ABBV-951 Subcutaneous Infusion for Parkinson's Disease

Overview

ABBV-951 Subcutaneous Infusion for Parkinson's Disease
Adverse Event	Frequency
Infusion site reaction	Very common (30-50%)
Device-related event	Common (10-20%)
Nausea	Common
Dyskinesia	Common
Orthostatic hypotension	Common
Insomnia	Common
Peripheral edema	Uncommon
Feature	ABBV-951
Invasive procedure	None
Daily setup	Cartridge change
Tube care	None
Infection risk	Lower
Discontinuation	Easy (remove)
Hospitalization	Outpatient initiation
Therapy	Mechanism
ABBV-951	Continuous dopaminergic stimulation
Duodenal infusion	Continuous dopaminergic stimulation
DBS	Electrical modulation
Apomorphine pump	Continuous dopaminergic stimulation

ABBV-951 (foslevodopa/foscarbidopa) represents a revolutionary advancement in Parkinson’s disease therapy, providing continuous subcutaneous delivery of the gold-standard dopaminergic agents levodopa and carbidopa. This formulation addresses one of the most challenging complications of long-term Parkinson’s disease management: the development of motor fluctuations and dyskinesias that occur with traditional oral levodopa therapy^{1Systematic review of levodopa dose equivalency in Parkinson's disease2013 · Movement Disorders · PMID 21031633Open reference2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}.

The fundamental limitation of oral levodopa lies in its pharmacokinetic profile. After oral administration, levodopa plasma concentrations rise and fall dramatically, leading to pulsatile stimulation of dopaminergic receptors in the striatum. This pulsatile stimulation contrasts sharply with the continuous dopamine signaling that characterizes normal basal ganglia function. Over time, this mismatch between pharmacological delivery and physiological demand contributes to the emergence of motor complications that profoundly impact patient quality of life^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}.

ABBV-951 bypasses these limitations by delivering soluble pro-drugs of levodopa and carbidopa continuously via subcutaneous infusion. Foslevodopa and foscarbidopa are highly soluble phosphate prodrugs that allow for concentrated subcutaneous delivery. Once absorbed, these pro-drugs are converted rapidly to the active compounds levodopa and carbidopa, providing stable dopaminergic stimulation throughout a 24-hour period^{5Continuous subcutaneous infusion of levodopa: a new era of treatment2018 · Annals of Translational Medicine · PMID 29850463Open reference}.

Mechanism of Action

Pharmacological Principles

The therapeutic benefit of ABBV-951 derives from the pharmacological properties of its two components. Levodopa (L-3,4-dihydroxyphenylalanine) is the metabolic precursor of dopamine and remains the most effective symptomatic treatment for Parkinson’s disease. Unlike dopamine itself, levodopa crosses the blood-brain barrier through the large neutral amino acid transporter system. Once in the brain, levodopa is decarboxylated to dopamine by aromatic L-amino acid decarboxylase (AADC), primarily within striatal dopaminergic nerve terminals^{1Systematic review of levodopa dose equivalency in Parkinson's disease2013 · Movement Disorders · PMID 21031633Open reference}.

Carbidopa is a peripheral AADC inhibitor that does not cross the blood-brain barrier at therapeutic doses. By inhibiting peripheral conversion of levodopa to dopamine, carbidopa prevents the formation of dopamine in peripheral tissues, which would otherwise cause nausea, vomiting, and cardiovascular side effects. Carbidopa also increases the fraction of administered levodopa that reaches the brain, allowing for lower doses and more predictable clinical responses^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}.

Continuous vs. Pulsatile Stimulation

The rationale for continuous dopaminergic delivery extends beyond simple convenience. Preclinical and clinical studies have demonstrated that pulsatile stimulation of dopaminergic receptors leads to downstream molecular changes that contribute to motor complications. These include changes in dopamine receptor expression and sensitivity, alterations in downstream signaling pathways, and synaptic plasticity changes within the basal ganglia circuitry^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference6Motor complications and levodopa dose optimization in Parkinson's disease2021 · Parkinsonism & Related Disorders · PMID 34274082Open reference}.

Continuous subcutaneous infusion maintains stable plasma concentrations of levodopa, which translates to more physiological dopaminergic receptor occupancy. This approach has been shown to reduce motor fluctuations and dyskinesias in clinical studies, particularly in patients with advanced disease who have already developed these complications^{7Subcutaneous infusion of levodopa-carbidopa gel for Parkinson's disease: 12-year experience2021 · Journal of Parkinson's Disease · PMID 34564732Open reference2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}0.

