Small Molecule · ND0612

ND0612 (levodopa/carbidopa continuous subcutaneous infusion)

Filed (NDA)NeuroDerm

Drug-device combination providing 24-hour/day continuous subcutaneous infusion of a proprietary liquid formulation of levodopa/carbidopa (60.0/7.5 mg/mL) through a non-surgical, belt-worn pump system, developed by NeuroDerm Ltd. (a wholly-owned subsidiary of Mitsubishi Tanabe Pharma Corporation) for motor fluctuations in Parkinson's disease. The rationale: oral immediate-release levodopa/carbidopa produces fluctuating plasma levodopa levels that drive OFF periods in advanced disease; continuous subcutaneous delivery maintains stable levodopa concentrations without the surgical procedure required by intrajejunal levodopa gel. NeuroDerm's chemistry achievement was formulating levodopa and carbidopa — poorly soluble molecules — as a stable liquid concentrated enough for subcutaneous minipump delivery. The pivotal Phase 3 BouNDless trial (published in Lancet Neurology, 2024) showed ND0612 plus supplemental oral IR-LD/CD gave an additional 1.72 h/day of ON time without troublesome dyskinesia versus optimized oral IR-LD/CD (p<0.0001). US NDA submitted 2023; FDA issued Complete Response Letters in June 2024 and again in October 2025 (the second citing manufacturing-site and nonclinical observations); a further resubmission is planned. An EMA marketing authorization application has been under centralized review since February 2025.

Also known as: ND0612, ND-0612, ND 0612, ND0612H, ND0612L

Data current as of

Key facts

Modality
Small molecule
DEA schedule
Unscheduled
Chemistry
Prodrug
Mechanism
AADC inhibitor
Highest phase
Filed (NDA)
Lead indication
Parkinson's disease
Developer
NeuroDerm
Trials
2 tracked · 160 sites

Mechanism of action#

Continuous dopamine-replacement therapy. Levodopa, the metabolic precursor of dopamine, crosses the blood-brain barrier and is decarboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC, gene DDC) in the CNS, restoring striatal dopaminergic tone lost in Parkinson's disease. Carbidopa is a peripherally restricted AADC inhibitor that does not cross the blood-brain barrier; it blocks premature peripheral conversion of levodopa to dopamine, increasing central levodopa availability and reducing peripheral dopaminergic adverse effects. The innovation in ND0612 is not the pharmacology — both molecules have been standard of care since 1975 — but the delivery: a stable liquid co-formulation (levodopa/carbidopa 60.0/7.5 mg/mL) infused subcutaneously 24 h/day via a wearable pump, which maintains near-constant plasma levodopa concentrations and thereby reduces the motor fluctuations (OFF periods) driven by the pulsatile pharmacokinetics of oral immediate-release dosing.

TargetActionAffinity
AADCprimaryDDCInhibitor—ⓘ

Formulations#

FormulationRouteRegimenPharmacokinetics
ND0612 liquid levodopa/carbidopa 60.0/7.5 mg/mL, 24 h/day continuous subcutaneous infusion24-hour/day continuous subcutaneous infusion via a non-surgical, wearable (belt-worn) pump system; drug-device combination
Proprietary liquid co-formulation of levodopa/carbidopa 60.0/7.5 mg/mL delivered as a continuous subcutaneous infusion 24 h/day, with supplemental oral immediate-release levodopa/carbidopa if needed; in the Phase 3 BouNDless trial each participant's infusion regimen was individually optimized during an open-label run-in of up to 12 weeks before randomization, so no single fixed daily dose applies.
SubcutaneousOther—

