Inventory: 5 Failed Clinical Trials Worth Noting in 2024

Drug development has always been challenging. For various reasons (including issues with the candidate drug itself, dosage, and adverse events), approximately 90% of investigational drugs fail. The failure rate for drugs targeting central nervous system (CNS) diseases in Phase II and Phase III trials is around 85%. A study found that between 1995 and 2007, the approval rate for CNS drugs by the FDA was less than half that of non-CNS drugs.

Over the past year, we have once again seen many disappointing late-stage clinical trial results in the field of neuroscience, including for diseases like amyotrophic lateral sclerosis (ALS), Huntington's disease, and schizophrenia. This reflects that drug development, especially in advancing new treatments for mental health and neurodegenerative diseases, remains one of the most challenging areas in the biotechnology and pharmaceutical industries.

From the following five failed clinical trials in 2024, we may gain some insights.

Emraclidine

Developing Company: AbbVie

Indication: Schizophrenia

In December 2023, AbbVie placed a significant bet of $8.7 billion on Cerevel Therapeutics, with high hopes for their leading product, Emraclidine.

Emraclidine is a positive allosteric modulator (PAM) of the muscarinic M4 receptor, a potential "best-in-class" next-generation antipsychotic for the treatment of schizophrenia. In a Phase 1b study, Emraclidine demonstrated promising efficacy and safety in treating schizophrenia patients.

In September of this year, the FDA approved Cobenfy as the first new class of schizophrenia treatment in 35 years. Like Emraclidine, Cobenfy also targets the muscarinic receptor, which raised hopes that Emraclidine might yield positive results.

However, in November 2024, Emraclidine failed to significantly improve schizophrenia symptoms in two Phase II trials. In the EMPOWER-1 and EMPOWER-2 studies, compared to a placebo, Emraclidine did not reach the primary endpoint of change from baseline on the Positive and Negative Syndrome Scale (PANSS) at week 6. In the EMPOWER-2 trial, lower doses even worsened symptoms.

With the failure of Emraclidine, Cobenfy remains the only winner in the muscarinic receptor category.

Dalzanemdor

Developing Company: Sage Therapeutics

Indications: Huntington's Disease, Alzheimer's Disease, Parkinson's Disease

2024 has been a tough year for Sage Therapeutics. The biotechnology company, based in Cambridge, Massachusetts, saw its stock drop by more than 90% over the past 18 months, largely due to the failure of its lead candidate, Dalzanemdor.

Dalzanemdor is a positive allosteric modulator of the N-methyl-D-aspartate (NMDA) receptor, being investigated for Huntington's disease, Alzheimer's disease, and cognitive impairment.

• In April 2024, Sage announced that Dalzanemdor failed to meet the primary endpoint in the Phase II PRECEDENT study, showing no significant difference compared to placebo in patients with mild cognitive impairment due to Parkinson's disease.
• In October, the candidate also failed in the Phase II LIGHTWAVE study for Alzheimer's disease, showing no significant improvement in cognition over placebo.
• Furthermore, Dalzanemdor did not meet the primary endpoint in the Phase II DIMENSION trial for Huntington's disease.

Following these setbacks, Sage announced it would discontinue the development of Dalzanemdor.

Fordadistrogene Movaparvovec

Developing Company: Pfizer

Indication: Duchenne Muscular Dystrophy (DMD)

After Sarepta's Elevidys was approved in June 2023, many viewed Pfizer's fordadistrogene movaparvovec as the next gene therapy for neuromuscular diseases.

Fordadistrogene movaparvovec is an intravenous gene therapy that uses an adeno-associated virus 9 (AAV9) vector to deliver a "mini" version of dystrophin under the control of a muscle-specific promoter for treating DMD.

Phase 1b trial results showed that after 12 months of treatment, patients exhibited durable and statistically significant improvements, including sustained levels of mini-dystrophin expression and improvements in NorthStar Ambulatory Assessment (NSAA) scores. However, in June this year, fordadistrogene movaparvovec failed to significantly improve motor function in boys aged 4 to 7 in the Phase III CIFFREO trial.

Additionally, the clinical trial progress for fordadistrogene movaparvovec has faced numerous setbacks. In December 2021, Pfizer had to suspend patient screening and dosing in Phase I after a patient unexpectedly died. In May 2024, one participant in the Phase II DAYLIGHT study died suddenly, leading to a suspension of dosing in the related Phase III CIFFREO trial.

Pfizer stated that although no clear therapeutic signal was observed, the safety of fordadistrogene movaparvovec was manageable, with most adverse events being mild to moderate in severity.

Relyvrio

Developing Company: Amylyx Pharmaceuticals

Indication: Amyotrophic Lateral Sclerosis (ALS)

Relyvrio is a combination of two drugs, sodium phenylbutyrate and taurursodiol, which aim to improve mitochondrial and endoplasmic reticulum health in cells, thereby delaying neurodegeneration. Relyvrio was approved in September 2022 as the third-ever drug for ALS.

The FDA granted approval for Relyvrio based on results from the Phase II CENTAUR trial, which showed that the combination of sodium phenylbutyrate and taurursodiol could slow ALS progression and extend patients' lives by several months. However, in the PHOENIX Phase III trial, Relyvrio failed to show a significant difference in the change from baseline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score at week 48 compared to placebo.

Before Relyvrio's approval, Amylyx co-CEOs Justin Klee and Josh Cohen had committed to removing the drug from the market if Phase III data was not promising. Following the failure of the PHOENIX trial, Relyvrio was withdrawn from the U.S. and Canadian markets in April 2024.

Trodelvy

Developing Company: Gilead Sciences

Indication: Non-Small Cell Lung Cancer (NSCLC)

Trodelvy is an antibody-drug conjugate (ADC) targeting TROP2, developed by Gilead. It was first approved in April 2020, becoming the first TROP2 ADC approved globally. The drug has since been approved for three indications:

1. Metastatic triple-negative breast cancer (mTNBC) in patients who have received at least two prior treatments.
2. Locally advanced or metastatic urothelial carcinoma (mUC) in patients previously treated with platinum-based chemotherapy and PD-(L)1 inhibitors.
3. Locally advanced or metastatic HR+/HER2- breast cancer in patients who have received prior endocrine therapy and at least two systemic therapies.

In January this year, Gilead announced that Trodelvy failed to meet the overall survival (OS) primary endpoint in the Phase III EVOKE-01 study. This global, multicenter, open-label trial (N=603) assessed Trodelvy compared to docetaxel in patients with metastatic or advanced NSCLC who had progressed on platinum chemotherapy and checkpoint inhibitors. The results showed that Trodelvy extended OS compared to docetaxel, although the difference was not statistically significant. However, in the subgroup of patients who had previously received PD-(L)1 inhibitors but did not respond, Trodelvy significantly extended OS by more than 3 months, while no such difference was observed in the responding subgroup. As a result, Gilead has decided to continue exploring Trodelvy in the targeted population.

In addition to the EVOKE-01 study, Gilead also launched the EVOKE-03 trial to evaluate the combination of Trodelvy and pembrolizumab versus pembrolizumab monotherapy in first-line treatment for PD-L1 positive metastatic NSCLC patients (TPS ≥50%).

Reference

https://www.biospace.com/drug-development/5-clinical-assets-that-flopped-in-2024