- Primary efficacy endpoint not achieved in overall
study
- ELND005 significantly (p value < .05) improved agitation
and aggression in a
sub-population of Alzheimer's disease patients with severe
agitation and aggression
- In this population, ELND005 demonstrated numerical
improvement in
20 of 21 symptoms measured as part of primary efficacy
endpoint
- ELND005 demonstrated acceptable safety and tolerability
profile
- Company intends to meet with regulators to seek guidance on
ELND005 Phase 3 program for AD patients with severe agitation and
aggression
TORONTO, Oct. 15, 2015 /CNW/ - Transition
Therapeutics Inc. ("Transition" or the "Company") (NASDAQ:
TTHI, TSX: TTH) announced that its subsidiary, Transition
Therapeutics Ireland Limited ("TTIL"), has completed a thorough
review of the data related to the Phase 2/3 study of ELND005 in
Alzheimer's disease ("AD") patients with moderate or severe
agitation and aggression. The analysis identified a significant
clinical benefit of ELND005 in AD patients with severe agitation
and aggression, and will serve as the basis for patient selection
in a Phase 3 clinical study. The review was performed in
consultation with a group of key opinion leaders in the field of
neuropsychiatry.
"This study was originally designed as a Phase 2 study, and
viewed from that perspective, it has provided TTIL with important
data to select a patient population, effectively screen for these
patients in a clinical setting and identify a dosing regimen with
acceptable safety and tolerability. The next step will be to
share these findings with regulators to discuss an ELND005 Phase 3
program in AD patients with severe agitation and aggression," said
Dr. Tony Cruz, Chairman and Chief
Executive Officer of Transition. "We believe that the overall data
generated in this Phase 2/3 study support the clinical advancement
of ELND005 into a Phase 3 clinical study and will aid us in the
identification of a target AD patient population with severe
agitation and aggression."
Anton P. Porsteinsson, M.D., Professor of Psychiatry at the
University of Rochester School of Medicine and
Dentistry and one of the investigators on the Phase 2/3
study commented, "Agitation and Aggression are a major cause of
distress and disease burden in Alzheimer's Disease. It is
critically important to find safe and well tolerated treatments for
these behavioral disruptions. Whereas non-pharmacological
interventions should always be first line treatments, they are less
likely to be adequate for those with more severe agitation and
aggression, thus necessitating the use of medications.
Currently, there are no FDA approved pharmacological treatments for
this indication and the medications used by default lack consistent
evidence of benefit but are well known to cause dangerous and
troublesome side effects in these patients. Finding safe and
effective treatment options for those who need relief the most is a
major public health need."
Efficacy Findings
As previously announced, the primary efficacy endpoint of the
Phase 2/3 study (12 week change from baseline of the NPIC A+A
scale) was not achieved in the overall study population of AD
patients with moderate or severe agitation and
aggression.
A post-hoc analysis demonstrated that ELND005 provided a
clinically meaningful 5.1 point improvement relative to placebo on
the NPIC A+A scale (p=0.047) in a severe agitation and aggression
population. An evaluation of progressively severe patient subsets
with baseline NPIC A+A scores greater than 22 showed a consistent
and greater improvement over the 5.1 points observed in the overall
severe population. Multiple analyses performed on the severe
agitation and aggression dataset determined that outliers, baseline
demographics, AD severity, and concomitant medications did not
appear to contribute to the improvement observed in the ELND005
treatment group.
The NPIC A+A scale is an aggregate score of severity related to
21 behavioral symptoms (13 agitation, 8 aggression
behaviors). Analysis of the patient population with a baseline
NPIC A+A < 22 showed that the major symptoms manifested were
upset, stubborn, resistance, ask and shouting, and the remaining 16
behavioral symptoms were much less prevalent and had lower
severity. As the baseline severity of NPIC A+A increased above
22 in AD patients, particularly above 26, many of the verbal and
physical aggression items (hit, push, intrusive, argue, complain,
danger, slam conflict), as well as the excessive motor activities
(restless, fidget, pace), also increased in prevalence and
severity. In this population of AD patients with severe agitation
and aggression, 20 of the 21 symptoms measured by the NPIC A+A
numerically favored ELND005 relative to placebo. These data
demonstrated that ELND005 appeared to have a more pronounced effect
on the verbal and physical aggression symptoms, as well as the
excessive motor activities, that were more prevalent in AD patients
with increasing agitation and aggression disease severity.
Safety and Tolerability Results
ELND005 was shown to have an acceptable safety and tolerability
profile in the study. The overall incidence of treatment
emergent adverse events ("TEAEs") in the ELND005 group and the
placebo group were similar (56.6% vs 54.3%), as was the incidence
of study drug-related TEAEs (13.1% vs 14.9%). Most TEAEs were
mild or moderate in severity. The most common TEAEs in the
ELND005 group that were ≥5% in incidence were: agitation (8.0% vs.
