Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage:

Sirolimus for the treatment of noninfectious uveitis Uwe Pleyer MD, FEBO & Stephan R. Thurau MD To cite this article: Uwe Pleyer MD, FEBO & Stephan R. Thurau MD (2016) Sirolimus for the treatment of noninfectious uveitis, Expert Opinion on Pharmacotherapy, 17:1, 127-135, DOI: 10.1517/14656566.2016.1124855 To link to this article:

Accepted author version posted online: 25 Nov 2015. Published online: 25 Jan 2016. Submit your article to this journal

Article views: 24

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at Download by: [RMIT University]

Date: 04 February 2016, At: 02:44

Drug Evaluation

Sirolimus for the treatment of noninfectious uveitis Uwe Pleyer† & Stephan R Thurau †




Introduction to the compound




Pharmacokinetics (PK) and

Downloaded by [RMIT University] at 02:44 04 February 2016

metabolism 5.

Clinical efficacy


Safety and tolerability


Regulatory affairs




Expert opinion

Department of Ophthalmology, Charité, Universitäts-Medizin Berlin, Campus Virchow-Klinikum, University Medicine Berlin, Berlin, Germany

Introduction: Noninfectious posterior uveitis (NIPU) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, common therapy includes (systemic) corticosteroids and immune modulatory agents. Most treatments bear the risk of significant adverse effects. Therefore efforts are made to administer therapeutic agents directly into the vitreous cavity. The purpose of this article is to identify the role of intravitreally applied sirolimus as a recently approved therapeutic option in NIPU. Areas covered: A MEDLINE database search was conducted through August 2015 using the terms: intravitreal injection, pharmacology, sirolimus, treatment and uveitis. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at were included. Sirolimus (Opsiria) was in licensed from SANTEN in 2015 and approved in Phase III registration trials in the US, Europe and other countries for NIPU. Current information results mainly from registration and Phase III trials. Expert opinion: Intravitreal sirolimus appears to be an interesting option in the treatment algorithms of NIPU because of its highly targeted molecular effects, nonsteroidal nature and good safety profile. It has the advantage to avoid systemic side effects, but this has to be balanced against the fact that treatment covers one eye only and bears the risks of any intraocular procedure. Nevertheless a careful evaluation of this agent has to be made, as current experience is almost exclusively based on registration trials and long-term effects still have to be explored. Keywords: intravitreal injection, mTOR inhibitor, sirolimus, uveitis Expert Opin. Pharmacother. (2016) 17(1):127-135




Uveitis – the treatment challenge

Uveitis is a general term referring to inflammation of the retina and uvea. It remains a leading cause of visual impairment and a significant burden of legal blindness. It is estimated that it affects 30,000 patients annually in the United States alone resulting in costs of around USD 242.6 million [1,2] per year. Based on its anatomical location, intraocular inflammation is commonly distinguished as anterior, intermediate or posterior uveitis.[3] The two latter ones are affecting the posterior segment of the eye. Noninfectious posterior uveitis (NIPU) bears a higher risk of secondary sequela and if remained untreated, often has a chronic relapsing clinical course resulting in significant permanent damage. Although its pathogenesis is not completely understood, it is believed to be an immune mediated disease driven by different lines of T lymphocytes.[4,5] Consequently, anti-inflammatory and immune modulatory agents are the mainstay of treatment in NIPU.

10.1517/14656566.2016.1124855 © 2016 Taylor & Francis ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted


Pleyer & Thurau

Downloaded by [RMIT University] at 02:44 04 February 2016


Competitor compounds

Anterior uveitis often can be controlled by topical corticosteroid treatment because of the good penetration into the anterior chamber and the short duration of treatment. Conversely, NIPU is more challenging to manage and often associated with permanent visual impairment. Frequently NIPU runs a chronic or recurrent course involves both eyes and is not accessible by topical application of medication. Subsequently systemic treatment is often used, in particular if bilateral involvement or associated systemic disorders are present. Initial therapy for acute NIPU is commonly based on systemic corticosteroids with its well known adverse effects.[6] As longterm modulators of recurrent intraocular inflammation, immune modulatory agents such as calcineurin inhibitors, antimetabolites and cytotoxic agents are used in a “step ladder” fashion as second and third line therapeutic approach.[7,8] Concerns are raised about the side effects of systemically applied agents that often become treatment-limiting. This includes adverse events related to immunosuppression like infection, leukopenia or malignancy as well as the potential teratogenicity, which restricts their use during pregnancy.[9,10] In addition, only very few of these agents underwent regulatory approval for uveitis, and the “off label use” imposes significant restrictions on the adequate treatment. Taken together these considerations raise the need of alternative options. Significant efforts are focusing on local and more selective interventions targeting intraocular inflammation. Indeed, the eye is one of the most attractive sites of the body for locally delivered therapy because it is a confined structure with a lack of vascularisation of the vitreous body and therefore a reduced washout rate. The success of intravitreal VEGF-inhibiting agents for the treatment of age related macular degeneration and cystoid macular edema in venous occlusion and diabetic retinopathy has demonstrated the usefulness of this approach. Another potential interesting indication for such approaches is NIPU. Since intraocular structures of the posterior segment are difficult to reach by topical application and are otherwise only accessible by systemic treatment, interest is focusing on the pros and cons of intravitreal injected (IVI) medications.[11,12] Given the fact that NIPU is causing unilateral blindness in >20% of affected patients, it clearly indicates that unilateral treatment might be of importance.[13] It is remarkable that “old agents” such as corticosteroids are enjoying a “revival” in this respect. An increasing spectrum of steroid preparations including nondegradable and biodegradable devices is currently available. This includes FDA-approved devices such as Ozurdex (dexamethasone; Allergan, Dublin, Ireland) and Retisert (fluocinolone acetonide; Bausch and Lomb, Rochester, USA). As repeated and long-term applications are often required, they bear the risk of steroid related complications and alternative agents are currently tested. Table 1 outlines studies indicating the effects/adverse effects of agents approved for intravitreal treatment in NIPU [14-18] including sirolimus. Sirolimus has potent immunosuppressive, antiangiogenetic and antiproliferative properties.[19] Oral sirolimus was reported to be effective 128

in the treatment of NIPU. However, gastrointestinal and dermatological side effects as well as an inhibition of scar formation have been observed and limit its use in the long-term treatment of NIPU.[20] 2.

Introduction to the compound

Sirolimus, also known as rapamycin is a macrolide antibiotic that was first isolated in the 1970s as a bacterial product of Streptomyces hygroscopicus on Easter Island also known as “Rapa Nui” (Box 1).[19] Similar to cyclosporin A, sirolimus was originally developed as an antifungal agent. However, soon it became clear that it’s immunosuppressive and antiproliferative “side” effects are dominant. In 1999 it was approved by the FDA for the use as an immunosuppressive agent in kidney transplantation.[21] It became available under the trade name Rapamune by Wyeth (now Pfizer). In addition, a sirolimus/ polymer-coated stent (CYPHER®) is available for improving coronary luminal diameter in patients with symptomatic ischemic disease.[22] 3.


Although sirolimus has similar immunosuppressive effects like cyclosporin A in inhibiting interleukin (IL)-2 and other cytokine receptor-dependent signal transduction mechanisms, its mode of action is completely different. Sirolimus interferes with cell-cycle progression by interaction with several intracellular proteins. Specifically it acts through the immunophilin FK binding protein 12 (FKBP-12) and the mammalian target of rapamycin (mTOR).[19,23,24] The resulting complexes inhibit mTOR and subsequently block IL-2 mediated signal transduction pathways and prevent cell-cycle progression from G1 to S phase in T cells, endothelial cells and smooth muscle cells.[19,23,24] In addition, sirolimus inhibits the production of antibodies (Figure 1).



Most information on pharmacodynamics of sirolimus is derived from animal experiments.[26,27] Data are typically obtained in noninflamed eyes and results may differ in active uveitis because of the altered blood-ocular barriers. For intraocular injection sirolimus is dissolved in an excipient consisting of polyethylene glycol and alcohol. Interestingly, when this solution is applied as IVI, the sirolimus aggregates spontaneously as an intraocular depot.[26] This is related to its hydrophobicity and its interaction within the hydrophilic vitreous humor (VH). When hydrophobic sirolimus comes in contact with VH it forms small crystals, resulting in a local drug deposit that slowly releases the agent over time. The dissolution within the VH in turn, is dependent on the clearance of sirolimus from the VH into peripheral ocular tissues, including the

Expert Opin. Pharmacother. (2016) 17(1)

