Sirolimus shows promise in diabetic macular edema

Both subconjunctival and intravitreal injection of the broad-acting, small molecule sirolimus were shown to be safe in a phase I study of patients with diabetic macular edema. Promising efficacy signals also were observed.

Key Points

Fort Lauderdale, FL-The broad-acting compound sirolimus (MacuSight Inc.) was shown to be safe and well tolerated following a single subconjunctival or intravitreal injection in patients with diabetic macular edema (DME) during a multicenter, open-label, phase I, dose-escalation study.

Functional and anatomic improvements were observed in patients randomly assigned to receive either form of injection, and no safety issues emerged, said investigator Mark S. Blumenkranz, MD. He described his research on this compound in a presentation at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) and also cited other promising work with sirolimus.

"We saw some efficacy signals that we thought were promising, and the benefits seemed to extend up to 180 days following a single injection," said Dr. Blumenkranz, chairman and professor of ophthalmology, Stanford University School of Medicine, Stanford, CA.

Regulates growth, metabolism

Sirolimus, formerly known as rapamycin, is an immunomodulatory agent that regulates growth and metabolism in a variety of ways, including nutrient availability and oxygen tension, and has profound effects on cytokines and other growth factors. It has multiple mechanisms of action relevant to the eye, principally its activity on the hypoxia-inducible factor 1 alpha pathway (HIF-1), a key regulator of oxygen homeostasis that is elevated in the diabetic eye. Sirolimus inhibits the mammalian target of rapamycin (mTOR), a regulatory protein kinase that regulates cell growth, proliferation, motility, and survival. Inhibition of mTOR by sirolimus down-regulates HIF-1.

An earlier study, conducted in a mouse model, showed that the administration of parenteral rapamycin reduced the amount of hypoxia-induced retinopathy of prematurity. Rapamycin is also a potent inhibitor of vascular endothelial growth factor-induced hyperpermeability with activity comparable to that of the most powerful agents available today, according to the results of a study presented at the ARVO annual meeting in 2007, Dr. Blumenkranz said.

Because sirolimus has immunosuppressive, antiangiogenic, antifibrotic, antimigratory, and antiproliferative activity, it has been applied in various clinical settings. It has been used to prevent organ rejection following renal transplantation, treatment of renal cancer, and in drug-eluting stents used in treatment of coronary restenosis.

Clinical trial

After performing preclinical studies in rabbits, Dr. Blumenkranz and colleagues proceeded with their clinical trial in which they administered sirolimus to 50 subjects with DME by either an intravitreal or subconjunctival route. Patients were randomly assigned to receive either a single intravitreal injection of 44, 110, 176, 264, or 352 µg or a single subconjunctival injection of 220, 440, 880, 1,320, or 1,760 µg of sirolimus.

Best-corrected visual acuity (BCVA) was assessed by ETDRS, and central subfield retinal thickness as determined by optical coherence tomography (OCT) was interpreted by an independent reading center at 14, 45, 90, and 180 days.

Patient characteristics were similar in the two main treatment groups of 25 subjects each. The average duration of DME in the subconjunctival group was about 35 months, the mean baseline BCVA was 51 letters, and the average foveal thickness was 462 µm. In the intravitreal group, the mean duration of disease was about 3 years, baseline BCVA was 55 letters, and mean foveal thickness was 450 µm.

Safety profile

"The safety profile was promising. We did not observe any dose-limiting toxicities in any of the patients, and there were no drug-related serious adverse events," Dr. Blumenkranz said. One patient had mild inflammation that resolved spontaneously, and no cases of endophthalmitis were reported. Two eyes developed acute elevation of IOP related to the injection itself. Several patients in the highest-dose subconjunctival injection group developed chemosis that was self-limited.

"One of the key points is that the amount of drug that was administered systemically via the intravitreal or subconjunctival route was well below that which would be expected to produce immunosuppression," Dr. Blumenkranz emphasized.

Reviewing the functional and anatomic outcomes, he noted that in the entire patient group, the average improvement in BCVA was about 4 letters, and the mean reduction in retinal thickness was about 50 µm.

The subgroup analysis showed that patients in both injection groups seemed to do equally well, Dr. Blumenkranz said, and certain subgroups had particularly promising results. Looking at the two lowest dose groups in the subconjunctival arm (220 and 440 µg), there was a substantial gain of a mean of 12 letters of BCVA improvement and just under 50 µm of thickness improvement followed out to day 180.

Mean BCVA improvements were 8.8 ± 4.4, 11.4 ± 7.6, and 7.4 ± 8.6 letters at 14, 45, and 90 days, respectively, after a single 440-µg subconjunctival injection. In the same subgroup, anatomic changes were mean OCT reductions of 33 ± 60, 78 ± 50, and 54 ± 93 µm at 14, 45, and 90 days, respectively. Similarly, in the group of patients who received a single 352-µg injection of sirolimus, mean BCVA improvements were 11.6 ± 7.7, 6.4 ± 7.1, and 7.8 ± 2.2 letters and mean OCT reductions were 72 ± 53, 42 ± 39, and 61 ± 47 µm at 14, 45, and 90 days, respectively.