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ASENT 2019 Abstracts

Poster #1

Active Immunotherapeutic vaccine platform targeting endogenous proteins for the treatment of neurodegenerative diseases

Sharon Tamir, Hui Jing Yu, JC Dodart, and Chang Yi Wang

United Neuroscience (UNS) is pioneering a new class of active immunotherapeutics to promote brain health, focusing on delivering safe, effective and accessible medicines to treat and ultimately prevent Alzheimer’s (AD), Parkinson’s disease (PD) and other neurological disorders. Leveraging a proven vaccine platform that has commercialized one of the only licensed active immunotherapies against an endogenous protein in the world and has scaled up manufacture to over 500 million doses annually for other animal indications.

Success for a vaccine approach aimed at endogenous targets relies on the ability to break immune tolerance and generate a humoral antibody response against the desired epitopes, while also avoiding T-cell-mediated autoimmune reactions. UNS has evolved a novel epitope specific vaccine platform that can break immune tolerance towards endogenous proteins and selectively generate B-cell antibody responses while avoiding activation of T-cell inflammation. This UBITh® vaccine platform utilizes a library of proprietary synthetic UBITh® peptides linked to the desired target epitopes, to enlist the minimal T-Helper assistance required for triggering proliferation of B-cells recognizing the targeted epitope. This approach avoids generation of T-cell responses to the target epitope. UBITh® peptides also do not elicit any antibody response against themselves, thus driving all the humoral response to the target. The first clinical therapeutic program utilizing this platform is the anti-beta amyloid (anti-Abeta) vaccine called UBITh® AD Immunotherapeutic Vaccine (UB-311), which selectively targets epitopes exposed on oligomeric and fibrillar Abeta aggregates and is being developed for the treatment of Alzheimer’s disease (AD). In a completed Phase 1 and Phase 2a clinical studies, UB-311 elicited high anti-Abeta antibody levels with outstanding responder rate in patients with no evidence of diminished vaccine response with age, or immunosenescence. UB-311 has been well tolerated, has not shown evidence of meningoencephalitis or brain edema [ARIA-E].

The second UBITh® vaccine platform called UB-312 is aimed at aggregated aSyn. UB-312 targets the Cterminus of aSyn and is chemically linked to a UBITh® peptide. Phase 1 clinical study testing UB-312 in Parkinson’s patients is positioned to be initiated later this year.

Poster #2

Neuroprotection by Endovascular Selective Cerebral Hypothermia; Experimental In Vivo Studies and Initial Clinical Experience

Ronald Solar

The neuroprotective effects of hypothermia following cardiac arrest and acute stroke have been demonstrated in experimental models and clinical trials. Experimental studies indicate that improved efficacy and broadened indications can be achieved with moderate to deep hypothermia. However, current techniques require systemic cooling, and are unable to cool rapidly and deeply without serious detrimental effects. A new catheter-based system and technique to rapidly, deeply and selectively cool the brain was investigated. Using a standard transfemoral technique in large swine (60-72 kg), the multilumen catheter was positioned to isolate the right or left common carotid artery. Blood was withdrawn from the aorta via one lumen, cooled extracorporeally, and reperfused through a second lumen into the carotid artery. Outflow blood was cooled to 5-20°C, and reperfused at rates of 80-250 ml/min for 30-180 minutes. Temperature was measured in bilateral frontal lobes, nasopharynx, ear, esophagus, jugular vein and descending aorta. In a porcine stroke reperfusion model, 25 pigs were randomly assigned to 3 hours of selective cerebral cooling to 26°C or normothermia following 3 hours of ischemia achieved by surgically clipping a middle cerebral artery. Brain MRI and histology were evaluated by experts who were blinded to the intervention. Cerebral cooling to as low as 15°C was achieved with no significant systemic cooling. Initial cooling rates of 1.8°C/min were attained, and were dependent on flow rate and temperature of the perfused blood. Passive rewarming did not result in rebound hyperthermia. No adverse events were observed. In the stroke reperfusion model, a significant reduction in stroke volume was observed by selective cerebral cooling to 26°C compared to the normothermic control group. In initial human experience, selective cerebral cooling to 26°C resulted in excellent outcomes with no neurological deficits in the settings of neurosurgery and out of hospital cardiac arrest. This new catheter-based system and technique shows promise in providing rapid, selective, deep cerebral hypothermia, and may offer an improved method for neuroprotection during neurosurgery, cardiac arrest, acute stroke and other ischemic insult.

 

Poster #3

EEG biomarkers to improve the discovery of new neurotherapeutics

Corinne Roucard, Céline Ruggiero, Alexis Evrard, Yann Roche and Venceslas Duveaum

The purpose of this presentation is to describe how EEG biomarkers can help to identify new neurotherapeutics in epilepsy and Parkinson’s disease. The development of new neurotherapeutics is nowadays facing a great challenge. In fact, a lot of clinical trials have over the last decades failed in critical brain disorders with unmet medical need, such as Alzheimer’s disease, epilepsy or Parkinson’s disease, mainly by lack of efficacy. SynapCell has identified translational EEG biomarkers used here as signatures of brain disorders in rodent models. They were used to develop drug discovery programs and make the bridge between preclinical and clinical stages to identify and select the best neurotherapeutics. Based on the detection of epileptic discharges by EEG, we have developed a program aiming at identifying the effect of new neurotherapeutics in two types of epilepsies: the absence epilepsy and the mesio-temporal lobe epilepsy.

Using these two non-convulsive models, we have developed a drug discovery program from the screening of small library of compounds to the selection and validation of lead compounds. Working with animal models of chronic epilepsy, they allow identification of drugs acting on disease-modification or epileptogenesis. In the field of Parkinson’s disease, based on BetaPark and GammaPark oscillations as EEG biomarkers, we have developed drug discovery programs allowing the evaluation of new neurotherapeutics on motor symptoms and L-DOPA induced dyskinesia using the 6-OHDA lesioned rat model. In this poster, we will present how our drug discovery programs in these two major brain disorders can help researchers to make decisions and to discover new innovative treatments.



Poster #4

Not Published 



Poster #5

Description of Division of Translational Research Funding Announcements

Rebecca Roof

The mission of the Division of Translational Research (DTR) at the National Institute of Neurological Disorders and Stroke (NINDS) within the National Institutes of Health (NIH) is to accelerate the preclinical discovery and development of new therapeutic interventions for neurological disorders. DTR helps academic and industry researchers create a bridge through which discoveries made in the laboratory lead to new and improved medical treatments. DTR provides several funding opportunities to accelerate preclinical research and technology. These include grants, cooperative agreements, and contracts to academic and industry researchers to advance early-stage therapeutic programs.

