An In-Depth Review of MK-5720: A Long-Acting Injectable PDE10A Inhibitor for Schizophrenia

I. Executive Summary

MK-5720, a small molecule drug candidate, has been under development by Merck Sharp & Dohme LLC (Merck) as a long-acting injectable (LAI) formulation targeting phosphodiesterase 10A (PDE10A) for the treatment of schizophrenia. Its development is intrinsically linked to MK-8189, an oral PDE10A inhibitor also from Merck. The primary clinical investigation for MK-5720, a Phase 1 trial (NCT05953740), which included an oral lead-in with MK-8189, was completed in early 2024, focusing on safety, tolerability, and pharmacokinetics. Concurrently, MK-8189 completed a Phase 2a trial (NCT03055338), the results of which, published in June 2024, indicated a trend towards efficacy on the primary PANSS total score endpoint and nominal significance on positive symptoms, alongside a favorable safety profile, notably inducing weight loss compared to placebo and active comparator risperidone.

Despite these developments, a critical observation is the absence of both MK-5720 and MK-8189 from Merck's publicly disclosed pipeline as of February 2025. This omission, following the completion of their respective trial phases, strongly suggests a potential discontinuation or strategic deprioritization of Merck's PDE10A inhibitor program for schizophrenia. This decision occurs within a challenging landscape for PDE10A inhibitors, a class that has seen multiple clinical trial failures from various pharmaceutical companies despite a strong preclinical rationale for treating the complex symptoms of schizophrenia. The precise reasons for Merck's apparent shift remain undisclosed, but likely reflect a comprehensive assessment of the clinical data, the historical difficulties in translating PDE10A inhibition into robust clinical efficacy, and broader portfolio management considerations.

II. Introduction to MK-5720

A. Overview of MK-5720

MK-5720 is an investigational small molecule drug candidate that was under development by the pharmaceutical company Merck Sharp & Dohme LLC, hereafter referred to as Merck.[1] As a major global pharmaceutical entity, Merck dedicates substantial resources to research and development across various therapeutic areas.[4] The primary therapeutic focus for MK-5720 has been Nervous System Diseases, with a specific active indication for the treatment of schizophrenia.[1] Schizophrenia is a severe and chronic mental disorder characterized by distortions in thinking, perception, emotions, language, sense of self, and behavior. It presents a significant global health burden, with substantial unmet medical needs, particularly for treatments that can effectively manage negative symptoms (e.g., apathy, social withdrawal) and cognitive impairments, in addition to the positive symptoms (e.g., hallucinations, delusions) targeted by existing therapies.[6]

B. Formulation: Long-Acting Injectable (LAI)

A key characteristic of MK-5720 is its formulation as a long-acting injectable (LAI), designed for intramuscular administration.[2] LAI formulations of antipsychotic medications have become increasingly important in the management of schizophrenia. Poor medication adherence is a common and significant challenge in this patient population, often leading to relapse, re-hospitalization, and poorer long-term outcomes.[8] LAIs address this by providing sustained plasma drug concentrations over extended periods (weeks or months) with less frequent dosing compared to oral medications. This approach can improve adherence, reduce the risk of relapse, and offer more predictable pharmacokinetic profiles.[8] The strategic decision to develop an LAI formulation like MK-5720 typically suggests an intention to provide a treatment option that enhances patient compliance and potentially offers a differentiated profile for a drug class or mechanism, particularly if an oral counterpart shows promise.

The development of an LAI often follows the establishment of efficacy and tolerability with an oral formulation of the same or a closely related compound. This allows for initial dose-finding and safety assessment before committing to a long-acting preparation. Merck's pursuit of MK-5720 as an LAI alongside its oral PDE10A inhibitor, MK-8189, aligns with this common developmental paradigm, indicating an initial strategy to establish the therapeutic utility of the PDE10A mechanism with an oral agent before offering a compliance-enhancing LAI option.

C. Chemical Identity and Nomenclature

MK-5720 is an internal development code used by Merck. Alternative nomenclatures found in various databases include "MK 5720" and "MK5720".[2] Such internal codes are standard practice in the pharmaceutical industry during the research and development phases, preceding the assignment of an International Nonproprietary Name (INN) or a commercial brand name.

Detailed chemical structure information or a specific Chemical Abstracts Service (CAS) number for MK-5720 as a distinct chemical entity is not readily available in the public domain through the provided research materials. It is important to note that some sources reference CAS numbers 5720-07-0 and 5720-05-8 [11]; however, these correspond to 4-Methoxyphenylboronic acid and p-Tolylboronic acid, respectively, and are unrelated to the MK-5720 therapeutic candidate.

