Report on Investigational Agent JNJ-89495120 (PIPE-307)

1. Introduction and Overview of JNJ-89495120 (PIPE-307)

1.1. Identification

JNJ-89495120 is an investigational, orally administered small molecule drug.[1] This compound is also prominently known in scientific literature and early development communications as PIPE-307.[1] Additional synonyms used include JNJ 89495120 and JNJ89495120.[6] The consistent use of these identifiers is important for accurately tracking the compound's development progress across different research groups and publications.

JNJ-89495120 (PIPE-307) is classified as a selective M1 muscarinic acetylcholine receptor (M1R) antagonist.[4] The M1R is one of five subtypes of muscarinic acetylcholine receptors (M1-M5), which are G-protein coupled receptors (GPCRs). M1Rs are predominantly expressed within the central nervous system (CNS), particularly in regions like the telencephalon, and are also found in autonomic ganglia. They play a significant role in mediating cholinergic neurotransmission and are implicated in various cognitive functions, including learning, memory, and attention, as well as modulating cellular responses through signaling pathways such as phospholipase C activation and the regulation of intracellular calcium levels.[8] The therapeutic strategy for PIPE-307 centers on its selective antagonism of this specific receptor subtype. For the indication of Relapsing-Remitting Multiple Sclerosis (RRMS), it is being investigated as a potentially first-in-class M1 receptor antagonist with a novel mechanism focused on remyelination.[10]

1.2. Developers and Collaborations

The primary development of PIPE-307 is being pioneered by Contineum Therapeutics (formerly known as Pipeline Therapeutics).[1] Contineum Therapeutics has entered into a significant global license and development agreement with Janssen Pharmaceutica NV, one of the Janssen Pharmaceutical Companies of Johnson & Johnson.[1]

Under this collaboration, Janssen is taking the lead in the clinical development of PIPE-307/JNJ-89495120 for Major Depressive Disorder (MDD).[1] Contineum Therapeutics, on the other hand, is spearheading the Phase 2 VISTA trial for RRMS.[4] The terms of the agreement grant Janssen the option, at its sole discretion, to further develop PIPE-307 for RRMS following the completion of the VISTA trial, and also for any other indications.[1]

The financial aspects of this partnership underscore the perceived value of PIPE-307. The agreement included an upfront payment of $50 million to Contineum, a $25 million equity investment by Johnson & Johnson Innovation – JJDC, Inc., potential future milestone payments that could exceed $1 billion, and tiered royalties on net sales ranging from low-double digits to high-teens.[13] Furthermore, Contineum retains an opt-in right to fund a portion of Phase 3 development costs in return for an increase in these royalty rates.[13] Such collaborations are a common feature in the pharmaceutical industry, enabling the specialized expertise of biopharmaceutical companies like Contineum in areas such as precision neuroregeneration to be combined with the extensive resources, and global development and commercialization capabilities of large pharmaceutical organizations like Janssen/Johnson & Johnson. The considerable financial commitment from a major pharmaceutical entity like Johnson & Johnson suggests a strong early belief in the therapeutic potential of PIPE-307 and its M1R antagonist platform, particularly for MDD where Janssen is directing development efforts.

1.3. Therapeutic Rationale and Potential Indications

JNJ-89495120 (PIPE-307) is being developed to address significant unmet medical needs within the neuroscience, inflammation, and immunology (NI&I) therapeutic areas.[1] The primary clinical investigations for PIPE-307 are focused on two distinct conditions:

• Relapsing-Remitting Multiple Sclerosis (RRMS): In RRMS, PIPE-307 is being investigated for its potential to promote remyelination—the repair of the damaged myelin sheath that protects nerve fibers.[1] This represents a novel therapeutic approach, as most current MS therapies primarily target the immune system to reduce inflammation and relapse rates, rather than directly fostering myelin repair.[11]
• Major Depressive Disorder (MDD): For MDD, targeting the M1R with PIPE-307 offers a novel mechanistic approach that is distinct from conventional antidepressant medications, which typically modulate monoaminergic systems (e.g., serotonin, norepinephrine, dopamine).[1]

The development of a single compound for two such different and significant neurological and psychiatric disorders, based on the modulation of the same M1 receptor target, is an ambitious strategy. It underscores the diverse and critical roles that the M1R plays in various CNS functions and pathologies. Successful clinical development in either RRMS or MDD would represent a substantial therapeutic advance. The dual development strategy, with Contineum leading RRMS efforts and Janssen leading MDD efforts, reflects a comprehensive approach to exploring the compound's potential while also distributing risk and leveraging the specific strengths of each partner. The designation of PIPE-307 as a "potentially first-in-class M1 receptor antagonist" for RRMS is particularly noteworthy.[10] This highlights its innovative nature, especially for a therapy focused on remyelination, which could address a critical unmet need in MS by potentially slowing or reversing disability progression, a significant leap beyond current treatment paradigms.[11]

Table 1: Drug Profile Summary for JNJ-89495120 (PIPE-307)

Feature	Details
Primary Name	JNJ-89495120
Alternative Name(s)	PIPE-307, JNJ 89495120, JNJ89495120
Drug Class	Selective M1 Muscarinic Acetylcholine Receptor (M1R) Antagonist
Developing Company	Contineum Therapeutics
Collaboration Partner	Janssen Pharmaceutica NV (a Johnson & Johnson company)
Key Investigated Indications	Relapsing-Remitting Multiple Sclerosis (RRMS), Major Depressive Disorder (MDD)
Current Highest Dev. Phase	Phase 2 (for both RRMS and MDD)
Route of Administration	Oral