In the earlier translational space, the (IGNITE) Program is a suite of funding opportunity announcements to enable grantees to build on their innovative basic science finding and initiate preclinical discovery and development. The Epilepsy Therapy Screening Program (ETSP) is a compound screening service to help investigators identify therapeutics to ameliorate the epilepsies. Current efforts emphasize unmet medical need including treatments for refractory epilepsies, epileptogenesis and disease progression.

In the later translational space, the NINDS Biomarker Program supports analytical and clinical validation of candidate biomarkers for neurological diseases. The BPN Program is a cooperative agreement program to support small molecule drug discovery and development. These programs are designed to maintain the grantees’ intellectual property while providing non-dilutive funding. For biologics development, NINDS has the CREATE BIO Program CREATE Bio that supports the development of peptides, proteins, oligonucleotides, gene therapies and cell therapies for disorders that fall within the NINDS mission. Lastly, the Translational Neural Devices Program supports the development, validation and verification, and early clinical studies of therapeutic devices.

In addition, DTR has two programs that cut across from early to late: CounterACT Program and the NINDS Small Business Programs (SBIR/STTR). The mission of the NIH CounterACT Program is to understand fundamental mechanisms of toxicity caused by chemical threat agents and the application of this knowledge to develop therapeutics for reducing mortality and morbidity. The SBIR/STTR Program is a congressionally-mandated set-aside program to encourage research and development leading to commercialization.

 

Poster #6

Long-term safety and tolerability of apomorphine sublingual film in patients with Parkinson’s disease and “OFF” episodes

William Ondo, Aaron L. Ellenbogen, Stuart Isaacson, Alberto J. Espay, Parul Bhargava, MaryAlice Worden, David Blum, Bradford Navia

Patients with Parkinson’s disease (PD) develop “OFF” episodes, a common complication that may negatively impact quality of life. Apomorphine sublingual film (APL) was found to be generally safe, well tolerated, and effective in a 12-week, double-blind, placebo-controlled, randomized phase 3 trial in patients with PD and “OFF” episodes. The long-term safety and tolerability of APL for the acute, intermittent treatment of “OFF” episodes were evaluated in a pooled analysis of patients with PD. Adult levodopa-responsive patients with PD and “OFF” episodes exposed to APL doses of 10–35 mg for ≥6 months as of the 19 January 2018 cutoff date were included in this pooled safety analysis. Analysis of treatment-emergent adverse events (TEAEs) were reported using descriptive statistics. One hundred patients were exposed to APL for ≥6 months (across both titration and treatment phases). Median exposure was 7.3 months (range, 6–13 months), with a total of 59.8 patient-years of exposure. Eighty-four percent of patients were exposed to APL for ≥6 to <9 months, 14% for ≥9 to <12 months, and 2% for ≥12 months. Among these 100 patients, TEAEs were reported in 90% of patients. Serious TEAEs occurred in only 6% of patients and 5% discontinued treatment due to a TEAE. No TEAEs resulted in death. The most common TEAEs were nausea (24%), oral mucosal erythema (12%), fall (12%), somnolence (10%), dizziness (9%), and yawning (9%). Lower rates of TEAEs were reported for orthostatic hypotension (6%), dyskinesia (5%), contusion (5%), and mouth ulceration (5%); less common TEAEs included syncope (2%), hallucinations (2%), and impulse control disorders (1%). No new or unexpected findings were identified in this long-term safety analysis of apomorphine administered as a sublingual film in patients with PD and “OFF” episodes. Consistent with shorter-term studies, APL was found to be generally safe and well tolerated.


Poster #7

Inhibition of Cholesterol 24-Hydroxylase Improves the Survival of a Mouse Model of Epileptic Phenotype and Modulates Extracellular Levels of Glutamate 

Toshiya Nishi, Sayuri Watanabe, Shigeo Hasegawa, Shinji Fujimoto, Eiji Sunahara, Momoko Ohori, Tatsuki Koike, Maki Miyamoto, Shinichi Kondo

Cholesterol 24-hydroxylase (CH24H) is an enzyme that converts brain cholesterol into 24S-hydroxycholesterol (24HC). Evidence supporting the therapeutic potential of CH24H inhibition was observed in the extended life expectancy of amyloid precursor protein (APP) and presenilin 1 (PS1) transgenic (Tg) mice cross-bred with homozygous or heterozygous CH24H knockout mice. The model carries transgenes implicated in familial Alzheimer disease and exhibits epileptic features and altered glutamate regulation. In this study, TAK-935 (OV935), a potent and selective CH24H inhibitor, was tested in the APP/PS1-Tg model. APP/PS1-Tg mice orally treated with TAK-935 showed a dose-dependent reduction in the brain level of 24HC. A 10 mg/kg dose was found to reduce the brain level of 24HC by approximately 50% compared with vehicle-treated control mice, recapitulating the heterozygous CH24H deficiency. Seven-week-old female APP/PS1-Tg mice were orally treated with vehicle or TAK-935 10 mg/kg once daily for 8 weeks (n=30). During the survival observation, the hazard ratio for sudden death was 5.849 in the vehicle-treated arm compared with TAK-935. A significant survival advantage was observed in the TAK-935 group (p<0.01 vs control). Based on an assumption that high seizure susceptibility is the underlying cause of mortality in these mice, 100 mM potassium chloride (KCl) was continuously injected through a microdialysis probe in the hippocampus to unmask their epileptic phenotype. KCl-challenged APP/PS1-Tg mice were more susceptible than wild-type (WT) control not only to seizure but also to extracellular glutamate elevation (fold increase from baseline: WT, 4.0; Tg, 22.8; n=4-5, p<0.05). Two-week treatment with TAK-935 (10 mg/kg orally every day) significantly suppressed KCl-induced glutamate elevation in APP/PS1-Tg mice (fold increase from baseline: vehicle, 28.9; TAK-935, 1.6; n=12, p<0.01). This indicates that TAK-935 normalized the susceptibility of APP/PS-Tg mice to extracellular glutamate elevation, leading to a hypothesis that CH24H inhibition is a potential new pharmacological approach to modulate seizure susceptibility in the epileptic brain, consistent with our previous studies in the kindling development model. The consistency in the survival advantage of genetic and chemical ablation of CH24H in APP/PS1-Tg mice highlights the relevance of CH24H inhibition as a new therapeutic strategy.

