The year 2024 has been a rollercoaster for the pharmaceutical industry, marked by groundbreaking advancements and sobering setbacks. While innovation continues to drive the sector forward, several high-profile clinical trials failed to meet their endpoints, leaving researchers and companies to reassess their strategies. Among the most notable failures were studies involving MDMA for PTSD, SGLT2 inhibitors for diabetes, and TROP2 ADCs for non-small cell lung cancer (NSCLC). These flops underscore the complexities of drug development and the challenges of translating promising preclinical data into clinical success.
MDMA for PTSD: A Promising Therapy Derailed
One of the most anticipated trials of 2024 was the investigation of MDMA (midomafetamine) as a treatment for post-traumatic stress disorder (PTSD). Developed in this indication by Lykos Therapeutics , MDMA-assisted psychotherapy had shown significant promise in earlier studies, earning Breakthrough Therapy Designation (BTD) from the US Food and Drug Administration (FDA) in 2017. However, the drug’s journey to approval hit a major roadblock last year.
Two pivotal Phase III trials, MAPP1 and MAPP2, demonstrated statistically significant improvements in PTSD symptoms compared to placebo. Despite these positive results, the FDA raised concerns about the trials’ design, particularly the issue of functional unblinding. Patients and therapists were often able to guess whether they were receiving MDMA or placebo, potentially biasing the results. Additionally, external scrutiny from organizations like the Institute for Clinical and Economic Review (ICER) highlighted ethical concerns, including allegations of undue influence on participants and underreporting of adverse events.
In August 2024, the FDA issued a Complete Response Letter (CRL) to Lykos, rejecting the application and requesting an additional Phase III study to address these concerns. This decision was a significant blow to Lykos, which had staked its future on MDMA’s success. The company subsequently laid off 75% of its workforce, though the drug did gain approval in Australia, offering a glimmer of hope for its future.
SGLT2 Inhibitors: Mixed Results in Diabetes and Beyond
SGLT2 inhibitors, a class of drugs initially developed for type 2 diabetes (T2D), have shown promise in treating chronic kidney disease (CKD) and heart failure. However, 2024 saw setbacks in their application for type 1 diabetes (T1D)-linked CKD and acute myocardial infarction (AMI).
Sotagliflozin for T1D and CKD
Sotagliflozin, a dual SGLT1/SGLT2 inhibitor developed by Lexicon Pharmaceuticals, Inc., faced a major setback in its bid for approval in T1D patients with CKD. Despite positive results in earlier trials, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 11-3 against the drug, citing concerns over diabetic ketoacidosis (DKA) risk. The committee questioned the extrapolation of data from T2D studies and the lack of robust safety data in T1D patients. This rejection marked the second time sotagliflozin failed to gain approval for a T1D indication, following its withdrawal from the European market in 2022 for commercial reasons.
Empagliflozin for AMI
Boehringer Ingelheim (BI) and Eli Lilly and Company’s empagliflozin, an SGLT2 inhibitor already approved for heart failure and CKD, also stumbled in 2024. The EMPACT-MI trial, which evaluated empagliflozin in patients with AMI, failed to show a significant reduction in the composite endpoint of heart failure hospitalization or all-cause mortality. While the drug was well-tolerated, the lack of efficacy in this population highlighted the limitations of SGLT2 inhibitors in addressing the diverse causes of AMI-related mortality, such as arrhythmias and stent thrombosis.
Emraclidine for Schizophrenia: A Promising Mechanism Falls Short
Schizophrenia, a complex and debilitating mental health disorder, has long posed significant challenges for drug development. In 2024, emraclidine, a novel M4 muscarinic acetylcholine receptor (mAChR) modulator created by Cerevel Therapeutics, emerged as a promising candidate. Unlike traditional antipsychotics, emraclidine targeted the M4 receptor, offering potential benefits for both positive symptoms and cognitive impairments. Early-phase trials showed encouraging signs of efficacy and a favourable safety profile, raising hopes for a breakthrough in schizophrenia treatment.
However, the optimism was short-lived. Two pivotal Phase II trials, EMPOWER-1 and EMPOWER-2, failed to demonstrate significant improvements in the primary endpoint, the change in Positive and Negative Syndrome Scale (PANSS) total score, compared to placebo. While higher doses showed a trend toward efficacy, the results were inconsistent, and the drug struggled to outperform placebo, a common challenge in schizophrenia trials. The failure highlighted the complexity of the disorder and the limitations of targeting a single receptor pathway.
