Ellex and its key research partners have undertaken or are undertaking a series of randomized control trials in order to validate the safety and efficacy of 2RT® in the treatment of early AMD and CSME.
2RT for Early AMD
LASER INTERVENTION IN EARLY AMD MULTI-CENTER TRIAL
Multi-center, randomized trial investigating the safety and efficacy of (2RT) nanosecond microsurgical laser intervention in early age-related macular degeneration.
Launched in 2012, 296 patients with bilateral high-risk early AMD (AREDS simplified severity score of 2-3) have been recruited. Patients in the treatment group will undergo the 2RT® procedure in one eye, with treatment to be repeated at six-monthly intervals, as required under the protocol design. Patients in the control group will undergo a sham procedure.
The primary endpoint is progression to advanced AMD in the treated eye, as assessed by ocular examination, color fundus photography, Ocular Coherence Tomography (OCT) and fluorescein angiography at 36 months post initial intervention. The secondary endpoint is progression to advanced AMD in the non-treated eye.
The complete trial protocol for the LEAD trial is available at the Clinical Trials Registry (ClinicalTrials. gov Identifier: NCT01790802).
24-MONTH PILOT STUDY RESULTS: “2RT for Early AMD”
Nanosecond laser therapy reverses pathological and molecular changes in age related macular degeneration without retinal damage
24-month clinical data, which is a follow-up to the 12-month pilot study “2RT for Early AMD” (ACTRN 1260900E1056280), conducted at the Centre for Eye Research Australia (CERA) by Professor Robyn Guymer, MB, BS PhD, FRANZCO. Fifty (50) AMD patients were treated with a single application of 2RT® with subsequent changes in drusen area compared against a natural history cohort at 12 months and 24 months post-treatment.
- Drusen reduction was maintained out to the second year, with fundus Autofluorescence exhibiting a stabilized RPE monolayer in the area of 2RT-induced drusen regression in 75% patients.
- At 12 months and 24 months drusen reduction was 40% and 35% respectively, compared to 11% in the natural history cohort.
- There was no sign of potential to progression to atrophy (as characterized by increase in fundus Auotfluorescence)
- No patient was observed to progress to advanced “wet” form of AMD: At 24 months post-treatment no patients had developed CNV.
E. L. Fletcher et al. Nanosecond laser therapy reverses pathological and molecular changes in age related macular degeneration without retinal damage. Federation of American Societies of Experimental Biology. November 2014; 28 (11).
12-MONTH PILOT STUDY RESULTS: “2RT for Early AMD”
Nanosecond-laser application in intermediate AMD- 12- month results of fundus appearance and macular function
12-month prospective non-randomised, pilot intervention study, “2RT for Early AMD” (ACTRN 1260900E1056280) conducted at the Centre for Eye Research Australia (CERA) by Professor Robyn Guymer, MB, BS PhD, FRANZCO. Fifty (50) patients with bilateral intermediate AMD (drusen > 125µm) were treated with a single application of 2RT® to assess the ability of 2RT® to delay the progression of early AMD.
- A single application of the 2RT® laser produced bilateral improvements in macular function and appearance.
- Drusen area was reduced in 44% of treated eyes and 22% in fellow eyes.
- 2RT produced benefits in visual function as measured by flicker perimetry sensitivity. The biggest changes occurred in the central one degree of the treated eye, where greatest pre-treatment dysfunction existed.
Guymer, R.H., et al., Nanosecond-laser application in intermediate AMD – 12-month results of fundus appearance and macular function. Clin Experiment Ophthalmol. 2013 Oct 3. doi: 10.1111/ceo.12247
2RT for CSME
PILOT STUDY – St. Thomas Hospital, UK
Retinal Rejuvenation Therapy for Diabetic Macular Edema
Prospective, open-labelled, pilot study conducted in 2012 to investigate the safety and efficacy of 2RT® in the treatment of CSME. Patients with newly diagnosed DME underwent 2RT® with pulsed energy 78 µJ to 131 µJ, with the number of shots dependant upon patient extent of edema and leakage on FFA.
- Mean change in LogMAR visual acuity between baseline and 6 months:
- o 11% patients improved ≥ 3 lines
- 32% patients improved ≥ 2 lines
- 43% patients stable (within ± 1 line)
- Central macular thickness decreased greater than 5% in 46% of treated eyes and stabilized (within ±5% change from baseline) in 39% treated eyes.