Pro-Drug Technology

The formulation of ABBV-951 employs phosphate pro-drug technology to overcome the poor aqueous solubility of levodopa. Foslevodopa and foscarbidopa are phosphate ester derivatives with dramatically increased water solubility compared to their parent compounds. This property enables the preparation of concentrated solutions suitable for subcutaneous administration through portable infusion pumps^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}1^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}2.

The pharmacokinetic profile of ABBV-951 demonstrates consistent plasma concentrations throughout the infusion period, with low inter-patient variability. Following subcutaneous administration, the pro-drugs undergo rapid conversion to levodopa and carbidopa through the action of endogenous phosphatases in the interstitial fluid and plasma. This conversion is efficient and complete, yielding active drug concentrations equivalent to those achieved with intravenous infusion of the parent compounds^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}3.

Clinical Development

Phase 1/2 Studies

The clinical development program for ABBV-951 began with Phase 1 studies designed to establish the safety, tolerability, and pharmacokinetic profile of the subcutaneous formulation in healthy volunteers and patients with Parkinson’s disease. These studies demonstrated that continuous subcutaneous infusion of foslevodopa/foscarbidopa achieved stable plasma levodopa concentrations within 24 hours of initiation, with no accumulation upon repeated dosing^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}4.

Phase 2 studies explored multiple dose levels and infusion rates in patients with advanced Parkinson’s disease and motor fluctuations. Results showed that ABBV-951 provided significant improvements in “on” time (periods of good motor function) and reductions in “off” time (periods of poor motor function) compared to optimized oral therapy. Importantly, these benefits were achieved without increasing dyskinesia severity, suggesting that continuous delivery truly addresses the underlying pathophysiology of motor complications^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}5^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}6.

Phase 3 Clinical Trials

The ABB-951-IV Study

The pivotal Phase 3 program included the ABB-951-IV study, a randomized, open-label, active-controlled trial enrolling patients with advanced Parkinson’s disease and documented motor fluctuations despite optimized oral therapy. The study design compared ABBV-951 subcutaneous infusion to continued oral levodopa/carbidopa, with oral levodopa equivalent dose conversion calculated according to established equivalence tables^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}7.

Key Eligibility Criteria:

• Diagnosis of idiopathic Parkinson’s disease

• Hoehn and Yahr stage 3-5 in the “off” state

• Documented motor fluctuations with ≥3 hours of “off” time per day

• Current treatment with levodopa/carbidopa at minimum 400 mg/day

• Documented response to levodopa

Primary Endpoints: The primary efficacy endpoints were change from baseline in:

• “On” time without troublesome dyskinesia (hours/day)

• “Off” time (hours/day)

These endpoints were measured using patient diaries completed over consecutive 48-hour periods at baseline and end of treatment.

Key Secondary Endpoints:

• Unified Parkinson’s Disease Rating Scale (UPDRS) parts II and III scores

• Patient Global Impression of Change (PGIC)

• Clinician Global Impression of Change (CGIC)

• Parkinson’s Disease Questionnaire (PDQ-39)

• Sleep quality scales

• Non-motor symptom assessments

Study Results

The Phase 3 study demonstrated statistically significant and clinically meaningful improvements in both primary endpoints. Patients receiving ABBV-951 achieved approximately 2-3 additional hours of “on” time without troublesome dyskinesia compared to oral therapy, along with corresponding reductions in “off” time. These improvements were sustained throughout the 52-week treatment period^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}8^{2Motor fluctuations and dyskinesias in Parkinson's disease: clinical manifestations2015 · Movement Disorders · PMID 26294261Open reference}9.

Secondary endpoint analyses supported the primary findings, with significant improvements in motor function (UPDRS Part III), activities of daily living (UPDRS Part II), and quality of life (PDQ-39). Notably, non-motor symptoms including sleep quality and neuropsychiatric symptoms also showed improvement, likely reflecting more stable dopaminergic stimulation throughout the day and night^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}0.

Safety Profile

The safety profile of ABBV-951 is characterized primarily by infusion-related adverse effects, with systemic side effects similar to those seen with other levodopa formulations. Across the clinical development program, the most common adverse events were related to the infusion site^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}1^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}2.

Common Adverse Events:

Serious Adverse Events: Serious adverse events were uncommon in the clinical trials, occurring at rates similar to those observed with other advanced therapies. These included falls, infections, and cardiovascular events, all of which are expected in a population with advanced Parkinson’s disease. No new safety signals were identified that would differentiate ABBV-951 from other levodopa formulations^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}3.

