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ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

As part of our ongoing coverage of the 2009 International Congress on Schizophrenia Research (ICOSR), 28 March to 1 April 2009, in San Diego, California, we bring you a meeting missive from researcher Tony Altar, Neurodrug Consulting, on a troubling development in schizophrenia trials.


17 April 2009. Increased placebo responses and diminishing efficacy in many antipsychotic drug trials present a serious issue for clinicians and drug developers. A report from Eli Lilly and Co. at the International Congress on Schizophrenia Research in San Diego, and recent publications on this topic, reveal an alarming trend for antipsychotic trials that until recently was a troubling burden mainly for antidepressant trials. The increase in clinical response for the placebo-treated patients in many, though not all, antipsychotic trials occurs in the U.S. as well as abroad. It would appear that sponsor's trials for new compounds in schizophrenia will require a better understanding and resolution of this issue. Clues as to why this unwelcome trend is occurring can probably be found in 1) comparisons of studies that did, and did not, generate such high rates, and 2) similar changes over time in recruiting patients for antidepressant and antipsychotic studies, since both diseases have produced increasing placebo responses over the years. Opinions are also hereby solicited from those Schizophrenia Research Forum readers who can elaborate on these and other possible explanations.

At an ICOSR morning symposium on March 29, Bruce Kinon from Eli Lilly and Co. presented the long-awaited results of a dose-range study of the metabotropic glutamate receptor (mGluR2/3) agonist prodrug, LY2140023 monohydrate, in patients who failed to respond to prior antipsychotic drugs. As we know from the equally anticipated report from Lilly several years ago, LY2140023 had been shown at a twice-a-day dose of 40 mg to treat schizophrenia over a four-week trial, and to an extent about equal to that of 15 mg olanzapine given daily. Both drugs were clearly superior to placebo in that initial trial, where placebo-treated patients got slightly worse (five points on the PANSS Total score) over time.

Such was not the case in the data presented here, a placebo-controlled, double-blind study of 669 patients, termed the HBBI study. LY2140023, at 5, 20, 40, or 80 mg, twice a day, and the daily dose of 15 mg olanzapine, improved the PANSS-total score with increasing effect over the four-week trial, and to about a similar degree. But there was no clear dose-response effect within the 16-fold dose range for LY2140023, and an even greater effect was observed in the placebo group than for any dose of LY2140023 or for olanzapine. A dose-response relationship for LY2140023 would have provided some pharmacological evidence of a cause-effect relationship, but that non-effect, and the strong placebo response, must be reconciled with the body weight increases that were anticipated and did occur with olanzapine, and the finding that 17 of the clinical sites contributed 25 percent of the patients and a large number of the placebo responders. When data were reanalyzed without those sites, the PANSS-positive scores showed at least the same order of effect seen in the initial clinical trial: placebo < LY2140023 < olanzapine, though statistical significance was not obtained.

The increasing placebo response in schizophrenia trials over the last decade has been documented by (Kemp et al., 2008). Figures 1 and 2 of this article show that greater improvements and less worsening in placebo patients are combining with reductions in active responses to 10 antipsychotic drugs over time. These trends have diminished significant changes in antipsychotic drug trials. The paper is co-authored by pharmaceutical and academic organizations, and lists some possible causes.

Remarkably, a 24-point improvement in PANSS Total of the placebo group of a palliperidone trial reported at the ICOSR meeting (Canuso et al.; Ortho-McNeil Janssen Scientific Affairs), and the large placebo improvement in the LY2140023 study reported by Kinon, fall pretty much along or even exceed the Figure 2 downward regression line in the Kemp et al. (2008) paper. In a poster from the 2008 NCEDU meeting (download NCEDU meeting abstracts), Szegedi et al. plotted a very similar graph showing the increasing placebo response for the last 10 antipsychotics tested, and boldly inserted a final column for the LY2140023 placebo but left the point blank, since the trial hadn't yet been reported. Interestingly, the five-point worsening of the placebo group in the first LY2140023 trial sits well above the regression line for this figure, so it appears more will be learned from a careful analysis of the two LY2140023 trials for any procedural differences. Not all antipsychotic studies at ICOSR provided large placebo effects, however; clinical trial reports of PANSS Total values showed little placebo response in results with lurasidone (Poster 81 by M. Ogasa et al. and Poster 83 by J. Guarino et al., both from Dainippon Sumitomo Pharma America) or armodafinil (Poster 187 by J. Kane et al., Zucker Hillside Hospital, New York).—C. Anthony Altar.

Comments on News and Primary Papers
Comment by:  Paul Shepard
Submitted 23 April 2009
Posted 26 April 2009

When the 17 sites with high placebo responders were removed from the analysis, were only participants randomized to placebo removed or were all subjects who were recruited at these sites removed?

View all comments by Paul ShepardComment by:  C. Anthony Altar
Submitted 28 April 2009
Posted 2 May 2009

Reply to P. Shepard
At ICOSR, Dr. Kinon presented the effects on PANSS positive values over 4 weeks for the placebo group, the groups receiving various LY2140023 doses, and those receiving olanzepine, but "without the 17 sites." I am reasonably sure, but not 100% positive, that this excluded all data from those sites, not just the placebo responders. Anything less would have introduced an unacceptable bias, even for a post-hoc analysis.