- Microperimetry examination confirmed preserved integrity of photoreceptors and improvement, correlated by decreased macular thickness.
- Therapeutic benefits were achieved without associated side effects of conventional (thermal) retinal photocoagulation.
|Energy/single Pulse, mJ (µJ)||Treated Eyes, n (%)||Number of Pulses, Mean (Range)||Total Energy, Mean (Range), mJ|
|0.3 (78)||22 eyes (75.8)||94.5 (78-232)||29.09 (2-77)|
|0.5 (109)||4 eyes (13.8)||75.75 (31-135)||39.75 (17-70)|
|0.6 (131)||3 eyes (10.3)||72 (14-124)||46 (18-74)|
Pelosini L, Hamilton R, et al., Retinal Rejuvenation Therapy for Diabetic Macular Edema – a pilot study, Retina 2013 Mar; 33(3) :548-58
PILOT STUDY – Royal Adelaide Hospital, Australia
Randomized Clinical Trial of a New Nanopulse Retinal Laser versus Conventional Photocoagulation for the Treatment of Diabetic Macular Edema
Pilot, Prospective, randomized non-inferiority trial conducted at the Royal Adelaide Hospital over 6-month follow up period. Patients with diabetic macular edema (250-550µm), BCVA (ETDRS) 19 or more letters ( ≥ 20/400) and retinal thickness (OCT) 250µm or more in the central subfield or 300µm or more in at least 1 of the inner subfields, underwent approx. 20-120 applications, grid pattern, of 2RT®.
- In the short-term 2RT® approximates the clinical efficacy of retinal photocoagulation.
- The difference in retinal thickness between the two groups was 5.6mm in favor of 2RT®, secondary outcome of change in VA of 0.02 in favor of the 2RT®.
- No observable adverse events reported.
- 2RT® used approx. 500 times less laser energy than retinal photocoagulation and induced no collateral damage.
Casson RJ. et al., Pilot randomized trial of a nanopulse retinal laser versus conventional photocoagulation for the treatment of diabetic macular oedema. Clin Experiment Ophthalmol. 2012 Aug;40(6):604-10
Ellex and its key research partners have undertaken extensive laboratory investigations to establish the therapeutic effect and safety profile of 2RT™. This research has shown that 2RT™ influences the transport properties of the RPE and Bruch’s membrane – key structures involved in the progression of AMD and Diabetic Retinopathy.
A summary of 2RT scientific data is provided below:
Nanosecond laser therapy reverses pathological and molecular changes in age-related macular degeneration without retinal damage
A. I. Jobling, R. H. Guymer, K. A. Vessey, U. Greferath, S. A. Mills, K. H. Brassington, C. D. Luu, K. Z. Aung, L. Trogrlic, M. Plunkett, and E. L. Fletcher
Federation of American Societies of Experimental Biology. November 2014; 28 (11).
Scientific data addressing the impact of 2RT® in two exenterated human eyes and a series of mouse eye models, conducted at the University of Melbourne, Australia, by Erica L. Fletcher, MScOptom, PhD. In both the mouse eye models and human eyes a process of PRE proliferation and migration with no increase in glial activity (Gliosis) was observed. Retinal structure was preserved over treated area on comparison with the untreated area. The process of improving hydraulic conductivity through thinning of Bruch’s membrane was demonstrated over the entire retina and not confined to lesion area on available animal models.
RESPONSE OF THE RETINAL PIGMENTED EPITHELIUM TO RETINAL REGENERATION THERAPY (2RT) LASER, IN VITRO AND IN VIVO
J.P. Wood, G. Chidlow, M. Tahmasebi, M. Plunkett, R.J. Casson.
Aim: To delineate the effects of retinal rejuvenation therapy (2RT®) laser to the retinal pigment epithelium (RPE), both in vitro and in vivo, concentrating on levels of ablation, and induction of proliferation and potential protective factors from surviving cells.
Outcome: RPE cells surrounding the 2RT® laser ablation sites actively respond to injury by producing a range of protein factors which likely have autocrine and paracrine effects. Thus, 2RT not only avoids causing significant collateral damage to photoreceptors, but it can also induce expression of potentially protective factors.
Nanosecond Laser Pulses for Retinal Treatment
J.P. Wood, G. Chidlow, V. Previn, M. Plunkett, R. Casson.