Development timeline#

20182020202220242026TodayPhase 24 May 2016 — phase change — Phase 2b open-label long-term safety study BeyoND (NCT02726386, ND0612H-012) started per ClinicalTrials.gov (214 enrolled, international). Earlier Phase 1/2 PK studies preceded this (e.g. NCT02096601), and development at the time was split into higher-dose ND0612H and lower-dose ND0612L before consolidation into a single ND0612 program after FDA feedback; BeyoND's start is used as the phase_2 anchor because it is the earliest clean registry date for the program that fed the NDA.Phase 39 Jan 2023 — readout (met) — BouNDless Phase 3 topline: ND0612 met the primary endpoint, delivering a clinically meaningful and statistically significant increase in ON time without troublesome dyskinesia vs optimized oral IR-LD/CD, and met the first secondary endpoints in the hierarchy.30 Sept 2019 — phase change — Pivotal Phase 3 BouNDless trial (NCT04006210, ND0612-317) started per ClinicalTrials.gov: multicenter, randomized, active-controlled, double-blind, double-dummy trial of continuous subcutaneous ND0612 vs oral IR-LD/CD in Parkinson's disease with motor fluctuations, at 117 sites in 16 countries.Filed (NDA)23 Oct 2025 — Complete Response Letter — FDA issues second Complete Response Letter for ND061228 May 2025 — NDA/BLA filed — FDA accepts NDA resubmission for ND061228 May 2025 — PDUFA date set — PDUFA target action date set for Q4 2025 for ND0612 resubmission20 Feb 2025 — EMA marketing authorization application filed — EMA accepts ND0612 marketing authorization application for review30 Sept 2024 — Conference presentation — BouNDless open-label-extension and additional Phase 3 data presented at MDS Congress 202411 Jun 2024 — Complete Response Letter — FDA issues first Complete Response Letter for ND061215 Mar 2024 — readout (met) — BouNDless full results published in Lancet Neurology (Espay et al. 2024;23(5):465-476): +1.72 h/day ON time without troublesome dyskinesia (95% CI 1.08-2.36, p<0.0001), OFF time -1.40 h/day; first four hierarchical secondary endpoints met; infusion-site reactions the most common adverse event.31 Dec 2023 — phase change — NDA submitted to the U.S. FDA during 2023. YEAR-PRECISION ANCHOR: no company release discloses the exact submission date — the FDA resubmission-acceptance announcement (2025-05-28) states only that the NDA 'was initially submitted to the FDA in 2023'. The 2023-12-31 date is a sortable year-end anchor, not a real date. The program has remained at 'filed' through two Complete Response Letters (announced 2024-06-11 and 2025-10-23; captured as events, not phase changes): the NDA is not withdrawn, a further resubmission is planned, and the EMA MAA (accepted 2025-02-20) is under active review.31 Dec 2023 — NDA/BLA filed — NDA for ND0612 submitted to U.S. FDA (2023)
Phase change Readout Event UpcomingHover a marker for details.
Filed (NDA)Dec 2023 – Oct 2025
  1. Complete Response LetterFDA issues second Complete Response Letter for ND0612↗
  2. NDA/BLA filedFDA accepts NDA resubmission for ND0612↗
  3. PDUFA date setPDUFA target action date set for Q4 2025 for ND0612 resubmission↗
  4. EMA marketing authorization application filedEMA accepts ND0612 marketing authorization application for review↗
  5. Conference presentationBouNDless open-label-extension and additional Phase 3 data presented at MDS Congress 2024↗
  6. Complete Response LetterFDA issues first Complete Response Letter for ND0612↗
  7. metBouNDless full results published in Lancet Neurology (Espay et al. 2024;23(5):465-476): +1.72 h/day ON time without troublesome dyskinesia (95% CI 1.08-2.36, p<0.0001), OFF time -1.40 h/day; first four hierarchical secondary endpoints met; infusion-site reactions the most common adverse event.↗
  8. NDA submitted to the U.S. FDA during 2023. YEAR-PRECISION ANCHOR: no company release discloses the exact submission date — the FDA resubmission-acceptance announcement (2025-05-28) states only that the NDA 'was initially submitted to the FDA in 2023'. The 2023-12-31 date is a sortable year-end anchor, not a real date. The program has remained at 'filed' through two Complete Response Letters (announced 2024-06-11 and 2025-10-23; captured as events, not phase changes): the NDA is not withdrawn, a further resubmission is planned, and the EMA MAA (accepted 2025-02-20) is under active review.↗
  9. NDA/BLA filedNDA for ND0612 submitted to U.S. FDA (2023)↗
Phase 3Sept 2019 – Jan 2023
  1. metBouNDless Phase 3 topline: ND0612 met the primary endpoint, delivering a clinically meaningful and statistically significant increase in ON time without troublesome dyskinesia vs optimized oral IR-LD/CD, and met the first secondary endpoints in the hierarchy.↗
  2. Pivotal Phase 3 BouNDless trial (NCT04006210, ND0612-317) started per ClinicalTrials.gov: multicenter, randomized, active-controlled, double-blind, double-dummy trial of continuous subcutaneous ND0612 vs oral IR-LD/CD in Parkinson's disease with motor fluctuations, at 117 sites in 16 countries.
Phase 2May 2016
  1. Phase 2b open-label long-term safety study BeyoND (NCT02726386, ND0612H-012) started per ClinicalTrials.gov (214 enrolled, international). Earlier Phase 1/2 PK studies preceded this (e.g. NCT02096601), and development at the time was split into higher-dose ND0612H and lower-dose ND0612L before consolidation into a single ND0612 program after FDA feedback; BeyoND's start is used as the phase_2 anchor because it is the earliest clean registry date for the program that fed the NDA.