 

Poster #8

Extended-Release Viloxazine (SPN-812) for the Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in Children: Topline Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (P301)

Azmi Nassar, Joseph T. Hull, Fatima A. Chowdhry, Toyin Adewole, Tesfaye Liranso, Ronald Marcus

SPN-812, a structurally distinct, bicyclic norepinephrine reuptake inhibitor with selective serotonergic activity, is in development for ADHD treatment in children/adolescents. Here we present results of the first Phase 3 study evaluating the efficacy and safety of 2 SPN-812 doses for ADHD treatment in children. P301 was a randomized, double-blind, placebo-controlled study of once-daily SPN-812 monotherapy dosed at 100mg or 200mg in children ages 6-11 with ADHD. Key inclusion criteria were DSM-5 diagnosis of ADHD confirmed with the MINI-KID, ADHD-RS-5 score ≥28, CGI-S score ≥4, and free from ADHD medication ≥1 week before randomization. Subjects were randomized 1:1:1 to placebo:100mg SPN-812:200mg SPN-812. The treatment period included up to 1 week of titration and 5 weeks of maintenance. The primary efficacy endpoint was change from baseline (CFB) to end of study (EOS) in ADHD-RS-5 total score. Selected secondary endpoints included ADHD-RS-5 hyperactivity/impulsivity and inattention subscales and the CGI-I. Safety and tolerability were assessed using AEs, laboratory tests, vital signs, physical examinations, electrocardiograms, and the C-SSRS. The ITT population included 460 subjects (N=155, placebo; N=147, 100mg; N=158, 200mg). CFB to EOS in ADHD-RS-5 scores were -10.9 (placebo), -16.6 (100mg, p=0.0004), and -17.7 (200mg, p<0.0001). SPN-812 reached statistical significance vs. placebo for 100mg (p=0.0004) and 200mg (p=0.0244) as early as week 1, which was maintained throughout the trial. CFB to EOS on the ADHD-RS-5 hyperactivity/impulsivity and inattention subscales were statistically significant vs. placebo in both SPN-812 groups, with p-values of 0.0026 (100mg) and <0.0001 (200mg), and 0.0006 (100mg) and <0.0001 (200mg), respectively. CGI-I scores at EOS were 3.1 (placebo), 2.7 (100mg, p=0.0020), and 2.6 (200mg, p<0.0001). Treatment-related AEs reported in ≥5% of SPN-812 subjects were somnolence, headache, and decreased appetite. This Phase 3 study of 100mg and 200mg SPN-812 met the primary endpoint with robust statistical significance. SPN-812 exhibited a broad spectrum of efficacy across both the hyperactivity/impulsivity and inattention subscales of the ADHD-RS-5. The primary efficacy endpoint, CFB to EOS in ADHD-RS-5 total score, was met following 1 week of SPN-812 treatment; significance was maintained throughout the 6-week trial. In this study, SPN-812 was efficacious, well tolerated, and associated with low discontinuation rates.

 

Poster #9

Extended-Release Viloxazine (SPN-812) for the Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in Adolescents: Topline Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (P302)

Azmi Nassar, Joseph T. Hull, Fatima A. Chowdhry, Toyin Adewole, Tesfaye Liranso, Ronald Marcus

SPN-812, a structurally distinct, bicyclic norepinephrine reuptake inhibitor with selective serotonergic activity, is in development for ADHD treatment in children/adolescents. Here we present results of the first Phase 3 study evaluating the efficacy and safety of 2 SPN-812 doses for ADHD treatment in adolescents. P302 was a randomized, double-blind, placebo-controlled, study of once-daily SPN-812 monotherapy dosed at 200mg or 400mg in adolescents ages 12-17 with ADHD. Key inclusion criteria were DSM-5 diagnosis of ADHD confirmed with the MINI-KID, ADHD-RS-5 score ≥28, CGI-S score ≥4, and free from ADHD medication ≥1 week before randomization. Subjects were randomized 1:1:1 to placebo:200mg SPN-812:400mg SPN-812. The treatment period included up to 1 week of titration and 5 weeks of maintenance. The primary efficacy endpoint was change from baseline (CFB) to end of study (EOS) in ADHD-RS-5 total score. Selected secondary endpoints included ADHD-RS-5 hyperactivity/impulsivity and inattention subscales and the CGI-I. Safety and tolerability were assessed using AEs, laboratory tests, vital signs, physical examinations, electrocardiograms, and the C-SSRS. The ITT population included 301 subjects (N=104, placebo; N=94, 200mg; N=103, 400mg). CFB to EOS in ADHD-RS-5 scores were -11.4 (placebo), -16.0 (200mg, p=0.0232), and -16.5 (400mg, p=0.0091). SPN-812 400mg reached statistical significance vs. placebo as early as week 1 (p=0.0085), which was maintained throughout the trial. CFB to EOS on the ADHD-RS-5 hyperactivity/impulsivity and inattention subscales were statistically significant vs. placebo in both SPN-812 groups, with p-values of 0.0069 (200mg) and 0.0005 (400mg), and 0.0424 (200mg) and 0.0390 (400mg), respectively. CGI-I scores at EOS were 3.0 (placebo), 2.5 (200mg, p=0.0042), and 2.4 (400mg, p=0.0003). Treatment-related AEs reported in ≥5% of SPN-812 subjects were somnolence, decreased appetite, fatigue, headache, and nausea. This Phase 3 study of 200mg and 400mg SPN-812 met the primary endpoint with robust statistical significance. SPN-812 exhibited a broad spectrum of efficacy across both the hyperactivity/impulsivity and inattention subscales of the ADHD-RS-5. The primary efficacy endpoint, CFB to EOS in ADHD-RS-5 total score, was met following 1 week of SPN-812 treatment; significance was maintained throughout the 6-week trial. In this study, SPN-812 was efficacious, well tolerated, and associated with low discontinuation rates.

