ND0612 · program

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

Filed (NDA)ActiveMitsubishi Tanabe Pharma Corporation

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.

Data current as of

Development timeline

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.

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 in Parkinson's disease

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 States, Spain, Italy, Israel)

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 States, France, Germany, Israel)

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—

Mechanism of action (compound-wide)

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—ⓘ

← Full ND0612 compound page (identity, identifiers, all indications)

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