2. Mechanism of Action

2.1. Detailed Elucidation of M1 Muscarinic Acetylcholine Receptor (M1R) Antagonism

JNJ-89495120 (PIPE-307) functions as a selective antagonist of the M1 muscarinic acetylcholine receptor (M1R).[4] The M1R is a G-protein coupled receptor (GPCR) predominantly found in the central nervous system, particularly in the cerebral cortex, hippocampus, and striatum, as well as in peripheral autonomic ganglia.[8] These receptors are integral to cholinergic neurotransmission, which involves the neurotransmitter acetylcholine (ACh). M1Rs play crucial roles in modulating higher cognitive functions such as learning, memory, and attention. Their activation by ACh initiates intracellular signaling cascades, notably through the Gq/11 G-protein, leading to the activation of phospholipase C, which in turn results in the generation of inositol trisphosphate (IP3​) and diacylglycerol (DAG). This cascade ultimately modulates intracellular calcium concentrations and protein kinase C activity, influencing neuronal excitability and synaptic plasticity.[8]

As an antagonist, PIPE-307 competitively binds to the M1R, thereby preventing ACh from binding and activating the receptor. This blockade inhibits the downstream signaling pathways normally triggered by M1R activation.[8] A critical characteristic of PIPE-307 is its high selectivity for the M1R subtype over the other four muscarinic receptor subtypes (M2, M3, M4, and M5).[7] This selectivity is therapeutically important because the various muscarinic receptor subtypes are distributed differently throughout the body and mediate diverse physiological functions. Non-selective muscarinic antagonists, such as atropine and scopolamine, interact with multiple M-receptor subtypes, leading to a wide range of peripheral and central side effects, including dry mouth, blurred vision, tachycardia, constipation, and cognitive impairment.[8] The development of a highly selective M1R antagonist like PIPE-307 aims to harness the specific therapeutic benefits associated with M1R modulation while minimizing these undesirable off-target effects. This refined targeting is central to the therapeutic hypothesis for PIPE-307 in both RRMS and MDD.

2.2. Hypothesized MOA in Relapsing-Remitting Multiple Sclerosis (RRMS): Focus on Remyelination

In the context of RRMS, the therapeutic action of PIPE-307 is primarily aimed at promoting remyelination, the process of restoring the myelin sheath around demyelinated axons. The M1R has been identified as a key negative regulator of oligodendrocyte differentiation and subsequent myelination.[2] Oligodendrocyte precursor cells (OPCs), the cells responsible for generating new myelinating oligodendrocytes in the CNS, express M1Rs. Notably, M1R-expressing OPCs are found in and around MS lesions, areas where active demyelination and inflammation occur.[7]

The core hypothesis is that by antagonizing M1Rs on these OPCs, PIPE-307 removes an inhibitory brake, thereby stimulating OPCs to differentiate into mature, myelin-producing oligodendrocytes.[7] This enhanced differentiation is expected to lead to increased myelin repair. Several specific molecular pathways, largely elucidated through studies with the non-selective antimuscarinic agent clemastine (which also possesses M1R antagonistic properties) but relevant to M1R blockade, are implicated [15]:

• Modulation of the Notch-1 Signaling Pathway: M1R antagonism may alter Notch-1 signaling. Specifically, it might shift signaling away from the canonical Jagged-1 pathway, which is known to inhibit OPC differentiation, towards the noncanonical F3/Contactin pathway, which promotes OPC maturation and myelination.[15]
• Regulation of NMDA Receptor Expression: Blockade of M1R might influence the expression or function of N-methyl-D-aspartate (NMDA) receptors on OPCs. It has been suggested that antimuscarinic action could extend the duration of NMDA receptor expression on OPCs, potentially making them more responsive to environmental cues that trigger differentiation.[15]
• Activation of the Extracellular signal-Regulated Kinases 1/2 (ERK1/2) Pathway: The ERK1/2 pathway is known to be involved in cell differentiation and survival. M1R antagonism may promote OPC differentiation through the activation of this pathway.[15]
• Prevention of Inhibitory Calcium (Ca2+) Oscillations: Activation of M1Rs can induce oscillations in intracellular Ca2+ concentrations within OPCs, and these oscillations have been shown to inhibit their differentiation. By antagonizing M1Rs, PIPE-307 may prevent these inhibitory Ca2+ signals, thereby facilitating OPC maturation.[15]

The therapeutic potential of a remyelinating agent like PIPE-307 is significant. Current disease-modifying therapies for MS primarily focus on modulating the immune system to reduce the frequency and severity of relapses and to slow the formation of new lesions. However, they do not directly repair existing myelin damage or fully prevent neurodegeneration and disability progression.[11] A therapy that effectively promotes remyelination could address this critical unmet need, potentially leading to the restoration of lost neurological function and a more profound impact on the long-term course of the disease. While the precise interplay of these downstream pathways following PIPE-307 administration in human OPCs requires further detailed investigation, the overarching principle of M1R antagonism releasing a brake on OPC differentiation forms a strong basis for its development in RRMS.

2.3. Hypothesized MOA in Major Depressive Disorder (MDD)

The rationale for using an M1R antagonist like PIPE-307 in MDD stems from the long-standing "cholinergic hypothesis of depression." This hypothesis posits that an overactivity or hyperresponsiveness of the central muscarinic cholinergic system contributes to the pathophysiology of depression.[24] By selectively antagonizing M1Rs, PIPE-307 may help to normalize this putative cholinergic overdrive, thereby exerting antidepressant effects.

Beyond simply reducing cholinergic tone, M1R antagonism is thought to induce changes in synaptic plasticity and neurocircuitry relevant to mood regulation. Preclinical studies with PIPE-307 have provided direct evidence for such effects. Specifically, administration of PIPE-307 resulted in an observed increase in the amplitude of miniature Excitatory Postsynaptic Currents (mEPSCs) and an increase in the frequency of presynaptic release events (indicated by decreased inter-event interval) in pyramidal neurons of the medial prefrontal cortex (mPFC) 24 hours after dosing.[13] The mPFC is a critical brain region involved in the regulation of mood, cognition, and emotional responses, and its dysfunction is strongly implicated in MDD. Enhancements in synaptic transmission and plasticity within the mPFC are considered to be potential mechanisms underlying the action of effective antidepressant treatments.