 

Poster #10

Extended-Release Viloxazine (SPN-812) for the Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in Children: Topline Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (P303)

Azmi Nassar, Joseph T. Hull, Fatima A. Chowdhry, Toyin Adewole, Tesfaye Liranso, Ronald Marcus 

SPN-812, a structurally distinct, bicyclic norepinephrine reuptake inhibitor with selective serotonergic activity, is in development for ADHD treatment in children/adolescents. Here we present results of the second Phase 3 study evaluating the efficacy and safety of 2 SPN-812 doses for ADHD treatment in children. P303 was a randomized, double-blind, placebo-controlled, study of once-daily SPN-812 monotherapy dosed at 200mg or 400mg in children ages 6-11 with ADHD. Key inclusion criteria were DSM-5 diagnosis of ADHD confirmed with the MINI-KID, ADHD-RS-5 score ≥28, CGI-S score ≥4, and free from ADHD medication ≥1 week before randomization. Subjects were randomized 1:1:1 to placebo:200mg SPN-812:400mg SPN-812. The treatment period included up to 3 weeks of titration and 5 weeks of maintenance. The primary efficacy endpoint was change from baseline (CFB) to end of study (EOS) in ADHD-RS-5 total score. Selected secondary endpoints included ADHD-RS-5 hyperactivity/impulsivity and inattention subscales and the CGI-I. Safety and tolerability were assessed using AEs, laboratory tests, vital signs, physical examinations, electrocardiograms, and the C-SSRS. The ITT population included 301 subjects (N=97, placebo; N=107, 200mg; N=97, 400mg). CFB to EOS in ADHD-RS-5 scores were -11.7 (placebo), -17.6 (200mg, p=0.0038), and -17.5 (400mg, p=0.0063). Both SPN-812 400mg and 200mg showed statistically significant differences from placebo starting at week 5 and continuing through week 8. CFB to EOS on the ADHD-RS-5 hyperactivity/impulsivity and inattention subscales were statistically significant vs. placebo in both SPN-812 groups, with p-values of 0.0020 (200mg) and 0.0039 (400mg), and 0.0087 (200mg) and 0.0248 (400mg), respectively. CGI-I scores at EOS were 3.1 (placebo), 2.6 (200mg, p=0.0028), and 2.6 (400mg, p=0.0099). Treatment-related AEs reported in ≥5% of SPN-812 subjects were somnolence, decreased appetite, fatigue, headache, and upper abdominal pain. This Phase 3 study of 200mg and 400mg SPN-812 met the primary endpoint with robust statistical significance. SPN-812 exhibited a broad spectrum of efficacy across both the hyperactivity/impulsivity and inattention subscales of the ADHD-RS-5. In this study, SPN-812 was efficacious, well tolerated, and associated with low discontinuation rates.

 

Poster #11

Phase 3, Randomized, Double-Blind, Placebo-Controlled Studies Evaluating Efficacy and Safety of Extended-Release Viloxazine (SPN-812) for Pediatric ADHD: Update on the Second Adolescent Study (P304)

Azmi Nassar, Joseph T. Hull, Fatima A. Chowdhry, Toyin Adewole, Tesfaye Liranso, Ronald Marcus

SPN-812, a structurally distinct, bicyclic norepinephrine reuptake inhibitor with selective serotonergic activity, is currently in development for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Here we provide an update on the second ongoing Phase 3 study of SPN-812 use in adolescents. P304 is a randomized, double-blind, placebo-controlled, multicenter study investigating the efficacy and safety of SPN-812 dosed at 400 mg or 600 mg once daily as an extended-release monotherapy in adolescents ages 12-17 with ADHD. Key inclusion criteria are Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnosis of ADHD confirmed with the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), baseline ADHD Rating Scale-5 (ADHD-RS-5) score ≥28 and Clinical Global Impression-Severity (CGI-S) score ≥4, and subjects free from ADHD medication ≥1 week prior to randomization and throughout the study. A total of 300 subjects will be randomized 1:1:1 to placebo:400 mg SPN-812:600 mg SPN-812. The treatment period includes up to 2 weeks of dose titration and 5 weeks of maintenance dosing. The primary efficacy endpoint is the change from baseline to end of study in the ADHD-RS-5 total score. Secondary endpoints include the Clinical Global Impression-Improvement scale (CGI-I), Conners 3–Parent and –Self composite T-scores, Weiss Functional Impairment Rating Scale–Parent Report (WFIRS-P) average score, 50% responder rate based on ADHD-RS-5 total score, the hyperactivity/impulsivity and inattention subscales of the ADHD-RS-5, and the Stress Index for Parents of Adolescents (SIPA) total score. SPN-812 safety and tolerability are assessed using adverse events, clinical laboratory tests, vital signs, physical examinations, electrocardiograms, and the Columbia-Suicide Severity Rating Scale (C-SSRS). Completers can enroll in an open-label extension. As of December 20, 2018, topline results are expected by the end of the first quarter of 2019. Based on efficacy and safety in the Phase 2 program and supported by three recently completed Phase 3 studies, 2 in children and 1 in adolescents, SPN-812 is being investigated in this fourth randomized, placebo-controlled, Phase 3 study for the treatment of adolescent ADHD.

 

 Poster #12

Clinical Innovation Network and Status of Patient Registry for Muscular Dystrophy (Remudy)

Harumasa Nakamura, Shinkichi Takeda 

Real-world evidence is derived from Real-world data (RWD), and can inform drug/device development, research on outcomes and health care systems, safety surveillance, well-controlled effectiveness studies, and patient care. Pharmaceutical regulatory schemes concerned with real world data have been changing remarkably in terms of both drug development and post-marketing. 

As for drug development, ICH proposed “GCP Renovation”, which includes modernization of E8 Guideline (General Consideration for Clinical Trials) and subsequent renovation of E6 Guideline (Good Clinical Practice). It covers pragmatic clinical trials, randomized controlled trials using patient registry data, and even observational studies using real world data. 
In Japan, Clinical Innovation Network (CIN) plan was announced. CIN is new concept supported by Ministry of Health, Labour and Welfare Japan to improve the environment of the clinical development that enables efficient clinical trial by utilizing patient registry that is a primary key source of RWD. 

In 2009, we developed a national registry of Japanese DMD/BMD patients (REgistry of MUscular DYstrophy; Remudy) in collaboration with TREAT-NMD. As of 2018, 1814 dystrophynopathy patients are registered in Remudy. We have demonstrated how this registry can enhance the readiness for clinical trials in Japan, and how this unique form of infrastructure can be used to accelerate international efforts in fighting orphan diseases. 

