Meeting News

HLD200 improves functioning in children with ADHD

SAN DIEGO — Data presented at the American Psychiatric Association Annual Meeting indicated efficacy and safety of HLD200, a delayed-release and extended-release formulation of methylphenidate from Ironshore Pharmaceuticals, for morning and evening functioning in pediatric ADHD.

“We know a child’s ADHD has an impact on the entire family unit, with parents experiencing much of the burden associated with their child’s inability to complete routine tasks during the morning and evening routine like brushing teeth, getting dressed, staying on schedule, sitting through meals and getting ready for bed,” Floyd R. Sallee, MD, PhD, chief medical officer of Ironshore Pharmaceuticals Inc., said in a press release. “These tasks can be difficult for all young children, but they are exacerbated in patients with ADHD. If approved by the FDA, HLD200 could potentially change the way ADHD is treated given the observed impact on clinical outcomes.

HLD200 for functioning in ADHD

To assess efficacy of HLD200 on early morning and late afternoon/evening functioning in ADHD, researchers conducted post-hoc analysis of randomized, double-blind, multicenter, placebo-controlled, parallel-group phase 3 trial results among an intent-to-treat population of 161 children, of which 80 received placebo. Impairments in early morning and late afternoon/evening functioning were evaluated via the Parent Rating of Evening and Morning Behaviors-Revised, Morning (PREMB-R AM) and Evening (PREMB-R PM) subscales. Each item was scored on a severity scale of 0 to 3, with 0 indicating no impairment and 3 indicating “a lot of impairment.”

Mean dose of HLD200 achieved after 3 weeks of treatment was 68.1 mg.

After 3 weeks of treatment, mean changes in PREMB-R AM (–1.39 vs. –0.73; P < .001) and PREMB-R PM (–0.85 to –0.47; P = .001) item scores were significantly reduced from baseline, compared with placebo.

From baseline to 3 weeks, mean individual item scores were significantly reduced on all PREM-B-R AM items, including getting up and out of bed, getting ready and arguing or struggling in the morning (P .0014 for all).

From baseline to 3 weeks, mean individual item scores were significantly reduced on four out of eight PREMB-R PM items, including sitting through dinner, playing quietly, settling down and getting ready for bed (P < .01 for all), and falling asleep (P < .05).

Researchers noted a trend towards reduction on the three other PREMB-R PM items (P .08).

A separate analysis of early morning functioning, measured by the 20-item Before School Functioning Questionnaire (BSFQ), was also conducted in the intent-to-treat population.

Participants who received HLD200 or placebo had comparable mean BSFQ item scores at baseline.

At 3 weeks, means BSFQ item scores were significantly reduced among participants who received HLD200, compared with placebo (0.91 vs. 1.43; P = .0002).

Mean individual item scores were also significantly reduced among participants who received HLD200 on 19 out of 20 items, including time awareness, listening, attention (P < .001 for all); being quiet, following directions, distraction, talkativeness, forgetfulness, organization, silliness, hygiene, breakfast, interrupting, getting to school (P < .01 for all); and procrastination, independence, awaiting turn, hyperactivity, and dressing (P < .05 for all).

Misplacing/losing items was the only individual item score with no significant difference.

Caregiver-reported improvement

To determine if 3 weeks of HLD200 improved caregiver-rated ADHD symptoms and reduced caregiver strain, researchers assessed parent ratings on the Conners’ Global Index-Parent (CGI-P) and the Caregiver Strain Questionnaire (CGSQ).

Baseline CGI-P and CGSQ scores were comparable between HLD200 and placebo groups.

At 3 weeks, caregivers of children who received HLD200 reported significant reductions in CGI-P scores, compared with placebo (12.3 vs. 174.; P < .001).

CGSQ scores were also significantly reduced after 3 weeks of HLD200 treatment, compared with placebo (41.2 vs. 49.1; P < .001).

Pharmacokinetics

To determine single-dose pharmacokinetics and tolerability of HLD200 in healthy adults, adolescents and children with ADHD and to compare pharmacokinetics and tolerability between these groups, two single-center, open-label studies were conducted among healthy adults (n = 12) and children (n = 11) and adolescents (n = 18) with ADHD.

The pharmacokinetic profile of HLD200 was characterized by an 8- to 10-hour delay in methylphenidate release followed by an extended, controlled-release period that established an ascending absorption profile coinciding with the early morning and afternoon.

Mean values of weight-adjusted endpoints were similar among adults and in adolescents and children with ADHD.