7.4% in placebo), diarrhea (8.0% vs. 2.9% in placebo), urinary
tract infection (6.9% vs. 4.0% in placebo), and falls (6.3% vs.
5.1% in placebo). Overall, the incidence of serious adverse
events was higher in the ELND005 group (9.7%) compared with the
placebo group (2.9%). There were no deaths reported in the
study. The overall patient discontinuation rate was low
(10.3%); 4.6% of patients discontinued the study due to an adverse
event in the ELND005 group versus 4.0% in the placebo group. No
clinically meaningful changes in electrocardiographic findings were
observed. ELND005 was not associated with cognitive impairment or
sedation in this study.
Insights from the Study on Agitation and Aggression Subjects,
Symptoms and Assessment Tools for Future Clinical
Development
The ELND005 Phase 2/3 study is one of the largest completed
agitation and aggression in AD clinical studies, and is the first
study to utilize the NPIC A+A endpoint in a placebo-controlled drug
trial. The study enrolled 350 AD subjects who were considered
to have moderate or severe agitation and aggression. This
study dataset provided unique insight into placebo changes with
various agitation and aggression patient populations, as well as
the prevalence of each of the 21 behavioral symptoms assessed in
NPIC A+A scale in patient populations with increasing
severity.
TTIL believes that these data support the use of the NPIC A+A
scale as a tool to provide a global assessment of agitation and
aggression as defined by a broad set of behaviors associated with
excessive motor activity, and physical and verbal aggression.
Plans for Further ELND005 Clinical Development
Over the next few months, TTIL intends to submit a request to
the FDA to discuss the data from the completed Phase 2/3
study. The objective of the meeting will be to seek guidance
on the design of Phase 3 clinical studies for the ELND005 program
in severe agitation and aggression in AD patients. Since AD
patients with severe agitation and aggression are in the most need
for treatment and most likely candidates for institutionalization,
ELND005 could provide significant benefit and impact to this
patient population and their caregivers, as well as reduce overall
costs in managing this patient population. In parallel, TTIL has
prepared sufficient drug supply for future phase 3 studies and
begun to identify potential clinical sites for enrolment.
The Phase 2/3 study data will be presented at the Clinical
Trials in Alzheimer's Disease meeting in Barcelona, Spain, which will take place
November 5-7, 2015.(1)
About the Phase 2/3 Study (Harmony AD Study; AG201
Study)
The Phase 2/3 clinical study evaluated the efficacy, safety and
tolerability of ELND005 over 12 weeks of treatment in patients with
mild to severe AD, who were experiencing at least moderate levels
of agitation/aggression. The randomized, double-blind,
placebo-controlled study enrolled 350 AD patients (175 subjects per
study arm). Subjects received either placebo or a fixed dosing
regimen of ELND005. The fixed dosing regimen consisted of a
loading dose of 1000 mg twice daily ("BID") for 4 weeks, followed
by a maintenance dose of 250 mg BID for a subsequent 8 weeks.
The primary efficacy endpoint of the study was the change
from baseline in the Neuropsychiatric Inventory – Clinician
("NPIC") scale of agitation and aggression at 12 weeks.
About Transition
Transition is a biopharmaceutical development company, advancing
novel therapeutics for CNS and metabolic disease indications. The
Company's wholly-owned subsidiary, Transition Therapeutics Ireland
Limited is developing CNS drug candidate ELND005 for the treatment
of Alzheimer's disease and Down syndrome. Transition's lead
metabolic drug candidate is TT401 (LY2944876) for the treatment of
type 2 diabetes and accompanying obesity. The Company's shares are
listed on the NASDAQ under the symbol "TTHI" and the Toronto Stock
Exchange under the symbol "TTH". For additional information about
the Company, please visit
http://www.transitiontherapeutics.com/.
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should be considered accurate only as of the date of the release
and may be superseded by more recent information we have disclosed
in later press releases, filings with the OSC, SEC or otherwise.
Except for historical information, this press release may contain
forward-looking statements, relating to expectations, plans or
prospects for Transition, including conducting clinical trials and
potential efficacy of its products. These statements are based upon
the current expectations and beliefs of Transition's management and
are subject to certain risks and uncertainties that could cause
actual results to differ materially from those described in the
forward-looking statements. These risks and uncertainties include
factors beyond Transition's control and the risk factors and other
cautionary statements discussed in Transition's quarterly and
annual filings with the Canadian commissions.
(1) For more information on the 8th Clinical Trials
in Alzheimer's Disease Conference, refer to
http://www.ctad-alzheimer.com/
SOURCE Transition Therapeutics Inc.