Sponsor
Integrative Research Laboratories AB
Intervention
IRL757 (NOP receptor antagonist)
Indication
Parkinson's Disease with Apathy
Enrollment
75 participants (planned)
Treatment Duration
12 weeks
IRL757 is a novel drug candidate being developed by Integrative Research Laboratories AB (IRLAB) in collaboration with Otsuka Pharmaceutical Development & Commercialization, Inc. for the treatment of apathy in Parkinson's disease. It is classified as a nociceptin receptor (NOP) antagonist, representing a fundamentally different therapeutic approach targeting the non-motor symptoms of PD.
The Phase 1b/2 LIFT-PD trial (NCT07461220) is a prospective, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and efficacy of multiple oral doses of IRL757 in participants with Parkinson's disease experiencing apathy.
Parkinson's disease affects approximately 10 million people worldwide and is characterized by both motor symptoms (bradykinesia, rigidity, tremor) and non-motor symptoms. Apathy is one of the most prevalent and disabling non-motor symptoms, affecting up to 50% of PD patients, yet it remains significantly undertreated.
The NOP receptor (also known as the nociceptin receptor, OPRL1, or orphanin FQ receptor) is a G-protein-coupled receptor that was identified in the mid-1990s. It is the fourth member of the opioid receptor family, which includes the classical mu (μ), delta (δ), and kappa (κ) opioid receptors. However, unlike classical opioids, NOP does not produce analgesia or reward — instead, it modulates motivation, emotional states, and cognitive functions.
Key characteristics of the NOP system:
-
Endogenous ligand: Nociceptin/orphanin FQ (N/OFQ) is the endogenous peptide that activates the NOP receptor. It is widely distributed throughout the central nervous system, particularly in brain regions involved in emotion, motivation, and reward.
-
Brain distribution: NOP receptors are highly expressed in:
- Prefrontal cortex — involved in executive function and decision-making
- Anterior cingulate cortex — critical for motivation and emotional processing
- Nucleus accumbens — central to reward processing
- Hippocampus — important for memory and emotional regulation
- Amygdala — processes emotions and stress responses
- Ventral tegmental area (VTA) — source of dopaminergic neurons
-
Signal transduction: NOP is primarily coupled to Gi/o proteins, which inhibit adenylate cyclase, reduce neuronal excitability, and modulate neurotransmitter release. Activation of NOP generally produces inhibitory effects on reward and motivation circuits.
The rationale for NOP antagonism in PD-related apathy is based on several interconnected mechanisms:
flowchart TD
A["Parkinson's Disease"] --> B["Neurodegeneration in VTA & LC"]
B --> C["Reduced Dopamine & Noradrenaline"]
C --> D["Elevated N/OFQ Tone"]
D --> E["NOP Receptor Overactivation"]
E --> F["Inhibition of Motivation Circuits"]
F --> G["Apathy Symptoms"]
H["IRL757"] --> I["NOP Receptor Antagonism"]
I --> J["Blockade of N/OFQ Signaling"]
J --> K["Disinhibition of VTA-NAc Pathway"]
K --> L["Enhanced Mesolimbic Dopamine Transmission"]
L --> M["Improved Motivation & Reward Processing"]
M --> N["Reduction in Apathy"]
O["Traditional Dopamine Therapies"] --> P["Dopamine Receptor Agonists"]
P --> Q["Primarily Target Motor Symptoms"]
Q --> R["Limited Efficacy for Apathy"]
Why NOP antagonism may help:
-
Counteracting elevated N/OFQ: In PD, neurodegeneration in the ventral tegmental area and locus coeruleus leads to compensatory changes that may elevate nociceptin/orphanin FQ tone. This hyperactive NOP signaling further suppresses already compromised dopaminergic and noradrenergic pathways involved in motivation.
-
Restoring mesolimbic function: By blocking NOP receptors, IRL757 may disinhibit the ventral tegmental area-nucleus accumbens pathway, enhancing dopamine release in response to natural rewards and improving motivational states.
-
Non-dopaminergic approach: Unlike traditional dopamine agonists used for motor symptoms, NOP antagonism specifically targets the motivational and reward circuits without directly stimulating dopamine receptors. This may avoid dopaminergic side effects such as hallucinations, impulse control disorders, and motor fluctuations.
-
Preclinical evidence: IRL757 has demonstrated efficacy in several preclinical models representing various aspects of cognitive function, with signals of improved motivation observed.
Apathy is defined as a syndrome of primary lack of motivation, distinguished from depression and cognitive impairment, though it frequently co-occurs with both. According to the International Society for CNS Clinical Trials (ISCTM), apathy is characterized by:
- Diminished initiative — less spontaneous and less likely to initiate usual activities
- Diminished interest — less enthusiastic, less curious about events, less interested in activities and plans
- Diminished emotional expression/responsiveness — less spontaneous emotions, less affectionate, less empathetic
For a diagnosis of apathy, these symptoms must:
- Be persistent or frequently recurrent (≥3 days per week)
- Last for ≥4 weeks
- Represent a significant change from the patient's baseline
- Cause significant impairment in personal, social, or occupational functioning
¶ Prevalence and Impact
Apathy affects approximately 30-50% of patients with Parkinson's disease, making it one of the most common non-motor symptoms. Its impact is profound:
- Quality of life: Apathy significantly reduces quality of life for both patients and caregivers
- Functional impairment: Patients with apathy are less likely to engage in rehabilitation, exercise, or social activities
- Caregiver burden: Apathy increases caregiver stress and reduces caregiver well-being
- Cognitive decline: Apathy is associated with faster cognitive deterioration in PD
- Treatment adherence: Apathetic patients may be less compliant with medications and lifestyle modifications
Current treatment options for PD-related apathy are extremely limited:
- Dopamine agonists: While some studies show modest benefits, dopamine agonists can cause significant side effects and are primarily approved for motor symptoms
- Antidepressants: SSRIs and other antidepressants may help if depression is present but have limited efficacy for pure apathy
- Non-pharmacological approaches: Exercise, cognitive behavioral therapy, and occupational therapy may provide some benefit but are often insufficient alone
This therapeutic gap highlights the significant unmet need that IRL757 aims to address.
