SPN-810 · program

SPN-810 (molindone ER) for Attention-deficit/hyperactivity disorder

DiscontinuedDiscontinuedSupernus Pharmaceuticals, Inc. (SUPN)
  • FDA Fast Track (Impulsive Aggression In ADHD; Granted 2014-08-14)

SPN-810 (low-dose extended-release molindone) for impulsive aggression (IA) in patients with ADHD — the sole SPN-810 indication, and the precise condition is narrower than the ADHD slug it is recorded under: impulsive aggression comorbid with ADHD, persisting despite optimized stimulant monotherapy and behavioral therapy. Development ran from a 2008 Phase 2a (810P201) through a positive 2012 Phase 2b (810P202: low and medium doses met the remission-of-aggression endpoint, p=0.009 and p=0.043), FDA Fast Track in August 2014, and a four-study Phase 3 CHIME program begun January 2016. Both pivotal trials in children 6-11 missed their primary endpoint of percent change in weekly impulsive-aggression episode frequency: P301 reported 2019-11-05 (median -58.6% vs placebo, p=0.092 on the combined stage 1+2 analysis, despite a significant stage-1 interim, p=0.029) and P302 reported 2020-02-25 (median -51.3%, p=0.961). A 2019-12-09 post-hoc excluding mild-IA patients turned P301 positive (p=0.017), but P302 — with its SAP amended to reflect that exclusion — still failed. On 2020-02-25 Supernus announced it would halt all development activities on SPN-810 in IA; the adolescent study (810P503) and open-label extension (810P304) were terminated, the latter's registry record stating the program was shut down due to lack of efficacy. The drug was consistently reported safe and well tolerated; the failure was efficacy, not safety.

Data current as of

Development timeline

DiscontinuedFeb 2020
  1. missedPhase 3 P302 (CHIME 2) of SPN-810 36 mg in impulsive aggression in children 6-11 with ADHD missed its primary endpoint (median 51.3% reduction in weekly IA episode frequency, p=0.961 vs placebo); Supernus halted all SPN-810 development in impulsive aggression.↗
Phase 3Jan 2016 – Nov 2019
  1. missedPhase 3 P301 (CHIME 1) of SPN-810 36 mg in impulsive aggression in children 6-11 with ADHD missed its primary endpoint: median 58.6% reduction in weekly IA episode frequency, p=0.092 vs placebo on the combined stage 1+2 analysis.↗
  2. Phase 3 CHIME program opened with 810P301 (NCT02618408, started 2016-01-25), followed by 810P302 (NCT02618434, 2016-02-16) and the 810P304 open-label extension (NCT02691182, April 2016). The advance to late-stage development had been announced 2012-11-20 on positive Phase 2b results, and FDA granted Fast Track designation 2014-08-14.
Phase 2Oct 2008 – Aug 2014
  1. Fast TrackFDA grants Fast Track designation to SPN-810 for impulsive aggression in ADHD↗
  2. Phase 2a study 810P201 (NCT00626236) started: safety and tolerability of SPN-810 in 78 children with ADHD and persistent serious conduct problems.

Readouts

  • 2020-02-25ReportedTopline datamissedNCT02618434

    Phase 3 P302 (CHIME 2) of SPN-810 36 mg in impulsive aggression in children 6-11 with ADHD missed its primary endpoint (median 51.3% reduction in weekly IA episode frequency, p=0.961 vs placebo); Supernus halted all SPN-810 development in impulsive aggression. ↗

  • 2019-11-05ReportedTopline datamissedNCT02618408

    Phase 3 P301 (CHIME 1) of SPN-810 36 mg in impulsive aggression in children 6-11 with ADHD missed its primary endpoint: median 58.6% reduction in weekly IA episode frequency, p=0.092 vs placebo on the combined stage 1+2 analysis. ↗

Clinical trials in Attention-deficit/hyperactivity disorder

NCT03638466810P204Phase 2Discontinuedn=7

Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With ADHD

Started May 2019· Primary completion Nov 2019· 📍 3 sites across 1 country (United States)

