Olanzapine Long-Acting Injection (LAI) Shown to Maintain Treatment Benefit in Schizophrenia...

Olanzapine Long-Acting Injection (LAI) Shown to Maintain Treatment Benefit in
Schizophrenia for up to Six Months

BARCELONA, Spain, Sept. 2 /PRNewswire-FirstCall/ -- Final results from a
24-week study presented today at a major medical meeting in Barcelona suggest
that investigational olanzapine long-acting injection (LAI) therapeutic doses
showed a maintenance of treatment benefit for up to six months. A review of
pooled safety data from all olanzapine LAI clinical trials was also presented
at the meeting.
Olanzapine LAI is an investigational formulation that combines Zyprexa(R)
(olanzapine), an atypical antipsychotic, with pamoic acid resulting in a salt
that sustains the delivery of olanzapine for a period of up to four weeks.
Long-acting injectable antipsychotics have been associated with improved
treatment of schizophrenia in patients who have difficulty adhering to daily
treatment regimens.(1)
"These studies offer insight into the role olanzapine LAI may play in the
treatment of patients with schizophrenia who have benefited from olanzapine
but continue to struggle with adherence," said David McDonnell, M.D., clinical
research physician at Lilly. "If approved, olanzapine LAI could be a valuable
treatment option due to the chronic and severe nature of schizophrenia,
persistent challenges with adherence and the limited number of available depot
formulations."
Independent regulatory reviews of olanzapine LAI applications are ongoing
in the European Union, Canada, Australia and United States. Olanzapine LAI is
currently being reviewed by CHMP and submission to regulators to obtain
country-specific marketing approval is dependent upon a CHMP opinion.
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 with 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, 300 mg every two weeks or 405 mg every four weeks), to a
low reference dose of olanzapine LAI (45 mg every four weeks), or remained on
oral olanzapine at their previously stabilized dose. No supplementation with
oral antipsychotics was permitted during the study.
An assessment of clinical stability was based on change in oral olanzapine
dose as well as standard measures including Clinical Global Impressions-
Improvement of Illness (CGI-I) and Brief Psychiatric Rating Scale (BPRS)
scales. Symptom severity was assessed using the Positive and Negative Syndrome
(PANSS), PANSS-derived BPRS, and the Clinical Global Impressions-Severity of
Illness (CGI-S) and CGI-I scales.
Therapeutic doses of olanzapine LAI were shown to provide positive
maintenance of treatment for up to six months. Mean baseline-to-endpoint
changes in PANSS total scores for patients treated with therapeutic olanzapine
LAI doses (150 mg every 2 weeks, 300 mg every 2 weeks and 405 mg every 4
weeks) differed significantly from those treated with the reference dose
(respectively, 2.7, -2.2, -0.1, vs. 7.3; all p<.001). Significant separation
in PANSS total scores was seen between the therapeutic doses (150 mg/two
weeks, 300 mg/two weeks, 405 mg/four weeks) versus the reference dose (45
mg/four weeks) starting at 11, three, and two weeks, respectively, and
maintained throughout the study (p<.05).
Similar differences between therapeutic and reference olanzapine LAI doses
were observed for the BPRS total, CGI-I, and CGI-S scores. Mean baseline-to-
endpoint change in PANSS total score for the oral olanzapine group (-1.7) did
not differ significantly from that of the highest olanzapine LAI dose group
(-2.2, 300 mg/2 weeks; p=0.606) but was greater than the other olanzapine LAI
doses (p<0.01).
The safety profile for olanzapine LAI was consistent with that of oral
olanzapine except for injection-related events. The rate of discontinuation
was low over six months of treatment. Incidence of weight gain of 7 percent or
more from baseline was significantly higher for patients treated with oral
olanzapine (21.4 percent), olanzapine LAI 150 mg every two weeks (16.4
percent), olanzapine LAI 300 mg every two weeks (20.7 percent) and olanzapine
LAI 405 mg every four weeks (15.2 percent) when compared with patients treated
with olanzapine LAI 45 mg every 4 weeks (8.3 percent, all p less than or equal
to .05). The incidence of all injection site reactions, including injection
pain, was 2.8 percent. 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
Olanzapine LAI Post-Injection Syndrome, which includes a range of symptoms of
sedation (ranging from mild in severity to unconsciousness) and/or delirium
(including confusion, disorientation, agitation, anxiety and other cognitive
impairment). Other symptoms include extrapyramidal symptoms, dysarthria,
ataxia, aggression, dizziness, weakness, hypertension and convulsion.
Earlier this year, data pertaining to the study's primary relapse endpoint
was disclosed at the Schizophrenia International Research Society (SIRS)
Conference. These data showed that patients treated with all three higher
doses of olanzapine LAI had longer time to symptom exacerbation than patients
who received the reference dose and that the four-week 405 mg and the pooled
two-week dosing regimens showed non inferiority when compared to oral
olanzapine and to each other.
About Olanzapine LAI Post-Injection Syndrome Analysis
As with all medications, there are risks associated with the use of long-
acting injections. Across all olanzapine LAI clinical trials, olanzapine LAI
showed a similar safety profile as the oral formulation except for injection-
related events, including Olanzapine LAI Post-Injection Syndrome.
The purpose of this analysis was to review the Olanzapine LAI Post-
Injection Syndrome cases observed in olanzapine LAI clinical trials to
determine appropriate recommendations for risk and medical management. Safety
data were pooled from all completed and ongoing olanzapine LAI clinical trials
through 30 September 2007; adverse event data through 31 May 2008 were also
reviewed.
As of 31 May 2008, the incidence of Olanzapine LAI Post-Injection Syndrome