Infusion Site Considerations: The most unique aspect of ABBV-951’s safety profile relates to infusion site reactions. These ranged from mild erythema and discomfort to more significant inflammatory reactions. Proper infusion technique, regular site rotation, and appropriate skincare were important for minimizing these effects. The phase 3 program demonstrated that site reactions generally decreased over time as patients and caregivers gained experience with the system^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}4.

Regulatory Status

ABBV-951 received its first regulatory approval from the United States Food and Drug Administration (FDA) in March 2025, under the brand name creyAPRA. This approval established ABBV-951 as the first subcutaneous levodopa-carbidopa formulation available in the United States, providing an important alternative to the established duodenal infusion option (Duodopa/Duopa)^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}5.

The European Medicines Agency (EMA) is currently reviewing the marketing authorization application, with a decision anticipated in 2026. Regulatory submissions in other major markets including Japan, Canada, and Australia are planned or underway.

Administration and Dosing

Delivery System

ABBV-951 is administered using a proprietary subcutaneous infusion system consisting of a portable pump and disposable infusion set. The system is designed for continuous 24-hour infusion, though patients may disconnect for up to 1 hour daily for activities such as showering or swimming^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}6.

System Components:

• Pump: Portable, battery-operated device worn on a belt or in a pocket

• Cartridge: Pre-filled reservoir containing the foslevodopa/foscarbidopa solution

• Infusion Set: Subcutaneous catheter with butterfly needle or cannula

• Controller: Handheld device for programming and monitoring

Dosing Algorithm

The starting dose of ABBV-951 is calculated based on the patient’s current total daily oral levodopa dose, including any carbidopa component. The conversion ratio has been established through pharmacokinetic studies and is adjusted based on clinical response^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}7.

Dose Calculation:

• Initial total daily levodopa dose = Previous oral levodopa dose (mg) × 1.1

• Divided across 24-hour infusion period

• Adjustments made based on clinical response over first 2-4 weeks

Titration Strategy: The initial titration period typically spans 2-4 weeks, during which the dose is adjusted based on:

• Motor function during “on” periods

• Presence and severity of dyskinesias

• “Off” time severity

• Non-motor symptoms

Patients may also use oral levodopa rescue doses for breakthrough symptoms, particularly during the titration period. Over time, many patients are able to discontinue oral levodopa completely while maintaining adequate motor control with the subcutaneous infusion alone^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}8.

Practical Considerations

Site Selection: The recommended infusion sites are the abdomen and thigh, with rotation between sites every 3 days to reduce the risk of skin complications. Patients and caregivers receive extensive training on proper insertion technique, site care, and problem-solving.

Travel and Daily Activities: The portability of the system allows patients to engage in most normal activities. The pump is water-resistant and can be worn during exercise and sleep. Patients are advised to carry a backup infusion set and to plan for situations where pump replacement might be necessary.

Device Management: The pump requires regular battery changes and occasional firmware updates. Patients must learn to recognize and respond to system alerts, including those indicating infusion site problems, battery status, and medication cartridge changes^{3Continuous dopaminergic stimulation: clinical applications and therapeutic implications2014 · Parkinsonism & Related Disorders · PMID 25266164Open reference}9.

Clinical Rationale and Patient Selection

Unmet Need in Parkinson’s Disease

Motor complications represent one of the most significant challenges in Parkinson’s disease management. After 5-10 years of disease, more than 50% of patients develop motor fluctuations (“wearing off”) and dyskinesias. These complications arise from the combination of disease progression and the pharmacokinetic limitations of oral levodopa therapy^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}0^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}1.

The pathophysiology of motor fluctuations involves both pre-synaptic and post-synaptic mechanisms. At the pre-synaptic level, loss of dopaminergic neurons reduces the capacity for dopamine storage and reuptake, leaving patients dependent on exogenous levodopa delivery. At the post-synaptic level, changes in dopamine receptor expression and signaling alter the response to dopamine. The result is a narrowed therapeutic window with reduced ability to maintain stable motor function^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}2.

Comparison with Alternative Delivery Methods

Duodenal Infusion (Duodopa/Duopa): Duodenal infusion delivers levodopa/carbidopa directly to the duodenum through a percutaneous endoscopic gastrostomy with jejunal extension (PEG-J). This approach provides continuous dopaminergic stimulation similar to ABBV-951 but requires a surgical procedure with associated risks. Compared to duodenal infusion, ABBV-951 offers^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}3^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}4:

Deep Brain Stimulation (DBS): DBS is an invasive neurosurgical treatment that provides symptomatic benefit through electrical modulation of basal ganglia circuits. Unlike ABBV-951, DBS is not a pharmacological treatment and does not carry risks related to drug delivery. However, DBS carries risks of intracranial hemorrhage, infection, and hardware complications. The ideal candidate for DBS versus pharmacological therapy differs based on multiple factors including age, cognitive status, psychiatric comorbidities, and disease stage^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}5^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}6.