The development of MK-5720 as an LAI is closely tied to Merck's oral PDE10A inhibitor, MK-8189. The Phase 1 clinical trial for MK-5720 (NCT05953740) incorporated an oral lead-in period with MK-8189.[13] MK-8189 is a pyrimidine derivative.[14] LAI formulations frequently involve chemical modification of the parent drug molecule to achieve sustained release characteristics (e.g., esterification to create a prodrug that is slowly hydrolyzed in vivo) or specific formulation technologies (e.g., microcrystalline suspensions). Given the integral role of MK-8189 in the MK-5720 clinical trial and the typical LAI development pathway, it is highly probable that MK-5720 is either a long-acting formulation of MK-8189 itself or a very closely related chemical derivative specifically engineered for sustained intramuscular release. The absence of a distinct, publicly available chemical structure for MK-5720, separate from that of MK-8189, further supports this close relationship. Consequently, the pharmacological properties, efficacy, and safety profile of MK-5720 are intrinsically linked to those of MK-8189.

Table 1: MK-5720 - Drug Profile Summary

Feature	Details
Internal Development Code	MK-5720 (also MK 5720, MK5720)
Developer	Merck Sharp & Dohme LLC
Drug Type	Small molecule 1
Therapeutic Class	Phosphodiesterase 10A (PDE10A) Inhibitor 2
Primary Indication	Schizophrenia 1
Formulation	Long-Acting Injectable (LAI) 3
Route of Administration	Intramuscular 2
Highest Reported Phase	Phase 1 (Completed) 1

This table provides a concise overview of the fundamental characteristics of MK-5720, collated from various sources.[1] It serves as an immediate reference to the drug's identity, its developer, its nature as a small molecule, its mechanism of action, its intended use, its formulation and route of administration, and the most advanced stage of clinical development it reportedly reached.

III. Pharmacological Profile and Rationale

A. Mechanism of Action: PDE10A Inhibition

MK-5720 functions as a Phosphodiesterase 10A (PDE10A) inhibitor.[2] Its oral counterpart, MK-8189, upon which MK-5720 is likely based, is characterized as a highly potent and selective inhibitor of the PDE10A enzyme.[14] PDE10A is a dual-substrate enzyme that hydrolyzes both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are crucial intracellular second messengers involved in a multitude of cellular signaling pathways.[6] The enzyme exhibits a highly restricted expression pattern, being predominantly found in the medium spiny neurons (MSNs) of the striatum—a core component of the basal ganglia that plays a critical role in motor control, reward, motivation, and cognitive functions.[6]

B. The Role of PDE10A in Schizophrenia Pathophysiology

The rationale for targeting PDE10A in schizophrenia stems from the enzyme's strategic location and function within striatal circuits, which are known to be dysregulated in the disorder. Dopamine signaling abnormalities in the striatum are a cornerstone of schizophrenia pathophysiology. PDE10A inhibition is hypothesized to normalize this dysfunctional striatal activity.[14] By preventing the degradation of cAMP and cGMP, PDE10A inhibitors elevate the levels of these second messengers within MSNs. This elevation is thought to modulate the activity of both the direct (D1-receptor expressing) and indirect (D2-receptor expressing) pathways of the basal ganglia. Specifically, PDE10A inhibition is proposed to enhance the functional output of the direct striatonigral pathway (which is generally associated with D1 receptor activation) and, concurrently, to constrain the functional output of the indirect striatopallidal pathway (which is influenced by D2 receptor signaling).[6]

This dual modulatory effect is theoretically attractive for schizophrenia treatment. The D2-like antagonism effect on the indirect pathway could address positive symptoms, similar to current antipsychotics. Simultaneously, the D1-like agonism effect on the direct pathway could potentially alleviate negative and cognitive symptoms, which are poorly addressed by existing medications and contribute significantly to long-term disability.[6] Some research has suggested that PDE10A enzyme levels or activity might be altered in individuals with schizophrenia, with some studies indicating a reduction [6], although other investigations have not found significant differences compared to healthy controls.[21]

The therapeutic strategy of PDE10A inhibition hinges on achieving a delicate balance in modulating these dopaminergic pathways. The striatum's complex circuitry implies that simply increasing second messenger levels may not uniformly lead to beneficial outcomes. An over-stimulation of the direct pathway or an improper balance between the direct and indirect pathways could potentially be detrimental or even counteract antipsychotic effects, as suggested by preclinical studies where excessive direct pathway activation nullified the effects of D2 antagonists.[27] The kinetic properties of the inhibitor, such as its off-rate from the enzyme, may also be critical in achieving the desired pharmacological profile.[27] The historical challenges and failures of other PDE10A inhibitors in clinical development underscore the difficulty of achieving this "Goldilocks" zone of modulation.[26] Merck's investment in this class, despite these prior setbacks, suggested a belief that their compounds, MK-8189 and subsequently MK-5720, possessed a differentiated profile (e.g., superior potency, selectivity, or pharmacokinetic/pharmacodynamic properties) that could overcome these translational hurdles. However, the therapeutic window for PDE10A inhibitors appears to be narrow, demanding precise dosing and target engagement to elicit the desired clinical response without untoward effects.