 

Poster #13

Pharmacokinetics of Clobazam and N-desmethylclobazam Following Administration of Clobazam Oral Film

Frank Nagy, Allen H. Heller, Stephen Wargacki, Cassie Jung, David J. Wyatt, A. Mark Schobel

RATIONALE:

Clobazam oral soluble film (COSF) is a novel dosage form under development for adjunctive treatment of seizures in Lennox-Gastaut syndrome (LGS). The film formulation has the potential to contribute to the care of patients with LGS by providing a means for easier and more reliable administration than the currently available clobazam formulations. We assessed the pharmacokinetics (PK) of clobazam and its active metabolite, N-desmethylclobazam, administered as single doses of COSF 20 and 10 mg (Aquestive Therapeutics) compared with clobazam tablets 20 and 10 mg (Lundbeck, US).

METHODS:

Healthy adult volunteers (N=51) were enrolled in a single-dose, open-label, randomized four-sequence, four-period, crossover: (A) COSF 20 mg; (B) clobazam tablet 20 mg; (C) COSF 10 mg; and (D) clobazam tablet 10 mg. PK sampling for both clobazam and N-desmethylclobazam was carried out until 21 days post-dose with a 28-day washout. Subjects were monitored for adverse events (AE) throughout the study.

RESULTS:

COSF at single doses of 10 and 20 mg was bioequivalent to the clobazam tablet at both doses for both clobazam and for N-desmethylclobazam. The time until maximal plasma concentration (Tmax) for clobazam was similar for COSF and the tablet (1.5 to 2 hours at both dose levels). The PK for parent drug and active metabolite were demonstrated to be dose-proportional. Adverse events were as expected for clobazam, and dose-related across the treatment groups, with somnolence the most common. Most events were mild and none serious or severe.

CONCLUSIONS:

COSF is a novel clobazam dosage form that is bioequivalent to the clobazam tablet with respect to both clobazam and its active metabolite N- desmethylclobazam. These data indicate that in healthy volunteers administered single doses of clobazam as COSF or tablet, the rate and extent of clobazam absorption are similar, and the rate and extent of clobazam metabolism to N-desmethylclobazam are similar.

FUNDING:

Funding for this study was provided by Aquestive Therapeutics, Inc.

 

 Poster #14

Pharmacokinetics of Diazepam Buccal Film in Adult Patients with Epilepsy: Comparison of Bioavailability with Periictal and Interictal Administration

Michael A. Rogawski, Hui Gong, Kore Liow, Sami Aboumatar, Pavel Klein, Michael A. Gelfand, Cassie Jung, Stephen Wargacki, Rikin Mehta, Allen H. Heller

RATIONALE:

Diazepam buccal soluble film (DBSF) is a novel dosage form of diazepam under development for the management of selected patients with refractory epilepsy who require intermittent use of diazepam to control episodes of increased seizure activity. In this study, we sought to assess pharmacokinetic (PK) performance during or immediately after a seizure. Subjects were investigated while undergoing a clinical epilepsy monitoring unit (EMU) evaluation and on another PK-only visit, with the visits separated by approximately 3 weeks. We investigated the diazepam maximal plasma concentration (Cmax), time to maximal concentration (Tmax), and partial area under the curve (partial AUC) at 2 or 4 hours following a single 12.5 mg dose administered during both visits.

METHODS:

Adult men and women ages 17-65 years with poorly controlled tonic clonic seizures or focal seizures with impaired awareness (N=35) were enrolled in a single-dose crossover study to receive DBSF 12.5 mg under both interictal (Treatment A) and ictal/peri-ictal (Treatment B) conditions in a clinical EMU setting.  Plasma samples for analysis of diazepam were obtained pre-dose and at intervals until 2 hours or 4 hours after dosing.  Administration was classified as interictal if there was no observed seizure activity in the preceding 4 hours and as ictal/periictal if DBSF was given during clinically observed seizure activity or within 5 minutes of cessation of seizure activity.   Subjects were monitored for adverse events (AE) throughout the study.

RESULTS:

Pharmacokinetic (PK) profiles valid for analysis for both treatment conditions were available for 21 subjects. Values for Cmax, AUC(0-2h), and AUC(0-4h) were similar in the interictal and ictal/periictal state, and median values for Tmax were not significantly different. DBSF 12.5 mg was safe and well tolerated. The most common adverse event possibly related to drug was somnolence reported in two (5.7 %) of 35 subjects. There were no serious adverse events related to study drug, and no subject withdrew because of an adverse event.

CONCLUSIONS:

These results demonstrate that a single dose of DBSF 12.5 mg administered to adults with epilepsy provides exposure to diazepam under ictal/peri-ictal conditions that is comparable to that obtained under inter-ictal conditions.

FUNDING:

Funded by Aquestive Therapeutics, Inc

 

Poster #15

Longitudinal 148-week Extension Study Of Anavex®2-73 For The Treatment Of Alzheimer’s Disease Demonstrates Maintained Activities Of Daily Living Score (Adcs-adl) And Reduced Cognitive Decline (Mmse) For Patient Cohort On Higher Drug Concentration And Confirms Role Of Precision Medicine Patient Selection Biomarkers

Harald Hampel, Mohammad Afshar, Frédéric Parmentier,  Coralie Williams, Adrien Etcheto, Federico Goodsaid, Christopher U. Missling

ANAVEX®2-73, a selective sigma-1 receptor (SIGMAR1) agonist was investigated in a 57-week Phase 2a study with 32 mild-to-moderate Alzheimer’s disease (AD) patients showing a favorable safety profile. An ANAVEX®2-73 concentration-dependent response was observed using exploratory functional Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) and cognitive Mini Mental State Examination (MMSE) endpoints. Status of a single genetic variant on the ANAVEX®2-73 target SIGMAR1 was shown to significantly impact the drug effect. Here we report the current results of the extension study (148 weeks). Relationship between all biomarkers and efficacy outcome measures were investigated using a non-linear rule based Formal Concept Analysis (FCA, implemented in Ariana’s KEM® software). Mixed Model Repeated Measures (MMRM), with a linear time effect hypothesis, and Linear Mixed Effect (LME) modeling, was performed. At 148 weeks into the five-year extended Phase 2a clinical study of ANAVEX®2-73, data confirmed a significant association between ANAVEX®2-73 concentration and both exploratory functional and cognitive endpoints as measured by the ADCS-ADL evaluation and the MMSE, respectively. The cohort of patients treated with higher ANAVEX®2-73 concentration maintained ADCS-ADL performance compared to the lower concentration cohort (p<0.0001). The patient cohort with the higher ANAVEX®2-73 concentration performed better at MMSE compared to the lower concentration cohort (p<0.0008). A significant impact on the drug response levels of both the SIGMAR1 (p<0.0080) and COMT (p<0.0014) genomic biomarkers, identified and specified at week 57, was also confirmed over the 148-week period. ANAVEX®2-73 demonstrated continued favorable safety and tolerability through 148 weeks.

