Introduction
The results of a long-term study of KarXT(Cobenfy) were recently published, and I thought the long-term efficacy of KarXT was quite high.
There has been some concern about whether the efficacy of muscarinic agonists would be sustained over the long term. With the confirmation of the long-term efficacy of KarXT, this concern has been largely allayed.
This article will compare the long-term efficacy of KarXT with that of other antipsychotics. After that, we will present the published data on side effects.
Long-Term Efficacy
The long-term efficacy of KarXT was measured by PANSS (Positive and Negative Symptom Scale) scores; the higher the PANSS score, the more severe the schizophrenia.
Efficacy was measured by how much patients’ mean score decreased after receiving KarXT.
It is not published how much the KarXT-treated patient group had scored just prior to the long-term study. However, we made our own estimate. We found an average score of 81.
After one year of treatment, the average score was 65.1. So, KarXT improved schizophrenia symptoms by about 16 points on average.
| Before the long-term study of KarXT | After a long-term study of KarXT | Improvement in schizophrenia severity | |
| PANSS score | ８１points | ６５points | -１６points |
In general, the severity of schizophrenia is rated by the PANSS score as follows
Normal 30-58
Mild 58-75
Moderate 75-95
Severe 95-116
Extremely severe 116-210
Patients treated with KarXT had an average score of 81 just before the long-term study. Symptoms were moderate.
After the long-term study (one year), the average score was 65. They were mild severity on average.
The improvement of 16 PANSS scores is a large number compared to other drugs.The table below shows the results of long-term trials of other antipsychotics, to the best of our knowledge. This is a very rough approximation.
| PANSS score before long-term study | PANSS score after long-term study | Improvement in schizophrenia severity | |
| Rexulti | ８３ | ６５ | -１８ |
| KarXT | ８１ | ６５ | -１６ |
| Invega | ９１ | ７７ | -１４ |
| Blonanserin | ６８ | ５７ | -１１ |
| Asenapine | ７１ | ６４ | -７ |
We will start with the drug at the top of the table. For patients who have settled down to a moderate level of symptoms, Rexulti works quite well. It improves the score by 18 points.
KarXT works about as well as Rexulti, improving by 16 points.
In the case of Invega, the score before the long-term dosing study was 91 points. Invega was administered to patients who nearly had severe symptoms. In patients with more severe symptoms, PANSS scores tend to decrease easily.
The improvement of 14 points with Invega was a fairly large effect. However, after one year of treatment with Invega, the patients still had a score of 77 points(moderate), which are not enough to cure the symptoms.
Conversely, the Blonanserin and Asenapine-treated patients have lower scores(mild) before the long-term treatment study, so their scores are less likely to decrease. Blonanserin improved by 11 points, while Asenapine improved by 7 points.
With the use of Blonanserin, the score was restored to 57 points (normal), which we would say was a significant effect.
We compared the long-term efficacy of KarXT with several medications; KarXT improved the score by 16 points. KarXT also reduced the score to 65 points. Based on those scores, I think it is safe to say that KarXT is highly effective.
Of course, long-term trials are not RCTs (randomized controlled trials), nor are they meta-analyses, so they are weak evidence of efficacy. But, to put it mildly, I think KarXT has more than average long-term efficacy.
Side Effects
In this section, I write about the side effects of KarXT in long-term dosing studies. First, it is important to note that weight gain, extrapyramidal symptoms, and hyperprolactinemia were few.
Weight Gain
On average, there was a 2.6 kg weight loss in the KarXT-treated patients. I have said before that Ulotaront is associated with more weight loss than KarXT.
But in the long term, KarXT has more weight loss than Ulotaront. Ulotaront had an average weight loss of 0.3 kg over six months.
KarXT has an average weight loss of 2.6 kg per year. 65% of patients treated with KarXT lost weight.
KarXT is virtually free of extrapyramidal symptoms and hyperprolactinemia. Long-term weight loss occurs more than with Ulotaront.
Common Side Effects
The most common side effects, occurring in more than 5% of patients, are nausea, vomiting, constipation, dry mouth, dyspepsia, dizziness, hypertension, and diarrhea.
As expected, digestive side effects are common. However, nearly all were mild or moderate in severity and transient in nature.
Incidence of Side Effects
62% of patients experienced some kind of side effect. We do not know if 62% incidence of side effects in one year is a lot.
In the case of Ulotaront, the side effect rate was 56.4% in six months. The most common side effects for Ulotaront are schizophrenia, headache, insomnia, anxiety, and so on.
In the long term, KarXT might have about the same side effect incidence as Ulotaront. I don’t think it is less than average.
KarXT seems to be prone to side effects, mainly digestive ones, even in the long term.
Discontinuation Rate
In the long-term study, 53% of patients discontinued KarXT. There were some reasons for discontinuation: treatment-related adverse events, withdrawn consent, participant lost to follow-up, etc.
I am not sure if 53% is a large number. This level of discontinuation might occur after one year of treatment.
The number of patients who discontinued due to side effects is 15%. Therefore, I do not think that a large number of patients discontinued due to gastrointestinal side effects.
The number of patients who discontinued dosing due to side effects is not extremely large. The digestive side effects may not be as severe as they are said to be.
Conclusion
- The long-term efficacy of KarXT is in the high category when looking at the data.
- Extrapyramidal symptoms are virtually non-existent.
- Patients on KarXT lose an average of 2.6 kg of body weight per year; 65% of patients lose weight. Long-term weight loss occurs more than with Ulotaront.
- The incidence of side effects, mainly gastrointestinal ones, is not low.
- The severity of gastrointestinal side effects is not as severe. It does not appear to cause many patients to discontinue dosing.
Comment
I have seen several people concerned about the long term sustainability of the efficacy of KarXT. I was a little concerned myself. I am relieved to see that the results were mostly favorable this time.
The long-term efficacy of other muscarinic agonists such as emraclidine and NBI-1117568 will probably be fine.They have no gastrointestinal side effects and I would like to keep an eye on them.
Related links are here.
There is an article summarizing KarXT(Cobenfy).
Five Advantages of Taking KarXT (Cobenfy)/ A Summary Article for Beginners
Positive and Negative Syndrome Scale(PANSS, Scale used to measure efficacy)
Innovative Schizophrenia Drugs【Summary part 1】Muscarinic Agonists
Overview of【KarXT】High efficacy, Little Weight Gain & Few EPS
EMERGENT-1【KarXT】Efficacy Compared to Current Drugs in Phase 2
EMERGENT-2【KarXT】Efficacy Compared to Current Drugs in Phase3
EMERGENT-3【KarXT】Efficacy Compared to Current Drugs in Phase3
References
- https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-New-Interim-Long-Term-Efficacy-Data-from-the-EMERGENT-4-Trial-Evaluating-KarXT-in-Schizophrenia-at-the-2024-Annual-Congress-of-the-Schizophrenia-International-Research-Society/default.aspx
- https://news.bms.com/news/corporate-financial/2024/Bristol-Myers-Squibb-Presents-New-Pooled-Interim-Long-Term-Safety-and-Metabolic-Outcomes-Data-from-the-EMERGENT-Program-Evaluating-KarXT-in-Schizophrenia-at-the-2024-Annual-Congress-of-the-Schizophrenia-International-Research-Society/default.aspx
コメント