C. Rationale for Developing a Long-Acting Injectable (LAI) Formulation

MK-5720 was specifically developed as an LAI to be administered intramuscularly.[2] The rationale for pursuing an LAI formulation for a novel antipsychotic mechanism like PDE10A inhibition is multifaceted. As previously mentioned, medication non-adherence is a pervasive issue in schizophrenia management, significantly impacting treatment efficacy and long-term prognosis.[8] LAIs offer a robust solution by ensuring sustained drug delivery over weeks or months, thereby reducing dosing frequency, improving patient compliance, providing more stable plasma drug concentrations (which can reduce side effects associated with peaks and troughs of oral dosing), and potentially leading to better prevention of relapses.[8]

The development of an LAI for a novel mechanism such as PDE10A inhibition typically signifies a strategic commitment by the pharmaceutical company. If the oral formulation (in this case, MK-8189) demonstrates convincing efficacy and an acceptable safety profile, an LAI version (MK-5720) would be a logical progression. This step aims to maximize the therapeutic potential of the new mechanism by addressing adherence challenges and enhancing convenience for patients and caregivers. Furthermore, LAIs can be part of a life-cycle management strategy for a successful oral drug, extending its market presence and offering a differentiated product. The technical requirements for a drug candidate to be suitable for LAI development include high potency (to allow for a reasonable injection volume) and physicochemical properties that permit slow release from the injection site and slow systemic clearance.[8] Merck's investment in an LAI formulation for its PDE10A program thus indicated initial confidence in the underlying pharmacology of MK-8189 and a strategic vision to offer a comprehensive treatment solution, contingent upon positive outcomes from the oral agent's clinical trials. The progression of MK-5720 was therefore heavily reliant on the success of MK-8189.

IV. The Oral Counterpart: MK-8189 – Context and Development

A. Overview of MK-8189

MK-8189, identified by CAS number 1424371-93-6, is an orally administered, highly potent, and selective PDE10A inhibitor developed by Merck.[14] Its chemical name is 2-Methyl-6-{methoxy}-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrimidin-4-amine.[16] This compound represents Merck's lead oral candidate for this particular mechanism of action and has been investigated for the treatment of schizophrenia and, to some extent, bipolar disorder.[22]

The discovery of MK-8189 was the result of a dedicated medicinal chemistry effort, involving the optimization of an isomeric pyrimidine chemical series. This work aimed to address liabilities observed in earlier lead compounds, focusing on enhancing physicochemical properties, improving selectivity to reduce off-target activities, and optimizing pharmacokinetic profiles for oral administration and brain penetration.[14] The detailed synthetic schemes and structure-activity relationship studies published by Merck scientists underscore the significant research investment in this chemical class.[14]

B. Summary of MK-8189 Clinical Development

MK-8189 progressed through multiple Phase 1 studies designed to assess its safety, tolerability, and pharmacokinetics in healthy volunteers and in patients with schizophrenia (including trials NCT05893862, NCT04506905, NCT03565068, NCT02181803, NCT05406440).[22] Following these early-phase evaluations, MK-8189 advanced into Phase 2 clinical development for schizophrenia.[14] At one point, it was reported to be in or progressing towards Phase 2b development.[14]

A pivotal study in its development was the Phase 2a trial NCT03055338. This was a multicenter, randomized, double-blind, placebo- and active-controlled (risperidone 6 mg) inpatient trial. It enrolled adults experiencing an acute episode of schizophrenia, who received once-daily treatment with MK-8189 12 mg, placebo, or risperidone for a duration of 4 weeks.[31] The primary outcome measure was the change from baseline in the total score on the Positive and Negative Syndrome Scale (PANSS) at the 4-week mark.[31]

The results of the NCT03055338 trial were published in Schizophrenia Research in June 2024 (though an electronic version was available earlier) [23]:

• Primary Efficacy: MK-8189 (n=90) demonstrated a trend towards improvement compared to placebo (n=89) on the PANSS total score. The difference was -4.7 points (95% CI: -9.8, 0.5), which did not reach statistical significance (P = 0.074).
• Assay Sensitivity: The active control, risperidone (n=45), was statistically superior to placebo on the PANSS total score (difference = -7.3 [95% CI: -14.0, -0.6], P = 0.033), confirming the trial's ability to detect an antipsychotic effect.
• Comparison with Active Control: There was no significant difference in PANSS total score change between MK-8189 and risperidone.
• Secondary Efficacy: MK-8189 showed a nominally significant effect on the PANSS positive subscale score when compared to placebo (difference = -2.2 [95% CI: -3.8, -0.5], P = 0.011). However, differences for negative symptoms were reported as non-significant.[23]

