Investigative Depression Drug Does Better in Europe than United States

Deborah Brauser

May 18, 2011

May 18, 2011 (Honolulu, Hawaii) — The experimental multimodal antidepressant Lu AA21004 (Takeda) was the subject of 2 phase 2 randomized controlled trials presented here at the American Psychiatric Association (APA) 2011 Annual Meeting.

In a multidose study of more than 500 patients from 4 continents with major depressive disorder (MDD), investigators found that those who received 1-, 5-, or 10-mg doses of Lu AA21004 experienced significantly reduced depression symptoms over 8 weeks compared with those who received placebo.

However, in a second study conducted with 600 US patients, no significant between-group differences in depression symptoms were found for those receiving a 5-mg dose of the treatment or placebo over 6 weeks.

"The multidose study gives us reason to think that this particular compound may indeed have value and there may be a range of doses that are valuable," investigator Michael Thase, MD, professor of psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, told Medscape Medical News.

Dr. Michael Thase

He reported that before conducting that study, the investigators speculated that the 5- and 10-mg doses of Lu AA21004 would do well but were pleasantly surprised when the 1-mg dose was effective also.

As for the second study, Dr. Thase said he's not sure if it failed because of the dose assessed "or because many studies fail in the US right now.

"That study humbles us because even half the studies of drugs that we know work have failed to show they work in the United States. And this is partly because the placebo response has been growing dramatically over the last 30 years."

He said placebo response rate was around 20% in 1970 and is about 45% now.

"Anytime the placebo response in a depression study goes over 40%, the chance of the study failing goes well over 50%. And the US study did have a high placebo response rate," said Dr. Thase.

"Although we won't know more until there are 3 or 4 or 5 more studies, our [multicountry] trial gives us reason to believe we're on the right track with this multiaction agent. And the US study tells us it's just not easy to demonstrate that an antidepressant works under these circumstances."

Considerable Unmet Needs

"Despite the large number of medications available to treat MDD, there remain considerable unmet needs in pharmacological treatment, including faster onset of action, improved response and remission rates, and improved tolerability," write the researchers.

"Antidepressants that act on multiple neurotransmitter systems and receptor subtypes targeted to specific aspects of the neurobiology of depression may offer advantages over currently available antidepressants," they add.

Lu AA21004, which is currently in clinical development for MDD treatment, acts as a 5-HT3 and 5-HT7 receptor antagonist, a 5-HT1A receptor agonist, a 5-HT1B receptor partial agonist, and an inhibitor of the 5-HT transporter in recombinant cell lines.

It has also been found to increase extracellular levels of norepinephrine, dopamine, and acetylcholine in nonclinical studies, report the investigators.

In the first study, 560 patients with MDD between the ages of 18 and 75 (mean age, 46.4 years; 63% female; 86% white) were enrolled at 48 sites in Europe, Asia, Australia, and South Africa. They were randomized to receive once-daily treatments of either placebo or 1-, 5-, or 10-mg doses of the study drug over 8 weeks (n = 140 per group).

At baseline, all participants had recorded a major depressive episode lasting at least 3 months and a Montgomery Asberg Depression Rating Scale (MADRS) total score over 26.

At weeks 1, 2, 4, 6, and 8, depressive symptoms were assessed. The primary outcome measure was overall reductions in total score between baseline and 8 weeks from the 24-item Hamilton Depression Rating Scale (HAM-D24).

At the 8-week mark, patients were also measured for response rates (at least a 50% decrease in HAM-D24 score from baseline), remission rates (MADRS total score <10), and mean Clinical Global Impression Scale–Global Improvement (CGI-I) scores.

Results showed significantly higher reductions in HAM-D24 total scores at the 8-week time point for all Lu AA21004 treatment groups compared with the placebo group (P < .001).

Response and remission rates and mean CGI-I scores for all Lu AA21004 doses were also improved.