ND0612 (levodopa/carbidopa continuous subcutaneous infusion) for Parkinson's disease#

Filed (NDA)ActiveParkinson's disease indication →

ND0612, a 24-hour/day continuous subcutaneous infusion of liquid levodopa/carbidopa (60.0/7.5 mg/mL) via a wearable non-surgical pump, for motor fluctuations in Parkinson's disease — NeuroDerm/Mitsubishi Tanabe's answer to the pulsatile pharmacokinetics of oral levodopa without the surgery required by intrajejunal gel. The pivotal Phase 3 BouNDless trial (NCT04006210; 259 randomized after open-label optimization of 381 enrolled) met its primary endpoint: ND0612 plus supplemental oral IR-LD/CD provided an additional 1.72 h/day of ON time without troublesome dyskinesia versus optimized oral IR-LD/CD (95% CI 1.08-2.36; p<0.0001), with the first four hierarchical secondary endpoints also met (OFF time -1.40 h/day, MDS-UPDRS Part II, PGIC, CGI-I); infusion-site reactions were the most common adverse event (published Lancet Neurology, May 2024). Long-term safety comes from the Phase 2b open-label BeyoND study (NCT02726386), with some participants in their eighth year of follow-up. Regulatory course has been rocky on CMC/device rather than efficacy: NDA submitted to FDA in 2023; first Complete Response Letter announced 2024-06-11; NDA resubmitted and accepted May 2025 with a PDUFA target in Q4 2025; second CRL announced 2025-10-23 citing observations on the manufacturing site and nonclinical information. Mitsubishi Tanabe states it will continue working with FDA on a further resubmission (not yet announced as submitted as of 2026-08-14). In the EU, EMA accepted a marketing authorization application on 2025-02-20 (centralized procedure), which remains under review with no public opinion timeline.

Readouts

  • 2024-03-15ReportedFull resultsmetNCT04006210

    BouNDless full results published in Lancet Neurology (Espay et al. 2024;23(5):465-476): +1.72 h/day ON time without troublesome dyskinesia (95% CI 1.08-2.36, p<0.0001), OFF time -1.40 h/day; first four hierarchical secondary endpoints met; infusion-site reactions the most common adverse event. ↗

  • 2023-01-09ReportedTopline datametNCT04006210

    BouNDless Phase 3 topline: ND0612 met the primary endpoint, delivering a clinically meaningful and statistically significant increase in ON time without troublesome dyskinesia vs optimized oral IR-LD/CD, and met the first secondary endpoints in the hierarchy. ↗

Clinical trials#

NCT04006210ND0612-317Phase 3Activen=381

A Multicenter, Randomized, Active-controlled, Double-blind, Double-dummy, Parallel-group Clinical Trial, Investigating the Efficacy, Safety, and Tolerability of Continuous Subcutaneous ND0612 Infusion in Comparison to Oral IR-LD/CD in Subjects With Parkinson's Disease Experiencing Motor Fluctuations (BouNDless)