Regarding safety and tolerability in the NCT03055338 trial [31]:

• The rate of discontinuation due to adverse events for MK-8189 was low, reported as less than 10%.
• Extrapyramidal symptoms (EPS), a common concern with antipsychotic medications, were observed with MK-8189 but were characterized as mostly mild and transient.
• A notable finding was the effect on body weight: compared with placebo, MK-8189 was associated with a reduction in body weight, whereas risperidone treatment led to an increase in weight. This weight loss effect associated with MK-8189 had also been observed in preclinical studies and was considered a potentially significant differentiating factor.[31]

The Phase 2a results for MK-8189 presented a nuanced picture. The failure to achieve statistical significance on the primary efficacy endpoint (PANSS total score) was a clear setback. In drug development, a "trend towards improvement" is often insufficient to support progression to more definitive and costly Phase 3 trials without compelling supportive data or a very strong biological rationale. However, the nominal significance observed on the PANSS positive subscale offered a glimmer of an antipsychotic signal. Perhaps more compelling was the safety profile, particularly the observed weight loss. Many currently available antipsychotics are associated with significant weight gain and metabolic disturbances, which are major health concerns for patients with schizophrenia and can contribute to treatment non-adherence.[31] A novel agent that could offer antipsychotic effects without this metabolic burden, or even induce weight loss, would represent a substantial clinical advance. The confirmation of assay sensitivity via the risperidone arm validated the trial's conduct and ability to detect treatment effects. These mixed findings likely prompted considerable internal discussion at Merck regarding the future of the MK-8189 program, weighing the modest efficacy signals against the favorable metabolic profile and the known challenges of the PDE10A inhibitor class.

Table 2: Summary of Key Clinical Data for MK-8189 (Oral PDE10A Inhibitor) from NCT03055338

Parameter	Details
Key Trial	NCT03055338 (Phase 2a) 31
Indication	Acute episode of schizophrenia
Dosage Regimen	MK-8189 12 mg QD vs. Placebo vs. Risperidone 6 mg QD (4 weeks)
Primary Efficacy Outcome	Change from baseline in PANSS Total Score at Week 4
MK-8189 vs. Placebo	Difference = -4.7 (95% CI: -9.8, 0.5), P = 0.074 (Trend, not statistically significant)
Risperidone vs. Placebo	Difference = -7.3 (95% CI: -14.0, -0.6), P = 0.033 (Statistically significant, assay sensitivity met)
Key Secondary Efficacy Outcome	Change from baseline in PANSS Positive Subscale Score vs. Placebo at Week 4
MK-8189 vs. Placebo	Difference = -2.2 (95% CI: -3.8, -0.5), P = 0.011 (Nominally significant)
Key Safety/Tolerability Findings
Discontinuation due to AEs (MK-8189)	<10%
Extrapyramidal Symptoms (EPS) (MK-8189)	Occurred, mostly mild and transient
Body Weight Change (MK-8189 vs. Placebo)	Reduction in body weight
Body Weight Change (Risperidone vs. Placebo)	Increase in body weight

This table summarizes the critical outcomes from the NCT03055338 trial for MK-8189.[31] These results are paramount for understanding the clinical potential of the PDE10A inhibition mechanism as pursued by Merck and provide the immediate context for decisions regarding the LAI formulation, MK-5720.

V. Clinical Development of MK-5720

A. Phase 1 Clinical Trial (NCT05953740 / MK-5720-001)

The cornerstone of MK-5720's clinical development has been the Phase 1 trial registered under the identifier NCT05953740, also internally designated by Merck as study MK-5720-001.[1]

The official title of this study was "A Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the Long-Acting Injectable of MK-5720 in Participants With Schizophrenia".[1] As a Phase 1 investigation, its primary objectives were to assess the safety, tolerability, and pharmacokinetic (PK) profile of single ascending intramuscular doses of MK-5720.[13] The core hypothesis underpinning the study was that the administration of MK-5720 would be safe and well-tolerated by the study participants.[13] The trial enrolled adult participants diagnosed with schizophrenia, typically within an age range of 18 to 60 years.[1] Initial planned enrollment was approximately 64 participants [33], although some later reports indicated that 17 participants completed the trial.[17] This discrepancy could reflect the actual number enrolled in specific cohorts or the total number who completed all study procedures.

The study was structured with two distinct periods [13]:

• Period 1: Participants received once-daily oral doses of MK-8189 for 7 days. This oral lead-in phase was followed by a 72-hour washout period.
• Period 2: Following the washout, participants received a single intramuscular dose of MK-5720. The study employed a single ascending dose design, meaning different cohorts of participants likely received progressively higher doses of MK-5720 to evaluate dose-related safety and PK.

