HRG2010 for Parkinson's Disease With Motor Fluctuations (NCT06596876)

HRG2010 Phase 3 Trial in Parkinson's Disease With Motor Fluctuations

Overview

NCT06596876 is a Phase 3 randomized, controlled, double-blind, double-dummy, multicenter clinical trial evaluating the efficacy and safety of HRG2010 in patients with Parkinson's disease (PD) experiencing motor fluctuations. Sponsored by Jiangsu HengRui Medicine Co., Ltd., this trial represents an important advancement in developing novel therapeutic options for the management of advanced PD.

Motor fluctuations, also known as "off" episodes, are a common complication of long-term levodopa therapy in PD. As the disease progresses, patients experience increasingly unpredictable transitions between "on" states (when medication is working and symptoms are controlled) and "off" states (when symptoms return). HRG2010 aims to provide more stable dopaminergic stimulation and reduce these disabling fluctuations.

The choice of "Off" time reduction as the primary endpoint reflects the substantial impact these fluctuations have on patient quality of life and daily functioning. This trial employs a double-dummy design, where both active treatment and placebo groups receive injections and oral medications, maintaining blinding while allowing comparison of the new formulation against standard therapy.

Trial Details

HRG2010 Phase 3 Trial in Parkinson's Disease With Motor Fluctuations

Overview

NCT06596876 is a Phase 3 randomized, controlled, double-blind, double-dummy, multicenter clinical trial evaluating the efficacy and safety of HRG2010 in patients with Parkinson's disease (PD) experiencing motor fluctuations. Sponsored by Jiangsu HengRui Medicine Co., Ltd., this trial represents an important advancement in developing novel therapeutic options for the management of advanced PD.

Motor fluctuations, also known as "off" episodes, are a common complication of long-term levodopa therapy in PD. As the disease progresses, patients experience increasingly unpredictable transitions between "on" states (when medication is working and symptoms are controlled) and "off" states (when symptoms return). HRG2010 aims to provide more stable dopaminergic stimulation and reduce these disabling fluctuations.

The choice of "Off" time reduction as the primary endpoint reflects the substantial impact these fluctuations have on patient quality of life and daily functioning. This trial employs a double-dummy design, where both active treatment and placebo groups receive injections and oral medications, maintaining blinding while allowing comparison of the new formulation against standard therapy.

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT06596876 |
| Phase | PHASE3 |
| Status | RECRUITING |
| Sponsor | Jiangsu HengRui Medicine Co., Ltd. |
| Enrollment | 450 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | 2024-11-06 00:00:00 |
| Completion Date | 2027-02-14 00:00:00 |
| Last Updated | 2025-05-02 00:00:00 |

Conditions Studied

• Parkinson's Disease with motor fluctuations (also known as "off" episodes)

Mechanism of Action

Understanding Motor Fluctuations in PD

Motor fluctuations in Parkinson's disease represent a significant therapeutic challenge. Understanding the pathophysiology is essential for appreciating HRG2010's potential mechanism:

Pathophysiology of Motor Fluctuations:

The underlying mechanisms include:

• Pulsatile dopamine receptor stimulation from intermittent oral levodopa
• Loss of striatal dopamine storage capacity as disease progresses
• Altered blood-brain barrier transport of levodopa
• Peripheral pharmacokinetics variability[@motor2021]

Proposed Therapeutic Mechanism

HRG2010 is designed to provide more continuous dopaminergic stimulation:

Potential Mechanisms:

• Extended half-life formulation providing longer plasma exposure
• More stable brain penetration reducing peaks and troughs
• Continuous dopamine receptor activation avoiding pulsatile stimulation
• Potential for reduced dyskinesia development through more physiological stimulation

• Dopamine agonists (ropinirole, pramipexole, rotigotine)
• Levodopa-carbidopa intestinal gel (Duodopa/Duopa)
• Extended-release levodopa formulations (IPX066, Rytary)

Dopamine Signaling in PD

Key dopaminergic pathways affected in PD:

• Nigrostriatal pathway - Primary motor symptoms
• Mesocortical pathway - Cognitive dysfunction
• Mesolimbic pathway - Mood and motivation
• Tuberoinfundibular pathway - Neuroendocrine function

