Immediate Impact

Although amisulpride, a benzamide D2 antagonist antipsychotic, is among the highest ranked antipsychotics for efficacy in acute schizophrenia (with doses of 600 to 800 mg/d) and has preliminary beneficial effects vs placebo for negative symptoms (with doses of 50 to 300 mg/d) in adults with schizophrenia, amisulpride has never been submitted or approved in the United States. 

Since amisulpride is not very blood-brain barrier penetrant, the molecule accumulates peripherally, which can lead to QTc prolongation and prolactin elevation. The investigational compound LB-102 is a methylated version of amisulpride that penetrates the blood-brain barrier much more readily, reducing peripheral side effects. In a 4-week, placebo-controlled study in adults with acute exacerbation of schizophrenia, LB-102 met its primary endpoint, demonstrating at all 3 active doses (ie, 50 mg, 75 mg/d, and 100 mg/d) statistically significant reduction from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at 4 weeks, with the 100 mg demonstrating the highest effect size vs placebo. Additionally, LB-102 was well tolerated. These data form the basis of a phase 3 program. 

Dr Correll –

Importance to Science: 9
Importance to the Molecule: 7
Importance to the Medication Class: 6

Dr Mattingly –

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

The methylation of amisulpride to increase central nervous system (CNS) penetration is scientifically interesting and may represent a potential strategy for other molecules to improve CNS penetration. According to GlobeNewswire, "At week 4 of the study, participants treated with the 50 mg dose (n=107) achieved a mean change in baseline Clinical Global Impressions-Severity (CGI-S) score of -0.72 compared to placebo (p=0.0008). Those who received the 75 mg dose (n=108) achieved a mean change in baseline CGI-S score of -0.67 compared to placebo (p=0.0048). Treatment with the exploratory dose of 100 mg (n=36) resulted in a mean change in baseline CGI-S score of -0.84 compared to placebo (p=0.0026)."

With the inherent limitations of any phase 2 study, these results are very promising and represent an obvious positive signal for this compound, which appeared to show meaningful improvement at doses of 50, 75, and 100 mg per day with relatively well-reported safety and tolerability.

Dr Kunovac – 

Importance to Science: 5
Importance to the Molecule: 3
Importance to the Medication Class: 3

The data does not represent any advances in the field. As a European-trained psychiatrist, I am familiar with the data and clinical information related to amisulpride. The authors made the assumption that the methylated amisulpride (m-amisulpride) will have fewer adverse reactions compared to the original molecule. However, they did not disclose any clinical data to support their claim. The study will have no impact on this molecule until the authors disclose the safety, in particular, the cardiovascular effects (QTc). There is no impact on the medication beyond what is already known about amisulpride. It will not affect practice until we have more data to confirm the assumed benign safety profile.

Dr Cutler – 

Importance to Science: 8
Importance to the Molecule: 7
Importance to the Medication Class: 6

Even though amisulpride is a very effective antipsychotic, it is not a new mechanism of action (MOA), and it will be hard to get it covered when there are so many similar generics. I feel like it should have been brought to America years ago, and now the market has kind of passed it by. It sounds like methylation was a good and creative way to increase CNS penetration, and if it decreases the side effects and risks, that would certainly be good. Amisulpride has issues with significant QTc prolongation, prolactin elevation, and extrapyramidal symptoms. Methylation would have to clearly decrease all 3 to perhaps make a case for getting the strong efficacy, including for negative symptoms, which has been its reputation. It is unlikely they will get an indication for negative symptoms or be able to promote that message unless they do dedicated studies for negative symptoms, which are complicated and expensive (and risky).

For the molecule itself, I would have given it a lower grade, but methylation is a clever and innovative formulation, especially if it decreases the side effects and risks as above. I just don’t see much in terms of class because amisulpride is essentially a dopamine/serotonin antagonist with a very similar MOA to other antipsychotics. There are some unique properties that they won’t be able to discuss in a promotional setting (such as high affinity for D3 and 5-HT7), and it has shown very strong efficacy at low doses for depression (eg, 50 mg worked better and faster than sertraline/Zoloft for depression) and for negative symptoms of schizophrenia, but again, unless they do dedicated studies for depression or negative symptoms and get the indications, they won’t be able to mention this.

Effectively treating negative symptoms is definitely a huge unmet need with current antipsychotics, and amisulpride might be uniquely effective for this, but again, they most likely won’t be able to mention this in their promotion of it. I like the methylation to increase CNS availability; that sounds like innovative science, and I like that they explored different doses to get a range of doses approved, but the clinical trials sound pretty routine, although I don’t know details. Again, I don’t see it making much of a dent in the market. I think it will be a tough sell to clinicians, since amisulpride is an old molecule and has a similar MOA to others in the class, and it will also be a tough sell to payers, unless they can somehow make the case for negative symptoms and depression.

Dr Jain – 

Importance to Science: 6

Importance to the Molecule: 6
Importance to the Medication Class: 6

This is an old molecule that has been repurposed to make it more bioavailable in the brain. That is wonderful. But how does this compare in terms of efficacy and safety to the original molecule? And how does it compare to other available generic and branded medications in America? In countries where it has been available for a while, it is not particularly popular. That tells us a great deal about its potential challenges in commercializing in America.

The molecule itself is exciting from a scientific perspective! To make a drug more brain penetrating is a significant success, especially if it means that the side effects in the body are reduced, but I’m not quite sure how this will play out in the commercial world. That’s a pretty significant unknown.
This molecule is not a radically different one than many others in the class of atypicals. I am rather impressed with how they have tweaked the molecule! From a pharmacologic perspective, this is a significant advance. The hope I have is that this pharmacologic advance converts into clinical benefits, both in terms of efficacy and particularly in terms of tolerability. That is a big unknown. Atypicals are a very busy and packed class of medications with a large number of generics and branded medications. Any new entrance really will have to prove its worth, and at the moment, I’m not certain of this particular molecule in terms of its commercial success and viability.

Without further studies, particularly with active competitors, I do not see this drug having any significant commercial success in the United States.