This study design is standard for the initial clinical evaluation of an LAI formulation. The oral lead-in with MK-8189 serves to ensure that participants can tolerate the active drug substance itself before being exposed to a long-acting depot formulation from which the drug cannot be quickly withdrawn. The single ascending dose approach allows for careful monitoring of safety and the characterization of how the drug is absorbed, distributed, metabolized, and excreted at different dose levels, which is crucial for determining appropriate dosing for subsequent studies.

B. Status and Timelines

The NCT05953740 / MK-5720-001 trial commenced recruitment around September 2023, with sources indicating a start date of September 15, 2023 [1], or an "Enrollment open" status as of September 22, 2023.[33] The trial is now reported as "Completed" across multiple databases.[1] The primary completion date is listed as February 15, 2024 [2], with one source noting completion by March 27, 2024.[17] The relatively rapid progression from initiation to primary completion is consistent with the typical duration of a Phase 1 single ascending dose study focused on safety and PK assessments over a defined observation period following administration of the LAI.

C. Reported Results and Publications

Despite the completion of the Phase 1 trial, specific data regarding the safety, tolerability, or pharmacokinetic outcomes of MK-5720 from NCT05953740 have not been made publicly available in the provided research materials.[36] While some sources confirm the trial's completion [17], they do not offer detailed results. Merck's own clinical trial portal lists the study but, as of the latest information, does not provide access to results or publications.[35]

It is not uncommon for Phase 1 results, particularly for investigational programs that may not be advancing to later stages, to remain unpublished or to be presented at scientific conferences at a much later date, if at all. The lack of publicly available data from the MK-5720 Phase 1 trial, especially when viewed in conjunction with recent updates to Merck's overall development pipeline, contributes to the uncertainty surrounding the program's future. While the trial's completion implies that initial safety and PK objectives were assessed, the absence of disclosed findings makes it difficult to ascertain whether MK-5720 itself met its specific Phase 1 endpoints or if any particular safety or PK issues arose. However, even if MK-5720 demonstrated an acceptable Phase 1 profile, the decision to advance it would have been heavily influenced by the broader strategic assessment of the PDE10A mechanism, primarily informed by the results from the oral MK-8189 program. The subsequent omission of MK-5720 from Merck's pipeline, following its Phase 1 completion and the mixed results from MK-8189's Phase 2a study, strongly suggests that the cumulative data did not provide sufficient support for continued development.

Table 3: Overview of Clinical Trial NCT05953740 (MK-5720-001)

Parameter	Details
Trial Identifier	NCT05953740 (also MK-5720-001)
Official Title	A Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the Long-Acting Injectable of MK-5720 in Participants With Schizophrenia
Phase	1
Sponsor	Merck Sharp & Dohme LLC
Status	Completed (Primary Completion: Feb 2024 / Mar 2024) 2
Primary Purpose	Evaluate safety, tolerability, and pharmacokinetics of single ascending intramuscular (IM) doses of MK-5720 13
Design	Two periods: Period 1 (Oral MK-8189 lead-in for 7 days, then washout), Period 2 (Single ascending IM dose of MK-5720) 13
Population	Participants with schizophrenia (N=17 completed 17, initially planned for ~64 33)
Key Outcome Measures	Safety (Adverse Events), Tolerability, Pharmacokinetic parameters (e.g., AUC, Cmax) of MK-5720
Results	Not publicly available in provided materials 36

This table consolidates the known information regarding the pivotal Phase 1 clinical trial for MK-5720, drawing from multiple sources.[1] It highlights the study's objectives, design including the oral MK-8189 lead-in, patient population, and its current status as completed but with unpublished results.

VI. Current Status and Future Prospects of MK-5720 and Merck's PDE10A Program

A. Analysis of Recent Merck Pipeline Updates

The trajectory of an investigational drug can often be gauged by its inclusion and positioning within a pharmaceutical company's publicly disclosed development pipeline. In February 2024, Merck's pipeline update listed MK-8189 as being in Phase 2 development for schizophrenia.[37] This would have been after the company had at least preliminary insights from the Phase 2a trial NCT03055338 and while the MK-5720 Phase 1 study was concluding.

However, a significant shift is evident in more recent disclosures. Neither MK-8189 nor MK-5720 appear in Merck's pipeline presentation dated February 21, 2025.[38] Furthermore, Merck's corporate website, displaying its product pipeline as of April 30, 2025, also omits any mention of MK-8189 or MK-5720.[39] The omission of a drug from a company's pipeline, particularly after the completion of a clinical trial phase and when it was previously listed, is a strong, albeit indirect, indicator of a change in its development status, most commonly discontinuation or significant strategic deprioritization.

This timeline suggests that a decision regarding Merck's PDE10A inhibitor program for schizophrenia was likely made between mid-2024 and early 2025. This period follows the completion of the MK-5720 Phase 1 trial (early 2024) and the availability and analysis of the full results from the MK-8189 Phase 2a trial (published June 2024, but internally available earlier).[31] The absence of these compounds from the current pipeline is the most compelling piece of evidence pointing towards a halt in their development for schizophrenia by Merck. While official discontinuation announcements are not always immediate or detailed, pipeline exclusion is a standard way companies communicate shifts in their R&D priorities.

B. Implications of Phase 1 Completion for MK-5720

The MK-5720 Phase 1 trial (NCT05953740) successfully reached completion.[1] Typically, the completion of a Phase 1 study indicates that the drug was evaluated for its primary objectives, which, in this case, were safety, tolerability, and pharmacokinetics in participants with schizophrenia.[13] If a drug demonstrates an unacceptable safety profile or highly unfavorable pharmacokinetics (e.g., inability to achieve target exposure, very rapid clearance unsuitable for an LAI) in Phase 1, it is usually discontinued at that stage.

However, even if MK-5720 itself met all its Phase 1 endpoints—demonstrating acceptable safety and a measurable pharmacokinetic profile suitable for a long-acting formulation—its progression to later-stage, more resource-intensive Phase 2 and 3 trials would not be guaranteed. The decision to advance an LAI formulation is critically dependent on the confidence in the therapeutic efficacy and overall viability of the parent drug or mechanism. In this context, the mixed results from the MK-8189 Phase 2a study would have been a primary determinant. If the efficacy signal from the oral compound was not deemed sufficiently robust to justify the substantial further investment required for later-phase LAI development, the MK-5720 program would likely be halted irrespective of its own Phase 1 performance, unless the LAI formulation itself presented an unexpectedly superior efficacy or safety profile not seen with the oral drug, which is uncommon. Thus, the fate of MK-5720 was inextricably linked to the broader assessment of MK-8189's potential and the overall prospects of Merck's PDE10A inhibitor strategy.

C. Potential Scenarios: Discontinuation, Strategic Hold, or Undisclosed Progression

The absence of MK-5720 and MK-8189 from Merck's current pipeline strongly points towards discontinuation for the schizophrenia indication. While less likely without further information, other scenarios could include placing the program on a strategic hold (pending new scientific insights or market changes) or out-licensing/partnering the assets. However, given the historical challenges with PDE10A inhibitors, discontinuation is the most probable interpretation.

External analyses sometimes provide predictive insights. For instance, prior to the most recent pipeline updates, Ozmosi/Pryzm assigned the MK-5720-001 Phase 1 trial a 9% "Probability of Success" (PoS).[2] This is notably low for a drug completing Phase 1. For context, GlobalData reports an average Phase 1 to Phase 2 transition success rate (PTSR) for schizophrenia drugs at 66%.[3] The significantly lower PoS for MK-5720 may have reflected early skepticism based on the known difficulties with the PDE10A class or perhaps early internal signals regarding the MK-8189 program. It is important to remember that general PTSRs are averages, and novel mechanisms often carry higher risk and thus lower PTSRs than drugs with established mechanisms. The subsequent removal of MK-5720 from the pipeline effectively reduces its PoS for schizophrenia to near zero, barring any new contradictory information from Merck.

D. Merck's R&D Strategy and Neuroscience Focus

Merck, like other major pharmaceutical companies, operates in a dynamic R&D environment, characterized by significant investments and the need to make strategic choices to maximize returns and address unmet medical needs. The company has been preparing for the eventual loss of exclusivity for its blockbuster drug Keytruda, driving efforts to build a portfolio of new growth drivers.[4] This involves substantial R&D expenditure, which saw a "rightsizing" in 2024 following a period of intense deal-making in 2023.[4] Such strategic adjustments often involve rigorous portfolio reviews and the prioritization of assets deemed to have the highest probability of technical and regulatory success and the greatest commercial potential.

While Merck's February 2024 pipeline did include MK-8189 for schizophrenia within its neuroscience programs [37], the February 2025 pipeline does not feature schizophrenia as prominently as other therapeutic areas like oncology or specific named assets.[38] This could reflect a broader strategic shift in focus within Merck's neuroscience R&D. The decision to likely discontinue the MK-8189/MK-5720 program may have been influenced by the mixed efficacy data for MK-8189, the high historical failure rate of PDE10A inhibitors in schizophrenia, and an internal assessment that the program no longer met the threshold for continued investment when compared against other opportunities in Merck's diverse pipeline. The CNS drug development landscape is notoriously challenging, with high attrition rates, particularly for novel mechanisms in complex disorders like schizophrenia.[7]

