Liafensine (Denovo Biopharma), a first-in-class triple-reuptake inhibitor targeting serotonin, norepinephrine, and dopamine transporters, was effective and well tolerated in patients with treatment-resistant depression (TRD) who are carriers of the ankyrin-3 (ANK3) gene, results of a phase 2b randomized trial showed.
Treatment with liafensine was associated with significantly greater decreases in symptoms of major depressive disorder than placebo, with improvements reported just 1 week after therapy initiation.
“This represents a first successful genetic biomarker-guided clinical trial in psychiatry, advancing a new treatment for TRD and providing a new path for developing precision medicines in the field,” the investigators wrote.
The findings were published online on September 10 in JAMA Psychiatry.
A Novel Drug, a Precision Approach
The ANK3 gene plays an important role in neuronal signaling through modulation of cell membrane proteins and is primarily expressed in the nervous system. Research links this gene to psychiatric disorders, including depression.
Unlike most commonly used antidepressants that inhibit reuptake of serotonin or serotonin and norepinephrine, liafensine inhibits the transporters for all three key monoamines, including dopamine transporters.
Despite expectations, the drug failed to demonstrate efficacy in two prior large-scale phase 2b trials in nonbiomarker-selected patients with TRD.
However, a genome-wide scan using DNA from patients in the earlier trials determined that there was a strong correlation between single-nucleotide polymorphism (SNP) rs12217173 status and efficacy in patients treated with liafensine. This SNP resides in the ANK3 gene and showed the strongest association with drug efficacy, the investigators wrote.
In the 20% of study participants in the original trials who were ANK3 biomarker positive, liafensine demonstrated significant efficacy compared with the control antidepressants duloxetine or escitalopram.
To prospectively confirm liafensine’s efficacy in ANK3-positive patients, the investigators launched a new trial at 59 sites in the US, Canada, and China. The ENLIGHTEN study was blinded and included 189 adults with TRD (mean age, 43 years; 63% women; 48% White).
Although most participants were ANK3-positive, the study included a few ANK3-negative patients who were enrolled for exploratory observation.
Clinically Meaningful
Participants had a median major depressive disorder duration of 7.8 years and, on average, had tried three prior antidepressants.
Overall mean baseline scores on the Hamilton Depression Rating Scale, Montgomery-Åsberg Depression Rating Scale (MADRS), and Clinical Global Impression-Severity (CGI-S) scale were 25.1, 33.0, and 4.8, respectively.
Study participants were randomly assigned to receive once-daily 1-mg liafensine, 2-mg liafensine, or placebo. The primary outcome was the change in MADRS scores (range, 0-60) at day 42 for the combined 1-mg and 2-mg doses.
Results showed a statistically significant mean difference of 4.4 points for the combined liafensine group over placebo (-15.4 vs -11.0; 95% CI, -7.6 to -1.3; P = .006).
The two liafensine doses separately demonstrated similar statistically significant MADRS improvements (mean treatment differences, -4.4 for 1 mg and -4.5 for 2 mg; P = .02 for both).
The standardized effect size was 0.42 for the combined liafensine group (0.41 for 1 mg and 0.44 for 2 mg), which the investigators said was clinically meaningful.
Improvements in MADRS scores were observed in the first week of liafensine treatment, suggesting a rapid onset of symptom relief.
The trend for increased improvement over time “may suggest further improvement in efficacy with longer treatment,” the investigators noted.
Liafensine was also superior in all secondary endpoints at day 42, including changes on the CGI-S and CGI-Improvement scales.
The proportion of patients who reported at least one treatment-emergent adverse event (TEAE) was comparable between the liafensine group (57.3%) and the placebo group (56.3%). The most common TEAEs were nausea and headache, and most were tolerable.
A Single Therapeutic Target
In liafensine-treated patients, 4% discontinued treatment due to adverse events compared with 14.1% of those who received placebo. One patient taking liafensine died of an unknown cause.
None of the side effects commonly associated with the two drugs currently approved for TRD — Symbyax (olanzapine/fluoxetine, Eli Lilly and Company) and Spravato (esketamine, Janssen) — were observed, the investigators reported. These include dissociation, respiratory depression, movement disorders, and metabolic dysfunction with significant weight gain.
This, the investigators noted, suggests liafensine “represents the potential for an improved risk-benefit profile using precision medicine in ANK3-positive patients with TRD.”
The results suggest “a single locus, if identified correctly, could be successfully used to predict antidepressant response, which represents major progress in advancing precision medicine in psychiatry,” the investigators wrote.
The 1-mg dose had comparable efficacy to the 2-mg dose and had better tolerability, so future studies will use the lower dose, they added.
The precise mechanism of how the ANK3 gene affects liafensine is likely related to the dopamine pathway but is not yet fully characterized. Although the 6-week study duration is consistent with FDA guidance for approval, long-term efficacy is yet to be tested.
The FDA granted Fast Track designation for developing liafensine to treat patients with TRD, and the company is moving ahead with a phase 3 study, Matthew A. Spear, MD, study investigator and chief medical officer/chief development officer for liafensine manufacturer Denovo Biopharma, told Medscape Medical News.
“We’re discussing that with regulatory agencies,” said Spear. “That would serve as a second pivotal study, which would potentially allow liafensine to be approved.”
Kudos and Caveats
Commenting for Medscape Medical News, Philip Muskin, MD, professor of psychiatry at Columbia University Irving Medical Center in New York City, said the findings underscore the potential of using genetic biomarkers to guide treatment in psychiatry, particularly with an agent that targets three neurotransmitter systems simultaneously.
Applying genetic profiles to determine which antidepressant works best for a particular patient represents the future of depression treatment, said Muskin.
“When we talk about personalized medicine, this is pretty personal,” he said, adding that the study represents an important step toward precision medicine and could signal a future in which treatments are increasingly tailored to individual patients.
Muskin said he envisions a scenario in which a clinician takes a detailed history, prescribes an initial antidepressant, and then uses genetic testing results to guide the next treatment if the first is ineffective.
For now, clinicians would likely prescribe the first medication without waiting for genetic results until such tests become widely available, rapid, and affordable. Muskin noted that genetic analysis could potentially guide nondrug treatments as well, including behavioral approaches.
While he finds the results promising, Muskin also expressed some concerns about the study. He described the genome-wide scan used to identify a relevant response marker as a broad, “shotgun” approach and noted that it is somewhat surprising that researchers identified only one marker given the genetic complexity of depression. However, he also acknowledged that he is not a genetics expert.
He also questioned the assertion that the drug has an exceptionally favorable side effect profile. While this may be true for the limited number of study participants, broader use in larger populations could reveal additional side effects, Muskin said. He also noted that the differences in MADRS scores between the drug and placebo were statistically and clinically significant but not dramatic.
The study was funded by Denovo Biopharma. Spear reports employment, salary, and equity from Denovo Biopharma during the conduct of the study and outside the submitted work. Muskin reported having no relevant conflicts of interest.
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