Comparison with Existing Treatments

| Treatment | Mechanism | Administration | Key Advantage |
|-----------|-----------|----------------|---------------|
| Oral Levodopa | DA precursor | Oral | Most effective |
| Dopamine agonists | DA receptor agonist | Oral/transdermal | Longer half-life |
| MAO-B inhibitors | Prevent DA breakdown | Oral | Adjunct therapy |
| COMT inhibitors | prolong levodopa | Oral | Reduce "off" time |
| Duodopa | DA precursor | Intestinal gel | Continuous infusion |
| HRG2010 | DA formulation | Subcutaneous | Novel delivery |

Study Design Details

Trial Structure

This is a Phase 3, randomized, double-blind, double-dummy, placebo-controlled, multicenter clinical trial:

| Design Element | Description |
|---------------|-------------|
| Randomization | 1:1 active vs. placebo |
| Duration | 21 weeks (including titration and maintenance) |
| Blinding | Double-dummy (both groups get injections + oral) |
| Setting | Multicenter, international |
| Phase | Phase 3 |
| Enrollment | 450 participants |

Double-Dummy Design

The double-dummy approach ensures both groups receive:

• Active injection (HRG2010 or matching placebo)
• Active oral medication (standard PD therapy or matching placebo)

Primary Endpoint

Change from baseline in "Off" time at Week 21:

• "Off" time - Hours per day when PD symptoms are not adequately controlled
• Baseline - Documented "off" time during screening period (typically 2-3 days using patient diaries)
• Assessment - Patient diaries completed over consecutive days at baseline and endpoint

Secondary Endpoints

Secondary measures likely include:

• "On" time - Hours with adequate symptom control
• Unified Parkinson's Disease Rating Scale (UPDRS) - Parts II (motor experience of daily living) and III (motor examination)
• Patient Global Impression of Change (PGIC)
• Quality of life measures (PDQ-39)
• Sleep quality (PDSS)
• Safety and tolerability

Eligibility Criteria

Inclusion Criteria (Anticipated)

Disease-related:

• Diagnosis of idiopathic Parkinson's disease (UK Brain Bank criteria)
• Motor fluctuations with ≥2 hours "off" time per day
• Stable antiparkinsonian therapy for ≥4 weeks
• Hoehn & Yahr stage 1-3 in "on" state
• MMSE ≥24 (or equivalent)

• Age 30-80 years
• Ability to complete diary assessments
• Adequate caregiver/observer for diary completion
• Written informed consent

Key Exclusion Criteria

• Neurological: Atypical parkinsonism, significant neurological disease
• Psychiatric: Severe depression, psychosis within past 6 months
• Medical: Uncontrolled hypertension, significant cardiac disease
• Medications: Current enrollment in another PD trial, recent deep brain stimulation
• Prior: Failure to respond to dopaminergic therapy

Scientific Background

Parkinson's Disease Overview

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting approximately 10 million people worldwide. The disease is characterized by motor symptoms including resting tremor, bradykinesia, rigidity, and postural instability, as well as non-motor symptoms such as cognitive impairment, depression, and sleep disorders[@parkinsons2023].

Pathologically, PD is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies, which are intracellular inclusions composed primarily of alpha-synuclein protein. Current treatments provide symptomatic relief but do not halt disease progression[@parkinsons2023].

Levodopa Therapy and Complications

Levodopa remains the most effective symptomatic treatment for PD, but chronic use is associated with complications:

Motor Complications:

• Levodopa-induced dyskinesia (LID) - Involuntary movements affecting up to 50% of patients after 5-10 years
• Motor fluctuations - "On-off" phenomenon with unpredictable response
• End-of-dose wearing off - Predictable return of symptoms

• Mood and anxiety fluctuations
• Pain and sensory symptoms
• Cognitive variations
• Autonomic dysfunction

• Disease duration >5 years
• Higher levodopa dose
• Younger age at onset
• Female sex[@pd2023]

Treatment Strategies for Motor Fluctuations

Current management approaches for motor fluctuations include:

Pharmacological:

Device-Based:

HRG2010 represents a potential oral pharmacological approach to this unmet need.