Excluding patients with the two identified biomarker variants (approximately 20% of the population), would lead to further clinically significant improved functional and cognitive scores. Our data support the clinical development of ANAVEX®2-73 by using genetic biomarkers identified within the study population itself. This approach allows pre-specified population (SIGMAR1 and COMT) selection in forthcoming, larger studies. Further clinical studies in multiple indications are underway, including a Phase 2b/3 study in 450 patients with early AD, a Phase 2 study in 120 patients with Parkinson’s disease dementia and a Phase 2 in Rett syndrome.

 

Poster #16

Advancing Screening Efficiency for Detecting Neuro-cognitive Disorders in Primary Care

Boaz Levy, Jacqueline Hogan, Courtney Hess, James M. Ellison, Sarah Greenspan, Matthew Hogan, Kathryn Falcon, Allison Elber, Daniel Driscoll, Ardeshir Hashmi 

Primary care clinicians often miss cognitive dysfunction in older patients. Improving screening efficiency in primary care will likely enhance early detection, the effectiveness of interventions and prognosis of neurocognitive disorders. The goal of the current study was to employ computerized testing and machine learning methods to achieve the efficiency that the busy primary care setting will require for incorporating cognitive screening into routine practice. For this purpose, the study examined the convergent validity of a very brief, self-administered, computerized assessment protocol against one of the most extensively used, clinician-administered instruments – the Montreal Cognitive Assessment (MoCA). We trained three machine learning algorithms to detect impairment (defined by MoCA clinical cutoff score < 26) in 206 participants (mean age = 67.44, SD = 11.63). Classification was based on 25 performance features of the computerized test. Gradient Boosting Trees achieved the best outcome (accuracy=0.81, specificity = 0.88, sensitivity = 0.74, F1 Score = 0.79 and AUC = 0.81). The convergence between the MoCA and computerized test was further demonstrated with K Mean clustering of the 25 predictive features. This analysis yielded three categories that corresponded to the unimpaired (mean=26.98, SD=2.35), mildly impaired (mean=23.58, SD=3.19) and moderately impaired (mean=17.24, SD=4.23) ranges of MoCA scores (F=222.36, p<0.00). In addition, a correlational analysis indicated that subsections of the computerized test were more predictive of age (r=0.48) than MoCA (r=-0.27) in unimpaired participants (i.e., MoCA ≥ 26, n=165). This analysis suggested that the computerized test may be more sensitive than the MoCA to the cognitive changes associated with healthy aging. Finally, the administration of the MoCA took about four times as long as the administration of the computerized test. In summary, this study demonstrated preliminary psychometric properties for cognitive screening with an exceptionally economical and efficient procedure. Further improvement to test sensitivity is warranted; however, results largely show that this technology has potential for enhancing community-wide screenings of neurocognitive disorders in primary care settings.

 

Poster #17

Proof-of-Concept, Double-Blind, Placebo-Controlled Study for CX-8998, a State-Dependent T-Type Calcium (TTCC) Modulator in Essential Tremor Patients (T-CALM): Efficacy and Safety Results

Spyros Papapetropoulos, Stacey Boyer and Margaret S. Lee 

The objective of this study was to determine the efficacy, safety, tolerability and plasma concentrations of CX-8998 in patients with essential tremor (ET) with inadequate response to standard of care anti-tremor medications. ET is among the most prevalent of movement disorders in adults. Propranolol is the only medication approved for the treatment of ET. The T-type calcium channel (TTCC) is a mediator of subthreshold oscillations and excessive rhythmicity in pathophysiologic states found in tremor and is highly expressed in functional tremor network regions. Tremor-related oscillations are a neuronal signature for ET and TTCCs play a critical role in their generation. CX-8998 is a potent, selective, and state-dependent small molecule modulator of TTCCs. We recently completed a randomized, double-blind, placebo-controlled, parallel-group study (NCT03101241) of 95 patients with ET that have an inadequate response to anti-tremor medication (e.g., propranolol). Following consent and screening, subjects were randomized to receive oral doses of either CX-8998 (titrated up to 10mg BID) or placebo for 28 days. Clinical rating scales, patient-reported outcomes and accelerometer recordings of tremor and digital spirography were collected at baseline (visit 1), day 15 (visit 3) and day 28 (visit 4). Investigator-rated TETRAS (The Essential Tremor Rating Assessment Scale) Performance Subscale (p=0.027), TETRAS ADL (p=0.049), TETRAS total score (p=0.007) and Clinician Global Impression of Improvement (p=0.001) significantly improved. Centrally-rated TETRAS Performance Subscale (primary endpoint) did not reach significance. There were no major safety and tolerability concerns. In conclusion, the study achieved proof-of-concept in ET and identified key pivotal study design parameters including primary and secondary efficacy endpoints, patient population and titration scheme. CX-8998 was safe and well tolerated in ET patients. Further studies are needed to evaluate the efficacy of CX-8998 in ET patients. These results are expected to enable late-stage development of CX-8998 in ET.

 

Poster #18

GM604 regulates developmental neurogenesis pathways and the expression of genes associated with Amyotrophic Lateral Sclerosis

William R. Swindell, Krzysztof Bojanowski, Mark S. Kindy, Raymond Chau, Dorothy Ko

GM604 (GM6) was developed as a candidate ALS therapy, which has demonstrated safety and encouraging outcomes in a phase 2A clinical trial. GM6 is a 6 amino acid active site fragment of an endogenous motoneuronotrophic factor (MNTF). The drug has a favorable pharmacokinetic profile and is able to cross the blood-brain barrier.

The purpose of this study was to develop hypotheses regarding the mechanism of action for GM6 using RNAseq transcriptome profiling combined with bioinformatic analysis, studying the responses in SH-SY5Y neuroblastoma cells following GM6 treatment (6, 24 and 48 hours).