NCT03597503810P503Phase 3Discontinuedn=41

Treatment of Impulsive Aggression (IA) in Adolescent With ADHD in Conjunction With Standard ADHD Treatment

Started Jul 2018· Primary completion Jan 2020· 📍 38 sites across 1 country (United States)

NCT02691182810P304Phase 3Discontinuedn=491

Treatment of Impulsive Aggression in Subjects With ADHD in Conjunction With Standard ADHD Treatment (CHIME 4)

Started Apr 2016· Primary completion May 2021· 📍 1 site across 1 country (United States)

NCT02618434810P302Phase 3Completedn=297

Treatment of Impulsive Aggression in Subjects With ADHD in Conjunction With Standard ADHD Treatment (CHIME 2)

Started Feb 2016· Primary completion Nov 2019· 📍 32 sites across 1 country (United States)

missedprimaryPercent change from baseline in average weekly frequency of impulsive aggression episodes — Median percent reduction 51.3% (SPN-810 36 mg) (0.961)

Primary endpoint decisively not met in children 6-11 — even after the statistical analysis plan had been amended (submitted to FDA per the 2019-12-09 update) to exclude mild-IA patients in line with the P301 post-hoc. Consistent with P301, the drug was safe and well tolerated. On these results Supernus halted all SPN-810 development in impulsive aggression.

NCT02618408810P301Phase 3Completedn=333

Treatment of Impulsive Aggression in Subjects With ADHD in Conjunction With Standard ADHD Treatment (CHIME 1)

Started Jan 2016· Primary completion Sept 2019· 📍 28 sites across 1 country (United States)

missedprimaryPercent change from baseline in average weekly frequency of impulsive aggression episodes — Median percent reduction 58.6% (SPN-810 36 mg) on the combined stage 1+2 analysis (0.092 (combined); 0.029 stage 1 interim; 0.537 stage 2)

Primary endpoint not met in children 6-11 on the prespecified combined analysis. The stage-1 interim had been significant (p=0.029); post-interim variability — attributed by Supernus to 6/135 mild-IA patients with baseline <=6 episodes/week — eroded the combined result. A post-hoc excluding mild-IA patients from both arms yielded p=0.017 (sensitivity analysis p=0.044). Drug safe and well tolerated. After the interim, the 18 mg arm had been dropped and all patients randomized to 36 mg or placebo.

NCT01364662810P202Phase 2Completedn=121

A Study to Evaluate the Efficacy and Safety of SPN-810 as Adjunctive Therapy in Children With Impulsive Aggression Comorbid With Attention-Deficit/Hyperactivity Disorder (ADHD)

Started Jun 2011· Primary completion Oct 2012· 📍 27 sites across 1 country (United States)

mixedprimaryChange in Retrospective-Modified Overt Aggression Scale (R-MOAS) score — R-MOAS score reduction of 62.6% (low dose) and 57.9% (medium dose) in all patients; 80.9% and 75.2% in patients >=30 kg (0.071/0.115 all patients; 0.024/0.049 in patients >=30 kg)

In the all-patients analysis the R-MOAS change co-primary narrowly missed significance at low/medium doses, but reached significance in the >=30 kg weight subgroup — the dose-finding basis for advancing to Phase 3.

metprimaryRate of remission of aggression (R-MOAS remission) — R-MOAS remission in 51.9% (low dose) and 40.0% (medium dose) of patients (0.009 (low dose); 0.043 (medium dose))

Low and medium doses of SPN-810 met the remission-of-aggression endpoint with statistical significance vs placebo across all 121 randomized children 6-12.