The concept of targeting muscarinic receptors for depression is further supported by clinical findings with scopolamine, a non-selective muscarinic antagonist. Intravenous administration of scopolamine has been shown to produce rapid and robust antidepressant effects in some individuals with MDD, often within days, which is significantly faster than traditional monoaminergic antidepressants.[25] While scopolamine's utility is limited by its non-selectivity and associated side effects, these findings provide proof-of-concept for the antidepressant potential of muscarinic antagonism. PIPE-307, with its high selectivity for M1R, aims to achieve similar or potentially enhanced antidepressant efficacy with a more favorable tolerability profile by avoiding the widespread effects of non-selective agents. Additionally, some preclinical research suggests that combining an M1R antagonist with an NMDA receptor antagonist could lead to synergistic, rapid, and long-lasting antidepressant effects, hinting at potential future therapeutic strategies.[29]

The development of PIPE-307 for both RRMS and MDD, leveraging M1R antagonism, highlights the pleiotropic roles of this receptor in the CNS. While the overarching mechanism is the same, the specific downstream cellular and neurophysiological consequences are tailored to the distinct pathophysiologies of these conditions: promoting OPC differentiation and myelin repair in RRMS, and modulating synaptic plasticity and normalizing cholinergic tone in MDD.

3. Preclinical Evidence

The progression of JNJ-89495120 (PIPE-307) into clinical trials is supported by a body of preclinical evidence demonstrating its activity in models relevant to both RRMS and MDD, as well as favorable pharmacological properties.

3.1. Studies in Relapsing-Remitting Multiple Sclerosis (RRMS) Models

Preclinical investigations for RRMS have provided compelling evidence for PIPE-307's potential as a remyelinating agent.

• In Vivo Efficacy in EAE Model: PIPE-307 was evaluated in the experimental autoimmune encephalomyelitis (MOG-EAE) mouse model, a widely accepted preclinical representation of MS. In these studies, PIPE-307 administration led to a significant reduction in clinical disability scores and the cumulative disease index at doses of 3 mg/kg and 30 mg/kg.[2] Histological examination of the lumbar spinal cord from these animals revealed an increased percentage of both myelinated and remyelinated axons compared to control groups. Furthermore, electron microscopy confirmed these findings. A key functional outcome, Visual Evoked Potential (VEP) latency, which measures the conduction velocity along the optic nerve and is sensitive to myelination status, was significantly improved in PIPE-307-treated animals. This functional improvement was corroborated by electron microscopy of the optic nerves, which also showed a higher proportion of myelinated and remyelinated axons.[7] The consistency of these findings across behavioral, histological, and electrophysiological measures in a standard MS model provides a strong rationale for its clinical development.
• Ex Vivo and In Vitro Myelination Studies: Complementing the in vivo data, PIPE-307 demonstrated direct effects on oligodendrocyte precursor cells (OPCs) and myelination in various culture systems. Treatment of cultured OPCs with PIPE-307 promoted their differentiation into mature oligodendrocytes, as evidenced by the expression of myelin basic protein (MBP), a key component of the myelin sheath.[7] In ex vivo slice cultures of acutely demyelinated nervous tissue, PIPE-307 not only induced OPC differentiation but also facilitated the formation of nodes of Ranvier, which are specialized axonal domains essential for rapid saltatory nerve conduction.[7] Importantly, studies using human cortical slice cultures also showed that PIPE-307 increased the number of oligodendrocytes, adding to the translational relevance of these findings. The efficacy of PIPE-307 in these assays was comparable to that of MT7, a highly potent and M1R-selective peptide antagonist, further confirming that the observed effects are mediated through M1R antagonism.[7] This comprehensive preclinical package for MS, demonstrating functional recovery and direct evidence of remyelination at cellular and tissue levels, including human-derived tissue, forms a robust foundation for the remyelination hypothesis.

3.2. Studies in Major Depressive Disorder (MDD) Models

Preclinical studies for MDD have focused on behavioral models and neurophysiological changes indicative of antidepressant potential.

• Behavioral Assessments (Forced Swim Test - FST): PIPE-307 exhibited antidepressant-like activity in the mouse Porsolt Forced Swim Test, a common behavioral despair model used to screen for antidepressant efficacy. Administration of PIPE-307 resulted in a significant decrease in immobility time, suggesting an antidepressant effect.[13] This effect was observed with both acute (single oral dose) and repeated (once daily for 7 days) dosing paradigms. Specifically, single oral doses of 3 mg/kg and 30 mg/kg significantly reduced immobility time (p<0.0001).[13] Similarly, repeated daily dosing at 3 mg/kg and 30 mg/kg for 7 days also led to a significant decrease in immobility (p<0.0001).[13] Notably, the efficacy of the lower 3 mg/kg/day dose improved with repeated administration to a level comparable to the 30 mg/kg/day dose.[27] The behavioral profile of PIPE-307 in the FST was reported to mimic that of scopolamine, a non-selective muscarinic antagonist with known rapid antidepressant effects in humans.[13]
• Electrophysiological Correlates in Medial Prefrontal Cortex (mPFC): To investigate the neurobiological underpinnings of its behavioral effects, preclinical studies examined the impact of PIPE-307 on synaptic function in the mPFC, a brain region critically involved in mood regulation. These studies revealed that PIPE-307 administration led to an increase in the amplitude of miniature Excitatory Postsynaptic Currents (mEPSCs) and an increased frequency of presynaptic release events (observed as a decreased inter-event interval) in pyramidal neurons of the mPFC, measured 24 hours after dosing.[13] Cumulative histogram analysis demonstrated statistically significant effects on both mEPSC amplitude (P<0.001) and frequency (P<0.0001).[13] These findings suggest that PIPE-307 can enhance excitatory synaptic transmission and potentially promote synaptic plasticity in this key mood-regulating brain area. The combination of positive behavioral data with evidence of modulation of synaptic function in a relevant brain circuit provides a plausible mechanistic basis for its potential antidepressant activity.