View all comments by C. Anthony AltarComment by:  Ralph Hoffman
Submitted 19 May 2009
Posted 20 May 2009

These placebo results are certainly irksome, but may be important in positive ways. I am thinking of two hypotheses to account for these results. First, perhaps second-generation antipsychotic drugs (that are now more widely in use than ever) have more sustained therapeutic effects after discontinuation, so when patients are taken off their prescribed drugs to participate in these trials, their vulnerability to symptomatic worsening is less.

Of course, this would not explain the greater improvements in placebo groups. But perhaps with growing expectations regarding patient safety and support during randomized clinical trials overall, participants are getting more contact with research staff, which may have non-specific positive effects. We have, for instance, solid data indicating that significant social isolation is a trigger for psychotic symptoms independent of neuropsychological impairment in vulnerable individuals (unpublished data). The combination of reduced social isolation, increased staff support, plus (perhaps) sustained protective effects of second-generation drugs might account for emergence of greater positive placebo response.

View all comments by Ralph Hoffman

Comments on Related News


Related News: ICOSR 2011—Some Hope for Alleviating Negative Symptoms

Comment by:  Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011

Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.

I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.

I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.

References:

Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.

Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.

View all comments by Kimberly E. Vanover

Related News: Opinions Mixed on Future for Lilly’s mGluR2/3 Agonist for Schizophrenia

Comment by:  Philip Seeman (Disclosure)
Submitted 15 August 2012
Posted 22 August 2012

The Lilly results of 11 July 2012 are not surprising, considering that the main ingredient of LY2140023 is LY404039, which is both a glutamate agonist and a weak partial dopamine agonist with only one-hundredth the potency of aripiprazole (Seeman and Guan, 2009; Seeman, 2012a), and considering that closer inspection of the clinical data (Kinon et al., 2011) showed that olanzapine was effective in schizophrenia, while LY2140023 was not (Seeman, 2012b).

References:

Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S, Jackson K, Kryzhanovskaya L, Jarkova N, . A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol . 2011 Jun ; 31(3):349-55. Abstract

Seeman P, Guan HC. Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2(High) receptor. Synapse. 2009 Oct ; 63(10):935-9. Abstract

Seeman P. An agonist at glutamate and dopamine D2 receptors, LY404039. Neuropharmacology. 2012a Jul 4. Abstract

Seeman P. Comment on "A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia" by Kinon et al. J Clin Psychopharmacol. 2012b Apr ; 32(2):291-2; author reply 292-293. Abstract

View all comments by Philip Seeman

Related News: Opinions Mixed on Future for Lilly’s mGluR2/3 Agonist for Schizophrenia

Comment by:  Hugo Geerts
Submitted 15 August 2012
Posted 22 August 2012

This is indeed another setback for the schizophrenia patient community, and it underscores the difficulty of translating animal model outcomes to the clinical situation. We have to think about introducing a new technology in schizophrenia drug discovery and development that would combine the best of preclinical animal information, but transplanted into a humanized environment to reverse this string of clinical failures.

One such approach is Quantitative Systems or Network Pharmacology, a computer-based mechanistic disease model of biophysically realistic neuronal networks that combines preclinical neurophysiology with human pathology, and clinical and imaging data (the topic of a recent NIH White Paper). Such an approach can be calibrated with retrospective clinical data, and then used to predict and examine future clinical trials. Applying this quantitative paradigm to the (also much publicized) failure of Dimebon in AD, researchers found that there was a fundamental off-target effect that precluded Dimebon from having cognitive benefits. Further analyses suggested that an imbalance in a common dopaminergic phenotype could increase part of the clinical signal difference as observed in the first (successful) Phase 2 trial.

In the case of schizophrenia, we find that affecting glutamatergic (such as with the mGluR2/R3 agonist) or GABA neurotransmission almost always leads to an inverse U-shaped dose response, because of the intrinsic balance between excitation and inhibition in cortical networks. Using such an approach forces discovery scientists to look beyond the single target and think about the impact on networks and circuits that ultimately drive human behavior and pathology in CNS disorders.

Unlike the traditional, currently used "cartoon"-based qualitative drawings, this approach allows for a quantitative outcome that, in principle, can help define the optimal "sweet spot" of the dose response by looking at the outcome of endophenotypes such as BOLD fMRI.

References:

Athan Spiros, Hugo Geerts. 2012. A quantitative way to estimate clinical off-target effects for human membrane brain targets in CNS Research and Development. Exp Pharmacology, 4; 53-61.

Athan Spiros, Patrick Roberts, Hugo Geerts. (2012) A Quantitative Systems Pharmacology Computer Model for Schizophrenia Efficacy and Extrapyramidal Side Effects, Drug Dev. Res, 73(4): 1098-1109.

View all comments by Hugo Geerts