The story of cariprazine
Interview with the developers

Zsófia Borbála Dombi
Hello everyone, and welcome to the Schizophrenia Awareness Week series!
It is a well-known fact that it takes several decades to develop a new medication from a single molecule. Indeed, this was not different in the case of cariprazine either.
As the last piece of our Schizophrenia Awareness Week series, we asked Doctor István Greiner, Director of Research and Development at Gedeon Richter Plc. about the story behind cariprazine, a third-generation antipsychotic that became the go-to medication for many psychiatrists who want to treat their schizophrenia patients for negative symptoms and more.
So, thank you again for accepting our invitation. My first question would be: when and how was the idea of cariprazine born?

Doctor István Greiner
Thank you for the question and approaching me.
If you are ready to travel back in time for around or even more than 20 years, then I can answer the question. So, all the story started before the millennium in the last century - the previous century - when certain pharmacologists had an idea that D3 receptor has role in the brain, an important role, maybe on the field of psychosis. And then they, here at Gedeon Richter and in several other companies, made a lot of investigations about this receptor. We did a compound selection for D3 receptor only, we synthesized hundreds of compounds and we found that the compound, which was acceptably good on D3 receptor only, had no effect on the antipsychotic pharmacological test.
So, we decided that since this antipsychotic effect was missing, we should kill the project. Nevertheless, we made one more experiment where we found that if we mix the D2 and the D3 receptors (the selective D3 receptor compound with the D2 receptor compound), then the side effect profile of the animal was much better. To be honest, what we saw that the size of the spike was much less than using only D2 active compound.
So finally, we decided that we were looking for a compound, which has a D3-D2 ratio around 10, and most probably we thought that this one will be a compound which in human, later on, will generate a less side effects than the traditional antipsychotic at that time - I'm talking about early 2000s. So that was the idea behind, and for this purpose, we synthesized more than 2000 compounds even using the pulmonary chemistry, very famous approach at that time, while we finally found the best one not only for the efficacy point of view, but definitely it was good for other pharmacokinetic parameters and so on and so on, which is needed for a drug. So that was the short story of cariprazine.

Zsófia Borbála Dombi
Thank you. And what were the biggest obstacles during the development of cariprazine?

Doctor István Greiner
When we found that cariprazine has a different metabolic profile in humans than what we saw previously in animals, we thought that it's a benefit and, honestly speaking, it is. But unfortunately, we were the only one with our partner, who thought that it is a benefit, as the FDA at the first-round investigation of the compound found that this long half-life has some risk for the patients. So, we finally got a so-called complete response letter from FDA to investigate a little bit more what will be the fate of this long half-life metabolite in human. And then when we asked this question, which was heavy activity on our side and on our partner’s side, it was around one and a half year when we found final result. And after having the final result, we refilled the documentation to the FDA (the US authority for drugs). And that was the successful filing because in 2015, finally, the FDA approved the compound. So, what I can say is that the biggest obstacle is one of the biggest benefit of the compound at the same time.

Zsófia Borbála Dombi
Great. Thank you. As you already mentioned, cariprazine has the highest dopamine D3 receptor affinity among the currently available antipsychotics. What clinical implications does this have and how intentional was to focus on this receptor specifically? You actually touched a bit on that already.
Doctor István Greiner
Definitely. I wish I could answer this question. Unfortunately, I can give you an answer, but it's not a clear one and it's not justified from every point of view, from every aspect.
What we see is that the clinical trials, the experiences and some feedbacks from the market show that we have a definitive improvement in negative symptoms with the use cariprazine. We have a very nice clinical trial about this, comparing cariprazine to one of the competitor products. It is very important that we made some analyses regarding all the clinical tests, and we found some kind of improvement on the cognitive symptoms as well, which is also very important. As we thought before, the side effect profile of cariprazine is better than a pure D2 agonist compound.
So, honestly speaking, we were right when we started this development, but of course we found some new information, some new data, which gives us a little bit more confidence on the usefulness of this compound, in the negative symptoms of psychiatric patients.
Also, it is important to mention that this compound is not just an antipsychotic. Now it has a couple of indications, and we hope so that it will improve further - I mean, in the number of indications. And it is very important because I think that so wide efficacy of this compound can be regarded to the D3 efficacy as well. Not only to D2, because there is no compound on the market, which could show this very, very wide range of indications where it is efficacious. And of course, this compound is safest one.

Zsófia Borbála Dombi
Yes. Thank you. And based on that, what do you think is the most unique characteristic of cariprazine that differentiates it from other medications? So, would you say the D3 or the long half-life or the metabolic side effect profile?

Doctor István Greiner
I have a list of it.
I don’t know how long the duration of this interview is, but definitely, I have to emphasize that we have a compound which has a high benefit on negative symptoms. That's important.
Also, the long half-life, which was - as mentioned earlier - an obstacle, now it is clearly seen that it has a benefit because in case of not taking the pill in one day, there is still an effect in the brain for a longer period of time. There is no chance that any kind of problem will arise if one pill-taking is missed.
So, I think the long half-life, the benefit on negative symptom, the improved side effect profile is important.

Zsófia Borbála Dombi
Thank you. And so, my final question would be: did you imagine such success for cariprazine and why? Also, if we can touch on that, how do you see the future of cariprazine? if this can be shared with our doctors.

Doctor István Greiner
Okay. I like these questions!
So no, definitely no. We were not able at that time to imagine a success like this one. Please bear in mind that it is a Hungarian company, which was a mid-size company, even at that time around the 60th or 70th in the rank of the top companies.
But we definitely investigated all of our options, how we can increase the chance of success. And also, we have to mention here that the company had no big knowledge on the antipsychotic market in the United States at that time. So, we saw the sales data and we hoped that we can reach some hundreds of millions of US dollars, but finally, we were very happy to see that it is a much better compound that we ever imagined.
Of course, I could say that we knew everything at that time, but it is not true. Definitely. It was not the reality. So that's the reason.
And what is about the future…
All of us may be aware about the fact that cariprazine is now applying for a new indication by the FDA. It is currently under evaluation, and we hope that at the very end of this year, or early next year, we will get the answer from the FDA, that this compound will also be good in this new indication.
And as a new indication is coming to the picture, it means that of course the sales will increase. And I think that cariprazine will be even more successful in the future than today.
Just one very short comment…Recently there was a release of a table, which describes the top 200 pharmaceutical compounds based on the sales of compounds and cariprazine was exactly the 100th of these compounds, which is a very big success, not only for this company and not only for the partner company in the US, but it is also a success for the patients because this number means that the compound is very successful in giving a better life chance for the patients.

Zsófia Borbála Dombi
Great. I think this is the best time to finish this interview. So, thank you again for accepting our invitation.

Doctor István Greiner
Thank you very much. Thank you for asking. My pleasure.