Started Sept 2019· Primary completion Nov 2022· 103 sites across 16 countries

United StatesSpainItalyIsrael

metprimaryChange from baseline in total daily ON time without troublesome dyskinesia (double-blind phase, ITT) — 1.72 (0.0001)

Subcutaneous ND0612 provided an additional 1.72 h/day of ON time without troublesome dyskinesia vs oral IR-LD/CD (95% CI 1.08 to 2.36; change from baseline -0.48 h vs -2.20 h; p<0.0001). Note: p-value recorded as 0.0001 for the published '<0.0001'; effect size is the between-group difference in hours.

metsecondaryChange from baseline in total daily OFF time (first hierarchical secondary endpoint) — -1.4

Treatment difference -1.40 h/day of OFF time favoring ND0612 (95% CI -1.99 to -0.80). The first four of nine prespecified hierarchical secondary endpoints were met (OFF time; MDS-UPDRS Part II -3.05 [95% CI -4.28 to -1.81]; PGIC OR 5.31; CGI-I OR 7.23); hierarchical testing stopped after the fourth. Per-endpoint p-values not stated in the open abstract, so left null.

metsafetySafety and tolerability (adverse events)

Infusion-site reactions were the most common adverse event (83% of participants during open-label optimization; 57% ND0612 vs 43% oral during the double-blind phase), mostly mild. Treatment-related serious adverse events in 4 ND0612 participants (infusion-site cellulitis n=2; infusion-site abscess/ulcer n=1; paraesthesia and peripheral sensorimotor neuropathy n=1). One death in the ND0612 group, not treatment-related. 'met' here means a benefit-risk profile the authors called favourable, not a formal endpoint.

NCT02726386ND0612H-012Phase 2Activen=214

A Multicenter, International, Open-label, Safety Study of ND0612, a Solution of Levodopa/Carbidopa Delivered Via a Pump System as a Continuous Subcutaneous Infusion in Subjects With Advanced Parkinson's Disease (BeyoND)

Started May 2016· Primary completion Sept 2019· 57 sites across 9 countries

United StatesFranceGermanyIsrael

Sources#

  1. Carbidopa, CID 34359 — molecular formula C10H14N2O4 (peripheral AADC-inhibitor component of the ND0612 combination; ChEMBL CHEMBL1200748) — PubChem (NCBI, U.S. National Library of Medicine)
  2. Espay AJ, et al. Safety and efficacy of continuous subcutaneous levodopa-carbidopa infusion (ND0612) for Parkinson's disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial. Lancet Neurol. 2024;23(5):465-476 — The Lancet Neurology (Elsevier) / PubMed
  3. Mitsubishi Tanabe Pharma America Announces U.S. FDA Acceptance of New Drug Application Resubmission for Investigational ND0612 (2025-05-28; PDUFA target Q4 2025; NDA initially submitted 2023) — Mitsubishi Tanabe Pharma America (via PR Newswire)
  4. Mitsubishi Tanabe Pharma America Presents Open-Label Extension Outcomes and Additional Data from Phase 3 BouNDless Trial at MDS 2024 (2024-09-30) — Mitsubishi Tanabe Pharma America (via PR Newswire)
  5. Mitsubishi Tanabe Pharma news release on ND0612 EMA MAA acceptance — Mitsubishi Tanabe Pharma
  6. NCT02726386 (ND0612H-012) — BeyoND: A Long Term Safety Study of ND0612 Administered as a Continuous SC Infusion in Advanced Parkinson's Disease — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT04006210 (ND0612-317) — BouNDless: Efficacy, Safety and Tolerability Study of ND0612 vs. Oral IR-LD/CD in Subjects With Parkinson's Disease Experiencing Motor Fluctuations — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NeuroDerm Announces Highly Positive Results from the Pivotal Phase III BouNDless Trial (topline, 2023-01-09) — NeuroDerm Ltd. (via PR Newswire)
  9. Receipt of Complete Response Letter from U.S. FDA for investigational ND0612 (2025-10-23; manufacturing-site and nonclinical observations) — Mitsubishi Tanabe Pharma Corporation
  10. Receipt of Complete Response Letter from U.S. FDA for ND0612 (2024-06-11) — Mitsubishi Tanabe Pharma Corporation