We identified 2867 protein-coding genes with expression significantly altered by GM6 (FDR < 0.10). Early (6 hour) responses included up-regulation of Notch and hedgehog signaling components, with increased expression of developmental genes mediating neurogenesis and axon growth. Prolonged GM6 treatment (24 and 48 hours) altered the expression of genes contributing to cell adhesion and the extracellular matrix. GM6 further down-regulated the expression of genes associated with mitochondria, inflammatory responses, mRNA processing and chromatin organization. The up-regulated transcription factors include STAT3, HOXD11, HES7, GLI1. We identified 77 ALS-associated genes with expression significantly altered by GM6 treatment (FDR< 0.10).

Our findings support the hypothesis that GM6 acts through developmental-stage pathways for neuron survival. Gene expression responses were consistent with neurotrophic effects, ECM modulation, and activation of the Notch and hedgehog neurodevelopmental pathways. This multifaceted mechanism of action is unique among existing ALS drug candidates and may be applicable to multiple neurodegenerative diseases. A phase 3 ALS clinical trial is planned.

 

Poster #19

GM604 Attenuates Alzheimer’s Disease Pathology in APP Mice

Mark S. Kindy, Jin Yu, Hong Zhu, Saeid Taheri, William Mondy, Cheryl Kirstein, Dorothy Ko

Motoneuronotrophic factor (MNTF) is an endogenous neurotrophin that is specific for the human nervous system, and some of the observed effects of MNTF include motoneuron differentiation, maintenance, survival, and reinnervation of target muscles and organs. GM6 is a hexapeptide fragment of MNTF that appears to replicate its activity spectrum. In this study, we investigated the effect of GM6 in a mouse model of AD before the development of amyloid plaques and determined how this treatment affected accumulation of Aβ peptide and related pathologic changes. Application of GM6 over a 4-month period in young APP/ΔPS1 double-transgenic mice resulted in improvements in histological and biochemical features. GM6 showed pathological changes in attenuation in Aβ peptide levels, reduction of amyloid load, reduction in inflammation markers including TNFα, IL1β, TGFβ, reduced inflammation mediators (CD-68 and GFAP) which can contribute to the pathologies, increased cathepsin B expression and cleavage of APP to Aβ, and improved spatial orientation. In addition, treatment with GM6 increased brain NGF levels and tempered memory impairment by ∼50% at the highest dose. These data suggest that GM6 may modulate disease-determining pathways involving lowering of Aβ and inflammation at an early stage to slow the histological and clinical progression of AD.

 

Poster #20

TAK-935 (OV935) Reduces Seizure Frequency and Severity and Prevents Premature Lethality in Scn1a+/– Dravet Mice

Jennifer Kearney, Nicole A. Hawkins, Toshiya Nishi, Brett S. Abrahams, Matthew J. During

Dravet syndrome is an epileptic encephalopathy often caused by mutation of SCN1A. Individuals with Dravet syndrome have treatment-resistant epilepsy, developmental delays, intellectual disability, and significantly elevated risk of sudden, unexpected death. TAK-935 (OV935) is the first potent, selective, central nervous system–penetrant inhibitor of the cholesterol 24-hydroxylase (CH24H) enzyme under clinical development for epileptic encephalopathies, including Dravet syndrome. CH24H converts brain cholesterol to 24S-hydroxycholesterol (24HC), a bioactive metabolite that potentiates NMDA signaling and inflammation. In this study, we evaluated the ability of TAK-935 to normalize Dravet-like abnormalities in an Scn1a+/– mouse model, including spontaneous and hyperthermia-provoked seizures, and premature lethality. A cohort of Scn1a+/– mice were monitored over several weeks. At postnatal day (P) P17-P18, mice were subjected to a single hyperthermia-priming seizure induced by slowly elevating core body temperature by ~0.5°C until seizure onset, and then were quickly cooled to 37°C. Mice were then provided ad libitum access to control chow or chow containing 0.02% or 0.07% of TAK-935 and video-monitored for spontaneous seizures over the subsequent 14 days. Survival was monitored until ~6 weeks of age. A separate cohort of Scn1a+/– mice were tested for hyperthermia-induced seizure thresholds at P25 after 7-day ad libitum access to control or TAK-935 chow. A significantly higher percentage of 14-day TAK-935–treated Scn1a+/– mice were seizure-free versus vehicle controls (p<0.0001; n=23-36), with >70% of TAK-935–treated mice seizure-free versus <30% of controls. TAK-935 treatment also resulted in significantly lower average frequency of generalized tonic-clonic seizures (p<0.0004; n=23-36), delayed seizure onset, and reduced seizure severity compared with vehicle controls (p<0.0001; n=25-35). TAK-935 administration completely prevented lethality throughout the experimental period (p<0.002; n=30-50). In the separate 7-day treatment cohort, TAK-935 administration resulted in slightly elevated thresholds for hyperthermia-induced seizure compared with vehicle controls (p<0.02; n=16-20). These data support the novel approach of inhibiting CH24H activity for treatment of refractory epilepsies.


Poster #21

Aquaporin-4 Inhibitor AER-271 Reduces Cerebral Edema and Improves Outcome in Clinically Relevant Models of CNS Injury

George Farr, Christopher H Hall, Susan M Farr, Ramon Wade, Joshua M Detzel, Amielia G Adams, Jasen M Buch, Derek L Beahm, Anthony Caggiano, Christopher A Flask, Kui Xu, Joseph C LaManna, Paul R McGuirk, Walter F Boron and Marc F Pelletier

Cerebral edema is a critical, often life-threatening consequence of severe, acute ischemic stroke. Unfortunately, current therapies are either relatively ineffective or highly invasive. The development of cerebral edema in an ischemic stroke involves movement of water across an intact blood-brain barrier through the Aquaporin-4 (AQP4) water channel.

We report the discovery and development of an effective AQP4 inhibitor designated AER-270, N-[3,5-bis(trifluoromethyl) phenyl]-5-chloro-2-hydroxybenzamide. Using a high-throughput assay based on osmotic shock of AQP4-expressing cells, we screened commercially available small molecule libraries for inhibitors that reduce AQP4-mediated water movement. Screening and validation assays revealed that derivatives of phenylbenzamide are effective at inhibiting AQP4. After medicinal chemistry efforts to improve potency, a compound emerged (AER-270) that has been previously investigated for conditions unrelated to cerebral edema. We tested the efficacy of this molecule in rodent models of CNS injury that are complicated by cerebral edema. In water intoxication, AER-270 and close analogues were effective at reducing the rate of cerebral edema and improving survival. A pro-drug strategy was employed to develop AER-271, 2-{[3,5-Bis(trifluoromethyl) phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate, with improved solubility and the necessary properties for an acute IV therapy. AER-271 was tested in both mouse and rat models of focal ischemic stroke where it reduced cerebral edema and improved neurological outcomes.

