Experimental Antidepressant Moves Closer to US Approval

Deborah Brauser

May 20, 2013

SAN FRANCISCO — The experimental antidepressant vortioxetine is safe and effective for treating major depressive disorder (MDD), findings from several new phase 3 randomized controlled trials (RCTs) suggest.

Three studies of a total of 1545 US patients with MDD showed that those who received 20 mg of vortioxetine had significantly decreased symptom scores on the Montgomery–Ǻsberg Depression Rating Scale (MADRS) after 8 weeks of treatment compared with those who received matching placebo. However, there was no difference in symptom scores between the 10-mg and the 15-mg dose compared with placebo.

Interestingly, a fourth study conducted in Europe and South Africa with 608 patients showed that both the 15-mg and 20-mg doses of vortioxetine were associated with significantly lower MADRS scores than placebo.

"We wanted to address the correct dose, and across the studies, the 20-mg had the most consistent findings over placebo," principal investigator Madhukar Trivedi, MD, professor of psychiatry at University of Texas Southwestern Medical Center in Dallas, told Medscape Medical News.

Dr. Trivedi noted that "it's very hard to figure out why" the 15-mg dose did well in the European study but not in the US studies, "but this often happens in antidepressant trials."

Dr. Madhukar Trivedi

"Overall, the way I think about this as both a clinician and a researcher is that there are currently a lot of antidepressants with varying degrees of efficacy. And yet we know a very large number of the patient population doesn't achieve remission with the currently available treatments. If [vortioxetine] gets approved, I think it will be a welcome addition," he said.

Data from 7 trials, including these 4 that were presented here at the American Psychiatric Association's (APA's) 2013 Annual Meeting, have been jointly submitted to the US Food and Drug Administration (FDA) by Takeda Pharmaceutical Company and H. Lundbeck A/S as part of a New Drug Application.

US Findings

"Vortioxetine is an investigational multimodal antidepressant thought to work through a combination of 2 pharmacological modes of action: serotonin (5-HT) receptor activity modulation and 5-HT reuptake inhibition," write the investigators.

In the first US study, 614 adults between the ages of 18 and 75 years with MDD were randomly assigned to receive daily 20 mg of vortioxetine (n = 154), 15 mg of vortioxetine (n = 147), 60 mg of duloxetine as a reference (n = 152), or placebo (n = 161) for 8 weeks.

Change in MADRS total score from baseline to end of treatment was the primary outcome measure.

Results at 8 weeks showed that the group who received the 20-mg dose of vortioxetine had a mean 15.57-point decline in MADRS score compared with a 12.83-point decline for the group receiving placebo (P = .023). The 14.43-point decrease for those receiving the 15-mg dose of vortioxetine was deemed not significantly different from the placebo group.

Those receiving duloxetine had a 16.9 decrease in total score (P < .001), "confirming assay sensitivity," report the researchers.

Treatment-related adverse events (AEs) reported by the vortioxetine groups (≥5%) included nausea, headache, dry mouth, dizziness, diarrhea, constipation, vomiting, insomnia, fatigue, nasopharyngitis, and respiratory tract infection. There were no differences between the vortioxetine and placebo groups for changes in scores on the Arizona Sexual Experience Scale, the Columbia-Suicide Severity Rating Scale, or the Discontinuance-Emergent Signs and Symptoms checklist.

In study 2, which included of 462 adults with MDD, those randomly assigned to receive 20 mg of vortioxetine had a significantly lower mean change in MADRS score compared with those assigned to receive placebo (-14.41 vs -10.77, respectively; P = .002). Those receiving 10 mg of vortioxetine were not statistically superior to those receiving placebo.

In addition, the 20-mg group had significantly improved scores on the Hamilton Anxiety Rating Scale, Clinical Global Impressions-Improvement, and the Sheehan Disability Scale vs the placebo group (all, P < .05).

Again, the most common AEs reported by the vortioxetine groups were nausea, headache, diarrhea, dizziness, constipation, vomiting, fatigue, and viral upper respiratory infection.

"The adverse events are not outside the realm of what is normally seen with antidepressants," said Dr. Trivedi.

A total of 68.7% of those receiving 20 mg of the investigational medication and 73.5% of those receiving the 10-mg dose reported incidents of AEs compared with 62.4% of those receiving placebo.

The one study that did not show significant efficacy for vortioxetine compared the 15-mg and 10-mg doses of vortioxetine with placebo in 469 patients. This RCT did show a similarly favorable safety profile as the other trials.

"To the question of whether another antidepressant is needed or not, I would argue that we have desperate need for new treatments — especially one with a different mechanism," said Dr. Trivedi.

"Still, we want to be cautious. Just because something is different doesn't mean it's better. But in this case, it can become part of the list of antidepressants available to help patients. And of course clinical experience will have to come into play as to the question of what dose is most efficacious to start a patient on."

European, South African Results

In the overseas trial, the participants who received 15 mg and 20 mg of vortioxetine had significantly larger mean changes in MADRS total scores between baseline and end of study than those who received placebo (mean between-group score difference, -5.5 and -7.1 points, respectively; both placebo comparisons, P < .0001).