3.3. Selectivity, Brain Penetration, and In Vitro Potency

Key pharmacological characteristics supporting PIPE-307's development include its receptor selectivity, ability to penetrate the CNS, and in vitro potency.

• Receptor Selectivity: PIPE-307 exhibits high affinity for the human M1R, with a reported Ki​ of 4.6 nM.[7] Crucially, it demonstrates significant selectivity for M1R over the other muscarinic receptor subtypes (M2-M5), with greater than 10-fold selectivity in binding assays and greater than 25-fold selectivity in functional assays.[7] An extensive off-target screening panel against 47 other biologically relevant targets (including GPCRs, nuclear hormone receptors, kinases, ion channels, transporters, and enzymes) showed no significant inhibitory or activating effects at a concentration of 10 µM, underscoring its specific M1R antagonism.[7] This high degree of selectivity is anticipated to contribute to a more favorable side effect profile compared to less selective antimuscarinic agents.
• Brain Penetration and Receptor Occupancy: As a CNS-targeted therapeutic, effective brain penetration is essential. Preclinical studies have confirmed that orally administered PIPE-307 readily crosses the blood-brain barrier.[2] In mice, the brain-to-plasma concentration ratio was approximately 1, and the unbound brain-to-plasma ratio was 1.3, indicating efficient distribution into the brain parenchyma.[7] In vivo receptor occupancy studies in mice determined an ED50 (dose required for 50% receptor occupancy) of 0.4 mg/kg for M1R in the CNS. A single oral dose of 3 mg/kg was shown to achieve $\geq$60% M1R occupancy for at least 8 hours, demonstrating sustained target engagement in the brain.[7] These data are critical for guiding dose selection in human clinical trials to ensure adequate target modulation.
• In Vitro Potency: PIPE-307 demonstrated potent M1R antagonism at the cellular level, with an IC50​ of 3.8 nM for the inhibition of acetylcholine-induced calcium mobilization in cells overexpressing the M1R.[7]

The establishment of dose-dependent effects in preclinical models and the ability to link these effects to brain M1R occupancy are fundamental to translating these findings into the clinical setting.

Table 2: Summary of Key Preclinical Findings for JNJ-89495120 (PIPE-307)

Indication	Model Type	Compound	Key Parameters Measured	Key Results	Selectivity/Potency	Brain Penetration
RRMS	MOG-EAE Mouse Model	PIPE-307	Clinical disability scores, Myelination (histology/EM), VEP latency	Reduced disability (3 & 30 mg/kg), Increased myelination, Improved VEP latency 7	M1R Ki​: 4.6 nM; >10x selectivity vs M2-5 (binding), >25x (functional) 7	ED50 (M1R Occupancy, mouse): 0.4 mg/kg; $\geq$60% occupancy for $\geq$8h at 3 mg/kg 7
RRMS	OPC Culture (rat, human)	PIPE-307	OPC differentiation (MBP expression), Oligodendrocyte number	Promoted OPC differentiation, Increased oligodendrocyte number 7	M1R IC50​: 3.8 nM (Ca<sup>2+</sup> mobilization) 7	Brain:Plasma ratio ~1 (mouse) 7
RRMS	Demyelinated Slice Culture (mouse, human)	PIPE-307	OPC differentiation, Nodes of Ranvier formation	Induced OPC differentiation, Promoted Nodes of Ranvier formation 7
MDD	Forced Swim Test (mouse)	PIPE-307	Immobility time	Decreased immobility (3 & 30 mg/kg, acute & 7-day repeat, p<0.0001) 13
MDD	mPFC Slice Electrophysiology (mouse)	PIPE-307	mEPSC amplitude & frequency	Increased mEPSC amplitude (p<0.001) & frequency (p<0.0001) 13

4. Clinical Development Program

The clinical development of JNJ-89495120 (PIPE-307) has progressed from initial safety and pharmacokinetic assessments in healthy volunteers to Phase 2 proof-of-concept trials in patient populations for both RRMS and MDD.

4.1. Phase 1 Studies in Healthy Volunteers (NCT04725175 and PET Imaging Study)

The initial human studies of PIPE-307 were designed to assess its safety, tolerability, and pharmacokinetic (PK) profile. The primary Phase 1 study (NCT04725175) was a randomized, double-blind, placebo-controlled trial conducted in Australia, enrolling 70 healthy adult volunteers aged 18 to 55 years.[16] This study comprised three parts:

• Part 1 (Single Ascending Dose - SAD): Participants received single oral doses of PIPE-307 or placebo. Doses investigated included 1 mg, 5 mg, 10 mg, and 20 mg.[13] An earlier SEC filing indicated SAD cohorts up to 80 mg were explored.[27]
• Part 2 (Multiple Ascending Dose - MAD): Participants received multiple oral doses of PIPE-307 or placebo. Dosing regimens included 1 mg once daily (QD) for 7 days, 3 mg QD for 7 days, and 10 mg QD for 14 days.[13] The earlier SEC filing mentioned MAD cohorts up to 20 mg QD for 7 days.[27]
• Part 3 (Food Effect): A selected SAD cohort was evaluated to determine the effect of food on the bioavailability of PIPE-307.[16]

