Small Molecule · SPN-810

SPN-810 (molindone ER)

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

Low-dose extended-release oral reformulation of molindone, a first-generation dihydroindolone antipsychotic (dopamine D2 receptor antagonist), developed by Supernus Pharmaceuticals for impulsive aggression in children with ADHD inadequately controlled by optimized stimulant monotherapy and behavioral therapy. Molindone was marketed as Moban for schizophrenia from 1974 until Endo halted sales in January 2010; SPN-810 repurposed the molecule at sub-antipsychotic doses (12-36 mg/day) for aggression symptom control. FDA Fast Track designation granted August 2014. Both pivotal Phase 3 trials in patients 6-11 years old missed their primary endpoint (P301 p=0.092 in November 2019; P302 p=0.961 in February 2020), and Supernus halted all SPN-810 development in impulsive aggression on 2020-02-25.

Also known as: SPN-810, SPN 810, molindone, molindone hydrochloride extended-release, 7416-34-4

Data current as of

Key facts

Modality
Small molecule
Chemical class
dihydroindolone, morpholine
Chemistry
Racemic
Mechanism
D2 antagonist
Highest phase
Discontinued
Lead indication
Attention-deficit/hyperactivity disorder
Developer
Supernus Pharmaceuticals, Inc. (SUPN)
Designations
FDA Fast Track (Impulsive Aggression In ADHD; Granted 2014-08-14)
Trials
7 tracked · 138 sites

Mechanism of action#

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—ⓘ

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——

Development timeline#

201020122014201620182020Phase 214 Aug 2014 — Fast Track — FDA grants Fast Track designation to SPN-810 for impulsive aggression in ADHD21 Oct 2008 — phase change — Phase 2a study 810P201 (NCT00626236) started: safety and tolerability of SPN-810 in 78 children with ADHD and persistent serious conduct problems.Phase 35 Nov 2019 — readout (missed) — 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.25 Jan 2016 — phase change — 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.Discontinued25 Feb 2020 — readout (missed) — 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.
Phase change Readout Event UpcomingHover a marker for details.
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.

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

DiscontinuedDiscontinuedAttention-deficit/hyperactivity disorder indication →

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.

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#

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.

Show all 7 trials

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

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
Show all 13 sources
  1. 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
  2. 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
  3. Supernus Receives FDA Fast Track Designation for SPN-810 (2014-08-14) — Supernus Pharmaceuticals, Inc. (via GlobeNewswire)