Zelnecirnon for Atopic Dermatitis: Hopes Derailed by Safety Concerns
Atopic dermatitis (AD), a chronic inflammatory skin condition, has seen significant advancements in treatment options in recent years. In 2024, zelnecirnon, a CC chemokine receptor 4 (CCR4) antagonist developed by RAPT Therapeutics, emerged as a potential game-changer. Targeting the CCR4 receptor, which plays a key role in immune cell trafficking and inflammation, zelnecirnon showed promise in early trials for reducing skin inflammation and improving symptoms in AD patients. Its mechanism of action offered a novel approach to managing this challenging condition, particularly for patients who did not respond to existing therapies.
However, zelnecirnon’s development came to an abrupt halt due to safety concerns. During a Phase II trial, a patient experienced severe liver toxicity, leading to liver failure. This adverse event prompted the FDA to pause the trial, and further investigation revealed that the patient had a complex medical history, including autoimmune thyroiditis and recent COVID-19 infection, which may have contributed to the reaction. Despite this, the incident raised significant concerns about zelnecirnon’s safety profile, ultimately leading RAPT Therapeutics to discontinue its development. The company’s stock plummeted by 40% following the announcement, underscoring the high stakes of drug development.
The failure of zelnecirnon highlights the delicate balance between efficacy and safety in drug development, particularly for inflammatory conditions. While the drug’s mechanism held promise, the safety risks proved insurmountable. This setback serves as a reminder of the importance of rigorous safety monitoring and patient selection in clinical trials. As the field of atopic dermatitis research continues to evolve, the lessons from zelnecirnon will inform future efforts to develop safer and more effective therapies for patients in need.
TROP2 ADCs: Disappointing Outcomes in NSCLC
Antibody-drug conjugates (ADCs) targeting TROP2 have been a focus of intense research in NSCLC, but 2024 brought mixed results. Two major trials, TROPION-Lung01 and EVOKE-01, evaluated TROP2 ADCs in advanced NSCLC patients who had progressed on prior therapies.
Datopotamab deruxtecan
Developed by AstraZeneca and Daiichi Sankyo, datopotamab deruxtecan showed a modest improvement in progression-free survival (PFS) compared to docetaxel in the TROPION-Lung01 trial. However, the overall survival (OS) data were underwhelming, particularly in squamous NSCLC, where the drug performed worse than the control. These results led AstraZeneca to voluntarily withdraw its marketing application in the EU, casting doubt on the drug’s future in this indication.
Sacituzumab govitecan
Gilead Sciences’s sacituzumab govitecan, another TROP2 ADC, also failed to meet its primary OS endpoint in the EVOKE-01 trial. While the drug showed a trend toward OS improvement in non-squamous NSCLC, the results were not statistically significant. These outcomes highlight the challenges of developing ADCs for NSCLC, where patient heterogeneity and resistance mechanisms complicate treatment strategies.
BLU-945 for NSCLC: A Fourth-Generation EGFR Inhibitor Falls Short
NSCLC with EGFR mutations has been a focal point of targeted therapy development, with third-generation EGFR inhibitors like osimertinib setting a high bar for efficacy. In 2024, BLU-945, a fourth-generation EGFR inhibitor developed by Blueprint Medicines, aimed to address resistance mechanisms such as the C797S mutation, which often emerges after osimertinib treatment. Early preclinical data suggested that BLU-945 could overcome this resistance, offering hope for patients with limited treatment options. However, the drug’s clinical performance failed to live up to expectations.
In the SYMPHONY trial, BLU-945 showed limited efficacy, with only a small number of patients achieving partial responses, both as a monotherapy and in combination with osimertinib. The underwhelming results, coupled with the relatively low prevalence of C797S mutations in the real-world patient population, led Blueprint Medicines to halt further development of BLU-945. This decision underscored the challenges of targeting niche resistance mechanisms and highlighted the need for broader-spectrum therapies in EGFR-mutant NSCLC. While BLU-945’s journey ended in disappointment, it provided valuable insights into the complexities of overcoming resistance and the importance of innovative approaches in lung cancer treatment.
PD-1/PD-L1 Combination Therapies: Mixed Results in 2024
Immunotherapy, particularly PD-1/PD-L1 inhibitors, has revolutionized cancer treatment, offering hope for patients with advanced or hard-to-treat cancers. In 2024, several high-profile trials explored combination therapies to enhance the efficacy of these immune checkpoint inhibitors. However, the results were mixed, with some studies failing to meet their primary endpoints, highlighting the challenges of optimizing immunotherapy strategies.