Peak plasma concentration was 9.1 ng/mL (35.2 mg/kg) in adults; 8.8 ng/mL (34.5 mg/kg) in adolescents; and 7.4 ng/mL (30.1 mg/kg) in children.

Time to peak concentration was 15.6 (11.1) hours in adults; 17.1 (14.5) hours in adolescents; and 17.7 (14.1) hours in children.

Median time to peak concentration was statistically different between adults and children (P = .003), but was not considered clinically meaningful by researchers.

Variability in mean time to achieve plasma methylphenidate concentrations of 2, 3, 4, and 5 ng/mL was low among all three groups.

Four adverse events were reported in adults, while 17 were reported among adolescents are children.

All adverse events were mild or moderate and none were sleep-related, according to researchers.

“We are delighted to be sharing pivotal trial data for HLD200, which are being presented for the first time. it is a noteworthy finding that HLD200-treated children demonstrated statistically significant improvements, relative to placebo, in ADHD functioning during both the early morning and evening bedtime routines,” Sallee said in the release. “These findings may correlate to the statistically significant reduction in measures of caregiver strain observed in the study data.” – by Amanda Oldt

Reference:

Childress A, et al. Single-dose pharmacokinetics of HLD200, a delayed-release and extended-release methylphenidate, in adults and in adolescents and children with ADHD.

Pliszka SR, et al. Effect of HLD200 on caregiver-reported ADHD symptom improvement in children with ADHD and caregiver strain: Results from a phase 3 trial.

Pliszka SR, et al. Efficacy of HLD200 on early morning and late afternoon/evening functioning assessed by individual item ratings on the PREMB-R in children with ADHD.

Wilens TE, et al. Consistent efficacy of HLD200 on early morning functioning in children with ADHD: Analysis of BSFQ item ratings.

Presented at: American Psychiatric Association Annual Meeting; May 20-24, 2017; San Diego.

Disclosure: Childress reports financial ties with Arbor Pharmaceuticals, Ironshore Pharmaceuticals, Neos Therapeutics Inc., Neurovance, Noven Pharmaceutical, Pfizer, Rhodes Pharmaceuticals, Shire, and Sunovion Pharmaceuticals Inc. Sallee reports financial ties with AstraZeneca Pharmaceuticals, Ironshore Pharmaceuticals, Otsuka Pharmaceuticals, and P2D Inc. The other researchers report no relevant financial disclosures.

SAN DIEGO — Data presented at the American Psychiatric Association Annual Meeting indicated efficacy and safety of HLD200, a delayed-release and extended-release formulation of methylphenidate from Ironshore Pharmaceuticals, for morning and evening functioning in pediatric ADHD.

“We know a child’s ADHD has an impact on the entire family unit, with parents experiencing much of the burden associated with their child’s inability to complete routine tasks during the morning and evening routine like brushing teeth, getting dressed, staying on schedule, sitting through meals and getting ready for bed,” Floyd R. Sallee, MD, PhD, chief medical officer of Ironshore Pharmaceuticals Inc., said in a press release. “These tasks can be difficult for all young children, but they are exacerbated in patients with ADHD. If approved by the FDA, HLD200 could potentially change the way ADHD is treated given the observed impact on clinical outcomes.

HLD200 for functioning in ADHD

To assess efficacy of HLD200 on early morning and late afternoon/evening functioning in ADHD, researchers conducted post-hoc analysis of randomized, double-blind, multicenter, placebo-controlled, parallel-group phase 3 trial results among an intent-to-treat population of 161 children, of which 80 received placebo. Impairments in early morning and late afternoon/evening functioning were evaluated via the Parent Rating of Evening and Morning Behaviors-Revised, Morning (PREMB-R AM) and Evening (PREMB-R PM) subscales. Each item was scored on a severity scale of 0 to 3, with 0 indicating no impairment and 3 indicating “a lot of impairment.”

Mean dose of HLD200 achieved after 3 weeks of treatment was 68.1 mg.

After 3 weeks of treatment, mean changes in PREMB-R AM (–1.39 vs. –0.73; P < .001) and PREMB-R PM (–0.85 to –0.47; P = .001) item scores were significantly reduced from baseline, compared with placebo.

From baseline to 3 weeks, mean individual item scores were significantly reduced on all PREM-B-R AM items, including getting up and out of bed, getting ready and arguing or struggling in the morning (P .0014 for all).

From baseline to 3 weeks, mean individual item scores were significantly reduced on four out of eight PREMB-R PM items, including sitting through dinner, playing quietly, settling down and getting ready for bed (P < .01 for all), and falling asleep (P < .05).

Researchers noted a trend towards reduction on the three other PREMB-R PM items (P .08).

