first quarter.
6. EMPACT-MI
Regarding Jardiance, the EMPACT-MI trial demonstrated that the Boehringer Ingelheim-partnered medication did not significantly reduce the risk of first heart failure-related hospitalization or all-cause mortality compared to placebo in patients who had experienced an acute myocardial infarction. Lilly reported that Jardiance's risk reduction was 10%, which was also not statistically significant.
7. ENHANCE-3
Gilead Sciences, Inc. has announced the discontinuation of the Phase 3 ENHANCE-3 study of magrolimab in acute myeloid leukemia (AML). Additionally, the U.S. Food and Drug Administration (FDA) has placed all magrolimab studies in myelodysplastic syndromes (MDS) and AML, including related expanded access programs, on full clinical hold. These decisions follow the recommendation of an independent Data Monitoring Committee, which reviewed top-line data from a planned interim analysis of ENHANCE-3 regarding overall survival (OS). This analysis revealed that the combination of magnolia with azacitidine and venetoclax showed futility, with an observed increased risk of death primarily due to infections and respiratory failure. Magrolimab was expected to generate nearly $330 million in sales by 2029, but the recent clinical trial hold may signal the end of its development. This news underscores the challenges of treating high-risk MDS, a field without a new class of treatments in nearly two decades. Gilead acquired magrolimab in its $4.9 billion purchase of Forty Seven in 2020, making a significant investment. Gilead’s shares have reached a one-year low, reflecting market reactions to multiple clinical trial holds over the past year.
8. AEGIS-II
CSL announced that the Phase III AEGIS-II trial of CSL112 failed to meet its primary endpoint of reducing the risk of major adverse cardiac events (MACE) in post-acute myocardial infarction (AMI) patients. AEGIS-II was the most ambitious study in CSL’s history. Although CSL informed investors that it had not included any financial contributions from CSL112 in its forward-looking estimates and did not anticipate any material impact from the trial's conclusion, its stock price fell sharply. While CSL hadn’t projected any financial benefits from CSL112, the market had expected a positive impact on the company’s margins, given that CSL112 would have largely been produced as a by-product of its existing treatments and resources.
9. EBO301
AN2 Therapeutics has announced a voluntary pause in patient enrollment for the Phase III segment of its seamless Phase II/III clinical trial (EBO-301). This trial is designed to evaluate the efficacy and safety of the oral small-molecule bacterial leucyl-tRNA synthetase inhibitor, epetraborole, for treating refractory lung disease caused by Mycobacterium avium complex (MAC). Following this announcement, AN2 Therapeutics' shares fell. The company clarified that the pause was not related to any safety concerns, but rather the result of an ongoing analysis. AN2 stated that this decision will allow time for a thorough evaluation of the data, with an independent group of experts conducting an assessment and recommending the next steps, which may include changes to the study's protocol.
