E-6742 Advanced Drug Monograph

E-6742 – A Novel TLR7/8 Antagonist for Systemic Lupus Erythematosus

I. Executive Summary

E-6742 is an investigational, orally administered small molecule developed by Eisai, which functions as a dual antagonist of Toll-like receptor 7 (TLR7) and Toll-like receptor 8 (TLR8).1 Its primary therapeutic target is Systemic Lupus Erythematosus (SLE), a complex autoimmune disease characterized by widespread inflammation and organ damage. The rationale for E-6742 in SLE stems from the critical role of TLR7 and TLR8 in the innate immune response, particularly in the production of type I interferons (IFNs) and other pro-inflammatory cytokines that drive SLE pathogenesis.2 Preclinical evidence supported this targeted approach. Early Phase 1 studies in healthy volunteers established a favorable safety and pharmacokinetic (PK) profile.6 Subsequent Phase 1/2 clinical trial data in SLE patients (NCT05278663) further demonstrated good safety and tolerability, consistent PK, and, importantly, evidence of target engagement through downregulation of the interferon gene signature (IGS) and preliminary signals of clinical efficacy.1 E-6742 represents a promising targeted immunomodulatory strategy for SLE, a condition with significant unmet medical needs where current treatments often involve broad immunosuppression with considerable side effect burdens. The specificity of E-6742 for TLR7/8 offers the potential for a more refined therapeutic intervention by directly addressing key molecular drivers of the disease.

II. Introduction to E-6742

A. Chemical Nature and Development

E-6742 is a novel, orally available small molecule inhibitor, more specifically characterized as a dual antagonist of Toll-like receptor 7 (TLR7) and Toll-like receptor 8 (TLR8).1 The development of E-6742 has been spearheaded by Eisai Inc. and its parent company Eisai Co Ltd..9 While initial exploratory development may have considered indications such as cancer and neurological disorders, these avenues were subsequently discontinued.3 The current and primary focus of E-6742 development is for the treatment of Systemic Lupus Erythematosus (SLE). This strategic shift to SLE likely reflects the compelling scientific rationale and promising early data supporting the role of TLR7/8 inhibition in this specific autoimmune disease, where these receptors are known to be key pathogenic drivers.

B. Therapeutic Rationale in Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus is a chronic, debilitating autoimmune disease marked by a breakdown of self-tolerance, leading to the production of autoantibodies, immune complex formation, and subsequent inflammation and damage across multiple organ systems.2 SLE predominantly affects young adult females and its global prevalence varies, highlighting a significant unmet medical need for more effective and safer therapies.5

The innate immune system, particularly the signaling pathways mediated by Toll-like receptors, plays a pivotal role in SLE pathogenesis. TLR7 and TLR8 are endosomal receptors that recognize single-stranded RNA (ssRNA) derived from self or pathogens.[5] In SLE, aberrant activation of these receptors by self-nucleic acids is a critical trigger. TLR7 is highly expressed on plasmacytoid dendritic cells (pDCs), which are major producers of type I interferons (IFN-α/β), key cytokines implicated in driving and sustaining the autoimmune response in SLE.[5] TLR8 is more abundantly found in neutrophils, monocytes, and myeloid dendritic cells, contributing to the production of inflammatory cytokines like Interleukin-6 (IL-6), Interleukin-1β (IL-1β), and Tumor Necrosis Factor-alpha (TNF-α) via nuclear factor-κB (NF-κB) signaling.[5] There is also strong evidence for a genetic contribution of TLR7 to SLE pathogenesis.[5]

The therapeutic strategy behind E-6742 is based on the hypothesis that dual inhibition of both TLR7 and TLR8 may offer a more comprehensive and potent immunomodulatory effect than targeting either receptor alone. This dual antagonism is expected to dampen the overactive innate immune responses characteristic of SLE, thereby reducing the production of type I IFNs and other pro-inflammatory cytokines.[5] Furthermore, preclinical studies have suggested that dual TLR7/8 inhibition may enhance the efficacy of glucocorticoids, potentially allowing for lower steroid doses (glucocorticoid-sparing effect), which is a significant clinical goal in SLE management due to the long-term side effects of steroid therapy.[5]

III. Mechanism of Action of E-6742

E-6742 functions as a selective dual antagonist of human TLR7 and TLR8.1 Its unique mechanism involves binding to a specific ligand-binding hydrophobic pocket that is exclusively present in the

inactivated dimeric form of both TLR7 and TLR8.[5] By binding to this site, E-6742 is thought to stabilize the inactive conformation of these receptors, thereby preventing their activation upon engagement with endogenous or exogenous ssRNA ligands. This mode of action differs from competitive antagonists that might vie for the ligand binding site on an activatable receptor. Stabilizing the inactive state effectively pre-empts the conformational changes necessary for downstream signaling.

The direct consequences of TLR7/8 inhibition by E-6742 include:

• Modulation of innate immune responses: By blocking the primary sensors of ssRNA, E-6742 curtails the initiation of pathogenic innate immune cascades.[5]
• Suppression of pro-inflammatory cytokine production: The drug significantly reduces the production of key cytokines implicated in SLE, such as type I interferons (particularly IFN-α), IL-6, and IL-1β.[5]
• Downregulation of the Interferon Gene Signature (IGS): IGS is a well-recognized biomarker reflecting the heightened type I IFN activity in SLE patients. E-6742 has been shown to effectively downregulate this signature, providing direct evidence of target engagement and biological activity in the relevant pathway.[1]

This precise targeting of the inactive TLR7/8 dimer offers a potentially more effective and safer approach to immunomodulation in SLE, by preventing the initial steps of receptor activation rather than trying to block already active signaling pathways.

IV. Preclinical Development

The progression of E-6742 into clinical trials for SLE was underpinned by a body of preclinical research. These studies provided evidence for its ability to inhibit TLR7 and TLR8 and consequently modulate autoimmune responses relevant to SLE.1 A particularly significant finding from preclinical investigations was the potential for E-6742 to enhance the effectiveness of glucocorticoids.5 This glucocorticoid-sparing potential is of high clinical relevance in SLE, where long-term and often high-dose steroid therapy is a major contributor to patient morbidity due to associated side effects, including infections, osteoporosis, and metabolic complications. A therapeutic agent that could allow for reduced glucocorticoid exposure while maintaining or improving disease control would address a critical unmet need in SLE management. The preclinical data suggested that E-6742 might achieve this by targeting the fundamental upstream TLR7/8 activation pathway, thereby diminishing the overall inflammatory cascade that necessitates aggressive steroid use.

V. Clinical Development Program

A. Phase 1 Study in Healthy Volunteers (NCT04683185)

The first-in-human (FIH) evaluation of E6742 was conducted to assess its safety, tolerability, and pharmacokinetics (PK) in healthy adult volunteers.2 The study design included both single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. In the SAD part, doses ranging from 10 mg to 800 mg were administered under fasted conditions, with an additional 100 mg cohort receiving the drug in a fed state to assess food effects.6 In the MAD part, subjects received E6742 at doses of 100 mg, 200 mg, or 400 mg twice daily (BID) for 7 days.6

Key pharmacokinetic findings from this study indicated that E6742 was rapidly absorbed, with a median time to maximum plasma concentration (Tmax​) ranging from 1.50 to 2.50 hours under fasted conditions. The median terminal elimination half-life (t1/2​) ranged from 2.37 to 14.4 hours across dose groups. Dose proportionality for Cmax​ and area under the curve (AUC) was observed in the SAD study for doses up to 800 mg, although exposure was slightly less than dose-proportional at the 10 mg dose. In the MAD study, Cmax​ and AUC0−12h,ss​ (AUC over a 12-hour dosing interval at steady state) increased in an almost dose-proportional manner between 100 mg and 200 mg BID, but showed a greater than dose-proportional increase at 400 mg BID. Steady-state plasma concentrations were achieved by day 7 of multiple dosing.[6] Pharmacodynamically, E6742 demonstrated a dose-dependent suppression of cytokine concentrations in ex vivo stimulated cultured peripheral blood from the healthy volunteers.[6] Overall, these Phase 1 studies in healthy adults indicated that E6742 had an adequate safety and tolerability profile, supporting its progression into studies involving SLE patients.[5]

B. Phase 1/2 Study in SLE Patients (NCT05278663 / "Study 101" in Japan)

Following the promising results in healthy volunteers, a first-in-patient, Phase 1/2, randomized, double-blind, placebo-controlled, multicenter study was initiated to evaluate E6742 in patients with SLE.1 This study is also referred to as Study 101 in Japan.10

• Study Design: The trial enrolled patients into two sequential cohorts. Patients received either E6742 at 100 mg BID or 200 mg BID, or a matching placebo, for 12 weeks. Randomization within each cohort was 2:1 (E6742:placebo).[1]
• Patient Population: A total of 26 patients were enrolled and received the study drug. Cohort 1 included 8 patients on E6742 100 mg and 4 on placebo. Cohort 2 included 9 patients on E6742 200 mg and 5 on placebo.[1] Some reports provide a slightly different consolidated number of n=8 or 9 for E6742 and n=9 for placebo across both cohorts [7], with the most detailed breakdown from RMD Open indicating 17 patients on E6742 (8 on 100mg, 9 on 200mg) and 9 on placebo.[5] Twenty-four of the 26 patients completed the 12-week treatment period.[1] Eligible patients were required to have active SLE, defined by at least one active clinical symptom according to the SLE Disease Activity Index 2000 (SLEDAI-2K) assessment.[5] Baseline demographics and disease characteristics were generally well-balanced between the treatment groups. The mean age was approximately 38 years, the majority of participants were female, and the mean disease duration was around 7 years. A significant proportion of patients were on background therapy with hydroxychloroquine (80.8%) and/or other immunosuppressants (46.2%), with a mean prednisone dose of 5.6 mg/day.[11]
• Endpoints: The primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetics (PK) and the effect on the Interferon Gene Signature (IGS). Exploratory endpoints encompassed various efficacy measures such as the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA), Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity (CLASI-A) scores, tender/swollen joint counts, and serological markers (e.g., anti-dsDNA antibodies, complement levels), as well as other biomarkers.[1]
• Safety and Tolerability Results: E6742 demonstrated a favorable safety profile and was well tolerated when compared to placebo.[1] The proportion of patients experiencing any treatment-emergent adverse events (TEAEs) was 58.8% in the combined E6742 groups (37.5% for 100 mg, 77.8% for 200 mg) compared to 66.7% in the placebo group.[1] Importantly, no TEAEs of Grade 3 or higher severity, nor any deaths, were observed during the study.[1] One patient in the placebo group and one in the E6742 200 mg group withdrew due to adverse events.[11] This early safety profile is particularly encouraging for an immunomodulatory agent being tested in a patient population often burdened by comorbidities and concomitant medications. The absence of severe adverse events suggests a potentially well-tolerated therapeutic window.
• Pharmacokinetic (PK) Results: The PK parameters of E6742 in SLE patients were found to be similar to those observed in the preceding studies with healthy adult volunteers, indicating no major disease-specific alterations in drug disposition.[1] Plasma concentrations of E6742 were dose-dependent at both 100 mg and 200 mg BID, as assessed on Days 1 and 15. The Tmax​ was reached within 1-2 hours post-dose, and the elimination half-life (t1/2​) was approximately 6 hours.[11]
• Biomarker Results: Robust target engagement was demonstrated by immediate downregulation of the IGS in patients treated with E6742 at both dose levels. These IGS levels returned to baseline after the cessation of treatment, indicating a reversible effect.[1] Furthermore, ex vivo stimulation of peripheral blood cells with a TLR7/8 agonist showed that E6742 treatment led to an immediate decrease in the production of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α.[1] Whole transcriptome analysis at week 12 revealed that 156 genes were significantly regulated by E6742, the majority of which were related to IFN or TLR7/8 pathways. This confirmed the specificity of E6742 in modulating the intended biological pathways without inducing widespread, non-specific immune responses.[11]
• Efficacy Results (Exploratory): Despite the relatively short 12-week treatment duration, promising preliminary efficacy signals were observed. The BICLA response rate at Week 12 showed a dose-dependent trend: 33.3% (3/9 patients) in the placebo group, 37.5% (3/8 patients) in the E6742 100 mg group, and 57.1% [5] in the E6742 200 mg group.[1] This improvement at the higher dose, even in a small cohort over a short period, is a noteworthy signal. Additionally, therapeutic effects were noted in other clinical manifestations of SLE, including improvements in skin inflammation as measured by CLASI-A scores, reductions in tender and swollen joint counts, and favorable changes in serological markers such as anti-dsDNA antibody levels and complement concentrations.[1] The convergence of these clinical observations with the direct evidence of target engagement (IGS and cytokine modulation) suggests that E6742 is exerting biologically relevant effects through its intended mechanism of action.

Table 1: Summary of E-6742 Phase 1/2 SLE Study (NCT05278663) Key Results

Parameter	Placebo (n=9)	E6742 100 mg BID (n=8)	E6742 200 mg BID (n=9)*
Safety
Any TEAEs	66.7% (6/9)	37.5% (3/8)	77.8% (7/9)
Grade ≥3 TEAEs	0	0	0
Withdrawals due to AEs	1	0	1
Pharmacokinetics
Tmax​ (median)	N/A	~1-2 hours	~1-2 hours
t1/2​ (median)	N/A	~6 hours	~6 hours
Biomarkers
IGS Downregulation	No significant change	Yes, rapid	Yes, rapid
Pro-inflammatory Cytokine Suppression (ex vivo)	No significant change	Yes	Yes
Efficacy (Week 12)
BICLA Response	33.3% (3/9)	37.5% (3/8)	57.1% (4/7 evaluable)
CLASI-A Improvement	Not specified quantitatively	Improvement noted	Improvement noted
Joint Count Reduction	Not specified quantitatively	Improvement noted	Improvement noted
Anti-dsDNA/Complement	Not specified quantitatively	Improvement noted	Improvement noted
*One patient in the 200mg E6742 group was not evaluable for BICLA. TEAE: Treatment-Emergent Adverse Event; PK: Pharmacokinetics; IGS: Interferon Gene Signature; BICLA: British Isles Lupus Assessment Group-based Composite Lupus Assessment; CLASI-A: Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity. Data sourced from.1

VI. Regulatory Status and Future Development

E-6742 has successfully completed Phase 1/2 clinical development for SLE, with results indicating a positive benefit-risk profile that warrants further investigation.1 The data from these initial studies strongly support the planning and execution of larger, longer-term clinical trials to definitively establish the efficacy and safety of E-6742 in the SLE patient population.1

A key aspect of E-6742's development is the collaboration with the Japan Agency for Medical Research and Development (AMED) under the Cyclic Innovation for Clinical Empowerment (CiCLE) program.[2] This initiative aims to foster the industrialization of Japan-originated research, and in the context of E-6742, it includes academia-led clinical research (UMIN000042037) focused on identifying specific biomarkers for the drug.[2] Such biomarker research is crucial for heterogeneous diseases like SLE, as it can potentially identify patient subpopulations most likely to respond to E-6742 or aid in the development of companion diagnostics, thereby optimizing future clinical trial designs and enhancing the probability of success.

Reviewing Eisai's pipeline disclosures over recent years provides a timeline of E-6742's progression. It was mentioned in the 2020 pipeline [14] and specifically listed for SLE in Phase 1/2 in Japan in the 2021 pipeline.[10] News releases and pipeline updates in 2022 and 2023 confirmed ongoing Phase 1 studies and the progression to Phase 1/2 in SLE patients.[16] While Eisai's 2025 pipeline announcements available in the provided materials focus heavily on other assets like Lecanemab and the oncology compound E7386 without specific updates on E-6742 [20], the Phase 1/2 SLE trial results were prominently published and presented at major scientific congresses in 2024. These presentations include the American College of Rheumatology (ACR) Convergence 2024 [3] and the European Alliance of Associations for Rheumatology (EULAR) Congress 2024 [1], underscoring continued activity and data dissemination for the compound. Future presentations at EULAR 2025 are anticipated based on general submission timelines, though not specifically confirmed for E-6742 in the provided information.[25]

VII. Discussion and Conclusion

E-6742 emerges as a novel, orally administered dual TLR7/8 antagonist representing a targeted therapeutic approach for Systemic Lupus Erythematosus. Its mechanism of action, focused on inhibiting key innate immune receptors implicated in SLE pathogenesis, offers a distinct strategy compared to broader immunosuppressive agents.

The strengths of E-6742, as evidenced by early clinical data, include its specific molecular target, a favorable safety and tolerability profile in both healthy volunteers and SLE patients, clear evidence of target engagement through modulation of the interferon gene signature and pro-inflammatory cytokine production, and promising preliminary signals of clinical efficacy in a challenging disease. The absence of any Grade 3 or higher TEAEs in the Phase 1/2 SLE study is particularly noteworthy for an immunomodulatory drug in this patient population [1], suggesting a potentially advantageous therapeutic index. This could position E-6742 favorably if robust efficacy is confirmed in later-stage trials.

However, the current data are derived from early-phase studies with relatively small patient numbers and a short treatment duration of 12 weeks. Therefore, the long-term efficacy, durability of response, and comprehensive safety profile of E-6742 remain to be established in larger, more extended clinical trials.

Future development will critically depend on the outcomes of these planned larger studies. A key area of interest will be the confirmation of the preliminary efficacy signals, particularly the dose-dependent BICLA response, and further exploration of E-6742's potential as a glucocorticoid-sparing agent, which would address a significant unmet need in SLE management. The ongoing biomarker research through the AMED CiCLE collaboration will also be vital in refining the patient population most likely to benefit from this targeted therapy.

In conclusion, E-6742 holds considerable promise as a new therapeutic option for SLE. Its novel mechanism, encouraging early clinical data, and oral route of administration position it as a candidate that could potentially improve the management of this complex autoimmune disease. Continued rigorous clinical investigation is warranted to fully delineate its role in the evolving SLE treatment landscape.

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EXN-407 – A Topical SRPK1 Inhibitor for Diabetic Retinal Diseases

I. Executive Summary

EXN-407 is an investigational small molecule, formulated as a topical eye drop, being developed by Exonate Ltd. for the treatment of diabetic retinal diseases, specifically Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME). Its novel mechanism of action involves the inhibition of Serine/Arginine Protein Kinase 1 (SRPK1), which in turn modulates the alternative splicing of Vascular Endothelial Growth Factor (VEGF) mRNA. This modulation aims to shift the balance from pro-angiogenic VEGF isoforms towards anti-angiogenic isoforms, thereby reducing pathological neovascularization and vascular permeability characteristic of diabetic eye diseases. Preclinical studies demonstrated promising efficacy and safety. The recently completed Phase 1b/2a clinical trial (NCT04565756) in patients with mild/moderate non-proliferative DR (NPDR) and mild DME showed that EXN-407 was safe, well-tolerated, had low systemic exposure, and exhibited encouraging signals of biological activity, including reductions in macular thickness and vascular leakage.26 Exonate is now planning to advance EXN-407 to a Phase IIb trial, designated CLEAR-DM.26 The development of a topical eye drop for these conditions is highly significant as it offers a non-invasive alternative to the current standard of care, which predominantly involves intravitreal injections, thus potentially reducing treatment burden and improving patient compliance.

II. Introduction to EXN-407

A. Chemical Nature and Development

EXN-407 is classified as a small molecule inhibitor. It is being developed by Exonate Ltd., a UK-based biopharmaceutical company that originated as a spin-out from the University of Nottingham and specializes in mRNA therapies targeting alternative splicing mechanisms. EXN-407 is formulated as a topical eye drop intended for twice-daily administration. The challenge of delivering therapeutic concentrations of a drug to the posterior segment of the eye via topical application is substantial due to ocular barriers. The advancement of EXN-407 suggests progress in overcoming this hurdle, which, if successful, would represent a significant improvement in the treatment paradigm for retinal diseases.

B. Therapeutic Rationale in Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME)

Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME) are common and severe microvascular complications of diabetes, representing leading causes of vision loss in working-age adults. These conditions are characterized by progressive damage to the retinal blood vessels, leading to pathological neovascularization (the growth of new, abnormal blood vessels), increased vascular permeability, and consequent macular swelling (edema).

The current mainstay of treatment for clinically significant DME and proliferative DR involves frequent intravitreal injections of anti-Vascular Endothelial Growth Factor (anti-VEGF) agents.[26] While effective, these injections are invasive, associated with potential complications such as endophthalmitis and intraocular pressure elevation, and impose a significant treatment burden on patients and healthcare systems due to the need for repeated clinic visits and procedures.

VEGF-A plays a crucial role in both physiological and pathological angiogenesis. Its biological activity is complex and mediated by multiple isoforms generated through alternative splicing of the VEGF-A pre-mRNA. Two main families of isoforms exist: the pro-angiogenic VEGF${xxx}afamily(e.g.,VEGF−A{165}a),whichpromotesbloodvesselgrowthandpermeability,andtheanti−angiogenicVEGF{xxx}bfamily(e.g.,VEGF−A{165}$b), which can inhibit these processes. In diabetic retinal diseases, there is often an upregulation of pro-angiogenic VEGF-A isoforms, contributing to the disease pathology. EXN-407 aims to provide a non-invasive, patient-friendly alternative by modulating this pathway topically.

III. Mechanism of Action of EXN-407

EXN-407 is a selective small-molecule inhibitor of Serine/Arginine Protein Kinase 1 (SRPK1). SRPK1 is a key enzyme that phosphorylates serine/arginine-rich (SR) splicing factors, most notably SRSF1 (Serine/Arginine-rich Splicing Factor 1, previously known as ASF/SF2).

The phosphorylation status of SRSF1 plays a critical role in regulating the alternative splicing of VEGF-A pre-mRNA. Specifically, SRPK1-mediated phosphorylation of SRSF1 promotes its nuclear localization and binding to pre-mRNA, favoring the selection of the proximal splice site in exon 8 of VEGF-A. This leads to the production of pro-angiogenic VEGF-A${xxx}aisoforms,suchasVEGF−A{165}$a, which contribute to increased vascular permeability and neovascularization in pathological conditions like DME and DR.

By inhibiting SRPK1, EXN-407 is designed to reduce the phosphorylation of SRSF1. This alteration in SRSF1 activity shifts the splicing machinery towards the utilization of the distal splice site in exon 8, resulting in an increased production of the anti-angiogenic VEGF-A${xxx}bisoforms,suchasVEGF−A{165}$b. This rebalancing of VEGF isoforms towards a more anti-angiogenic profile is expected to reduce pathological retinal neovascularization, decrease vascular leakage, and thereby alleviate macular edema. This mechanism represents a novel therapeutic strategy, as it aims to modulate the balance of endogenous VEGF isoforms rather than broadly suppressing all VEGF activity. Such an approach could potentially preserve some of the physiological functions of VEGF, which are important for neuronal health and normal vascular homeostasis, potentially offering a more nuanced and safer long-term therapeutic effect compared to complete VEGF blockade.

IV. Preclinical Development

The clinical development of EXN-407 was supported by a robust preclinical program. Studies in in vivo models of neovascularization demonstrated positive results for EXN-407. Notably, these SRPK1 inhibitors, when applied as topical agents, showed superior efficacy in preclinical models of wet age-related macular degeneration (AMD), a condition that shares pathological angiogenesis with diabetic retinal diseases. Preclinical investigations also confirmed EXN-407's ability to affect neovascularization and retinal vascular permeability induced by diabetes, without raising significant tolerability or safety concerns.

Pharmacokinetic studies in Non-Human Primates (NHPs) were particularly crucial. These studies indicated that topically administered EXN-407 eye drops could achieve effective concentrations in the retina. Concurrently, the drug was found to reduce pro-angiogenic VEGF-A$_{165}$a isoforms at the target site and was rapidly cleared from systemic circulation.[34] This NHP data provided strong support for the feasibility of topical delivery for a posterior segment eye disease and suggested a low risk of systemic side effects. The ability to achieve local therapeutic effects in the retina with minimal systemic exposure is a key desired attribute for ophthalmic drugs, potentially offering a significant safety advantage over systemically absorbed or intravitreally injected therapies.

V. Clinical Development Program

A. Phase 1b/2a Study (NCT04565756)

EXN-407's initial clinical evaluation was conducted in a Phase 1b/2a trial (NCT04565756). This was a randomized, double-masked, vehicle-controlled (placebo-controlled), multiple-dose, dose-escalation, and dose-expansion study.

• Patient Population: The trial enrolled 48 treatment-naïve patients diagnosed with mild to moderate non-proliferative diabetic retinopathy (NPDR) and mild diabetic macular edema (DME). Specific inclusion criteria included a central subfield thickness (CST) greater than 325 microns, best-corrected visual acuity (BCVA) better than 69 ETDRS letters, and central macular thickness (CMT) between 280 and 420 microns.[26]
• Treatment Regimen: Patients received EXN-407 eye drops or a placebo twice daily. The study incorporated a dose-escalation phase with cohorts receiving 0.5 mg/mL, 1.0 mg/mL, or 1.5 mg/mL of EXN-407 for 3 or 7 days. This was followed by a dose-expansion phase where patients received the highest well-tolerated dose (determined as 1.5 mg/mL) or placebo for an extended period of up to 85 days (12 weeks).
• Endpoints: The primary endpoints focused on the safety and tolerability of EXN-407, assessing ocular and systemic adverse events, as well as drop comfort. Secondary endpoints included systemic exposure (pharmacokinetics) of EXN-407.[26] Exploratory endpoints aimed to detect signals of biological activity, primarily by measuring changes in CMT and vascular leakage.[26]
• Safety and Tolerability Results: The Independent Dose Escalation Committee characterized EXN-407 as safe and well-tolerated. A key finding was that 100% of patients completed the study without needing anti-VEGF rescue therapy. No major or serious adverse events (SAEs) related to EXN-407 were reported. There were four TEAEs deemed probably related to treatment (two in the EXN407 group and two in the placebo group), and one additional event considered definitely related to EXN407. All these were mild ocular AEs that resolved without intervention and did not lead to study discontinuation.[26] Drop comfort scores for EXN-407 were similar to those for placebo and artificial tears, indicating good local tolerability.
• Pharmacokinetic (PK) Results: Systemic exposure to EXN-407 was found to be low.[26] Maximal plasma concentrations ( Cmax​) were typically observed within 30 minutes post-administration of the eye drops.[26] Blood concentration levels returned to below the limit of quantification (BLOQ) by approximately four hours post-dose.[26] These findings suggest a minimal risk of systemic adverse drug reactions and little to no risk of drug accumulation with twice-daily dosing.[26] At the 1.5mg/ml dose, the mean plasma Cmax​ was 88±41pg/ml, a level significantly below that required for systemic efficacy (free concentration <0.001% of the in vitro IC50​).[34]
• Efficacy Signals (Biological Activity): The study reported promising signals of biological activity for EXN-407. Treatment with EXN-407 led to sustained decreases in macular thickness relative to the placebo group, with effects comparable to those previously reported for intravitreal anti-VEGF injections. A significant decrease in central macular thickness was observed after 85 days of treatment.[35] Furthermore, EXN-407 treatment resulted in a significant decrease in vascular leakage in 60% of treated patients, compared to 20% in the placebo group. EXN-407 also inhibited further increases in vascular leakage in treated patients (10% of EXN407-treated patients showed increased leakage versus 50% in the placebo group).

The successful completion of this Phase 1b/2a trial, demonstrating a favorable safety profile, low systemic absorption, and, critically, signals of biological efficacy comparable to invasive treatments, provides a strong foundation for advancing EXN-407 into later-stage clinical development. The ability of all patients to complete the study without needing anti-VEGF rescue is a particularly compelling outcome, suggesting EXN-407's potential to reduce the significant treatment burden associated with current therapies.

An interesting development in Exonate's journey was the regaining of full rights to its ophthalmology portfolio, including EXN-407, from Janssen Pharmaceuticals, Inc. (a Johnson & Johnson company) after the completion of this Phase 1b/2a trial, during which the companies had collaborated.[30] This move, occurring after EXN-407 met all its endpoints, suggests Exonate's confidence in the asset and its strategy to either independently drive the next phase of development or to seek new partnerships potentially under more favorable terms, leveraging the strength of the accumulated data.

