ABOUT CLS-AX

CLS-AX (axitinib injectable suspension) is a proprietary suspension of axitinib for suprachoroidal use. Axitinib is a tyrosine kinase inhibitor (TKI) currently approved to treat renal cell cancer that achieves pan-VEGF blockade, directly inhibiting VEGF receptors-1, -2, and -3 with high potency and specificity. We believe this broad VEGF blockade may have efficacy advantages over existing retinal therapies and may benefit patients who sub-optimally respond to current, more narrowly focused anti-VEGF therapies.

Suprachoroidal injection of this proprietary suspension of axitinib has demonstrated meaningful potential in preclinical studies in multiple species. With CLS-AX, there is the potential to achieve prolonged duration and targeted delivery to affected tissue layers. We are currently developing CLS-AX as a long-acting therapy for the treatment of wet AMD.

POTENTIAL BENEFITS

  • Longer lasting treatment may reduce patient burden from monthly injections
  • Pan-VEGF inhibition is potentially more efficacious than current approaches

  • Targeted, high drug levels may improve long-term, real-world visual outcomes

  • Protection of the vitreous and anterior chamber may eliminate certain side effects
  • In-office procedure can be easily adopted in current clinical practice

TARGET INDICATION

Neovascular Age-Related Macular Degeneration (wet AMD)

Neovascular Age-related macular degeneration (wet AMD) causes a progressive loss of central vision and is the most common cause of legal blindness in individuals over age 55. Wet AMD is generally caused by abnormal blood vessels that leak fluid or blood into the macula, the part of the retina responsible for central vision, and accounts for the majority of vision loss in patients with this disorder. In the U.S., approximately 11 million patients are living with AMD, and about 20% have the wet form. Current treatments require life-long, frequent injections to maintain efficacy. This treatment regimen tends to cause a treatment burden for patients resulting in reduced compliance and under-treatment leading to potentially limited outcomes.

OUR APPROACH

We are developing CLS-AX (axitinib injectable suspension) for administration to the suprachoroidal space as a longer-acting therapy for wet AMD.

Current wet AMD therapy has a ceiling of efficacy as increased dosage or more intense regimens yield limited or no additional visual benefit, and is associated with a significant treatment burden. This treatment burden is further highlighted by recent large “real-world” retrospective studies of wet AMD which underscore the difficulty in adhering to regimens. These real-world studies demonstrate that patients are undertreated, receiving only 6 to 7 injections per year on average, resulting in mean improvement of only one to three letters in visual acuity after one year of treatment.

Axitinib achieves pan-VEGF blockade by acting at a different level of the angiogenesis cascade, directly inhibiting VEGF receptors-1, -2, and -3 with high potency and specificity. Based on preclinical data in multiple species, we believe that CLS-AX could benefit patients for several reasons.

  • Axitinib has intrinsic high potency and can achieve pan-VEGF inhibition through receptor blockade, which may benefit patients who respond suboptimally to current anti-VEGF-A therapy.
  • Axitinib has been observed to have a pharmacodynamic effect, with reduced growth of experimental neovascularization and decreased fluorescein leakage.

  • Suprachoroidal administration of axitinib can potentially achieve prolonged duration and targeted delivery to affected tissue layers.

Suprachoroidal Injection of CLS-AX Provides Greater Targeted Delivery

Abbreviations: SCS: Suprachoroidal Space | RPE: Retinal pigment epithelium

PIPELINE STATUS

OASIS Phase 1/2a Clinical Trial

OASIS is an open-label, dose-escalation Phase 1/2a trial in wet AMD patients to assess the safety and tolerability of a single dose of CLS-AX administered by suprachoroidal injection via Clearside’s SCS Microinjector®. Eligible patients are those who demonstrate stable visual acuity following two or more previous injections with an intravitreal anti-VEGF agent. All enrolled patients undergo diagnostic imaging on screening, followed by masked reading center confirmation of persistent active disease.

TRIAL DESIGN

Enrolled patients initially receive aflibercept at the first visit followed by a single dose of CLS-AX at the second visit one month later. The primary endpoint for the trial will assess the safety and tolerability of CLS-AX for the three months following the administration of CLS-AX, and secondary endpoints will evaluate the pharmacokinetics, visual function, ocular anatomy, and the need for additional treatment with intravitreal aflibercept during the three-month period.

The study design is planned with 3 cohorts of approximately five patients each. Dose escalation will then proceed following review of the safety data by the Safety Monitoring Committee and their recommendation to advance to the next higher dose cohort. Additional information on the Phase 1/2a trial can be found on https://clinicaltrials.gov (NCT04626128).

References:

Medscape: F Ryan Prall, MD, et al Assistant Professor of Ophthalmology, Indiana University School of Medicine | Pennington, Katie L and DeAngelis, Margaret M Eye and Vision, Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors, Dec 22, 2016. | Cabral T et al. Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers. Ophthalmol Retina. 2018 January; 2(1): 31–37. doi:10.1016/j.oret.2017.04.004. | Lieu et al. The Association of Alternate VEGF Ligands with Resistance to Anti-VEGF Therapy in Metastatic Colorectal Cancer. PLoS ONE 8(10): e77117. | Ciulla TA et al. Ophthalmology Retina. 2019 May 25. pii: S2468-6530(19)30280-5. | Viral S. Kansara, Leroy W. Muya, Thomas A. Ciulla; Evaluation of Long-Lasting Potential of Suprachoroidal Axitinib Suspension Via Ocular and Systemic Disposition in Rabbits. Trans. Vis. Sci. Tech. 2021;10(7):19.