Lasers in Surgery and Medicine, 2011; 43(6):499-510
Aim: To determine the therapeutic range of a new, non-thermal, nanopulse laser (2RT®) and to produce greatest therapeutic range without causing collateral damage in porcine ocular explants.
Outcome: Nanosecond pulses can provide a very wide therapeutic range of energies in which RPE treatment can be performed. At energy levels more than 200 times less than conventional thermal laser, 2RT® produces therapeutic benefit without damage to the neuroretina. The therapeutic range of up to 6:1 produced by the speckle beam profile of 2RT® is wider than previously reported.
Laser-Mediated Activation of Matrix Metalloproteinases (MMPs)
Leading to Increased Transport Across Ageing Bruch’s Membrane: Implications for Treatment of ARMD
Aim: To investigate cellular dynamics and associated matrix metalloproteinase release patterns of human retinal pigment cells subsequent to 2RT® nanopulse laser application. On human ocular explants.
Outcome: 2RT® produced non- visible lesions resulting in diffuse loss of RPE cells followed by repopulation by cells migrating from the periphery of the lesions. Concomitant with migrating cells was the release of activated matrix metalloproteinase enzymes. Of note were increases in activated MMP 2 & 9.>/p>
Retinal Damage Profiles and Neuronal Effects of Laser Treatment: Comparison Between a Novel, Non-Thermal Laser and a Conventional Photocoagulator.
G. Chidlow, J.P.M. Wood, R.J. Casson, M. Plunkett.
Invest Ophthalmol Vis Sci 2013 Mar 28;54(3):2305-18. Epub 2013 Mar 28.
Aim: Laboratory animal study on rats. Evaluate retinal cell and neurons in response to application of conventional thermal laser and new 2RT nanopulse laser to determine if 2RT can specifically ablate RPE cells without collateral damage to other retinal cells. 2RT laser was applied at two distinct energy settings: above and below visible effect threshold.
Outcome: Treatment with conventional thermal laser caused the rapid appearance of lesions that were associated with ablated RPE, induction of both delayed and instant photoreceptor death and widespread edema. Treatment with 2RT at both the high and low setting led to RPE loss with sparing of Bruch’s membrane. 2RT applied at energy levels clinically significant for treatment of DME patients resulted in an RPE lesion that was entirely specific to the treated cells, leaving an intact basement membrane, which was largely repaired within 7 days. 2RT has wide number of potential applications as it does not cause the same degree of collateral tissue damage when kept at sub-visible energy levels, as compared to conventional thermal laser.
Glial Cell and Inflammatory Responses to Retinal Laser Treatment: Comparison of a Conventional Photocoagulator and a Novel, 3-Nanosecond Pulse Laser
G. Chidlow, O. Shibeeb, M. Plunkett, R.J. Casson and J.P.M. Wood.
Invest. Ophthalmol. Vis. Sci. March 28, 2013 vol. 54 no. 3 2319-2332
Aim: To study inflammatory and glial cell responses resulting from treatment of rats with a conventional thermal laser and with new nanopulse, non-thermal laser (2RT®).
Outcome: Conventional thermal laser produces marked photoreceptor damage, leukocyte activation and infiltration. Glial responses consistent with an inflammatory response to thermal injury. In contrast, 2RT® produced drastically less retinal damage and cellular responses at clinically relevant energy levels and marginal effects at elevated energy levels. The results show that the 2RT® produced an insult at the RPE level whilst causing little collateral damage to the neuroretina as normally associated with conventional thermal laser.
Laser mediated activation of human retinal pigment epithelial (RPE) cells and concomitant release of matrix metalloproteinases (MMPs)
J.J.Zhang, Y. Sun, A.A. Hussain and J. Marshall.
Invest. Ophthalmol. Vis. Sci. May 17, 2012 vol 53 no. 6 2928-2332
Aim: To investigate cellular dynamics and associated matrix metalloproteinase (MMP) release patterns of human retinal pigment epithelium (RPE) cells subsequent to irradiation by nanosecond pulsed laser at energy levels below visual threshold.
Outcome: 2RT® provides an avenue for transiently increasing the RPE-mediated release of active MMP enzymes. The likely impact of this enzymatic release on the structural and functional aspects of aging Bruch’s membrane requires further evaluation.