Clinical Significance

Addressing an Unmet Need

Motor fluctuations represent one of the most significant unmet needs in Parkinson's disease management:

• Prevalence: 40-50% of PD patients develop motor fluctuations within 5 years of levodopa initiation
• Impact: "Off" time correlates with reduced quality of life, impaired daily functioning, and increased caregiver burden
• Treatment gaps: Current options require invasive procedures (DBS, pumps) or complex polypharmacy

Competitive Landscape

| Agent | Company | Target | Status | Key Feature |
|-------|---------|--------|--------|-------------|
| Opicapone | Novartis | COMT | Approved | Once-daily |
| Rytary | AbbVie | Levodopa | Approved | Extended release |
| Devo | Intec | Levodopa | Phase 3 | Transdermal patch |
| ABBV-951 | AbbVie | Levodopa/carbidopa | Phase 3 | Subcutaneous infusion |
| HRG2010 | Jiangsu HengRiu | Levodopa | Phase 3 | Novel formulation |

Strategic Considerations

Jiangsu HengRui's approach with HRG2010 includes several strategic elements:

Safety Considerations

Expected Adverse Events

Based on the mechanism of action, HRG2010 may cause:

Common (≥10%):

• Nausea and vomiting
• Dyskinesia (may increase with improved "on" time)
• Somnolence
• Orthostatic hypotension
• Hallucinations (especially in older patients)

• Impulse control disorders (pathological gambling, shopping, eating)
• Psychosis
• Sleep attacks
• Cardiac valve fibrosis (rare, with ergot derivatives)

Drug Interactions

HRG2010 may interact with:

• Other dopaminergic agents - Additive effects
• Antipsychotics - May reduce efficacy
• Antihypertensives - Additive hypotension
• Food - Protein may reduce absorption

Monitoring Recommendations

During clinical trials and post-approval:

• Regular neurological assessment
• Cardiac monitoring (if ergot-derived)
• Psychiatric screening
• Motor diary documentation
• Dyskinesia assessment

Participating Sites

The trial is being conducted at multiple centers worldwide, including:

• Beijing, Beijing Municipality, China
• Additional international sites (specific locations to be confirmed)

Regulatory Context

Development Pathway

HRG2010's development pathway includes:

Potential Indications

If approved, HRG2010 may be indicated for:

• Treatment of motor fluctuations in PD
• Adjunctive therapy to levodopa
• First-line treatment for advanced PD

Global Market Context

The Parkinson's disease treatment market is substantial:

• Global PD population: >10 million
• Market for dopaminergic therapies: >$5B annually
• Growing demand for improved delivery systems

Related Resources

• [Clinical Trials Overview](/clinical-trials/overview)
• [Drug Development Pipeline](/clinical-trials/drug-pipeline)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyloid Beta](/proteins/amyloid-beta)
• [Tau Protein](/proteins/tau)

External Links

• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT06596876)
• [PubMed Search](https://pubmed.ncbi.nlm.nih.gov/?term=NCT06596876)

References

HRG2010: Novel Levodopa/Carbidopa Formulation

Product Profile

HRG2010 is a novel oral formulation of levodopa/carbidopa developed by Jiangsu HengRui Medicine. The formulation is designed to provide more stable plasma levodopa levels compared to standard immediate-release levodopa/carbidopa.

Why New Levodopa Formulations?

Standard levodopa/carbidopa (Sinemet) has significant limitations:

Formulation Technology

HRG2010 utilizes an extended-release technology:

• Multi-matrix system for sustained release
• Optimized ratio of immediate and extended-release components
• Improved bioavailability compared to standard formulation

Parkinson's Disease: Motor Complications

Epidemiology of Motor Fluctuations

Motor complications develop in approximately:

• 40% of patients within 5 years of levodopa initiation
• 70% of patients within 10 years
• Risk increases with higher levodopa doses and longer disease duration

Pathophysiology

The "wearing-off" phenomenon occurs due to:

• Fewer dopaminergic neurons to store and release levodopa
• Loss of buffering capacity

• With disease progression, neurons cannot store adequate levodopa
• Results in dependence on plasma levodopa levels

• Postsynaptic receptor changes
• Altered signal transduction

Clinical Manifestations

"Off" State:

• Return of PD symptoms between doses
• Usually occurs in early morning before first dose
• May include tremor, bradykinesia, rigidity, gait freezing

• Adequate symptom control after medication
• Optimal function possible

• Involuntary movements
• Often peak-dose related
• Can be choreiform or dystonic

Study Design Details

Phase 3 Trial Structure

This is a pivotal Phase 3 registration trial:

Design: Randomized, double-blind, double-dummy, active-controlled Comparator: Immediate-release levodopa/carbidopa Duration: 21 weeks (including 1-week screening, 20-week treatment)

Double-Dummy Design

The double-dummy design ensures blinding:

• Participants receive both HRG2010 and IR levodopa
• But only one is active, the other is placebo
• Ensures equal pill burden between groups

Treatment Arms

| Arm | Treatment | Dose |
|-----|-----------|------|
| Active | HRG2010 | Titrated to optimal control |
| Active | IR Levodopa/Carbidopa | Titrated to match exposure |

Randomization

• 1:1 randomization
• Stratified by:
• Geographic region
• Baseline "Off" time
• Levodopa dose at entry

Patient Population

Inclusion Criteria

Exclusion Criteria

Outcome Measures

Primary Endpoint

Change in "Off" Time at Week 21

• Measured via patient diaries
• 3-day diary at baseline and end point
• Recorded every 30 minutes for "On"/"Off"/dyskinetic status

Secondary Endpoints

Diary Variables

| Parameter | Description |
|-----------|-------------|
| Total "Off" time | Hours per day with PD symptoms |
| Total "On" time | Hours per day with good symptom control |
| "On" time with dyskinesia | Hours with involuntary movements |
| Sleep quality | Hours of nighttime sleep |

Clinical Rationale

Unmet Need in PD

Despite available treatments, significant unmet need remains:

Current Treatment Options

| Treatment | Mechanism | Pros | Cons |
|-----------|-----------|------|------|
| Immediate-release levodopa | Dopamine replacement | Effective | Short half-life |
| Extended-release levodopa | Sustained release | Less frequent | Variable absorption |
| COMT inhibitors | Reduce metabolism | Reduce "Off" time | Liver monitoring |
| MAO-B inhibitors | Reduce metabolism | Neuroprotective | Limited effect |
| Dopamine agonists | Direct receptor activation | Long half-life | Dyskinesias, impulse control |
| Apomorphine infusion | Continuous delivery | Very effective | Pump required, site infection |

HRG2010 Position

HRG2010 would provide:

• Oral alternative to infusion therapies
• Simplified regimen vs. multiple daily doses
• Potentially better QoL for motor fluctuation patients

Safety Assessment

Common Adverse Events

Expected AEs based on levodopa class:

| Adverse Event | Frequency |
|--------------|-----------|
| Nausea | 10-20% |
| Dyskinesia | 10-30% |
| Headache | 5-10% |
| Dizziness | 5-10% |
| Insomnia | 5-10% |
| Orthostatic hypotension | 5-10% |

Special Considerations

Dyskinesia Management

• May increase with more stable levodopa levels
• Dose adjustment may be needed
• Existing dyskinesia medications may help

• Hallucinations (3-5%)
• Impulse control disorders (rare)
• Depression (monitor)

Drug Interactions

Levodopa interactions:

• MAO inhibitors (hypertensive crisis - contraindicated)
• Antipsychotics (reduced efficacy)
• Antihypertensives (additive hypotension)
• Iron supplements (reduced absorption)

Competitive Landscape

Parkinson's Disease Motor Fluctuation Treatments

| Drug/Device | Company | Type | Dosing |
|-------------|---------|------|--------|
| Rytary | AbbVie | Extended-release oral | 3-5x daily |
| Sinemet CR | Merck | Extended-release | 3-4x daily |
| Stalevo | Orion | Levodopa + COMT | 3-4x daily |
| Duopa | AbbVie | Infusion | Continuous |
| Crexont | Amneal | Extended-release | 3-4x daily |
| Kynmobi | Sunovion | Sublingual | As needed |
| Ongentys | Bial | COMT inhibitor | Once daily |
| HRG2010 | HengRui | Novel ER | TBD |

Differentiation

HRG2010 differentiation factors:

• Novel formulation technology
• Potentially better pharmacokinetics
• Global development program (China + international)

Statistical Analysis

Sample Size Calculation

• 450 participants (225 per arm)
• Expected difference: 1.5 hours "Off" time reduction
• Power: 80%
• Alpha: 0.05 (two-sided)

Analysis Plan

• Primary: MMRM (mixed-effects model for repeated measures)
• Per-protocol analysis as sensitivity
• Non-inferiority on secondary endpoints

Regulatory Pathway

China NMPA

The trial supports registration in China:

• Required for NMPA approval
• Chinese patient population
• Domestic manufacturing

US FDA / EU EMA

Potential for international registration:

• If successful, may support US/EU filings
• Would require additional studies
• Could be first Chinese-developed PD medication in Western markets

Clinical Significance

For Patients

If successful, HRG2010 would provide:

For Field

Broader significance: