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Transition Therapeutics, Inc.

Partner : Elan Corporation

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Dr. Tony Cruz, Chief Executive Officer, maintained guidance for data from the phase-II study of ELND-005 for agitation and aggression in patients with Alzheimers Disease. He stated, "We are very pleased to announce that the 350 patient agitation/aggression study in mild-to-severe Alzheimer’s patients has been complete. The Transition team is currently performing all the activities necessary to lock the clinical database. We expect the announcement of top-line data by mid-July 2015."
Source: Q3 FY 2015 earnings conference call, 5/12/15.

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Transition Therapeutics Announces Enrolment Completion of ELND005 Phase 2 Clinical Study in Agitation and Aggression in Patients with Alzheimers Disease

TORONTO, ON, March 2, 2015 Transition Therapeutics Inc. (Transition or the Company) (NASDAQ: TTHI, TSX: TTH) announced that its wholly owned subsidiary, Transition Therapeutics Ireland Limited (TTIL) completed enrolment of the Phase 2 clinical study evaluating neuropsychiatric drug candidate ELND005 as a treatment for agitation and aggression in patients with mild, moderate and severe Alzheimers disease (AD).
The objectives of the Phase 2 clinical study (Harmony AD Study) are to evaluate the efficacy, safety and tolerability of ELND005 over 12 weeks of treatment in patients with mild to severe AD, who are experiencing at least moderate levels of agitation/aggression. The randomized, double-blind, placebo-controlled study has enrolled 350 AD patients at 69 clinical sites in the United States, Canada, Spain and the United Kingdom. The primary efficacy endpoint of the study is the change from baseline in the Neuropsychiatric Inventory Clinician (NPI-C) scale of agitation and aggression. It is anticipated that the top-line data from the Harmony AD Study will be announced mid-year 2015.

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Transition Therapeutics’ ELND005 Showed No Prolongation of QT Interval
TORONTO, ON, November 24
th, 2014 – Transition Therapeutics Inc. (“Transition” or the “Company”) (NASDAQ: TTHI, TSX:TTH) today announced results from a thorough QT (tQT) study in which no QT effects were observed at supra-therapeutic single doses of neuropsychiatric drug candidate, ELND005. A tQT study is a specialized clinical trial required by the United States Food and Drug Administration (“FDA”) for the approval of most drugs in development. Transition’s wholly-owned subsidiary, Transition Therapeutics Ireland Limited (“TTIL”) presented the tQT study data at the Clinical Trials in Alzheimer’s Disease conference on November 21, 2014.

From a safety perspective, drugs that have no QT prolongation effects are particularly desirable for administration to an elderly Alzheimer’s disease (“AD”) population. AD patients are especially challenging for novel drug development, since they typically have multiple medical co-morbidities and receive multiple medications. The use of some antipsychotics and anti-depressants may increase the risk of QT prolongation, arrhythmias, and sudden death in AD patients.

Single doses, 2000mg and 7000mg of ELND005, appeared to be safe and well-tolerated by healthy subjects in this study. ELND005 exposures in this study are five-fold higher than the loading dose of 1000mg BID in the current Agitation and Aggression in AD clinical study (AG201). These ELND005 doses did not have any clinically relevant effects on electrocardiogram (“ECG”) parameters and the study represents a clearly negative thorough QT (tQT) study.
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Source: press release, 11/24/14. http://transitiontherapeutics.com/media/press_releases/20141124.pdf

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Agitation and Aggression in AD: Transition has reviewed all the Agitation and Aggression data from the previously completed phase 2 trials in mild to moderate Alzheimer's Disease (AD201 and AD251), as well as all of the blinded data from the large ongoing ELND005 clinical trials of Agitation and Aggression (AG201 and AG251). Based on this in-depth review and analysis, Transition is fully committed to allocating all the financial and human resources necessary to support the Phase 2 study evaluating ELND005 in mild to severe Alzheimer's disease patients who are experiencing agitation and aggression. This ongoing clinical study (AG201) is called the "Harmony AD" study (www.harmonyadstudy.com) and has a projected enrollment of up to 400 subjects. Transition expects enrollment to be completed by the first quarter of 2015 with results from the study expected in mid-2015. A safety extension study (Study "AG251") is ongoing and is enrolling subjects who have completed the placebo-controlled "HarmonyAD" study. To date, the large majority of subjects completing the "HarmonyAD" study are participating in the AG251 extension study. This Agitation and Aggression in AD program has received fast track status from the United States Food and Drug Administration.
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Source: press release, 4/07/14. http://transitiontherapeutics.com/media/news.php

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Dr. Tony Cruz, Chief Executive Officer, commented on the timing for data from the phase-II trial with ELND-005 in AD. He stated, "Aggression in Alzheimer's patients is considered a major problem for caregivers and a major cost for the health care system. It is the major reason why AD patients or Alzheimer's patients are institutionalized. The 400-patient aggression trial is a placebo-controlled safety and efficacy study with primary endpoints being severity of aggression following a 12-week trial or 12 weeks of treatment. According to clinicaltrials.gov, the efficacy trial is expected to be completed by the end of the year."
Source: Q3 FY 2013 earnings conference call, 5/07/13.

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Transition Therapeutics Announces Enrollment of the First Patient in Phase 2 Study of ELND005 (Scyllo-inositol) for the Treatment of Agitation/Aggression in Patients with Alzheimer's Disease

- Approximately 90% of AD patients develop neuropsychiatric symptoms
- Approximately 60% of AD patients develop agitation/aggression

TORONTO, ON, November 28th, 2012 - Transition Therapeutics Inc. ("Transition" or the "Company") (NASDAQ: TTHI, TSX: TTH) today announced its licensing partner, Elan Corporation, plc ("Elan") has enrolled the first patient in a Phase 2 study of ELND005 (Study AG201) for the treatment of agitation/aggression in patients with moderate to severe Alzheimer's disease (AD).

The objectives of Study AG201 are to evaluate the efficacy, safety and tolerability of ELND005 over 12 weeks of treatment in patients with moderate to severe AD, who are experiencing at least moderate levels of agitation/aggression. The study is expected to enroll approximately 400 patients at multiple sites in the US, Canada and potentially other selected regions. In the Phase 2 AD Study (AD201), ELND005 appeared to decrease the emergence and severity of specific neuropsychiatric symptoms, an effect which seemed to correlate with drug exposure for some symptoms. ELND005 also led to a sustained reduction of brain Myo-inositol levels that are thought to play a role in phospho-inositol signaling pathways and synaptic activity. More information on Study ELND005-AG201 will be available at http://www.clinicaltrials.gov/.
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Source: press release, 11/28/12. http://www.transitiontherapeutics.com/media/news.php

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ELND005 (AZD-103) for Alzheimer's Disease

Transition's lead Alzheimer's disease compound ELND005 (AZD-103) is a disease modifying agent with the potential to both prevent and reduce disease progression, and improve symptoms such as cognitive function.

The recently completed Phase II study was a randomized, double-blind, placebo-controlled, safety and efficacy study of ELND005 (AZD-103) in approximately 340 patients with mild to moderate Alzheimer's disease. The study evaluated both cognitive and functional endpoints, and each patient's participation lasted approximately 18 months. Elan and Transition announced topline summary results of the Phase II study and plans for Phase III for ELND005 (AZD-103). The AD201 study did not achieve significance on co-primary outcome measures (NTB and ADCS-ACL) in mild to moderate patients. The study identified a dose with acceptable safety and tolerability. The dose demonstrated a biological effect on amyloid-beta protein in the cerebrospinal fluid and effects on clinical endpoints in an exploratory analysis. Based on the preponderance of evidence, and input from the experts in this field, the companies intend to advance ELND005 (AZD-103) into Phase III studies.
Source: press release, 2/09/12. http://www.transitiontherapeutics.com/media/news.php

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ELND005 (AZD-103) for Alzheimer's Disease

Transition's lead Alzheimer's disease compound ELND005 (AZD-103) is a disease modifying agent with the potential to both prevent and reduce disease progression, and improve symptoms such as cognitive function.

The recently completed Phase II study was a randomized, double-blind, placebo-controlled, safety and efficacy study of ELND005 (AZD-103) in approximately 340 patients with mild to moderate Alzheimer's disease. The study evaluated both cognitive and functional endpoints, and each patient's participation lasted approximately 18 months. Elan and Transition announced topline summary results of the Phase II study and plans for Phase III for ELND005 (AZD-103). The AD201 study did not achieve significance on co-primary outcome measures (NTB and ADCS-ACL) in mild to moderate patients. The study identified a dose with acceptable safety and tolerability. The dose demonstrated a biological effect on amyloid-beta protein in the cerebrospinal fluid and effects on clinical endpoints in an exploratory analysis. Based on the preponderance of evidence, and input from the experts in this field, the companies intend to advance ELND005 (AZD-103) into Phase III studies.
Source: press release, 9/19/11. http://www.transitiontherapeutics.com/media/news.php

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The recently completed Phase II study was a randomized, double-blind, placebo-controlled, safety and efficacy study of ELND005 (AZD-103) in approximately 340 patients with mild to moderate Alzheimer's disease. The study evaluated both cognitive and functional endpoints, and each patient's participation lasted approximately 18 months. Elan and Transition announced topline summary results of the Phase II study and plans for Phase III for ELND005 (AZD-103). The AD201 study did not achieve significance on co-primary outcome measures (NTB and ADCS-ACL). The study identified a dose with acceptable safety and tolerability. The dose demonstrated a biological effect on amyloid-beta protein in the cerebrospinal fluid and effects on clinical endpoints in an exploratory analysis. Based on the preponderance of evidence, and input from the experts in this field, the companies intend to advance ELND005 (AZD-103) into Phase III studies.
Source: press release, 5/10/11. http://www.transitiontherapeutics.com/media/news.php

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TORONTO, Dec. 27, 2010 -- Transition Therapeutics Inc. ("Transition" or "Company") (TSX:TTH) (Nasdaq:TTHI) today announced that the Company and Elan Corporation, plc ("Elan") (NYSE:ELN) have mutually agreed to modify their collaboration agreement for the development and commercialization of ELND005.
Source: press release, 12/27/10. http://www.transitiontherapeutics.com/news/article.php

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A Prospective, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Efficacy and Safety Study of Oral ELND005 for Treatment of Agitation and Aggression in Patients With Moderate to Severe Alzheimer's Disease
Estimated Enrollment: 400
Study Start Date: November 2012
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
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Source: clinical trials.gov. http://clinicaltrials.gov/ct2/show/NCT01735630?term=ELND005&rank=4

Compound/DeviceSpecialtyIndicationCompound ClassTarget
ELND-005 (AZD-103) AlzheimerNeurologyAlzheimers DiseaseBeta-amyloid and myo-inositol modifying agentBeta-amyloid and myo-inositol

Mechanism of action: ELND-005 (AZD-103), a SM, significantly reduce both beta-amyloid and myo-inositol levels in the brain leading to the break down of neurotoxic fibrils, allowing amyloid peptides to clear the body rather than form amyloid plaques and also regulating myo-inositol-dependent neuronal signalling. This limits disease progression and improves symptoms such as cognitive function.

Phase of Development: II

Event Type: Data: Phase II trial results

Dates: 2015-07-01 - 2015-07-31

Results:

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Transition Therapeutics Announces Results of Data Analysis from ELND005 Phase 2/3 Clinical Study in Agitation and Aggression in Alzheimer’s Disease Patients
. 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 behavioral 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, ON, October 15, 2015 – 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.

Data Tables: http://transitiontherapeutics.com/media/press_releases/20151015.pdf

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.

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.
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Source: press release, 10/15/15. http://transitiontherapeutics.com/media/press_releases/20151015.pdf

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Transition Therapeutics Announces Results of Clinical Study of ELND005 in Agitation and Aggression in Patients with Alzheimer’s Disease

TORONTO, ON, June 24, 2015 – Transition Therapeutics Inc. (“Transition” or the “Company”) (NASDAQ: TTHI, TSX: TTH) announced that a Phase 2/3 clinical study of
neuropsychiatric drug candidate ELND005 did not meet its primary efficacy endpoint. In the study, both the treatment and placebo groups showed a significant, but similar, reduction in agitation and aggression relative to baseline. There was a greater than expected reduction in agitation and aggression observed in the placebo group as measured in weeks 4, 8 and 12 in the study. The safety and tolerability profile of ELND005 was consistent with previous studies in AD at the 250mg bid dose.

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). The primary efficacy endpoint of the study was the change from baseline in the Neuropsychiatric Inventory – Clinician (“NPI-C”) scale of agitation and aggression.

An analysis of the full study dataset is being performed. An external clinical advisory committee will be consulted in determining any future development of ELND005.
Data from the Phase 2/3 clinical study will be presented at a future medical meeting.
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Source: press release, 6/24/15. http://www.transitiontherapeutics.com/media/press_releases/20150624.pdf

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