Article

The Role of Sirolimus in the Management of Uveitis

Evolution of intravitreal sirolimus through clinical trials.

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Uveitis is comprised of a group of ocular disorders characterized by inflammation that can lead to significant visual loss if left untreated. Uveitis is among the leading causes of preventable blindness worldwide.1,2 The primary goals in the management of uveitis are to achieve quiescence and to prevent recurrence of disease. The first line of treatment for noninfectious uveitis (NIU) in many cases is pan-blockage of cytokines via corticosteroids. However, ocular and systemic adverse events associated with corticosteroids limit their long-term use.3 Over the past 2 decades, the treatment paradigm for NIU has encompassed the use of immunomodulatory therapeutic (IMT) agents, such as antimetabolites, calcineurin inhibitors, biologics, and interleukin inhibitors. The goal in using these agents is to reduce the need for long-term therapy with corticosteroids.4,5

Sirolimus, with its potential for T-cell immunosuppression, received approval by the FDA in 1999 for use in renal transplant recipients as Rapamune (Wyeth Pharmaceuticals). Four years later, a sirolimus-eluting stent (Cypher, Johnson & Johnson), was approved by the FDA for use in patients with coronary artery disease. Such achievements for a potential immunosuppressive agent have initiated significant research into the therapeutic potential of sirolimus in ocular inflammatory diseases. Here we focus on the mechanism of action of sirolimus, the results of preclinical and clinical studies of NIU, and updates on the current clinical trials evaluating locally delivered sirolimus for NIU.

MECHANISM OF ACTION

Sirolimus is a lipophilic microcyclic lactone that is isolated from the actinomycete Streptomyces hygroscopicus, a fungus discovered at Rapa Nui (Easter Island) in the 1970s, with immunoregulatory, antiangiogenic and antiproliferative potency.6 It inhibits the activity of the serine-threonine kinase mechanistic (previously termed as mammalian) target of rapamycin (mTOR).7

mTOR protein is an intracellular coordinator of ribosomal biogenesis, protein translation, and proper cell growth.8 It forms a complex in the intracellular environment called mTOR complex 1 (mTORC1), and this complex promotes messenger RNA (mRNA) translation by phosphorylating and activating S6K1 (p70-S6 kinase 1) while phosphorylating and inactivating eukaryotic initiation factor 4E binding protein 1, which is a known repressor of mRNA translation (Figure 1).9

Figure 1. Outline of the mechanistic target of rapamycin (mTOR) pathway and the role of sirolimus in its blockage.

This major pathway modulates cellular responses to insulin, insulin-like growth factors, nutrient levels, hypoxia, and redox status. Sirolimus forms a complex with cellular protein receptor FKBP-12, and this complex binds to mTOR, leading to arrest of mTOR activity in mTORC1 via autophosphorylation and dissociation of mTORC1 (Figure 1).9

Inhibition of mTOR pathway by sirolimus also inhibits cytokine-driven T-cell proliferation by inhibiting the progression from the G1 phase to the S phase of the cell cycle.10 Additionally, sirolimus blocks T-cell activation in response to interleukin (IL)-2, IL-4, and IL-5, and it inhibits IL-2-dependent and -independent proliferation of B lymphocytes. It also suppresses expression of many inflammatory genes, including Il-8, granulocyte chemotactic protein-2, inducible nitric oxide synthase, cyclooxygenase-1 and cyclooxygenase-2, and endothelial monocyte-activating polypeptide II.

Sirolimus also impedes hypoxia-inducible factor-1α through a different mechanism. In the presence of activated mTOR, the regulatory-associated protein of mTOR, which is part of mTORC1, activates hypoxia-inducible factor-1α.11

PRECLINICAL STUDIES

Preclinical studies in animal models provided a foundation for the use of sirolimus in human clinical trials. Ikeda et al found in 1997 that a combination of tacrolimus (0.1 mg/kg/day) with a high dose of sirolimus (0.1 mg/kg/day) effectively suppressed inflammation in murine models of experimental autoimmune uveitis.12 However, a lower sirolimus dose (0.03 mg/kg/day) in combination with tacrolimus or monotherapies with either drugs or dose doubling for either drug resulted in only a partial response.

Zhang et al demonstrated in 2012 a paradoxical dose-dependent role of intraperitoneal sirolimus injections in EAU.13 The data showed that a low dose (1.5 µg per day) of sirolimus exacerbated the disease, whereas a high dose (7.5 µg per day) lowered the disease severity. In another study, Hennig et al investigated the efficacy of oral everolimus (2-hydroxyethyl derivative of sirolimus) in a mouse model of EAU. A dose of 5 mg/kg/day demonstrated significant decreases in inflammation compared to the sham group (treated with 5% glucose).14

Recently, Wu et al studied the effects of intravitreal (IVT) sirolimus loaded with polymeric micelles on a rat EAU model. IVT rapamycin micelles were found to be superior to IVT rapamycin suspension, in terms of higher water solubility, tolerance, compatibility, distribution, and accumulation within the retinal pigment epithelium, establishing another potential mode of drug delivery.15

CLINICAL STUDIES

Early Clinical Studies

In 2005, Shanmuganathan et al demonstrated the efficacy of orally administered sirolimus in recalcitrant cases of uveitis.16 Eight subjects with uncontrolled disease with at least 2 or more corticosteroid-sparing agents and requiring high-dose corticosteroids were treated with oral sirolimus (4 mg/day with increasing by increments of 2 mg based on disease activity and trough blood levels). Oral therapy was found to be effective in 5 of 8 subjects, while treatment in 3 patients was considered a failure due to the inability to control the uveitis and the development of severe side effects.