Sirolimus for the treatment of noninfectious uveitis

Downloaded by [RMIT University] at 02:44 04 February 2016

Table 1. Treatment effect of intravitreal drug delivery in studies with noninfectious uveitis (modified from ref. 11). Retisert® (0.59 mg fluocinolone acetonide implant)

Retisert® (0.59 mg fluocinolone acetonide implant)

Study design

Callanan et al., 2008 Multicenter, randomized, historically controlled trial

Number of patients Follow-up period Uveitis recurrence rates during 1-year period before treatment Uveitis recurrence rates after treatment

110 3 years 62%

Pavesio et al., 2010 Randomized, controlled, phase 2b/3, open-label, multicenter superiority trial 66 3 years NM

Decrease in macular thickness (CMT)

Improvement in fluorescein leakage Improvement in visual acuity (at least 3 lines) Reduction in the number of patients requiring systemic medications Cataract surgery Glaucoma surgery

Sirolimus (352 µg intravitreal injection or 1320 µg subconjunctivally**)

Ozurdex® (0.7 mg dexamethasone implant)

Ozurdex® (0.7 mg dexamethasone implant)

Sirolimus (352 µg intravitreal injection)

Williams et al., 2009 Randomized, prospective, single-masked, controlled trial

Lowder et al., 2011 Prospective, multicenter, masked, randomized

Nguyen QD Ibrahim et al., 2015 et al., 2013 Prospective Prospective

41 6 months NM

77 6 months NM

15 6 months NM

30 12 months NM

4% (1-year); 35% (2-year) 10% (2-year); 20% (3-year) NM NM






−99 µm (at 2-months)

− 75 μm (at 3 months); – 105 μm (at 6 months)






No significant changes of CMT in patients with macular edema –30/–47 μm (at 6/12 months); +105/+106 μm (at 6/12 months**) or without macular edema. No changes of CMT in patients without macular edema NM








40% (approximately) NM

93% 40% at 3-year

88% 21%

NM* None

1.3% None

1 eye/15 None

Approx. 80%

4%/0% (at 6/12 months) in both treatment groups Approx. 60%

NM None

NM: Not mentioned. *Rate of cataract surgery cannot be detected appropriately as 18 patients were pseudophakic at the beginning of the study.

retina and choroid and the washout by the flow of intraocular fluid from the ciliary body to the draining trabecular meshwork and episcleral veins. During this dissolution process, an almost steady-state concentration of sirolimus is maintained in the VH.


Vitreous humor

Animal studies in New Zealand White (NZW) rabbits indicate that with a single IVI high concentrations of sirolimus can be obtained within the VH.[26] In an extended animal study it was possible to measure drug concentrations

in this compartment. NZW rabbits received either 22 or 220 μg of sirolimus and were followed for 3, 7, 14, 29, 62, 90 and 162 days (6 eyes per group). Following a single IVI, peak levels of sirolimus in the crystalline VH depot were achieved at 3 – 6 h post-injection (13,188.3 and 263,166.7 ng/ml) for eyes injected with 22 and 220 μg, respectively. [26] In contrast, sirolimus concentrations in the non-depot portion of the VH were relatively low, although they were also dose-related and disproportionately higher for the larger 220 μg dose. A maximum concentration of 117.5 and 420.4 ng/ml was obtained in eyes injected with 22 and 220 μg, respectively.

Expert Opin. Pharmacother. (2016) 17(1)


Pleyer & Thurau

Box 1. Drug summary Drug name (generic) Phase (for indication under discussion) Indication (specific to discussion) Pharmacology description/mechanism of action Route of administration Chemical structure

Sirolimus (Rapamycin) Pre-registration Noninfectious posterior segment uveitis mTOR kinase inhibitor; Cell cycle inhibitor; Immunosuppressant; Protein kinase inhibitor; T cell inhibitor Intravitreal injection

Downloaded by [RMIT University] at 02:44 04 February 2016


Pivotal trial(s)

SAVE Study; SAKURA Study [18,31-33]

220 μg dose. A sharp decline in tissue concentration occurred in the lower dose group between days 14 and 30, while significant levels were still present in the retina/choroid through day 30 (approx. 800 ng/g) for the higher dosage.

