Novel drug in pipeline for comorbid schizophrenia, substance abuse

HOLLYWOOD, FLA. – A novel agent early in development for the treatment of schizophrenia aims for an efficacy trifecta: the well-established potent antipsychotic benefits of olanzapine, but without the associated substantial weight gain, and with expanded utility in patients with comorbid substance abuse, according to Dr. Bernard L. Silverman.

The drug, known for now as ALKS 3831, is a fixed oral combination of olanzapine plus the opioid modulator ALKS 33, a centrally acting mu antagonist far more potent and bioavailable than naltrexone.

The appeal of this investigational medication stems from the fact that roughly 50% of all patients with schizophrenia have a comorbid substance abuse disorder. Substance abuse is the leading cause of medication noncompliance in schizophrenia. It is associated with more severe schizophrenia symptoms, an increased risk of relapse, more frequent and lengthier hospitalizations, and more violent episodes. A drug that simultaneously addresses both conditions in these dual-diagnosis patients would be most welcome, Dr. Silverman said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

"ALKS 33 has potential applicability in many reward disorders, including alcohol use disorders. There are no predicted adverse effects on olanzapine’s safety or efficacy, as there is no drug-drug pharmacokinetic interaction between the two, and their neurotransmitter profiles are distinct," explained Dr. Silverman of Alkermes, Waltham, Mass., which is developing the olanzapine/ALKS 33 combination.

He noted that in a phase II, company-sponsored, 12-week randomized clinical trial involving 406 patients with alcohol dependence in which comorbid schizophrenia was an exclusion criterion, a 41% reduction in heavy drinking days relative to placebo was seen in patients on ALKS 33 at 10 mg/day. A heavy drinking day was defined as five or more alcoholic drinks in a day for men and at least four in women.

"Extending such reductions in heavy drinking to subjects with schizophrenia would be expected to provide significant therapeutic benefit to dual-diagnosis patients," Dr. Silverman said.

He noted that in the landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, sponsored by the National Institute of Mental Health, olanzapine demonstrated efficacy superior to that of quetiapine, risperidone, ziprasidone, and perphenazine. However, olanzapine also had the highest dropout rate because of weight gain and metabolic side effects (N. Engl. J. Med. 2005;353:1209-23).

With animal studies showing diminished olanzapine-related weight gain with concomitant ALKS 33, Dr. Silverman and his coinvestigators conducted a phase I proof-of-concept study in 106 healthy young men with a baseline body mass index of 18-25 kg/m². Again, schizophrenia was a contraindication to study participation. Subjects were randomized to 3 weeks of olanzapine (Zyprexa) at 10 mg/day, olanzapine plus ALKS 33 at 5 mg/day, ALKS 33 alone, or placebo.

The group on olanzapine alone showed rapid weight gain, averaging 3.4 kg in just 3 weeks. In contrast, subjects on the olanzapine/ALKS 33 combination averaged a weight gain of 2.5 kg, nearly a full kilo less (P = .014). Participants on ALKS 33 alone and those on placebo had a similarly minimal change in body weight.

Adverse events were those typically seen with olanzapine therapy in schizophrenia. The most common were orthostatic hypotension and sleepiness, each of which was present in about 20% of subjects on olanzapine alone or the combination.

Moving beyond this proof-of-concept study, the investigators plan to conduct trials using olanzapine in combination with higher doses of ALKS 33 for longer time periods, and in patients with schizophrenia.

[email protected]

HOLLYWOOD, FLA. – A novel agent early in development for the treatment of schizophrenia aims for an efficacy trifecta: the well-established potent antipsychotic benefits of olanzapine, but without the associated substantial weight gain, and with expanded utility in patients with comorbid substance abuse, according to Dr. Bernard L. Silverman.

The drug, known for now as ALKS 3831, is a fixed oral combination of olanzapine plus the opioid modulator ALKS 33, a centrally acting mu antagonist far more potent and bioavailable than naltrexone.

The appeal of this investigational medication stems from the fact that roughly 50% of all patients with schizophrenia have a comorbid substance abuse disorder. Substance abuse is the leading cause of medication noncompliance in schizophrenia. It is associated with more severe schizophrenia symptoms, an increased risk of relapse, more frequent and lengthier hospitalizations, and more violent episodes. A drug that simultaneously addresses both conditions in these dual-diagnosis patients would be most welcome, Dr. Silverman said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

"ALKS 33 has potential applicability in many reward disorders, including alcohol use disorders. There are no predicted adverse effects on olanzapine’s safety or efficacy, as there is no drug-drug pharmacokinetic interaction between the two, and their neurotransmitter profiles are distinct," explained Dr. Silverman of Alkermes, Waltham, Mass., which is developing the olanzapine/ALKS 33 combination.

He noted that in a phase II, company-sponsored, 12-week randomized clinical trial involving 406 patients with alcohol dependence in which comorbid schizophrenia was an exclusion criterion, a 41% reduction in heavy drinking days relative to placebo was seen in patients on ALKS 33 at 10 mg/day. A heavy drinking day was defined as five or more alcoholic drinks in a day for men and at least four in women.