Pharmacokinetics (PK):

The Phase 1 program yielded important PK data. PIPE-307 demonstrated a favorable PK profile, with data generally consistent with preclinical modeling.31 Linear and dose-proportional pharmacokinetics were observed across the dose ranges studied.13

A critical component of the early clinical development was Positron Emission Tomography (PET) imaging, which may have been conducted as part of NCT04725175 or a separate dedicated study.27 This PET imaging confirmed M1R target engagement in the human brain and established a relationship between plasma concentrations of PIPE-307 and receptor occupancy.13 The estimated human EC50​ (plasma concentration required for 50% M1R occupancy) was determined to be 28.8 ng/mL (95% Confidence Interval: 21.3-36.2 ng/mL). This finding supported a projected therapeutic daily dose range of 10 to 20 mg of PIPE-307 to achieve significant M1R occupancy in the CNS.27 These PK and target engagement data were pivotal for selecting appropriate doses for subsequent Phase 2 trials in patient populations.

Safety and Tolerability:

The primary endpoint of the Phase 1 SAD/MAD study was the assessment of safety and tolerability.31 PIPE-307 was reported to be well-tolerated across all single and multiple dose cohorts tested.7 No dose-limiting adverse events (AEs) or significant toxicities were observed.13

A particularly important safety finding was the absence of substantial PK or dose-associated adverse effects on cognitive functions. Comprehensive neuropsychological assessments, including tests for psychomotor speed, attention, learning, and executive function, did not reveal any significant impairment.7 This is a key differentiator from non-selective antimuscarinic agents, which are often associated with cognitive side effects, and supports the potential benefits of PIPE-307's M1R selectivity. Safety monitoring in these trials included regular electrocardiograms (ECGs), blood laboratory analyses, vital sign measurements, physical examinations, and systematic AE recording.16 The favorable safety and tolerability profile, especially the lack of cognitive concerns, established in healthy volunteers provided a strong basis for advancing PIPE-307 into patient studies.

Table 3: Summary of Phase 1 Data for JNJ-89495120 (PIPE-307)

Study Feature	Details
Trial ID(s)	NCT04725175 (SAD/MAD/Food Effect); Separate PET Imaging Study (or part of NCT04725175)
Design	SAD Doses: 1, 5, 10, 20 mg (potentially up to 80 mg) 13 <br> MAD Doses: 1mg QD x7d, 3mg QD x7d, 10mg QD x14d (potentially up to 20mg QD x7d) 13 <br> PET Doses: 10, 20, 40 mg 27
Population	Healthy Volunteers (N=70 for SAD/MAD) 31
Key PK Findings	Dose-proportional PK.13 Brain M1R occupancy confirmed by PET.13 Human M1R Occupancy EC50​: 28.8 ng/mL (95% CI: 21.3-36.2 ng/mL).27 Projected efficacious daily dose for target engagement: 10-20 mg.27
Key Safety/Tolerability	Well-tolerated across SAD & MAD cohorts.13 No dose-limiting AEs or toxicity.13 No significant adverse effects on cognitive function.13

4.2. Phase 2 Study in Relapsing-Remitting Multiple Sclerosis (VISTA Trial - NCT06083753)

Following the encouraging Phase 1 results, Contineum Therapeutics initiated the VISTA trial to evaluate PIPE-307 in patients with RRMS.

• Official Title: A Study to Evaluate the Safety and Efficacy of PIPE-307 in Subjects With Relapsing-Remitting Multiple Sclerosis (VISTA).[11]
• Sponsor: Contineum Therapeutics.[12]
• Phase: Phase 2.[1]
• Study Design: This is a randomized, double-blind, placebo-controlled, multi-center, proof-of-concept trial.[1] The study involves three parallel arms with a 1:1:1 randomization ratio: PIPE-307 Dose A, PIPE-307 Dose B, and Placebo. Participants receive daily oral dosing for a treatment duration of 26 weeks (approximately 6.5 months), preceded by a 28-day screening period.[11]
• Objectives and Endpoints: The trial is designed to assess both the efficacy and safety of PIPE-307.
• Co-Primary Objectives:

1. Evaluation of safety and tolerability, primarily through the incidence of treatment-emergent adverse events (TEAEs).[13]
2. Assessment of the effect of PIPE-307 on the change from baseline in binocular 2.5% low contrast letter acuity (LCLA).[13] LCLA is a sensitive measure of visual function that can be impaired in MS due to optic nerve demyelination and can reflect remyelination.

• Key Secondary Objectives: These include changes in monocular LCLA, overall neurological disability as measured by the Multiple Sclerosis Functional Composite (MSFC), MRI measures indicative of myelination status (such as Magnetization Transfer Ratio (MTR) and Diffusion Tensor Imaging (DTI)), levels of serum neurofilament light chain (NfL, a biomarker of neuroaxonal damage), and plasma population pharmacokinetics of PIPE-307.[13] Other functional assessments include the Timed 25-Foot Walk Test, the 9-Hole Peg Test (for upper extremity function), and the Symbol Digit Modalities Test (for cognitive processing speed).[13] A sub-study will also evaluate Visual Evoked Potentials (VEP).[35] The comprehensive nature of these endpoints aims to provide a multi-faceted evaluation of PIPE-307's potential remyelinating and neuroprotective effects.
• Patient Population and Enrollment: The trial targets adults aged 18 to 50 years diagnosed with RRMS according to the 2017 Revised McDonald Criteria, with a disease duration of less than 10 years.[11] Participants are required to have an Expanded Disability Status Scale (EDSS) score between 0 and 6.0 (inclusive) and must be on a stable immunomodulatory disease-modifying therapy (DMT) for at least 6 months prior to screening.[11] The targeted enrollment for the VISTA trial was 168 patients.[10]
• Status and Timelines: Enrollment of the 168 participants was completed in December 2024, reportedly ahead of schedule. The trial is being conducted across 21 sites in the United States.[10] The last patient is expected to complete the trial in the third quarter of 2025.[10] Topline data from the VISTA trial are anticipated in the second half of 2025.[1] The efficient enrollment is a positive indicator for the operational conduct of the study.