VII. The Landscape of PDE10A Inhibitors in Schizophrenia

A. Therapeutic Promise and Unmet Needs Addressed

Phosphodiesterase 10A inhibitors have long been regarded as a promising novel therapeutic class for schizophrenia. Their unique mechanism of action, centered on the modulation of cAMP and cGMP signaling predominantly within the striatal medium spiny neurons, offers a theoretical advantage over existing treatments.[6] By potentially stimulating D1 receptor-mediated pathways while concurrently dampening D2 receptor-mediated pathways, PDE10A inhibitors held the promise of addressing not only the positive symptoms of schizophrenia but also the often-refractory negative and cognitive symptoms.[6] Current standard-of-care antipsychotics, primarily dopamine D2 receptor antagonists, are effective for positive symptoms but have limited efficacy for negative and cognitive domains and are frequently associated with burdensome side effects, including metabolic syndrome and extrapyramidal symptoms.[7] A therapy that could offer broader symptomatic improvement with a more favorable side effect profile would represent a significant advancement.

B. Historical Challenges and Discontinuations

Despite the strong preclinical rationale and significant industry investment, the clinical development of PDE10A inhibitors for schizophrenia has been fraught with challenges and notable discontinuations.[23] Several compounds from different pharmaceutical companies have failed to demonstrate sufficient efficacy or acceptable tolerability in mid- to late-stage clinical trials:

• PF-02545920 (Pfizer): This compound was extensively studied but ultimately failed to show efficacy in both monotherapy and adjunctive therapy settings for patients with schizophrenia.[25] The reasons cited for such failures in the class are complex, potentially involving an incomplete understanding of striatal PDE10A function in human pathology, the development of tolerance to drug effects, or intricate interactions within intracellular signaling pathways.[42]
• TAK-063 (Balipodect, Takeda): Development of TAK-063 for schizophrenia was discontinued due to insufficient efficacy. A Phase 2 trial did not demonstrate statistical superiority over placebo on the primary endpoint (PANSS total score), although there were some supportive signals from secondary endpoints. The interpretation of these results was confounded by the lack of dose-ranging and an active reference in that specific study design.[29]
• Other Programs: Reports indicate that PDE10A inhibitors from at least three major companies (Pfizer, Takeda, and Lundbeck) did not achieve antipsychotic activity comparable to standard D2 antagonists in clinical trials.[26] The unexpected emergence of motor side effects, such as dyskinesia, with some PDE10A inhibitors also raised concerns.[26]

This pattern of translational failure, where promising preclinical findings do not translate into robust clinical benefit for schizophrenia, highlights fundamental difficulties with targeting PDE10A for this indication. The reasons are likely multifactorial, including potential species differences in brain neurobiology and PDE10A function, challenges in selecting optimal doses and titration schedules in human trials, complex pharmacodynamic interactions with concomitant medications (especially prior antipsychotic exposure which might alter PDE10A levels or localization), and fundamental differences in the broad pharmacology of PDE10A inhibitors compared to clinically successful antipsychotics.[26] Merck's MK-8189/MK-5720 program was thus navigating a field with a high historical rate of attrition. The "trend towards improvement" observed with MK-8189 [31], while encouraging in some aspects, may not have been sufficiently compelling to overcome the general skepticism and perceived risk associated with this class, particularly when viewed against this backdrop of widespread clinical failures.

C. Lessons Learned and Future Directions for the Class

The collective experience with PDE10A inhibitors underscores the need for a more profound understanding of their mechanism of action within the human brain, particularly concerning the activity of MSNs and the broader cortico-striato-thalamo-cortical (CSTC) circuits implicated in schizophrenia.[23] Factors such as the inhibitor's binding kinetics, including its off-rate from the PDE10A enzyme, may be critical determinants of its ultimate pharmacological effect and therapeutic window.[27]

Despite the numerous setbacks in schizophrenia, research into PDE10A inhibitors has not entirely ceased. Some companies continue to explore this mechanism. For instance, Celon Pharma's CPL500-036 reportedly showed efficacy in a Phase 2 trial for acute schizophrenia, with results presented at the APA Annual Meeting in 2025.[25] Another compound, EM-221, is being investigated for Tourette syndrome, suggesting potential applications in other CNS disorders characterized by basal ganglia dysfunction.[41] Additionally, some PDE10A inhibitors have shown intriguing effects in preclinical models or early human studies for conditions like Huntington's disease, particularly on motor symptoms.[25]

The path forward for PDE10A inhibitors may require more nuanced strategies. This could involve the development of compounds with highly refined pharmacological profiles (e.g., specific enzyme occupancy levels, optimized kinetic properties), the identification of specific patient subpopulations within schizophrenia who are more likely to respond, or a shift in focus towards other CNS indications where the underlying pathophysiology might be more directly amenable to PDE10A modulation. Unless a significant breakthrough occurs, such as robust and replicable efficacy from a compound like CPL500-036 in larger, well-controlled trials, the broad application of PDE10A inhibitors for schizophrenia remains uncertain.

