title: A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema.
abstract: OBJECTIVE
  To evaluate the safety and tolerability of a single subconjunctival (SCJ) or intravitreal (IVT) injection of an ophthalmic sirolimus formulation in eyes with diabetic macular edema (DME).
  
  
  METHODS
  Randomized, open-label, dose-escalating phase I study.
  
  
  METHODS
  Fifty eyes among 50 patients with DME, retinal thickness ≥ 300 microns and best-corrected visual acuity (BCVA) 20/40 to 20/200.
  
  
  METHODS
  A single dose of sirolimus administered SCJ (220, 440, 880, 1320, or 1760 μg) or IVT (44, 110, 176, 264, or 352 μg) on day 0; observation through day 90.
  
  
  METHODS
  Primary end points were the frequency and severity of ocular and systemic adverse events. Secondary end points were changes in BCVA and retinal thickness.
  
  
  RESULTS
  No dose-limiting toxicities were observed and ocular adverse events were mostly mild and transient. Conjunctival hyperemia, hemorrhage, and edema were common after the SCJ injection procedure and conjunctival hemorrhage was common after the IVT injection procedure. Three patients experienced ocular adverse events considered possibly related to study drug: Conjunctival edema and reduced visual acuity were reported in 1 SCJ patient each and iritis was reported in 1 IVT patient. No serious ocular adverse events were reported. No nonocular adverse events were considered related to study drug. Systemic exposure to sirolimus was low, with blood concentrations below levels necessary for systemic immunosuppression. For the SCJ group (n = 25), a median increase in BCVA started at day 7 (5.0 letters) and was 3.0, 4.0, and 4.0 letters at days 14, 45 and 90, respectively. At day 45, median decrease in retinal thickness was -23.7 μm. For the IVT group (n = 25), the median increase in BCVA was 2.0 letters at day 7; at days 14, 45, and 90, the median increase was maintained (4.0 letters); the median decrease in retinal thickness was -52.0 μm at day 45.
  
  
  CONCLUSIONS
  Locally administered sirolimus was well-tolerated with minimal systemic exposure at all doses tested in this small phase I population. These findings support advancing the present sirolimus formulation into phase II studies.
  
  
  BACKGROUND
  Proprietary or commercial disclosure may be found after the references.
authors: Retinal Consultants of Arizona, Phoenix, Arizona 85014, USA. pdugel@gmail.com
authors: Pravin U
authors: PU
authors: Dugel
authors: Mark S
authors: MS
authors: Blumenkranz
authors: Julia A
authors: JA
authors: Haller
authors: George A
authors: GA
authors: Williams
authors: Wayne A
authors: WA
authors: Solley
authors: David M
authors: DM
authors: Kleinman
authors: Joel
authors: J
authors: Naor
mesh_terms: D003228:Conjunctiva / Q000187:drug effects; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D058449:Intravitreal Injections; D008269:Macular Edema / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009883:Ophthalmic Solutions / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity / Q000502:physiology
chemical_list: D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D020123:Sirolimus