Olanzapine Long-Acting Injection (LAI) Data Presented at First Annual Schizophrenia International Research Society Conference

23 Jun 2008

VENICE--23 Jun--PRNewswire-AsiaNet/InfoQuest


Efficacy and safety data were generally consistent with oral olanzapine with the exception of injection-related events

Results from olanzapine long-acting injection (LAI) clinical trials showed that the efficacy and safety profile of olanzapine LAI was generally consistent with that of Zyprexa(R) (olanzapine) with the exception of injection-related events. Results from a 24-week maintenance study (HGKA) and interim findings from an ongoing open-label study (HGKB) were presented at the first annual

Schizophrenia International Research Society (SIRS) Conference in Venice, Italy.

Olanzapine LAI is an investigational formulation that combines olanzapine with a pamoate salt, resulting in an extended delivery of up to four weeks. Since olanzapine was introduced in 1996, it has been prescribed to approximately 24 million people worldwide.

"These studies offer insight into the potential of olanzapine LAI as a maintenance treatment for patients with schizophrenia who may have difficulty taking medication on a daily basis," said David McDonnell, M.D., clinical research physician at Lilly. "Schizophrenia is a challenging and complex disease to manage, which is why finding new ways to support patient compliance

with medication is so important."

Regulatory reviews of olanzapine LAI applications are ongoing in the European Union, Canada, Australia and United States.


Notes for editors:


About HGKA (24-week maintenance of effect study)

In this 24-week double-blind maintenance study, a total of 1,065 adult outpatients with schizophrenia who had been stabilized previously on open-label oral olanzapine (10, 15, or 20 mg daily) for four to eight weeks were randomized to one of three therapeutic dosing regimens of olanzapine LAI (150 mg every two weeks, 405 mg every four weeks, or 300 mg every two weeks),

or to a low reference dose of olanzapine LAI (45 mg every four weeks), or remained on oral olanzapine at their previously stabilized dose.

At the three higher doses, olanzapine LAI showed maintenance of treatment effect for schizophrenia for up to 24 weeks. Patients remained free of symptom exacerbation (relapse), as assessed by the Brief Psychiatric Rating Scale (BPRS), at a rate of 95 percent with 300 mg/two weeks, 90 percent with 405 mg/four weeks, and 84 percent with 150 mg/two weeks of olanzapine LAI.

Comparatively, 93 percent of patients receiving oral olanzapine remained free of symptom exacerbation during the study. The 405 mg/four weeks and the pooled two-week dosing regimens showed non-inferiority when compared to oral olanzapine as well as to each other. All three higher olanzapine LAI doses had longer time to symptom exacerbation than the reference dose (all p<.01).

The safety profile for olanzapine LAI was consistent with that of oral olanzapine except for injection-related events. Incidence of weight gain of 7 percent or more from baseline was significantly higher for oral olanzapine (21.4 percent), olanzapine LAI 300 mg/two weeks (20.7 percent), olanzapine LAI 405 mg/four weeks (15.2 percent) and olanzapine LAI 150 mg/two weeks

(16.4 percent) when compared with olanzapine LAI 45 mg/4 weeks (8.3 percent, all p less than or equal to .05). Adverse events reported in 5 percent or more of patients were insomnia, weight increase, anxiety, nasopharyngitis, somnolence and headache.

In HGKA, two patients experienced and recovered fully from Post-Injection Delirium/Sedation Syndrome (PDSS), which describes a range of signs and symptoms such as sedation, delirium, dizziness, confusion, disorientation, slurred speech and altered gait.

Across all olanzapine LAI clinical trials, PDSS events have been seen in 0.07 percent of injections and 1.4 percent of patients. As of 31 May, 2008, 29 events have been reported in 28 patients, all of whom have recovered fully. Given that awareness and recognition of these events are key aspects of identifying and minimizing them, Lilly has proposed a plan for managing PDSS

risks that is comprised of a detailed product label, extensive healthcare provider training before product availability and an ongoing educational program.

About HGKB (160-week Interim Results of Open-label Extension Trial)

Adult patients with schizophrenia or schizoaffective disorder (n=931) were enrolled in this ongoing open-label trial of olanzapine LAI following participation in one of three randomized, controlled studies of olanzapine LAI. At study onset, patients received flexibly-dosed olanzapine LAI at intervals of approximately two to four weeks.

At the time of analysis, all patients had had the opportunity to be in the study for at least one year of open-label treatment; some had been enrolled for up to three years of treatment.

Treatment response was measured by the Clinical Global Impression Severity of Illness (CGI-S) scale, which examined severity of illness, global improvement and efficacy. Baseline-to-endpoint mean change on the CGI-S was -0.16, from a baseline of 2.92.

At 160 weeks, the discontinuation rate was low (39.6 percent). The most common reasons for discontinuation were that a patient withdrew consent (20.1 percent), experienced an adverse event (6.3 percent) or was lost to follow up (5.6 percent).


Adverse events reported in 5 percent or more of patients were increased weight, insomnia, somnolence, anxiety, headache, and nasopharyngitis. The mean weight change of study participants was an increase of 1.4 kilograms, with 28.1 percent of patients experiencing an increase of 7 percent or more in weight.

The percentage of patients with a fasting glucose increase from normal to high at any time was 4.7 percent. The percentage of patients with a random total cholesterol increase from normal to high at any time was 5.2 percent. The percentage of patients with a random triglycerides increase from normal to high at any time was 11.9 percent.