Table 2: Summary of EXN-407 Phase 1b/2a (NCT04565756) Key Results

Parameter	EXN-407 (1.5 mg/mL BID)	Placebo BID
Safety & Tolerability
Study Completion (no rescue)	100%	100% (comparative completion for placebo not explicitly stated but implied by overall 100% completion for study)
Major/Serious AEs (drug-related)	None reported	None reported
Drop Comfort	Similar to placebo & artificial tears	Similar to EXN-407 & artificial tears
Pharmacokinetics
Systemic Exposure	Low	N/A
Time to Cmax​ (plasma)	~30 minutes	N/A
Time to BLOQ (plasma)	~4 hours	N/A
Accumulation Potential	Little to none	N/A
Efficacy Signals
Macular Thickness	Sustained decrease (comparable to anti-VEGF injections)	Less decrease / Increase
Vascular Leakage (Decrease)	60% of patients	20% of patients
Vascular Leakage (Inhibition of further increase)	10% of patients experienced increase	50% of patients experienced increase
BID: Twice daily; AE: Adverse Event; Cmax​: Maximum plasma concentration; BLOQ: Below Limit of Quantification. Data primarily sourced from.26

VI. Regulatory Status and Future Development

EXN-407 has successfully completed its Phase 1b/2a clinical trial. The next planned step is the CLEAR-DM (Clinical Evaluation of a New Eyedrop for Alleviating Retinopathy in Diabetic Macular Oedema) Phase IIb clinical trial. This trial was anticipated to begin in 2024, although specific updates on its initiation or recruitment status for 2025 are not available in the provided snippets.46 The primary objective of the CLEAR-DM trial is to comprehensively demonstrate the clinical benefits of EXN-407, particularly in patients with more severe NPDR and DME, thereby expanding on the findings from the initial patient cohort.26 Exonate is actively seeking strategic partnerships to support this pivotal Phase IIb study.

Regarding regulatory milestones, Exonate received Clinical Trials Notification approval from the Therapeutic Goods Administration (TGA) in Australia for the initiation of the Phase Ib/IIa study in October 2020. There is no specific information in the provided documents regarding marketing approval applications to the FDA or EMA for EXN-407 at this stage. The intellectual property for EXN-407 is protected by patents, although specific details of these patents are not elaborated upon in the available materials beyond their existence.

The full data from the Phase 1b/2a trial were selected for presentation at the Association for Research in Vision and Ophthalmology (ARVO) annual meeting in May 2024. An abstract focusing on the pharmacokinetic results, confirming low systemic exposure of EXN-407 despite high retinal exposure, was presented at ARVO 2024.[34] The progression to a Phase IIb trial targeting a population with more advanced disease is a critical step. Success in the CLEAR-DM study would substantially bolster the clinical value of EXN-407 and its potential to transform the treatment landscape for diabetic eye diseases.

VII. Discussion and Conclusion

EXN-407 stands out as a first-in-class, topical SRPK1 inhibitor eye drop, offering a novel mechanistic approach to the treatment of diabetic retinopathy and diabetic macular edema. Its development addresses a significant unmet need for non-invasive therapies in a field currently dominated by burdensome intravitreal injections.

The key strengths of EXN-407, as demonstrated in early clinical trials, are its non-invasive topical delivery route, a favorable safety and tolerability profile, minimal systemic exposure, and, most notably, promising signals of biological activity. The observed reductions in macular thickness and vascular leakage are clinically relevant and suggest a therapeutic effect comparable to established, more invasive treatments. This potential to reduce treatment burden for patients is a major advantage. The consistent positive messaging from Exonate, backed by data from the NCT04565756 trial and presentations at scientific conferences like ARVO, builds a strong case for EXN-407's potential. The ARVO 2024 presentation of full Phase 1b/2a data was a key event for the scientific community to scrutinize these findings.

However, it is important to acknowledge the limitations. The current data are from an early-phase trial with a relatively small number of patients and a focus on milder disease. The efficacy of EXN-407 in patients with more severe diabetic eye disease and its long-term benefits and safety are yet to be established.

The future of EXN-407 hinges on the outcomes of the upcoming CLEAR-DM Phase IIb trial. This study will be crucial in confirming the initial efficacy signals in a larger and potentially more diverse patient population, including those with more advanced disease. If successful, EXN-407 has the potential to become the first topical eye drop treatment for these prevalent and sight-threatening retinal vascular diseases, which would represent a paradigm shift in patient management. The successful development of EXN-407 could significantly improve the quality of life for millions of individuals affected by diabetic eye disease by offering an effective, safe, and more convenient treatment option.

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