This innovative anti-edema strategy targets AQP4 in an environment where no aquaporin inhibitors have successfully entered clinical trials or pre-clinical development. We have completed preclinical safety/toxicology studies, GMP manufacturing and filed an IND for AER-271. Our Phase 1 clinical trial to assess the safety, tolerability and pharmacokinetics of AER-271 is currently underway (ClinicalTrials.gov Identifier NCT03804476).


Poster #22
 

Efficacy and safety of apomorphine sublingual film for the treatment of “OFF” episodes in patients with Parkinson’s disease: A phase 3, double-blind, placebo-controlled trial

Stewart A. Factor,  Stuart Isaacson, Robert A. Hauser, Rajesh Pahwa, Ken Sciarappa, Parul Bhargava, Gazal Vakili, David Blum,  Bradford Navia, C. Warren Olanow

Most patients receiving chronic levodopa treatment for Parkinson’s Disease (PD) develop motor fluctuations with “OFF” episodes. A previous phase 2 study suggested that apomorphine sublingual film (APL) is efficacious for treatment of individual “OFF” episodes. This phase 3, double-blind, placebo-controlled study evaluated the efficacy and safety of APL as an acute, intermittent therapy for “OFF” episodes in patients with PD. Adult patients with PD and ≥1 “OFF” episode per day while on stable doses of levodopa/adjunctive PD medications received increasing doses of APL (10–35 mg) in an open-label titration phase until a FULL “ON” response was achieved. Patients were randomized to placebo or APL at the dose determined during titration for 12 weeks. The primary endpoint was change from predose to 30 minutes postdose in MDS-UPDRS Part III Motor Examination score at week 12. The key secondary endpoint was the percentage of patients with a self-rated FULL “ON” response within 30 minutes at week 12. In total, 109 patients who completed the open-label titration phase were randomized in the double-blind treatment phase (APL=54, placebo=55). Least squares mean (± standard error) change from predose to 30 minutes postdose in MDS-UPDRS Part III at week 12 was –11.1 ± 1.46 with APL and –3.5 ± 1.29 with placebo (difference, –7.6 points; P=0.0002). Separation from placebo was seen as early as 15 minutes and persisted up to the 90-minute timepoint. The self-rated FULL “ON” response rate within 30 minutes postdose at week 12 was significantly higher for APL versus placebo (35% vs 16%; P=0.0426). The most common APL-associated, treatment-emergent adverse events (TEAEs) were nausea (28%), somnolence (13%), and dizziness (9%); the most common oral TEAE was oral mucosal erythema (7%); most TEAEs were mild and reversible upon treatment discontinuation. APL was an efficacious and well-tolerated treatment for the acute, intermittent management of “OFF” episodes associated with PD.


Poster #23

Neurological Disease and the Influence of Neurovascular Coupling

Robert Black

Neurovascular coupling (NVC) is the subject of significant research interest for its contributory or causal relationships with the pathogenesis of neurodegenerative disease. NVC underpins BOLD (blood oxygen level dependent) MRI and that imaging method, in turn, can provide insights into NVC dysfunction. Time-varying caloric vestibular stimulation (tvCVS) is a new therapeutic treatment modality that has been studied for the reduction of pain in episodic migraineurs and for the mitigation of a range of symptoms associated with Parkinson’s disease. Though migraines and PD are not usually viewed as having common origins, both may include NVC dysfunction as a component in disease development. We have found that tvCVS induces oscillations in cerebral blood flow velocity (CBFv), with the period of oscillation matching that of B waves. B waves are generated in the pons and are part of the autoregulatory response. The induction of CBFv oscillations presents two possibilities for clinical study: as a probe of the health of NVC and as a potential therapeutic method for improving NVC. The latter possibility draws conceptual support from the literature both in terms of helping to clear metabolic waste and by increase the passage of neurotropic molecules through the blood-brain-barrier. We will review our clinical data through the lens of a model that focuses on the entrainment of brain oscillators as a means to show how measures of slow oscillations in neuronal functional connectivity have a common origin with slow CBF oscillations, thereby providing a new perspective on the wider implications of NVC and brain function.


Poster #24

Population exposure-response modeling of the effects of apomorphine sublingual film on QTc in patients with Parkinson’s disease

Felix Agbo,Yu-Yuan Chiu, Sunny Chapel, Gerald Galluppi, David Blum, Bradford Navia

A thorough QT study was conducted to evaluate the effect of apomorphine sublingual film (APL) on the QT interval in patients with Parkinson’s disease (PD) and “OFF” episodes. Modeling was performed to characterize the relationship between plasma apomorphine concentrations and QTc (QT interval corrected for heart rate) and predict changes in QTc from baseline at clinically-relevant apomorphine concentrations in patients with PD. Concentration-QTc models were developed from 447 time-matched apomorphine concentrations and electrocardiogram data from 39 patients with PD who received placebo or APL (10–50 mg) in a thorough QT study using nonlinear mixed effects modeling (NONMEM®, version 7.3). QTc was assessed using Bazett’s, Fridericia’s (QTcF), and population (QTcP) correction methods. Various models were evaluated. The final model was used to predict changes in QTc from baseline at clinically-relevant apomorphine concentrations. A final linear mixed effects model using QTcP with fixed effects for sex on baseline and random effects on intercept adequately described the relationship between apomorphine concentration and QTc interval. The slope of the QTcP-exposure relationship was minimal with a confidence interval (CI) that included zero (–0.0976 msec·mL/ng [95% CI: –0.8091, 0.6139]), indicating no strong correlation between QT prolongation and increasing apomorphine concentration. A sensitivity analysis with QTcF, which failed to adequately correct for heart rate, resulted in a slope estimate of the concentration-QTcF relationship of 0.274 msec·mL/ng (95% CI: –0.37, 0.92) and demonstrated a nonsignificant plasma concentration-QTc relationship. At the highest proposed dose of APL (35 mg), the estimate of the 95% CI upper bound for QTcP change from baseline was 4 msec at maximum plasma concentration, which is below the regulatory threshold of 10 msec, indicating no clinically relevant effect of APL on QTc. APL had no clinically relevant effect on QTc prolongation across the proposed therapeutic dose range of 10 to 35 mg. 

 


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