4.3. Phase 2 Study in Major Depressive Disorder (Moonlight-1 Trial - NCT06785012; Study ID 89495120MDD2001)

Concurrently, Janssen Research & Development, LLC, is evaluating JNJ-89495120 (PIPE-307) for MDD.

• Official Title: A Study to Explore the Efficacy of JNJ-89495120 in the Treatment of Major Depressive Disorder (Moonlight-1).[17]
• Sponsor: Janssen Research & Development, LLC (a Johnson & Johnson company).[4]
• Phase: Phase 2.[1]
• Study Design: This is a randomized, double-blind, multicenter, placebo-controlled, proof-of-concept study. JNJ-89495120 is being investigated as a monotherapy.[1]
• Objectives and Endpoints: The primary purpose of the study is to evaluate the antidepressant efficacy and tolerability of JNJ-89495120 compared to placebo in reducing the symptoms of MDD.[17] Specific primary and secondary outcome measures (e.g., change in MADRS or HAM-D scores) and their respective timeframes are not detailed in the currently available information, but would be standard for such a trial.
• Patient Population and Enrollment: The trial is enrolling adults aged 18 to 64 years.[17] Key inclusion criteria include a primary psychiatric diagnosis of recurrent MDD (without psychotic features) based on DSM-5 criteria and confirmed by the Mini International Neuropsychiatric Interview (MINI); at least one previous MDD episode; current depressive episode duration of at least 2 months but not longer than 24 months; and having received 0, 1, or 2 antidepressant treatments for the current episode.[17] Participants must also have a Body Mass Index (BMI) within the range of 18 to 35 kg/m2 at screening.[17] Significant exclusion criteria include a history of bipolar disorder, psychotic disorders, borderline or antisocial personality disorder, current obsessive-compulsive disorder, post-traumatic stress disorder within the past three years, dementia or other neurocognitive disorders, alcohol or substance use disorders (excluding nicotine, caffeine, and mild cannabis use disorder) within 6 months of screening, and previous treatment with vagus nerve stimulation (VNS), electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), or ketamine/esketamine for any MDD episode.[17] The estimated enrollment is approximately 124 adult participants.[1]
• Status and Timelines: Recruitment for the Moonlight-1 trial began in December 2024.[1] As of May 2025, the study was listed as recruiting participants across 24 sites, primarily in the United States.[17] Topline data from this MDD trial are anticipated in 2026.[38] The leadership of this trial by Janssen, including the substantial planned enrollment, signals a significant commitment to exploring PIPE-307's potential in MDD.
• Intervention Details: Participants will receive either JNJ-89495120 or a matching placebo.[36] While specific dosage regimens for this trial are not provided in the available materials, PIPE-307 is known to be an oral small molecule.[1]

Table 4: Overview of Key Clinical Trials for JNJ-89495120 (PIPE-307)

Trial ID (NCT)	Indication	Phase	Brief Design	Key Primary Endpoint(s)	Est. Enrollment	Status (as of early-mid 2025)	Sponsor/Lead	Anticipated Topline Data
NCT04725175	Healthy Volunteers	1	R, DB, PC, SAD/MAD, Food Effect	Safety, Tolerability, PK	70 (actual)	Completed	Contineum	Data reported (used for Ph2 design)
NCT06083753 (VISTA)	RRMS	2	R, DB, PC, MC, PoC	Safety/Tolerability, Change in binocular LCLA	168	Enrollment Completed (Dec 2024)	Contineum	H2 2025 4
NCT06785012 (Moonlight-1)	MDD	2	R, DB, PC, MC, PoC, Monotherapy	Efficacy (symptom reduction), Tolerability	~124	Recruiting (Started Dec 2024)	Janssen R&D	2026 38

(R: Randomized, DB: Double-Blind, PC: Placebo-Controlled, MC: Multi-Center, PoC: Proof-of-Concept, SAD: Single Ascending Dose, MAD: Multiple Ascending Dose, LCLA: Low Contrast Letter Acuity)

The staggered timelines for data readouts from the RRMS and MDD trials will provide key insights into PIPE-307's therapeutic utility in these distinct CNS disorders over the next 1-2 years.

5. Safety and Tolerability Profile (Aggregated)

The safety and tolerability of JNJ-89495120 (PIPE-307) are critical aspects of its development, particularly given its novel mechanism of action and the historical context of antimuscarinic agents. Current understanding is based on preclinical studies and completed Phase 1 trials in healthy volunteers, with further data to emerge from ongoing Phase 2 trials in patient populations.

5.1. Preclinical Safety

Detailed preclinical toxicology findings for PIPE-307 are not extensively reported in the available documents. However, the successful progression of the compound from preclinical research to Phase 1 human trials inherently implies that it demonstrated an acceptable safety margin in requisite animal toxicology studies, as mandated by regulatory authorities. For context, Contineum Therapeutics has noted the completion of chronic toxicity studies for another of its pipeline compounds (PIPE-791) as a necessary step to support Phase 2 trials, indicating that such comprehensive preclinical safety evaluations are standard practice for the developer.[1]

5.2. Phase 1 Clinical Safety (Healthy Volunteers)

The Phase 1 program for PIPE-307, primarily encompassing study NCT04725175, provided the first human safety data. Across both single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, PIPE-307 was reported to be generally well-tolerated by healthy volunteers.7

A key finding from these Phase 1 studies was the absence of dose-limiting adverse events (AEs) or significant toxicity.13 This favorable early safety signal is crucial for any investigational drug.