"Extending such reductions in heavy drinking to subjects with schizophrenia would be expected to provide significant therapeutic benefit to dual-diagnosis patients," Dr. Silverman said.

He noted that in the landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, sponsored by the National Institute of Mental Health, olanzapine demonstrated efficacy superior to that of quetiapine, risperidone, ziprasidone, and perphenazine. However, olanzapine also had the highest dropout rate because of weight gain and metabolic side effects (N. Engl. J. Med. 2005;353:1209-23).

With animal studies showing diminished olanzapine-related weight gain with concomitant ALKS 33, Dr. Silverman and his coinvestigators conducted a phase I proof-of-concept study in 106 healthy young men with a baseline body mass index of 18-25 kg/m². Again, schizophrenia was a contraindication to study participation. Subjects were randomized to 3 weeks of olanzapine (Zyprexa) at 10 mg/day, olanzapine plus ALKS 33 at 5 mg/day, ALKS 33 alone, or placebo.

The group on olanzapine alone showed rapid weight gain, averaging 3.4 kg in just 3 weeks. In contrast, subjects on the olanzapine/ALKS 33 combination averaged a weight gain of 2.5 kg, nearly a full kilo less (P = .014). Participants on ALKS 33 alone and those on placebo had a similarly minimal change in body weight.

Adverse events were those typically seen with olanzapine therapy in schizophrenia. The most common were orthostatic hypotension and sleepiness, each of which was present in about 20% of subjects on olanzapine alone or the combination.

Moving beyond this proof-of-concept study, the investigators plan to conduct trials using olanzapine in combination with higher doses of ALKS 33 for longer time periods, and in patients with schizophrenia.

[email protected]

HOLLYWOOD, FLA. – A novel agent early in development for the treatment of schizophrenia aims for an efficacy trifecta: the well-established potent antipsychotic benefits of olanzapine, but without the associated substantial weight gain, and with expanded utility in patients with comorbid substance abuse, according to Dr. Bernard L. Silverman.

The drug, known for now as ALKS 3831, is a fixed oral combination of olanzapine plus the opioid modulator ALKS 33, a centrally acting mu antagonist far more potent and bioavailable than naltrexone.

The appeal of this investigational medication stems from the fact that roughly 50% of all patients with schizophrenia have a comorbid substance abuse disorder. Substance abuse is the leading cause of medication noncompliance in schizophrenia. It is associated with more severe schizophrenia symptoms, an increased risk of relapse, more frequent and lengthier hospitalizations, and more violent episodes. A drug that simultaneously addresses both conditions in these dual-diagnosis patients would be most welcome, Dr. Silverman said at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

"ALKS 33 has potential applicability in many reward disorders, including alcohol use disorders. There are no predicted adverse effects on olanzapine’s safety or efficacy, as there is no drug-drug pharmacokinetic interaction between the two, and their neurotransmitter profiles are distinct," explained Dr. Silverman of Alkermes, Waltham, Mass., which is developing the olanzapine/ALKS 33 combination.

He noted that in a phase II, company-sponsored, 12-week randomized clinical trial involving 406 patients with alcohol dependence in which comorbid schizophrenia was an exclusion criterion, a 41% reduction in heavy drinking days relative to placebo was seen in patients on ALKS 33 at 10 mg/day. A heavy drinking day was defined as five or more alcoholic drinks in a day for men and at least four in women.

"Extending such reductions in heavy drinking to subjects with schizophrenia would be expected to provide significant therapeutic benefit to dual-diagnosis patients," Dr. Silverman said.

He noted that in the landmark Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, sponsored by the National Institute of Mental Health, olanzapine demonstrated efficacy superior to that of quetiapine, risperidone, ziprasidone, and perphenazine. However, olanzapine also had the highest dropout rate because of weight gain and metabolic side effects (N. Engl. J. Med. 2005;353:1209-23).

With animal studies showing diminished olanzapine-related weight gain with concomitant ALKS 33, Dr. Silverman and his coinvestigators conducted a phase I proof-of-concept study in 106 healthy young men with a baseline body mass index of 18-25 kg/m². Again, schizophrenia was a contraindication to study participation. Subjects were randomized to 3 weeks of olanzapine (Zyprexa) at 10 mg/day, olanzapine plus ALKS 33 at 5 mg/day, ALKS 33 alone, or placebo.

The group on olanzapine alone showed rapid weight gain, averaging 3.4 kg in just 3 weeks. In contrast, subjects on the olanzapine/ALKS 33 combination averaged a weight gain of 2.5 kg, nearly a full kilo less (P = .014). Participants on ALKS 33 alone and those on placebo had a similarly minimal change in body weight.

Adverse events were those typically seen with olanzapine therapy in schizophrenia. The most common were orthostatic hypotension and sleepiness, each of which was present in about 20% of subjects on olanzapine alone or the combination.

Moving beyond this proof-of-concept study, the investigators plan to conduct trials using olanzapine in combination with higher doses of ALKS 33 for longer time periods, and in patients with schizophrenia.

[email protected]