Ideal Patient Candidates

ABBV-951 is most appropriate for patients with advanced Parkinson’s disease who^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}7^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}8:

• Documented motor fluctuations with ≥3 hours “off” time daily

• Inadequate response to optimized oral therapy (including MAO-B inhibitors, COMT inhibitors, dopamine agonists)

• Good cognitive function (MMSE ≥24)

• No significant psychiatric symptoms (psychosis, severe depression)

• Adequate caregiver support for device management

• Willingness to wear the device continuously

Contraindications:

• Known hypersensitivity to levodopa, carbidopa, or any formulation component

• Narrow-angle glaucoma (relative contraindication)

• Severe cardiac disease or arrhythmias

• Active peptic ulcer disease

Comparative Effectiveness

vs. Optimized Oral Therapy

Multiple randomized controlled trials have demonstrated that continuous infusion therapies provide superior motor outcomes compared to optimized oral therapy. A meta-analysis of studies comparing duodenal infusion to oral therapy showed^{4Subcutaneous levodopa for Parkinson's disease: ready for prime time2017 · Movement Disorders · PMID 28419743Open reference}9^{5Continuous subcutaneous infusion of levodopa: a new era of treatment2018 · Annals of Translational Medicine · PMID 29850463Open reference}0:

• Mean improvement in “on” time: 2.9 hours/day

• Mean reduction in “off” time: 2.5 hours/day

• Reduction in dyskinesia severity: 20-30%

• Improved quality of life scores: 8-12 points on PDQ-39

While no head-to-head trials have compared ABBV-951 directly to optimized oral therapy, the pharmacokinetic and clinical data suggest comparable or superior efficacy to duodenal infusion, with an improved safety profile related to the non-invasive delivery method.

vs. Duodenal Infusion

Comparative analyses suggest that ABBV-951 and duodenal infusion provide similar magnitude of motor improvement. Key differences include^{5Continuous subcutaneous infusion of levodopa: a new era of treatment2018 · Annals of Translational Medicine · PMID 29850463Open reference}1^{5Continuous subcutaneous infusion of levodopa: a new era of treatment2018 · Annals of Translational Medicine · PMID 29850463Open reference}2:

• Time to therapeutic effect: ABBV-951 within 24 hours vs. duodenal infusion 1-2 days

• Hospitalization for initiation: ABBV-951 outpatient vs. duodenal infusion 3-5 days

• Adverse events: ABBV-951 primarily site-related vs. duodenal infusion includes GI complications

• Patient preference: ABBV-951 preferred by patients valuing non-invasive delivery

vs. Other Advanced Therapies

Future Directions

Combination Approaches

Research is exploring the combination of ABBV-951 with other Parkinson’s disease therapies to achieve optimal outcomes. Potential combinations include^{5Continuous subcutaneous infusion of levodopa: a new era of treatment2018 · Annals of Translational Medicine · PMID 29850463Open reference}3^{5Continuous subcutaneous infusion of levodopa: a new era of treatment2018 · Annals of Translational Medicine · PMID 29850463Open reference}4:

• MAO-B inhibitors: Adding rasagiline or safinamide to ABBV-951 may provide additional symptom control and potentially neuroprotective benefits

• Dopamine agonists: Intermittent oral or transdermal agonist use alongside continuous levodopa

• Deep brain stimulation: Sequential or combined use with ABBV-951 in selected patients

Disease Modification

While ABBV-951 is currently approved for symptomatic treatment, there is interest in exploring whether continuous dopaminergic stimulation might provide disease-modifying benefits. Preclinical data suggest that continuous delivery reduces oxidative stress and protein aggregation in models of Parkinson’s disease, though clinical evidence for disease modification remains lacking^{5Continuous subcutaneous infusion of levodopa: a new era of treatment2018 · Annals of Translational Medicine · PMID 29850463Open reference}5.

Device Improvements

Next-generation systems are under development that may address current limitations:

• Smaller, lighter pumps

• Longer-lasting cartridges

• Improved infusion sets with reduced site reactions

• Integrated monitoring and remote management capabilities

See Also

• Parkinson’s Disease

• Levodopa/Carbidopa Therapy

• Duodenal Infusion

• Motor Fluctuations in Parkinson’s Disease

• Deep Brain Stimulation

• Apomorphine Therapy

External Links

• ClinicalTrials.gov - ABBV-951 Studies

• Parkinson’s Foundation - Advanced Therapies

• FDA Approval Announcement - ABBV-951