臨床研究等提出・公開システム

A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED,PARALLEL STUDY TO ASSESS THE EFFICACY,SAFETY, TOLERABILITY, PK, AND BIOMARKER EFFECTS OF PTC857 IN ADULT SUBJECTS WITH AMYOTROPHIC LATERAL SCLEROSIS (CARDINALS)

CARDINALS

336

Approximately 340 participants were planned to be randomized to ensure that 307 participants were randomized into the ITT1 Analysis Set. In total, 336 participants were randomized, of which 306 participants were included in the ITT1 Analysis Set. Participants randomized to placebo in Part A received equivalent quantities of placebo to match the 250 mg BID dose of active study drug.

This was a Phase 2, global, randomized, double-blind, placebo-controlled, parallel efficacy, safety, tolerability, and biomarker study of utreloxastat (PTC587) in adult participants with ALS between the ages 18 and 80. After the initial 8-week Screening Period, eligible participants entered the 24-week double-blind Treatment Period (Part A). Participants were randomized 2:1 to 1 of 2 treatment groups: utreloxastat (250 mg BID) or matching placebo, stratified by amount of change in ALSFRS-R score during the Screening Period by points total loss (<1, 1-2, 3-4, or >4) and the use of standard-of-care therapy for the treatment of ALS at Screening (edaravone, sodium phenylbutyrate/taurursodiol, or neither). After successful completion of Part A, all participants were offered the opportunity to enter the 28-week long-term extension period (Part B) to continue open-label treatment with utreloxastat 250 mg BID. Participants remained blinded to their original treatment from the Treatment Period (Part A). Those who chose not to enter the LTE Period stopped treatment and had Telephone Follow-Up Visit. After successful completion of Part B, all participants were offered the opportunity to enter the Continued LTE Period (Part C). In Part C, participants were offered the opportunity to continue treatment with open-label utreloxastat 250 mg BID for an additional 108 weeks. All participants remained blinded to their original treatment from Part A. At the end of this period, a Telephone Follow-Up Visit was conducted. The study was terminated by the sponsor following readout of results from the double-blind Treatment Period (Part A) as the study did not meet its primary endpoint or any secondary endpoint.

Overall, utreloxastat was relatively safe and well tolerated in participants with ALS. The most commonly reported TEAEs included fall, headache, and diarrhoea. In Part A, 36 (16.4%) and 11 (9.6%) participants reported at least 1 treatment-emergent SAE for utreloxastat and placebo, respectively, of which 1 in the utreloxastat group was considered related to treatment. Nine (4.1%) and 3 (2.6%) participants reported a TEAE leading to death, and 19 (8.6%) and 7 (6.1%) participants reported a TEAE leading to withdrawal of study drug, for utreloxastat and placebo, respectively. In Parts B and C combined, 73 (26.7%) participants reported at least 1 treatment-emergent SAE, of which 2 participants had such events considered related to treatment. Thirty-eight (13.9%) participants reported a TEAE leading to death, and 39 (14.3%) participants reported a TEAE leading to withdrawal of study drug. There were generally no significant differences between utreloxastat and placebo with regard to laboratory parameters, with the exception of apolipoprotein B (increased for utreloxastat), high density lipoprotein (decreased for utreloxastat), low density lipoprotein (increased for utreloxastat), and triglycerides (increased for utreloxastat). No significant findings were observed with regard to vital signs, weight, physical examination, ECGs, or C-SSRS.

Primary Objective Eevaluated the efficacy of PTC857 in reducing disease progression in subjects with amyotrophic lateral sclerosis (ALS). Secondary Objectives The secondary objectives of the study were to assess the following in subjects with ALS: - Safety and tolerability of PTC857 - Respiratory function in subjects randomized to PTC857 versus placebo - Motor/limb and bulbar function in subjects randomized to PTC857 versus placebo - Survival in subjects randomized to PTC857 versus placebo - Quality of life via 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) in subjects randomized to PTC857 versus placebo - Evaluated the efficacy of PTC857 in reducing disease progression in subjects with ALS with any baseline rate of functional decline - Effects on plasma neurofilament light chain (NfL) activity in subjects randomized to PTC857 versus placebo - Pharmacokinetics (PK) of PTC857

No differences between the utreloxastat and placebo groups were observed for the primary or the secondary efficacy endpoints. Overall, utreloxastat was relatively safe and well tolerated in participants with ALS. The most commonly reported TEAEs include fall, headache, and diarrhoea. The majority of SAEs, deaths, and TEAEs leading to discontinuation were not considered related to utreloxastat treatment and were consistent with ALS disease progression.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2011230043

Tansy Aaron

PTC Therapeutics, Inc.

100 Corporate Court South Plainfield, NJ 07080 US

atansy@ptcbio.com

Kim Min

Worldwide Clinical Trials Japan K.K.

2-15-1, Konan, Minato-ku, Tokyo Shinagawa Intercity, Tower A, Level 28

+81-3-6717-4360

min.kim@worldwide.com

Complete

Oct. 12, 2023

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

other

1. Males or females aged between 18 and 80 years with a body mass index between 18
and 35 kg/m2 at the time of the initial Screening Visit
2. Onset of the first symptom leading to the diagnosis of ALS is within 24 months at the time of the initial Screening Visit
3. Revised El Escorial criteria of either:
(i) Clinically definite ALS
(ii) Clinically probable ALS
4. A total ALSFRS-R score of at least 34 at the start of the Screening Period

1.History of allergies or adverse reactions to any of the excipients in the study drug formulation
2. Liver failure (except in Gilbert syndrome, defined as AST and/or ALT 3 times the upper limit of normal [ULN] or liver function test [LFT] with bilirubin 1.5 times the ULN))
3. Moderate to severe renal failure (defined as estimated glomerular filtration rate [eGFR] less than 60 mL/min)
4. Currently participating in a clinical trial of another investigational drug, or have participated 30 days prior to the start of the screening period or 5 half-lives from the most recent dose of the investigational drug, whichever is longer.
5. History of alcohol or drug abuse within 6 months prior to the start of the screening period
6. Patient has received combination therapy with edaravone and sodium phenylbutyrate/taurursodiol within 30 days prior to the start of the screening period.
7. History of breast cancer (regardless of remission status) or history of breast cancer in a first-degree relative

amyotrophic lateral sclerosis

Subjects will receive oral BID of either placebo or active drug during the 24-week treatment period.
For the optional long-term treatment period of 28 weeks, all subjects will receive 250 mg of PTC857 oral BID. For subjects who do not proceed to the long-term study, treatment will be discontinued and a follow-up telephone consultation will be conducted 4 weeks (Allowance 3 days) after the last dose of study drug.

amyotrophic lateral sclerosis ALS

The primary endpoint is the change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) in the Intent-To-Treat 1 (ITT1) Analysis Set after 24 weeks of treatment.

1. Safety and tolerability of PTC857
2. Subject's respiratory function
3. Subject's motor/limb function and medullary function
4. Neuropsychological functioning of subjects
5. Subject survival period
6. Subject's quality of life
7. Pharmacokinetics of PTC857

July. 18, 2023

Argentina/Australia/Belgium/Brazil/Canada/Czech Republic/France/Germany/Italy/Ireland/Mexico/Netherlands/Norway/Poland/Spain/Sweden/US