One notable setback was KEYNOTE-789, which evaluated MSD top-seller Keytruda (pembrolizumab) in combination with chemotherapy for EGFR-mutant non-small cell lung cancer (NSCLC). Despite promising early data, the trial failed to show significant improvements in progression-free survival (PFS) or overall survival (OS) compared to chemotherapy alone. Similarly, KEYNOTE-585, which tested Keytruda in the perioperative setting for gastric and gastroesophageal junction cancer, yielded mixed results. While the drug improved pathological complete response (pCR) rates, it did not significantly enhance event-free survival (EFS) or OS. These outcomes underscore the limitations of PD-1 inhibitors in certain patient populations and the need for better biomarkers and combination strategies.
The failures of these trials serve as a reminder of the complexities of immunotherapy and the importance of tailoring treatments to specific cancer types and patient subgroups. While PD-1/PD-L1 inhibitors remain a cornerstone of cancer therapy, their full potential will only be realized through continued innovation and a deeper understanding of the tumour microenvironment.
SAR442257 for Hematologic Malignancies: A Promising Tri-Specific Antibody Faces Challenges
The development of multi-specific antibodies has opened new avenues for treating complex cancers, including hematologic malignancies. In 2024, Sanofi’s SAR442257, a tri-specific antibody targeting CD3, CD28, and a tumour-associated antigen, emerged as a promising candidate for blood cancers such as multiple myeloma (MM) and lymphoma. By engaging T cells and co-stimulatory pathways, SAR442257 aimed to enhance immune activation and tumour cell killing, offering a novel approach to immunotherapy. Early-phase trials showed encouraging signs of efficacy, with some patients achieving durable responses.
However, the drug’s development faced significant challenges, particularly related to safety and tolerability. In clinical trials, SAR442257 was associated with high rates of cytokine release syndrome (CRS) and other immune-related adverse events, necessitating dose modifications and careful patient monitoring. These safety concerns raised questions about the drug’s therapeutic window and its potential for broader use. Despite these hurdles, SAR442257 remains a compelling candidate, with ongoing studies exploring optimized dosing regimens and combination strategies to mitigate toxicity.
The journey of SAR442257 highlights the promise and challenges of tri-specific antibodies in hematologic malignancies. While the road to approval may be complex, the insights gained from these trials will pave the way for safer and more effective multi-specific therapies in the future.
SHP2 Inhibitors for Solid Tumors: A Promising Target Faces Clinical Hurdles
SHP2, a protein tyrosine phosphatase involved in multiple signalling pathways, has emerged as a promising target for cancer therapy, particularly in solid tumours. In 2024, several SHP2 inhibitors, including Bristol Myers Squibb’s BBP-398 and Roche’s migoprotafib, entered clinical trials with the goal of disrupting oncogenic signalling and enhancing the efficacy of existing therapies. Early preclinical data suggested that SHP2 inhibition could synergize with targeted therapies and immune checkpoint inhibitors, offering a potential breakthrough for patients with resistant or refractory cancers.
However, the clinical performance of these inhibitors has been mixed. While some trials showed signs of antitumor activity, others struggled with issues of efficacy and tolerability. Dose-limiting toxicities, including gastrointestinal side effects and hematologic abnormalities, have been a recurring challenge, complicating the development of these agents. Additionally, the complexity of SHP2’s role in cellular signalling has made it difficult to identify predictive biomarkers and optimal patient populations.
Despite these setbacks, the field remains optimistic. Ongoing research is focused on refining dosing strategies, exploring combination therapies, and identifying biomarkers to better target SHP2 inhibition. While the journey of SHP2 inhibitors has been fraught with challenges, their potential to transform cancer treatment continues to drive innovation and investment in this promising area of oncology.
Lessons Learned and the Path Forward
The failures of 2024 serve as a reminder of the inherent risks in drug development. They also underscore the importance of robust trial design, patient selection, and biomarker development. For companies like Lykos, Lexicon, and MSD, these setbacks are not the end of the road but rather opportunities to refine their approaches and learn from their mistakes.
As the industry moves forward, collaboration between researchers, regulators, and patient advocates will be crucial to overcoming these challenges. By leveraging advances in AI, genomics and real-world evidence, the pharmaceutical sector can continue to push the boundaries of innovation while minimising the risks of future trial flops.
These failures are not just setbacks but stepping stones toward better science and more effective therapies. The lessons of 2024 will undoubtedly shape the future of drug development, paving the way for safer, more effective treatments for patients worldwide.