Of particular importance for an M1R antagonist, especially one targeting CNS indications, was the assessment of potential cognitive side effects. Muscarinic receptors, including M1R, are known to play roles in cognitive processes, and non-selective antimuscarinic drugs are often associated with cognitive impairments such as confusion, memory problems, and reduced attention. However, comprehensive neuropsychological assessments conducted during the Phase 1 trials of PIPE-307 (evaluating psychomotor function, attention, learning, and executive function) revealed no substantial pharmacokinetic-related or dose-associated adverse effects on cognitive function in healthy volunteers.[7] This finding is highly significant as it suggests that the selectivity of PIPE-307 for the M1R subtype may indeed mitigate the risk of cognitive side effects commonly seen with less selective agents. This clean cognitive safety profile in healthy individuals was a major hurdle successfully cleared in early development.

5.3. Safety Monitoring in Ongoing Phase 2 Studies

The safety and tolerability of JNJ-89495120 (PIPE-307) continue to be rigorously evaluated as primary or key objectives in the ongoing Phase 2 trials in patient populations: the VISTA trial (NCT06083753) for RRMS and the Moonlight-1 trial (NCT06785012) for MDD.4

Data on the incidence and nature of AEs in these specific patient populations, who may have different sensitivities, comorbidities, or concomitant medications compared to healthy volunteers, will emerge as these trials are completed and analyzed. The design of these trials incorporates comprehensive safety monitoring protocols.

The exclusion criteria for these Phase 2 studies are also relevant to safety considerations. For instance, the MDD trial (Moonlight-1) excludes patients with a history of certain psychiatric comorbidities or prior treatments like ECT or ketamine, which could confound safety assessments or pose additional risks.17 Similarly, the RRMS trial (VISTA) has exclusions related to recent optic neuritis or use of certain medications that could interfere with safety or efficacy evaluations.30 These criteria are implemented to help ensure patient safety and the interpretability of the trial results.

The experience with clemastine, an older antihistamine with M1R antagonistic properties that showed some remyelination potential in MS models but also raised concerns about potentially accelerating disability in some clinical contexts [39], serves as an important reference. While PIPE-307's high selectivity for M1R is hypothesized to offer a better safety profile, the clemastine experience underscores the necessity for careful and thorough long-term safety monitoring for any M1R-targeting agent in MS. The upcoming data from the Phase 2 trials will be crucial in further characterizing the safety profile of PIPE-307 in individuals with RRMS and MDD.

6. Discussion and Future Perspectives

JNJ-89495120 (PIPE-307) stands as a novel investigational therapeutic with a distinct mechanism of action, selective M1 muscarinic acetylcholine receptor (M1R) antagonism, being explored for two significant and challenging CNS disorders: Relapsing-Remitting Multiple Sclerosis (RRMS) and Major Depressive Disorder (MDD). The development program, supported by promising preclinical data and encouraging early clinical safety findings, is at a pivotal stage with Phase 2 proof-of-concept trials underway.

6.1. Synthesis of Current Knowledge and Potential Clinical Impact

For RRMS, PIPE-307 offers a fundamentally different therapeutic strategy compared to existing treatments. The primary aim is to promote remyelination, the repair of damaged myelin sheaths, which is a process largely unaddressed by current immunomodulatory therapies.[10] Preclinical studies have demonstrated PIPE-307's ability to enhance oligodendrocyte precursor cell (OPC) differentiation and improve functional and histological outcomes in MS models.[7] If the positive signals from preclinical work and the favorable safety profile from Phase 1 translate into clear evidence of remyelination and clinical benefit in the Phase 2 VISTA trial (as measured by endpoints like Low Contrast Letter Acuity (LCLA) and MRI markers of myelination), PIPE-307 could represent a paradigm shift in MS management. Such an outcome would signify a move towards neurorestorative therapies, addressing the critical unmet need of halting or potentially reversing disability progression, rather than solely managing inflammatory aspects of the disease.[11]

For MDD, PIPE-307's M1R antagonist mechanism provides a novel approach, diverging from the predominantly monoaminergic targets of most current antidepressants (e.g., SSRIs, SNRIs).[24] The cholinergic hypothesis of depression suggests that hyperactivity in this system contributes to depressive symptoms, and M1R antagonism could help normalize this imbalance. Preclinical evidence showing PIPE-307's ability to modulate synaptic plasticity in the medial prefrontal cortex (mPFC) – a key brain region in mood regulation – and its antidepressant-like effects in behavioral models like the Forced Swim Test, lends support to this hypothesis.[13] The rapid antidepressant effects observed with the non-selective muscarinic antagonist scopolamine in some clinical studies, albeit with side-effect limitations, provide a historical precedent for the potential of this mechanistic class.[25] If PIPE-307 demonstrates efficacy in the Phase 2 Moonlight-1 trial, particularly with a favorable safety and tolerability profile attributable to its M1R selectivity, it could offer a valuable new therapeutic option for individuals with MDD, including those who do not respond adequately to or cannot tolerate existing treatments.

6.2. Comparison with Existing Therapies and Unmet Medical Needs Addressed

In RRMS, current disease-modifying therapies (DMTs) have significantly improved outcomes by reducing relapse rates and inflammatory activity. However, they have limited impact on repairing existing myelin damage or preventing the progressive neurodegeneration that often leads to long-term disability.[11] PIPE-307, by aiming to directly promote remyelination, seeks to fill this therapeutic void, potentially offering neuro-restorative and neuroprotective benefits.

