This year has seen smashing clinical successes and gut-wrenching failures, opening new markets for some biopharma firms while sending others back to the drawing board.
Several companies have celebrated big clinical wins. Vertex’s non-opioid painkiller secured positive results in three Phase III trials, leading to the FDA’s acceptance of a new drug application; Bristol Myers Squibb got a Phase III win with its purchased schizophrenia asset KarXT, approved in September as Cobenfy; and Alnylam’s Amvuttra aced a Phase III trial in transthyretin amyloid cardiomyopathy (ATTR-CM), a space that saw the recent FDA approval of BridgeBio’s Attruby.
But drug development is challenging. For myriad reasons—including the drug candidate itself, dosing and adverse events—around 90% of investigational drug trials fail. The statistics are particularly grim in neurological indications, with relatively high rates of mid- and late-stage failures. The Phase II and III failure rate of drugs targeting diseases of the central nervous system (CNS) is approximately 85%, according to Clinical Endpoints. One study found that between 1995 and 2007, CNS drugs achieved FDA approval at less than half the rate of non-CNS drugs.
Some of this year’s most notable clinical trial failures were in neurological indications such as amyotrophic lateral sclerosis (ALS), Huntington’s disease and schizophrenia.
“Unfortunately, over this past year, we’ve again seen way too many disappointing mid- and late-stage clinical trial outcomes in neuroscience,” Graig Suvannevejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, told BioSpace in an email. “But this simply reflects the nature of drug development, especially when it comes to advancing new treatments for psychiatric disorders and neurodegenerative diseases, which remains one of the most challenging areas for the biotech and pharmaceutical industry.”
Here, BioSpace looks at five failed assets or clinical trials that have grabbed headlines in 2024.
AbbVie’s Emraclidine
Schizophrenia
In December 2023, AbbVie bet $8.7 billion on Cerevel Therapeutics, with high hopes for the biotech’s lead asset emraclidine. These hopes—and a large portion of the acquisition’s value—came crashing down last month when emraclidine failed to significantly improve symptoms of schizophrenia in two Phase II trials.
In both EMPOWER-1 and EMPOWER-2, emraclidine missed the primary endpoint of change in baseline on the Positive and Negative Syndrome Scale, which measures the different symptoms of schizophrenia, compared to placebo at week 6. In the EMPOWER-2 trial, the lower dose led to an increase in the score, indicating a worsening of symptoms.
The failure was shocking to analysts—Stifel said it was “outright surprising” to see emraclidine “flat out fail” in both pivotal trials—and left investors questioning AbbVie’s long-term neuroscience strategy, the center of which had been emraclidine.
The result was also a coup for BMS, which won FDA approval in September for Cobenfy as the first new treatment class for schizophrenia in 35 years. Like emraclidine, Cobenfy targets the muscarinic receptors—a fact that may have portended a better result for the former. With emraclidine’s demise, BMO Capital Markets’ Evan David Seigerman declared BMS “the sole muscarinic winner.”
Sage Therapeutics’ Dalzanemdor
Huntington’s, Alzheimer’s and Parkinson’s
2024 has not been a good year for Sage Therapeutics. The Cambridge, Mass.–based biotech has seen its stock plummet more than 90% in the past 18 months, spurred in large part by a hat trick of clinical trial failures for lead asset dalzanemdor.
The trouble began in April when dalzanemdor missed the primary endpoint in the Phase II PRECEDENT study, failing to show statistically significant differences versus placebo in patients with mild cognitive impairment in Parkinson’s disease. Then in October, the candidate was unsuccessful in the Phase II LIGHTWAVE study in Alzheimer’s disease, failing to significantly improve intelligence versus placebo. Finishing off the unfortunate trifecta—and dalzanemdor as an asset—was the Phase II DIMENSION trial in Huntington’s disease, where the drug once again failed to meet the primary endpoint. After this latest miss, Sage announced it would discontinue the drug’s development.
The failure of dalzanemdor, along with a scant pipeline and soon to be just one marketed product—postpartum depression drug Zurzuvae—has led some analysts to question Sage’s future profitability.
Pfizer’s Fordadistrogene Movaparvovec
Duchenne muscular dystrophy
One of the most closely watched assets in the Duchenne muscular dystrophy space came up short in June when Pfizer’s fordadistrogene movaparvovec failed to significantly improve motor function in boys four to seven years of age in the Phase III CIFFREO trial.
Widely anticipated to be the next gene therapy for the neuromuscular disease after Sarepta’s Elevidys was approved in June 2023, fordadistrogene movaparvovec also failed the trial’s key secondary endpoints, including 10-meter run/walk velocity and time to rise from floor.
The gene therapy has a rocky history. In May, Pfizer halted dosing in the Phase II DAYLIGHT study after a patient death. And that wasn’t the first fatality in a study of fordadistrogene movaparvovec. In December 2021, Pfizer was forced to pause screening and dosing in a Phase Ib study after an unexpected patient death.
Despite showing no significant signals of efficacy, Pfizer said fordadistrogene movaparvovec had a manageable safety profile, with most adverse events being mild to moderate in severity.
Amylyx’s Relyvrio
Amyotrophic lateral sclerosis
Approved in September 2022 as just the third-ever drug for amyotrophic lateral sclerosis, Amylyx’s Relvyrio was pulled from U.S. and Canadian markets in April of this year after failing the Phase III PHOENIX trial.
Relvyrio won FDA approval based on results from the Phase II CENTAUR trial, where the drug—a combination of sodium phenylbutyrate and taurursodiol—was shown to slow the progression of ALS and extended the lives of patients by several months. However, in PHOENIX, there was no significant difference in the ALSFRS-R total score change from baseline at Week 48 compared to placebo. Survival data were not yet available at the time of this readout.
Prior to Relyvrio’s approval, Amylyx co-CEOs Justin Klee and Josh Cohen pledged that they would pull the drug from the market if the Phase III data were not positive. It took the execs less than a month to make good on that promise.
“We are surprised and deeply disappointed by the PHOENIX results following the positive data from the CENTAUR trial,” Klee and Cohen said in a statement after the readout.
Gilead’s Trodelvy
Non-small cell lung cancer
One of the hottest spaces in biopharma (again) in 2024, antibody-drug conjugates (ADCs) have shown promise in numerous cancer indications. Unfortunately for Gilead Sciences, second-line non-small cell lung cancer (NSCLC) was not one of these areas for Trodelvy.
In January, Gilead announced that its ADC missed the primary endpoint of overall survival in the Phase III EVOKE-01 study. EVOKE-1 had pitted Trodelvy against docetaxel in patients with metastatic or advanced NSCLC that had progressed on or after platinum-based chemotherapy and checkpoint inhibitor therapy.
Gilead did note a more than three-month difference in median overall survival favoring Trodelvy in a sub-group of patients non-responsive to prior anti-PD-L1 therapy, and Chief Medical Officer Merdad Parsey expressed optimism about the readout.
“The totality of our data gives us continued confidence in Trodelvy’s potential in metastatic NSCLC and our broader lung cancer clinical development program,” Parsey said in a statement in January.
Indeed, Trodelvy has shown benefit in first-line NSCLC. In September 2023, the ADC combined with Merck’s anti-PD-1 therapy Keytruda demonstrated promising efficacy in patients with metastatic NSCLC in the Phase II EVOKE-02 study. The trial did reveal concerning safety signals, however, with 18% of participants dropping out due to side effects.
https://www.biospace.com/drug-development/5-clinical-assets-that-flopped-in-2024