¶ Connection to Dopamine and Mesolimbic Pathways
The mesolimbic dopamine pathway originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens (NAc), prefrontal cortex, amygdala, and hippocampus. This system is fundamental to:
- Reward processing — detecting and responding to rewarding stimuli
- Motivation — driving goal-directed behavior
- Learning — associating stimuli with rewards
- Emotional regulation — processing positive and negative emotions
In Parkinson's disease, the mesolimbic pathway is compromised by:
- Neurodegeneration: PD affects not only the substantia nigra pars compacta (motor dopamine neurons) but also the VTA (mesolimbic dopamine neurons)
- Levodopa-induced changes: Chronic levodopa treatment can lead to dysregulation of dopamine signaling
- Lewy pathology: Lewy bodies (alpha-synuclein aggregates) are found in limbic structures including the amygdala and hippocampus
The NOP system and dopamine system have extensive interactions:
flowchart LR
subgraph VTA [Ventral Tegmental Area]
D["DA Neurons"]
N["NOP Receptors"]
end
subgraph NAc [Nucleus Accumbens]
DA["DA Release"]
end
N -->|"Inhibits"| D
D -->|"Stimulates"| DA
IRL757 -.->|Blocks NOP| N
IRL757 -->|"Disinhibits"| D
D -->|"Increases"| DA
DA -->|"Enhances"| M["Motivation"]
style IRL757 fill:#c8e6c9
style M fill:#98FB98
Key interactions:
- VTA NOP modulation: NOP receptors on VTA dopamine neurons inhibit their activity. NOP antagonism removes this inhibition, potentially increasing firing rates
- NAc terminal modulation: NOP receptors on nucleus accumbens terminals further modulate dopamine release in response to rewards
- Prefrontal cortical circuits: NOP in the prefrontal cortex affects executive function and decision-making, which are crucial for motivated behavior
This multi-level interaction makes NOP antagonism an attractive target for addressing the motivational deficits in PD.
The LIFT-PD trial (NCT07461220) is a Phase 1b/2 prospective, randomized, double-blind, placebo-controlled study:
| Parameter |
Details |
| Design |
Parallel group, 1:1:1 randomization |
| Duration |
12 weeks of treatment |
| Arms |
IRL757 low dose, IRL757 high dose, placebo |
| Blinding |
Quadruple-blind (participant, care provider, investigator, outcomes assessor) |
| Population |
PD patients with moderate to severe apathy |
| Enrollment |
75 participants (estimated) |
| Timeline |
February 2026 — May 2027 |
Key eligibility criteria include:
- Age: 50-90 years
- PD diagnosis: According to Movement Disorders Society Clinical Diagnostic Criteria
- Disease stage: Hoehn and Yahr stage ≤4
- Cognitive function: MoCA score ≥20
- Apathy definition: Meets ISCTM definition of apathy with ≥1 symptom in ≥2 of 3 dimensions (initiative, interest, emotional responsiveness), persistent for ≥4 weeks
- Apathy severity: Lille Apathy Rating Scale (LARS) score ≤-16 (moderate to severe apathy)
- Caregiver requirement: Availability of primary caregiver (≥10 hours/week)
Primary Endpoints (Safety & Tolerability):
- Adverse events classified by severity and relationship to study drug
- Vital signs (blood pressure, heart rate, respiratory rate)
- Electrocardiogram (ECG) parameters
- Physical examination findings
Secondary Endpoints (Efficacy):
- NPI-C apathy domain: Change from baseline in Neuropsychiatric Inventory Clinician (NPI-C) apathy scores
- Lille Apathy Rating Scale (LARS): Change from baseline in LARS global score (range: -36 to +36, higher scores = greater apathy)
The trial is being conducted at multiple sites across Europe:
- Bulgaria: Pleven, Sofia
- Germany: Berlin, Dresden
- Poland: Bydgoszcz, Katowice, Lodz, Szczecin, Warsaw
- Spain: Barcelona, Elche, Madrid
| Milestone |
Date |
| Regulatory approval for Phase I |
Spring 2024 |
| SAD/MAD studies completed |
2024 |
| Phase I in subjects aged 65+ completed |
2024 |
| Michael J. Fox Foundation grant awarded |
Late 2023 |
| Otsuka collaboration announced |
May 2024 |
| Phase 1b/2 trial (LIFT-PD) started |
February 2026 |
| Expected completion |
May 2027 |
¶ Funding and Partnerships
- Michael J. Fox Foundation: Awarded over SEK 20 million grant (late 2023) to support development
- Otsuka Pharmaceutical Development & Commercialization, Inc.: Collaboration to finance development through clinical Proof-of-Concept (announced May 2024)
If successful, IRL757 could represent a breakthrough in treating apathy in Parkinson's disease:
- Potential expansion: Based on the mechanism, IRL757 may also have applicability to apathy in other neurological disorders, including Alzheimer's disease
- Combination potential: NOP antagonists could potentially be combined with other therapies targeting different aspects of PD
- Biomarker development: Understanding the NOP system's role may lead to biomarkers for identifying patients most likely to benefit