following administration of olanzapine LAI was 29 cases (in 28 patients) after
more than 40,000 injections, yielding a per-injection rate of 0.07 percent and
a per-patient rate of 1.4 per cent - or approximately one event per 1,400
injections. No clinically significant decreases in vital signs were observed
and all patients recovered completely from signs and symptoms of Olanzapine
LAI Post-Injection Syndrome within 1.5 to 72 hours. Approximately 70 percent
of patients continued to receive injections after the event. The cumulative
risk of experiencing an Olanzapine LAI Post-Injection Syndrome event after one
year of treatment was 0.7 to 1.2 percent. (These data were presented as a
range due to variable injection intervals).
Across all clinical trials, as of 31 July, no additional cases of
Olanzapine LAI Post-Injection Syndrome were reported.
Based on the extensive review of pooled safety data from all olanzapine
LAI clinical trials and given that awareness and recognition of these events
are key aspects of identifying them and minimizing associated symptoms, Lilly
has proposed a comprehensive plan for managing Olanzapine LAI Post-Injection
Syndrome risks that includes a detailed product label including a post-
injection observation period and an extensive healthcare provider training and
educational program.
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.(2)
Long-acting antipsychotic formulations have been associated with improved
treatment adherence and reduced treatment failures.(3) 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.(4) 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.(5)
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.(6) In addition to
these symptoms, patients with schizophrenia are at greater risk for medical
comorbidities than the general population.
About Olanzapine
Since olanzapine was introduced in 1996, it has been prescribed to
approximately 24 million people worldwide. Olanzapine is not recommended for
use in patients under 18 years of age.
In Europe, olanzapine is indicated for schizophrenia and in clinical
trials, it has shown to be effective in maintaining the clinical improvement
during continuation therapy in patients who have shown an initial treatment
response. It is also indicated for the treatment of moderate to severe manic
episodes and, in those patients whose manic episode has responded to
olanzapine treatment, it is indicated for the prevention of recurrence in
patients with bipolar disorder.
SAFETY INFORMATION
Hyperglycaemia and/or development or exacerbation of diabetes occasionally
associated with ketoacidosis or coma has been reported rarely, including some
fatal cases. In some cases, a prior increase in body weight has been reported,
which may be a predisposing factor. Appropriate clinical monitoring is
advisable, particularly in diabetic patients and in patients with risk factors
for diabetes mellitus for which regular glucose control is recommended.
Undesirable alterations in lipids have been observed in olanzapine-treated
patients in placebo-controlled clinical trials. Mean increases in fasting
lipid values (total cholesterol, LDL cholesterol, and triglycerides) were
greater in patients without evidence of lipid dysregulation at baseline. Lipid
alterations should be managed as clinically appropriate, particularly in
dyslipidemic patients and in patients with risk factors for the development of
lipids disorders.
The proportion of patients who had adverse, clinically significant changes
in weight gain, glucose, total/LDL/HDL cholesterol or triglycerides increased
over time. In adult patients who completed 9-12 months of therapy, the rate of
increase in mean blood glucose slowed after approximately 4-6 months.
As with all antipsychotic medications, a rare and potentially fatal
condition known as Neuroleptic Malignant Syndrome (NMS) has been reported
rarely 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 increases as the duration of treatment. If signs and symptoms of
TD are observed a dose reduction or discontinuation should be considered and
it should be noted that the symptoms can temporally deteriorate or even rise
after discontinuation.
Other potentially serious adverse events include low blood pressure,
seizures, elevated prolactin levels, elevated liver enzymes, thromobembolism,
neutopenia, sweating, insomnia, tremor, anxiety, nausea, or vomiting.
Olanzapine should not be used in patients who have a hypersensitivity to
the drug nor those with narrow angle glaucoma. It should not be used to treat
dementia-related psychosis and/or behavioural disturbances because of an
observed increase in death and cerebrovascular accident. It should also not be
used in the treatment of dopamine agonist associated psychosis in patients
with Parkinson's disease.
The most frequently (seen in greater than or equal to 1% of patients)
reported adverse reactions associated with the use of olanzapine in clinical
trials were somnolence, weight gain, eosinophilia, elevated prolactin,
cholesterol, glucose and triglyceride levels, glucosuria, increased appetite,
dizziness, akathisia, parkinsonism, dyskinesia, orthostatic hypotension,
anticholinergic effects, transient asymptomatic elevations of hepatic
transaminases, rash, asthenia, fatigue and oedema.
About Lilly
Lilly, 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 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.
(1) 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.
(2) 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
(3) 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.
(4) 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.
(5) 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.
(6) American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders, fourth edition, 2000, pp. 298.
(Logo: http://www.newscom.com/cgi-bin/prnh/20031219/LLYLOGO )
SOURCE Eli Lilly and Company

Charlie McAtee, +1-317-997-1627 (mobile), +1-317-277-1566,
mcatee_charles@lilly.com, or David Shaffer, +1-317-614-5106 (mobile),
+1-317-651-3710, shaffer_david@lilly.com, both of Eli Lilly and Company