NCT00626236810P201Phase 2Completedn=78

Phase 2a Study of Safety and Tolerability of SPN-810 in Children With ADHD and Persistent Serious Conduct Problems

Started Oct 2008· Primary completion Sept 2009· 📍 9 sites across 1 country (United States)

Formulations

FormulationRouteRegimenPharmacokinetics
SPN-810 extended-release oral molindone (12-36 mg/day)Extended-release oral formulation of molindone hydrochloride
Phase 2b (810P202) tested three weight-adjusted dose bands across 121 children. The Phase 3 CHIME program tested 18 mg/day and 36 mg/day; after the planned P301 interim analysis the 18 mg arm was dropped and all patients were randomized to 36 mg/day or placebo. Doses are deliberately below the legacy antipsychotic range for molindone.
Oral——

Mechanism of action (compound-wide)

Molindone is a first-generation dihydroindolone antipsychotic whose principal pharmacology is antagonism of the dopamine D2 receptor. SPN-810 applied the molecule at low, sub-antipsychotic extended-release doses (12-36 mg/day, versus 50-225 mg/day for the legacy schizophrenia indication) on the hypothesis that modest D2 blockade would reduce the frequency of impulsive aggression episodes in children with ADHD without full antipsychotic-range exposure. The hypothesis was not confirmed: both pivotal Phase 3 trials missed their primary endpoint on the prespecified analysis.

TargetActionAffinity
D2primaryDRD2Antagonist—ⓘ

← Full SPN-810 compound page (identity, identifiers, all indications)

Sources

  1. Ceresoli-Borroni G, Nasser A, Adewole T, et al. A Double-Blind, Randomized Study of Extended-Release Molindone for Impulsive Aggression in ADHD. J Atten Disord. 2021;25(11) — Journal of Attention Disorders (SAGE) / PubMed
  2. Molindone, CID 23897 — C16H24N2O2, (±)-molindone (racemic), CAS 7416-34-4, UNII RT3Y3QMF8N, ChEMBL CHEMBL460; 'SPN-810' listed as synonym; dopamine-antagonist pharmacologic classification — PubChem (NCBI, U.S. National Library of Medicine)
  3. NCT00626236 (810P201) — Phase 2a Study of Safety and Tolerability of SPN-810 in Children With ADHD and Persistent Serious Conduct Problems — ClinicalTrials.gov (U.S. National Library of Medicine)
  4. NCT01364662 (810P202) — SPN-810 as Adjunctive Therapy in Children With Impulsive Aggression Comorbid With ADHD (Phase 2b) — ClinicalTrials.gov (U.S. National Library of Medicine)
  5. NCT02618408 (810P301, CHIME 1) — Treatment of Impulsive Aggression in Subjects With ADHD in Conjunction With Standard ADHD Treatment — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT02618434 (810P302, CHIME 2) — Treatment of Impulsive Aggression in Subjects With ADHD in Conjunction With Standard ADHD Treatment — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT02691182 (810P304, CHIME 4) — open-label extension; terminated: 'The program was shut down due to a lack of efficacy.' — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT03597503 (810P503) — Treatment of Impulsive Aggression in Adolescents With ADHD; terminated: 'Business decision, not related to safety.' — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT03638466 (810P204) — Exploratory fMRI Study on the Treatment for Impulsive Aggression in Children With ADHD; terminated: 'Financial decision.' — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. Supernus Announces Fourth Quarter and Full Year 2019 Financial Results — P302 primary endpoint miss (p=0.961) and decision to halt all SPN-810 development in IA (press release dated 2020-02-25; 8-K EX-99.1 filed 2020-02-27) — Supernus Pharmaceuticals, Inc. via SEC EDGAR
  11. Supernus Announces Positive Phase IIb Results on SPN-810 and Decision to Advance to Late Stage Development (press release dated 2012-11-20; 8-K EX-99.2 filed 2012-11-21) — Supernus Pharmaceuticals, Inc. via SEC EDGAR
  12. Supernus Announces Third Quarter 2019 Financial Results and Topline Data from Phase III Study of SPN-810 — P301 primary endpoint miss, p=0.092 (press release dated 2019-11-05; 8-K EX-99.1) — Supernus Pharmaceuticals, Inc. via SEC EDGAR
  13. Supernus Receives FDA Fast Track Designation for SPN-810 (2014-08-14) — Supernus Pharmaceuticals, Inc. (via GlobeNewswire)