A separate analysis of early morning functioning, measured by the 20-item Before School Functioning Questionnaire (BSFQ), was also conducted in the intent-to-treat population.

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Participants who received HLD200 or placebo had comparable mean BSFQ item scores at baseline.

At 3 weeks, means BSFQ item scores were significantly reduced among participants who received HLD200, compared with placebo (0.91 vs. 1.43; P = .0002).

Mean individual item scores were also significantly reduced among participants who received HLD200 on 19 out of 20 items, including time awareness, listening, attention (P < .001 for all); being quiet, following directions, distraction, talkativeness, forgetfulness, organization, silliness, hygiene, breakfast, interrupting, getting to school (P < .01 for all); and procrastination, independence, awaiting turn, hyperactivity, and dressing (P < .05 for all).

Misplacing/losing items was the only individual item score with no significant difference.

Caregiver-reported improvement

To determine if 3 weeks of HLD200 improved caregiver-rated ADHD symptoms and reduced caregiver strain, researchers assessed parent ratings on the Conners’ Global Index-Parent (CGI-P) and the Caregiver Strain Questionnaire (CGSQ).

Baseline CGI-P and CGSQ scores were comparable between HLD200 and placebo groups.

At 3 weeks, caregivers of children who received HLD200 reported significant reductions in CGI-P scores, compared with placebo (12.3 vs. 174.; P < .001).

CGSQ scores were also significantly reduced after 3 weeks of HLD200 treatment, compared with placebo (41.2 vs. 49.1; P < .001).

Pharmacokinetics

To determine single-dose pharmacokinetics and tolerability of HLD200 in healthy adults, adolescents and children with ADHD and to compare pharmacokinetics and tolerability between these groups, two single-center, open-label studies were conducted among healthy adults (n = 12) and children (n = 11) and adolescents (n = 18) with ADHD.

The pharmacokinetic profile of HLD200 was characterized by an 8- to 10-hour delay in methylphenidate release followed by an extended, controlled-release period that established an ascending absorption profile coinciding with the early morning and afternoon.

Mean values of weight-adjusted endpoints were similar among adults and in adolescents and children with ADHD.

Peak plasma concentration was 9.1 ng/mL (35.2 mg/kg) in adults; 8.8 ng/mL (34.5 mg/kg) in adolescents; and 7.4 ng/mL (30.1 mg/kg) in children.

Time to peak concentration was 15.6 (11.1) hours in adults; 17.1 (14.5) hours in adolescents; and 17.7 (14.1) hours in children.

Median time to peak concentration was statistically different between adults and children (P = .003), but was not considered clinically meaningful by researchers.

Variability in mean time to achieve plasma methylphenidate concentrations of 2, 3, 4, and 5 ng/mL was low among all three groups.

PAGE BREAK

Four adverse events were reported in adults, while 17 were reported among adolescents are children.

All adverse events were mild or moderate and none were sleep-related, according to researchers.

“We are delighted to be sharing pivotal trial data for HLD200, which are being presented for the first time. it is a noteworthy finding that HLD200-treated children demonstrated statistically significant improvements, relative to placebo, in ADHD functioning during both the early morning and evening bedtime routines,” Sallee said in the release. “These findings may correlate to the statistically significant reduction in measures of caregiver strain observed in the study data.” – by Amanda Oldt

Reference:

Childress A, et al. Single-dose pharmacokinetics of HLD200, a delayed-release and extended-release methylphenidate, in adults and in adolescents and children with ADHD.

Pliszka SR, et al. Effect of HLD200 on caregiver-reported ADHD symptom improvement in children with ADHD and caregiver strain: Results from a phase 3 trial.

Pliszka SR, et al. Efficacy of HLD200 on early morning and late afternoon/evening functioning assessed by individual item ratings on the PREMB-R in children with ADHD.

Wilens TE, et al. Consistent efficacy of HLD200 on early morning functioning in children with ADHD: Analysis of BSFQ item ratings.

Presented at: American Psychiatric Association Annual Meeting; May 20-24, 2017; San Diego.

Disclosure: Childress reports financial ties with Arbor Pharmaceuticals, Ironshore Pharmaceuticals, Neos Therapeutics Inc., Neurovance, Noven Pharmaceutical, Pfizer, Rhodes Pharmaceuticals, Shire, and Sunovion Pharmaceuticals Inc. Sallee reports financial ties with AstraZeneca Pharmaceuticals, Ironshore Pharmaceuticals, Otsuka Pharmaceuticals, and P2D Inc. The other researchers report no relevant financial disclosures.

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