VIII. Expert Analysis and Conclusion

A. Synthesis of Findings on MK-5720

MK-5720 emerged from Merck's research program as a long-acting injectable (LAI) formulation of a phosphodiesterase 10A (PDE10A) inhibitor, developed with the primary indication of schizophrenia. Its clinical development was closely intertwined with that of MK-8189, Merck's oral PDE10A inhibitor. The Phase 1 clinical trial for MK-5720 (NCT05953740), designed to assess its safety, tolerability, and pharmacokinetics following single ascending intramuscular doses with an oral MK-8189 lead-in, was completed in early 2024. The results of this trial have not been publicly disclosed.

The oral compound, MK-8189, completed a Phase 2a trial (NCT03055338) in patients with acute schizophrenia. Published results from this study indicated that MK-8189 12 mg daily did not achieve statistical significance on its primary endpoint (change in PANSS total score versus placebo) but demonstrated a trend towards improvement (P=0.074). It did show a nominally significant improvement on the PANSS positive subscale score compared to placebo (P=0.011). Importantly, MK-8189 exhibited a favorable safety and tolerability profile, including a notable reduction in body weight compared to placebo, and in contrast to the weight gain observed with the active comparator, risperidone.[31]

B. Critical Assessment of the Development Trajectory and Current Uncertainty

The most significant development concerning MK-5720 and its oral counterpart MK-8189 is their absence from Merck's publicly available R&D pipeline as of February 2025 [38] and subsequent website updates.[39] This omission, following the completion of their respective Phase 1 and Phase 2a trials, strongly implies a strategic decision by Merck to discontinue or substantially deprioritize the development of its PDE10A inhibitor program for schizophrenia.

This decision was likely multifactorial:

1. Modest Efficacy of MK-8189: While the trend towards improvement and the positive signal on some symptoms were noted, the failure to meet the primary efficacy endpoint with statistical significance in the Phase 2a trial is a substantial hurdle for progression to more extensive and costly Phase 3 development.
2. Historical Context of PDE10A Inhibitors: The PDE10A inhibitor class has a well-documented history of clinical trial failures in schizophrenia across multiple pharmaceutical companies.[25] This challenging track record inherently raises the bar for demonstrating compelling efficacy and safety for any new entrant.
3. Internal Portfolio Prioritization: Pharmaceutical companies continuously evaluate their R&D pipelines, allocating resources to programs with the highest perceived probability of success and commercial value. Given the high risks and costs associated with schizophrenia drug development, particularly for novel mechanisms, the MK-8189/MK-5720 program may have been deemed less competitive against other assets in Merck's broader portfolio, especially in light of the company's strategic focus on areas like oncology.[4]
4. MK-5720 Phase 1 Outcome (Undisclosed): While the results of the MK-5720 Phase 1 trial are not public, any unfavorable safety signals or a pharmacokinetic profile not supportive of the desired long-acting dosing interval could have contributed to a negative decision. However, even with positive Phase 1 data for MK-5720, its advancement would have remained contingent on the perceived viability of the oral MK-8189.

C. Concluding Remarks on the Potential of MK-5720 within the Evolving Schizophrenia Treatment Paradigm

Should the discontinuation of Merck's PDE10A program for schizophrenia be confirmed, it would mark another significant setback for this novel mechanistic approach in a therapeutic area with profound unmet needs. The allure of a treatment capable of addressing the full spectrum of schizophrenia symptoms (positive, negative, and cognitive) while offering an improved side effect profile, such as a favorable metabolic impact, remains a critical goal in psychiatric drug development.

PDE10A inhibitors, by their proposed dual modulation of striatal pathways, theoretically offered such potential. However, the journey from preclinical promise to clinical efficacy has proven exceptionally challenging for this class. The case of MK-8189, with its intriguing weight loss effect but modest symptomatic improvement, exemplifies this translational difficulty.

MK-5720, as a long-acting injectable, was positioned to enhance the clinical utility of the PDE10A mechanism by improving treatment adherence. Nevertheless, the viability of an LAI formulation is predicated on the robust efficacy and safety of its underlying active moiety. The available evidence suggests that MK-8189, despite some positive attributes, did not meet the threshold for Merck to continue its large-scale development, thereby likely sealing the fate of MK-5720 as well.

The future of PDE10A inhibitors in CNS disorders now rests on whether other investigational compounds, such as CPL500-036 [43], can demonstrate a clearly differentiated and superior clinical profile in well-designed trials, or if the mechanism finds a more suitable niche in other neurological or psychiatric conditions where the underlying pathophysiology is more directly amenable to PDE10A modulation. For schizophrenia, the search for novel therapeutic targets that can offer comprehensive symptom control with better tolerability continues to be a paramount challenge for the field.

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