Table 1. Efficacy Measures

Endpoint Lu AA21004, 1 mg Lu AA21004, 5 mg Lu AA21004, 10 mg Placebo
Response rates, % 47.5 45.3 49.6 23
Remission rates, % 25.9 28.8 26.6 16.5
CGI-I scores 2.37 2.37 2.29 2.84

CGI-I = Clinical Global Impression Scale–Global Improvement

In addition, "reductions in HAM-D24 and MADRS total scores were detected by week 2 in all Lu AA21004 groups compared with placebo," reported Dr. Thase.

Nausea, headache, nasopharyngitis, and dizziness were the most common adverse events (AEs) reported throughout the study.

Table 2. Treatment-Related Adverse Events

Adverse Event Lu AA21004, 1 mg, % Lu AA21004, 5 mg, % Lu AA21004, 10 mg, % Placebo, %
Nausea 7.9 15.7 12.9 4.3
Headache 6.4 11.4 5.0 7.9
Nasopharyngitis 3.6 5.0 2.2 5.7
Dizziness 0.7 3.6 6.5 2.1

 

"This experimental treatment is a little bit different than some of the ones we currently have on the market," Don Hilty, MD, professor of psychiatry and behavioral sciences at the University of California–Davis in Sacramento, told Medscape Medical News.

"There's a little bit of an overlap with selective serotonin reuptake inhibitors as well as with buspirone. If it's approved, then there may be some head-to-head studies eventually, and it would be interesting to see how it compares," said Dr. Hilty, who is also the APA Scientific Program Committee cochair and was not involved in the research.

He noted that "the side effects were not too bad" and similar to comparable drugs. Also, the response rates "were comparable to other good rates" found in antidepressant studies.

"When you look at response rates, depending on the study, it can be anywhere from 45% to 65%. But the main thing you look at is the difference between the treatment and the placebo. There's usually about a 30% gap and that's what we see here," said Dr. Hilty.

"We do have some new antidepressants coming out, but it's always nice to have another one. And if it's a little bit different, then maybe some people will respond to it better."

US Study Fails

Dr. Don Hilty

In the second study, 600 patients in the same age range (mean age, 42.4 years) with MDD were enrolled at 48 sites in the United States and randomized to receive 6 weeks of either Lu AA21004, 5 mg (n = 300, 62% female, 69.7% white, 27% black), or placebo (n = 300, 54.7% female, 72% white, 26% black), followed by a 2-week discontinuation period.

In addition to having experienced a 3-month major depressive episode, these participants had a MADRS score over 30. Efficacy was again measured using the HAM-D24 at weeks 1, 2, 4, and 6, and response and remission rates were measured at the 6-week mark.

Results showed no significant differences between the groups for reduced HAM-D24 total scores at any time point or in overall response or remission rates.

"The majority of AEs were considered mild to moderate in intensity, with the most common across the Lu AA21004 and placebo groups being headache (17.1% and 15.1%), nausea (19.1% and 9.4%), diarrhea (11.4% and 7.0%), dry mouth (8.4% and 6.4%), and dizziness (6.4 % and 7.4%), respectively," report the researchers.

A total of 9 participants in each of the groups withdrew due to AEs.

"Lu AA21004 is a novel antidepressant that affects the serotonin system through a number of different mechanisms that are hopefully additive and may help correct or minimize certain side effects," said Dr. Thase.

He said that "we still believe" that the medication's 5- and 10-mg doses will be most effective, but there are plans to study even higher doses in the United States in the future.

"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. "Still, I'd say we're some number of years away from approval."

Both studies were funded by Takeda Pharmaceutical Company Ltd and H. Lundbeck A/S. Dr. Thase reports having worked as a consultant to and on the advisory board for Lundbeck and Takeda. Three of the other 5 study authors work directly for Takeda Global Research and Development Center. Dr. Hilty has disclosed no relevant financial relationships.

American Psychiatric Association (APA) 2011 Annual Meeting: Posters NR04-22 and NR04-29. Presented May 15, 2011.

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