At the time of the interim analysis of HGKB, 23 PDSS events were reported in 22 patients. Between 30 September, 2007 and 31 May, 2008, four additional events have been reported in this ongoing trial.


About Long-acting Injectable Antipsychotic Medications

The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines state that poor or partial treatment compliance is a major problem in the long-term treatment of schizophrenia. Depot formulations should be considered as a treatment option when a patient expresses a preference for such treatment due to convenience or if it is determined that a depot formulation is necessary to help avoid nonadherence to oral medications.(i)

Long-acting antipsychotic formulations have been associated with improved treatment adherence and reduced treatment failures.(ii) By administering long-acting medications, healthcare professionals know when patients have received their medication and can immediately detect non-adherence when a patient fails to return for a scheduled injection.(iii) Different from both

oral and injected short-acting formulations, long-acting formulations of antipsychotics allow for stable concentrations of the active drug to remain at a therapeutic range for an extended period of time.(iv)

About Schizophrenia

Schizophrenia is a severe and debilitating illness with symptoms such as delusions (false beliefs that cannot be corrected by reason), hallucinations (usually in the form of non-existent voices or visions), disorganized speech and severe disorganized or catatonic behavior. These signs and symptoms are associated with marked social or occupational dysfunction. Features of

schizophrenia consist of characteristic signs and symptoms that have been present for a significant portion of time during a one-month period, with some signs of the disorder persisting for at least six months.(v) In addition to these symptoms, patients with schizophrenia are at greater risk for medical comorbidities than the general population.

About Olanzapine

Olanzapine is indicated in the United States for the treatment of schizophrenia, acute mixed and manic episodes of bipolar disorder, and maintenance treatment of bipolar disorder. In Europe, olanzapine is indicated for the treatment of schizophrenia and olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response. Olanzapine is also indicated in patients whose manic episode has responded to olanzapine treatment and it is indicated for the prevention of recurrence in patients with bipolar disorder.

Since olanzapine was introduced in 1996, it has been prescribed to approximately 24 million people worldwide. Olanzapine is not approved for patients under 18 years of age.

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including olanzapine. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics. Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or who have borderline increased blood glucose level. Patients taking olanzapine should be monitored regularly for worsening of glucose control. Persons with risk factors for diabetes who are starting on atypical antipsychotics should undergo baseline and periodic fasting blood glucose testing. Patients who

develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing.

Undesirable alterations in lipids have been observed with olanzapine use. Clinical monitoring, including baseline and follow-up lipid evaluations in patients using olanzapine, is advised. Significant, and sometimes very high, elevations in triglyceride levels have been observed with olanzapine use.

Potential consequences of weight gain should be considered prior to starting olanzapine. Patients receiving olanzapine should receive regular monitoring of weight.

As with all antipsychotic medications, a rare and potentially fatal condition known as Neuroleptic Malignant Syndrome (NMS) has been reported with olanzapine. If signs and symptoms appear, immediate discontinuation is recommended. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

Also, as with all antipsychotic treatment, prescribing should be consistent with the need to minimize Tardive Dyskinesia (TD). The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Other potentially serious adverse events include low blood pressure, seizures, elevated prolactin levels, elevated liver enzymes, cognitive and motor impairment, body temperature elevation, and trouble swallowing.

The most common treatment-emergent adverse event associated with Zyprexa in placebo-controlled, short-term schizophrenia and bipolar mania trials was somnolence. Other common events were dizziness, weight gain, personality disorder (COSTART term for nonaggressive objectionable behavior), constipation, akathisia, postural hypotension, dry mouth, asthenia, dyspepsia, increased appetite and tremor.


About Lilly

Lilly (NYSE: LLY), a leading innovation-driven corporation, is developing a growing portfolio of first-in-class and best-in-class pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers -- through medicines and information -- for some of the world's most urgent medical needs. Additional information about Lilly is available at http://www.lilly.co.uk .


P-LLY


This press release contains forward-looking statements about the safety and efficacy of olanzapine long acting injection (LAI) and reflects Lilly's current beliefs. However, as with any investigational pharmaceutical product, there are substantial risks and uncertainties in the process of research, development, regulatory milestones and commercialization. There is no guarantee that olanzapine LAI will be approved for the treatment of schizophrenia or that if approved, it will be commercially successful. For

further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

(i) Falkai P., Wobrock T., Lieberman J., Glenthoj B.,Gattaz W.F., Moller
H.J & Wfsbp Task Force On Treatment Guidelines For Schizophrenia. The
World Journal of Biological Psychiatry, 2006; 7(1): 5/40.
(ii) Maxine X. Patel and Anthony S. David. Why aren't depot
antipsychotics prescribed more often and what can be done about it?
Advances in Psychiatric Treatment (2005) 11: 203-211.
(iii) Kane J.M et al. Guidelines for depot antipsychotic treatment in
schizophrenia. European Neuropsychopharmacology, Volume 8, Number 1,
1 February 1998, pp. 55-66(12). p. 58.
(iv) Maxine X. Patel and Anthony S. David. Why aren't depot
antipsychotics prescribed more often and what can be done about it?
Advances in Psychiatric Treatment (2005) 11: 203-211.
(v) American Psychiatric Association. Diagnostic and Statistical Manual
of Mental Disorders, forth edition, 2000, pp. 298.

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SOURCE: Eli Lilly and Company


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[email protected], or


David Shaffer,

+1-317-651-3710, +1-317-614-5106, Mobile,

[email protected]


both of Eli Lilly and Company


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