In MDD, despite the availability of numerous antidepressant medications, a substantial proportion of patients fail to achieve full remission with initial treatments, and many experience troublesome side effects.[24] There is a clear and persistent need for antidepressants with novel mechanisms of action that can offer improved efficacy, faster onset of action, or better tolerability for specific patient subgroups. PIPE-307's unique M1R-targeted mechanism could address this need, potentially benefiting patients with treatment-resistant depression or those who experience side effects with conventional agents.

6.3. Competitive Landscape

The development of selective M1R modulators for CNS disorders is an area of active research, though the pipeline for highly selective M1R antagonists specifically targeting remyelination in RRMS or as a primary antidepressant appears less congested than for other mechanisms. Many older compounds possess some M1R antagonistic activity as part of a broader, non-selective receptor binding profile (e.g., some tricyclic antidepressants or antipsychotics), but these are not direct comparators to a highly selective agent like PIPE-307.

Some M1 receptor modulators are in development, such as KarXT (xanomeline-trospium), which is an M1/M4 receptor agonist approved for schizophrenia and under investigation for other psychiatric conditions.40 This differs mechanistically from PIPE-307. Reports mention TNX-102 SL (a cyclobenzaprine formulation) in Phase 3 for fibromyalgia, with M1 antagonism being part of its broader pharmacology, but it is not a direct M1 selective antagonist in the same class as PIPE-307 for MS or MDD.42

A review of the acetylcholine receptor antagonist pipeline by DelveInsight mentions Onix Pharmaceuticals and Bristol Myers Squibb as companies with M1 antagonist programs.21 However, further investigation into the specific compounds, their selectivity profiles, and their targeted indications (MS or MDD) is needed to determine direct competition. For instance, information on Onix Pharmaceuticals primarily points to M4 positive allosteric modulators 43, and Bristol Myers Squibb's pipeline includes M1/M4 agonists rather than selective M1 antagonists for these specific indications.40 This landscape suggests that PIPE-307, with its high selectivity for M1R and its focused development for remyelination in MS and as a novel antidepressant, may indeed hold a unique position and could be among the most advanced, if not the leading, selective M1R antagonist for these specific CNS applications.

6.4. Potential Challenges and Opportunities

Challenges:

• Translation to Clinical Efficacy: A significant hurdle in CNS drug development is translating promising preclinical findings into robust clinical efficacy in humans. This is particularly true for remyelination in MS, where the complexity of the disease and the limitations of current clinical trial endpoints pose challenges.
• Long-Term Safety: While early clinical data for PIPE-307 are encouraging, long-term safety and tolerability in larger patient populations exposed for extended durations will need to be thoroughly established. The historical experience with less selective antimuscarinics, including the mixed outcomes of clemastine in MS (which showed some remyelination signals but also concerns about potentially accelerating disability in some studies [39]), underscores the importance of vigilance, even with a selective agent.
• Defining a Clinical Niche in MDD: If effective in MDD, PIPE-307 will need to demonstrate a clear advantage or a distinct clinical profile (e.g., efficacy in treatment-resistant patients, faster onset, better tolerability on specific parameters) to find its place in a market with many established antidepressants.
• Complexity of M1R Biology: The M1R is involved in diverse physiological processes. While selectivity is a key design feature of PIPE-307, unforeseen effects related to M1R modulation in specific patient populations or over long-term use cannot be entirely ruled out.

Opportunities:

• Addressing Major Unmet Needs: Success in either RRMS (by providing a neuro-restorative treatment) or MDD (by offering a novel mechanistic approach for patients unresponsive to current therapies) would address substantial unmet medical needs and could transform patient care.
• Strong Pharmaceutical Partnership: The collaboration with Janssen Pharmaceutica NV (Johnson & Johnson) provides significant financial resources, extensive clinical development expertise, and global commercialization capabilities, which are invaluable for advancing PIPE-307.[1]
• Favorable Early Clinical Profile: The positive safety, tolerability, and pharmacokinetic data from Phase 1 studies, particularly the confirmation of CNS M1R target engagement without adverse cognitive signals, provide a solid foundation for current Phase 2 trials.[7]
• Potential for Future Combinations: Depending on its profile, PIPE-307 could potentially be explored in combination with other therapeutic agents in the future (e.g., with immunomodulatory DMTs in MS to provide a dual approach of immune control and myelin repair, or with other classes of antidepressants for MDD, as suggested by preclinical concepts [29]).

6.5. Concluding Remarks on the Therapeutic Promise of JNJ-89495120 (PIPE-307)

JNJ-89495120 (PIPE-307) represents an innovative therapeutic strategy, leveraging selective M1 muscarinic acetylcholine receptor antagonism to address the distinct pathophysiologies of RRMS and MDD. The compound is built on a strong scientific rationale, supported by compelling preclinical efficacy in relevant disease models and encouraging safety, tolerability, and target engagement data from Phase 1 clinical studies in healthy volunteers.

The ongoing Phase 2 proof-of-concept trials are critical junctures in its development. The VISTA trial in RRMS (NCT06083753), with anticipated topline data in the second half of 2025, will provide the first insights into its remyelinating potential in patients. The Moonlight-1 trial in MDD (NCT06785012), with data expected in 2026, will assess its efficacy as a novel antidepressant.

Should these trials yield positive results, JNJ-89495120 (PIPE-307) could offer significant advancements. In RRMS, it could pioneer a new class of neuro-restorative therapies. In MDD, it could provide a much-needed alternative for patients who do not benefit from or tolerate existing treatments. The journey of PIPE-307 through clinical development will be closely watched, as its success would not only validate selective M1R antagonism as a therapeutic approach but also bring new hope to patients suffering from these complex and often debilitating CNS disorders. The broader implications of successfully modulating M1R could also stimulate further research into this target for other neurological and psychiatric conditions where M1R dysfunction is implicated.[9]

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