"Separation from placebo was seen from Week 2 onwards for vortioxetine 20mg and duloxetine and Week 4 onwards for vortioxetine 15mg," write the investigators.

Commonly reported AEs again included nausea, headache, diarrhea, dry mouth, and dizziness.

Dr. Jean-Philippe Boulenger

"For this study, there was a huge difference demonstrated at 8 weeks," lead author Jean-Philippe Boulenger, MD, from the Department of Adult Psychiatry at La Colombière Hospital at the University of Montpellier, France, told Medscape Medical News.

The large differences between group scores "are rarely seen in [RCTs] of new drugs. Clinically significant differences are 2 or 3 points. So the 5 and 7 points we found are really significant," added Dr. Boulenger.

When asked about the differences between this and the US trials, coinvestigator Christina Olsen, PhD, from Lundbeck A/S in Copenhagen, Denmark, noted that "there is usually less compliance in US studies."

At the 2011 APA annual meeting, as reported at the time by Medscape Medical News, results from two phase 2 RCTs assessing efficacy and safety of the medication (then called Lu AA21004) were presented.

The study that examined 600 US patients with MDD showed no significant between-group differences in symptom scores for those receiving 5 mg of the medication vs placebo. However, the study of 500 patients from 4 continents showed that those who received 1-, 5-, or 10-mg doses of the treatment all did significantly better than the placebo group.

At the time, lead author Michael Thase, MD, from the University of Pennsylvania School of Medicine in Philadelphia, said that he was not sure whether the US study failed because of the dose used or because "many studies fail in the US right now" because of the growing placebo response, or even because of weight issues with the population.

"You know, we're heavier in the US than Europe and other areas. So, 5 mg here may be more like 2 or 3 mg there," said Dr. Thase.

Seeking Approval

Dr. Trivedi echoed that the placebo response has grown over the years in all types of antidepressant RCTs.

"Many of those drugs — even those approved by the FDA — do not separate from placebo. Therefore, I think the interesting thing about the current 4 studies, in terms of at least the higher doses, is the significant superiority over placebo," said Dr. Trivedi.

"My take is that any one study might not be the most sufficient answer to these questions. But if you have 3 or 4 trials and find this consistency, then I think the results seem even more robust."

He added that the patients in these trials had moderate to severe MDD. For example, the patients in the European study had mean baseline MADRS total scores ranging from 31.2 to 31.8.

"It's been shown in the past that studies with very mild patient populations have a harder time showing that separation from placebo," he explained.

Stephen Brannan, vice-president and therapeutic area leader for neuroscience at Takeda, told Medscape Medical News that the New Drug Application package for this medication was submitted to the FDA last October and that they hope to hear a decision late this year.

"We're very excited to see something that's very promising. It is under review, but we think it will be a valuable addition to the treatment armamentarium for depression," said Brannan.

"Another Great Choice"

"First of all, the quality of the research for these studies and the poster presentations are very good," Don Hilty, MD, professor of psychiatry at the University of California-Davis in Sacramento and a specialist in mood and anxiety disorders, told Medscape Medical News.

Dr. Don Hilty

"I think this medication will be another great choice for clinicians. It works in the same way that some of the selective serotonin reuptake inhibitors do, as well as with the serotonin transporter," said Dr. Hilty.

He noted that a serotonin transporter "isn't a new idea. It came out 10 or 15 years ago as clinically relevant and perhaps a better way to measure activity."

Dr. Hilty is currently on the APA Scientific Program Committee and cochaired the committee at the 2011 annual meeting. He was not involved with this research.

"This new treatment will be proven a valid treatment. We'll start at a low dose and go up as we usually do. And most patients with mild to moderate depression will do well on the low dose, whereas those who are more severe will use the higher dose or in combination with other antidepressants."

He added that he was glad to see that the MADRS was used in these trials.

"It's a little harder to show efficacy with that compared with the Hamilton Depression Scale. The Hamilton has been our standard for decades. But this is a little cleaner scale."

When asked to speculate about why the 15-mg dose of vortioxetine did well in the European study but not in the US studies, Dr. Hilty said that "sometimes the populations are just a little different. Plus, patients report their experiences and side effects differently, depending on the culture. So we have to be sensitive to differences between countries and continents and not over-react."

"So basically, these smaller things will be washing out with the laundry as you put all of the studies together and the medication is used in massive numbers of patients," he said.

"This will be a good tool, and it won't have to be reserved for people who don't respond to other medications. It'll work well, and in some patients it'll work better, and for others it might not be the right medication. But it's nice to have another option. And it'll probably be a fairly safe drug to combine with other treatments with different mechanisms of action."

The studies were funded by H. Lundbeck A/S as part of a joint clinical development program with the Takeda Pharmaceutical Company, Ltd. Dr. Trivedi reports being a paid consultant to Lundbeck and Takeda. Dr. Hilty has reported no significant financial relationships.

The American Psychiatric Association's 2013 Annual Meeting. Abstract NR3-55, presented May 18, 2013. Abstracts NR9-01, NR9-02, and NR9-06, presented May 20, 2013.

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