3.4 Pharmacodynamics after repeated dosing in NZW rabbits

Figure 1. The chemical structure of sirolimus (rapamycin).[25]

Measurements 3 days after a single IVI indicate that sirolimus concentrations remained dose dependent and higher for the larger 220 μg dose. That is, approximately 16 – 24 times higher than the 22 μg dose. Sirolimus concentrations in the depot portion of the VH were more than 2 orders of magnitude higher than in the non-depot portion.[26] Sirolimus levels diminished quite rapidly for the 22 μg dose, but appreciable concentrations persisted through day 90 for the 220 μg group. 3.3

Retina/choroid levels

The levels of sirolimus in retina/choroid are of key interest. Across dose levels, sirolimus concentrations were proportional to VH concentrations. Peak levels of sirolimus in the retina/ choroid at 6/12 h post-injection were 700 – 800 ng/g for eyes injected with 22 μg and 4000 ng/g for 220 μg.[26] The rate of decline was greater for the 22 μg dose and much slower for the 130

Noninfectious posterior uveitis is a chronic recurrent disorder, therefore repeated IVI are likely to be necessary. In a multipledose study, rabbits received 132 μg of sirolimus with up to five IVI´s.[26] The injections were given approximately every 8 weeks over an 11-months period. After the first injection, 71% of the eyes displayed a visually detectable depot and after the fourth injection up to 97% of the eyes. The maximum concentration of sirolimus in the VH was achieved 2 – 4 weeks after the last IVI (approx. 9,000 – 12,000 ng/ml). At 2 – 4 weeks after each injection, the target tissues, retina and choroid, accumulated significant levels of sirolimus (approx. 1000 ng/g), and remained measureable for up to 8 weeks.[26] Small concentrations of Sirolimus (max. 3 – 8 ng/g) could also be detected in the sclera and conjunctiva in this experimental set up. 4.

Pharmacokinetics (PK) and metabolism


PK studies in animals

Sirolimus is extensively metabolized as a substrate for CYP3A4 and P-glycoprotein (P-gp) and was evaluated within the systemic circulation. Peak systemic concentrations were observed in whole blood (WB) of NZW rabbits 1 h after each injection

Expert Opin. Pharmacother. (2016) 17(1)

Sirolimus for the treatment of noninfectious uveitis

at a dose of 132 μg sirolimus/eye.[26] The highest drug levels were measured 1 h after the injection (8.02 ng/ml), which decreased to 1.64 ng/ml within 2 weeks. Follow up measurements in WB, revealed very low sirolimus levels that became negligible by weeks 7 – 9 (approx. 0.03 ng/ml). Since the therapeutic range of sirolimus appears to be 5 – 15 µ/l, systemic effects following IVI are unlikely to occur.

Downloaded by [RMIT University] at 02:44 04 February 2016


PK studies in humans

Only very few PK data are available in humans. In general, they indicate that with IVI administration, systemic exposure is negligible.[28,29] In a Phase I/II clinical study in patients with diabetic macular edema, the highest blood concentrations of sirolimus were observed at day 2 ( sclera > WB could be detected. Intraocular sirolimus concentrations were maintained for approximately 2 months after each injection. The agent was relatively well tolerated and in rare cases may induce an inflammatory response in the eye within 2 days of injection. 5.

Clinical efficacy

Sirolimus has immunosuppressive effects, which are used for the treatment of uveitis. 5.1

Phase I studies

In a first study five patients suffering from long standing active anterior uveitis received 1320 µg of sirolimus in a total volume of 30 µl subconjunctivally.[30] Three of the five patients met the primary outcome criteria by showing at least a 2-step decrease in anterior chamber inflammation within 4 weeks; two patients showed a 1-step decrease in inflammation within the same time frame. No recurrence was encountered during a 4-month follow-up. There were no serious adverse events. This study showed potential efficacy in intraocular inflammatory disease as well as tolerability. 5.2

Phase II studies

In a Phase II trial (SAVE: Sirolimus as a Therapeutic Approach for Uveitis) two different routes of local administration have been explored .[18,31] In this study 30 patients with intermediate or posterior uveitis were enrolled and randomized in 1:1 ratio to receive either intravitreal

injections of 352 µg sirolimus or subconjunctival injections of 1320 µg at days 0, 60 and 120, with primary endpoint at month 6 (after 3 injections per eye) [18] and another primary endpoint at month 12 in an extension study with additional 3 injections per eye.[31] Sirolimus was dissolved in an excipient composed of polyethylene glycol 400 (PEG 400) and ethanol (≥99.5%). The major advantage of this excipient is the ease of injection with a very small needle (30G) and a precise dosing. 5.2.1

