Immediate Impact

After a positive phase 2 trial of the glycine transporter-1 (GLYT-1) inhibitor iclepertin, which aims to increase the intrasynaptic availability of the N-methyl-D-aspartate (NMDA) receptor coagonist glycine, vs placebo for the composite score of the MATRICS Consensus Cognitive Battery (MCCB) in adults with schizophrenia, researchers conducted a large phase 3 trial. 

The program included three 26-week studies in over 1800 clinically stable adults with schizophrenia. It did not show any statistically significant results for the active compound vs placebo on any primary or secondary outcomes.

Since the study methodology was sound and the placebo effect was comparable to prior studies, this trial program, together with the recent failure of luvadaxistat, a d-amino acid oxidase (DAAO) inhibitor that aims to increase the intrasynaptic availability of the other NMDA receptor coagonist, d-serine, suggests that coagonist enhancement may be insufficient in and of itself to significantly improve cognitive functioning in people with schizophrenia.  

Dr Correll –

Importance to Science: 9
Importance to the Molecule: 7
Importance to the Medication Class: 9

Dr Mattingly –

Importance to Science: 9
Importance to the Molecule: 9 
Importance to the Medication Class: 9

The failed phase 3 program for iclepertin is scientifically highly important in that cognitive improvement in schizophrenia has been an elusive and difficult goal. These three 26-week trials were well-powered and designed with 1800 patients. The finding of no significant improvement in any of the 3 trials is highly concerning for the group of NMDA/glycine modulating medications attempting to improve cognition or other aspects of schizophrenia.

Dr Kunovac –

Importance to Science: 4
Importance to the Molecule: 9
Importance to the Medication Class: 9

A molecule with the same mechanism (bitopertin) was previously tested in schizophrenia with negative symptoms and disorganized thoughts. This confirms previous observations. No additional research should be conducted with this mechanism of action. There will be no impact on practice until an effect is observed with any mechanism on cognition in schizophrenia. 

Dr Cutler –

Importance to Science: 8
Importance to the Molecule: 8
Importance to the Medication Class: 8

Unfortunately, these studies were pretty clear failures. Cognitive impairment in schizophrenia is probably the most important unmet need in the treatment of schizophrenia, as it is the major driver of functional impairment and reduced quality of life. Several drugs have been studied and failed for cognitive impairment associated with schizophrenia (CIAS), like this one, despite positive early studies. It is possible that despite a neurobiologic rationale for increasing the levels of the NMDA glutamate receptor co-agonist (glycine or D-cycloserine), it is not an effective strategy, at least for the overall population of patients with schizophrenia. It is possible that a subset would benefit, but we don’t have biomarkers to identify them. This is the second GLYT-1 inhibitor to fail after bitopertin, and other drugs, such as DAAO inhibitors, have also failed. Apparently, the FDA did not allow Boehringer Ingelheim to restrict the study population to those who demonstrated significant cognitive impairment at baseline and therefore would have the most potential for improvement. While most, if not all, patients with schizophrenia have some degree of cognitive impairment, there is a range of severity.

This is important because it will probably halt development of this molecule, although it would be good if they would do a post-hoc analysis of those patients who demonstrated significant impairment at baseline, such as a standard deviation below the norm. This post-hoc analysis was done with Cobenfy, and it demonstrated significant improvement in cognition. It probably ends development of all GLYT-1 inhibitors. While this is another failure for the treatment of CIAS and might give others pause to pursue the indication, it is such an important unmet need that hopefully, people will still pursue it with drugs with other novel mechanisms of action. This was a very large global phase 3 program, and the studies were well-designed and well-executed, thus demonstrating good science. It is very disappointing for clinicians and patients, and it could really give both industry and investors serious pause to pursue this indication.

Dr Jain – 

Importance to Science: 9
Importance to the Molecule: 9
Importance to the Medication Class: 9

Failed studies often inform us. This failed development program informs us about what doesn’t work, and the study program quite convincingly demonstrates the futility and targeting glycine. This in itself is very valuable information. As a result, the importance to science is a 9, and importance to the medication class is a 9. Obviously, the importance to the molecule is 1 because this development program has been completely put aside.

Because it’s a failed program, it tells us that glycine is not, at least for the foreseeable future, at target in the treatment of specific symptoms of schizophrenia. It makes me think very negatively about modulators of glycine in schizophrenia. Glycine modulation as a mechanism of action appears to be a dead end. The studies were, in fact, quite well conducted. I would not criticize the study design or patient selection. It genuinely appears that the mechanism of action is the problem. Obviously, with this development program completely shattered, there is no commercial issue to consider.