Intraocular injection for uveitis

In 21 eyes of 15 patients with inactive and active uveitis, with or without systemic treatment 62 intraocular injections of 325 µg sirolimus were performed and data of 14 patients were available for evaluation.[18] At baseline all patients had vitreous haze scores of ≥0.5. After 3 months 6/14 patients and after 6 months 3/14 patients achieved a haze score of 0. None of the patients deteriorated. Average visual acuity increased approx. by 1 line with more patients gaining than loosing visual acuity throughout the study. Central macular thickness decreased in patients with macular edema at month 3 but returned at month 6. The use of concomitant steroids could be reduced significantly. During an extension of the study up to 12 months another 43 intravitreal injections were given resulting in improvement in vitreous haze in 71% of patients at 12 months, while 7% deteriorated.[31] 5.2.2

Subconjunctival injection for uveitis

Twenty-five eyes from 15 patients received 66 subconjunctival injections of 1320 µg sirolimus and data of 14 patients were available for evaluation.[18] All patients had vitreous haze scores of ≥0.5 and after 3 and 6 months, 7 and 4 patients achieved a score of 0, respectively, while none of the patients deteriorated. Again, visual acuity improved only marginally, while central macular thickness improved at month 3 but returned at month 6. Like in intravitreal injections the use of systemic steroids could be reduced significantly. During the extension of the SAVE-study to 12 months, additional 50 subconjunctival injections were performed and vitreous haze improved in 71.4% of the patients and deteriorated in none of them.[31] 5.2.3

Quality of life (QoL) assessment

The majority of patients in the SAVE-trial were investigated for their quality of life using the National Eye Institute 39Question Visual Function Questionnaire (NEI VFQ-39).[32] Patients receiving intravitreal injection of sirolimus showed overall improvement of vision-related health while those receiving subconjunctival injections did not. Specifically patients receiving the intraocular route of therapy reported significant improvements in the areas of general vision, near activities, distance activities, vision-specific social functioning and vision-specific mental health.

Expert Opin. Pharmacother. (2016) 17(1)


Pleyer & Thurau

Phase III studies

Downloaded by [RMIT University] at 02:44 04 February 2016


Probably in view of the better tolerability and QoL results a decision was made to restrict further development of the drug dissolved the non-aqueous excipient for the intravitreal application. The Phase III trial (Study Assessing Double-masKed Uveitis tReAtment; SAKURA) was a multinational, multicenter, randomized, double-masked study assessing the safety and efficacy of intravitreal injections of three doses of sirolimus for the treatment of active, noninfectious uveitis of the posterior segment of the eye.[33] This included intermediate and posterior uveitis as well as pan-uveitis with activity in the anterior segment being less than in the posterior part of the eye. In this trial 347 patients were included and randomized to three different treatment groups 1:1:1 at doses of 44, 440 and 880 µg in a total volume of 20 µl. It is noteworthy that there was no true control group without active ingredient. Instead a very low dose of 44 µg was chosen, which was regarded as minimal effective. Each individual received three injections of the same dose at days 1, 60 (month 2) and 120 (month 4). The primary efficacy endpoint was the percentage of subjects with vitreal haze score of 0 at month 5.[33] The secondary endpoints at month 5 included vitreal haze scores of 0 or 0.5+, corticosteroid tapering success and changes in best corrected visual acuity. Safety was monitored throughout the study until month 6. Most subjects had signs of moderate inflammation, with vitreous haze scores at baseline of 1.5+ (37%), 2+ (52%), 3+ (10%), or 4+ (1%).[33] The baseline mean best-corrected visual acuity was 65.3 ETDRS letters (equivalent to Snellen 20/50; range, 3 – 95 letters).[31] The primary efficacy end point (at month 5) of a vitreal haze score of 0 was reached by 23% in the 440 µg group. Similarly, the percentage of patients achieving the secondary endpoint, which is quiescence defined as vitreal haze scores of 0 or 0.5+, was greatest in the 440 µg group (53%). The visual acuity increased most in the 440 µg group, but was on average

Sirolimus for the treatment of noninfectious uveitis.

Noninfectious posterior uveitis (NIPU) remains a significant burden of legal blindness. Because of its immune mediated and chronic recurrent nature, c...
566B Sizes 1 Downloads 12 Views