Sen et al at the National Eye Institute (NEI) conducted an open-label pilot study to assess the safety and efficacy of a single subconjunctival injection of sirolimus in subjects with chronic active anterior uveitis.17 Five subjects received 1,320 µg (30 µL) at the baseline visit and were followed until month 4. The drug was well tolerated with no serious adverse events, and 3 subjects demonstrated a 2-step decrease in inflammation with 4 weeks on treatment.

Successful Tapering of Oral Corticosteroids With IVT Sirolimus

RAJ MATURI, MD

Oral corticosteroids and oral immunomodulatory agents are the foundation of current medical management of noninfectious uveitis of the posterior segment (NIU-PS), but they are associated with a wide range of well-characterized systemic and ocular adverse events. Oral steroids cause many changes, including weight gain and other serious metabolic effects. Chronic use of intravitreal or sub-Tenon steroids causes cataract formation and increased intraocular pressure (IOP) in a substantial proportion of patients. The development of a novel treatment for NIU-PS, the mTOR inhibitor sirolimus, raises the possibility that utilization of systemic or intravitreal steroids can be reduced or eliminated in these patients. We explored this potential in a subgroup analysis of the SAKURA program, the results of which were presented at this year’s ARVO meeting.1

In the SAKURA protocol, all systemic immunosuppressive agents other than corticosteroids were discontinued 30 days before day 1 baseline evaluation, and topical ocular corticosteroids were rapidly tapered to the point of discontinuation on day 1. Subjects in the integrated intent-to-treat (ITT) population who were receiving systemic corticosteroids at baseline at a prednisolone-equivalent dose of more than 5 mg per day comprised the intent-to-taper population. Over the course of the SAKURA program, this group was tapered off of systemic steroids according to a schedule that reduced the dose by 10 mg per week until 40 mg/day was reached, then by 5 mg per week until 20 mg/day was reached, and then by 2.5 mg per week until discontinuation.

Corticosteroid-tapering success was evaluated in 46 patients from the 440-μg group and 32 from the 44-μg active control group, who began the trial on an overall prednisone-equivalent dose of more than 5 mg/day. Tapering success was defined as achieving an overall prednisone-equivalent dose of 5 mg/day or less at month 5 without the use of rescue therapy.

A majority of subjects in the intent-to-taper population achieved tapering success (69.6% and 68.8% in the 440-μg and 44-μg groups, respectively). Although the difference did not meet statistical significance due to the small sample size, the proportion of patients who achieved tapering success with an improvement of vitreous haze to 0 or trace (0.5+) at month 5 (the prespecified secondary end point in the SAKURA program) was numerically higher in the 440-μg dose group than in the 44-μg dose group (43.5% vs 28.1%, respectively; P=.1676).

Serious ocular adverse events reported during the SAKURA program were generally manageable and have been observed with intravitreal therapy. The overall rates were similar between the study and active control groups in the SAKURA safety population. Of greatest relevance to this subanalysis, there were no clinically significant changes in IOP at any visit in either dose group.

Given the challenges of managing uveitis, a new therapy that has the potential to reduce the signs of inflammation without steroid-associated adverse events, particularly increases in IOP, and that allows patients to taper rapidly off systemic corticosteroid therapy would be a valuable addition to therapeutic options for uveitis.

REFERENCE

  1. Maturi R. Corticosteroid tapering success with every-other-month intravitreal sirolimus for non-infectious uveitis of the posterior segment: results of the SAKURA program. Poster presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; May 6-11, 2017; Baltimore, MD.

Phase 1 and 2 Clinical Trials

The Sirolimus as a therapeutic Approach for uVEitis (SAVE) study was a proof-of-concept, randomized, open-label clinical study to assess the safety, tolerability, and efficacy of intravitreal (group 1; 352 µg) and subconjunctival (group 2; 1,320 µg) sirolimus, administered at baseline, month 2, and month 4, in 30 subjects with NIU.18 Starting at month 6 and proceeding to month 12, subjects with residual and recurrent disease were allowed to receive sirolimus up to every 2 months.

The primary 6-month results of the SAVE study demonstrated that locally administered sirolimus, irrespective of the route of administration, was safe and tolerable with no systemic or local drug-related serious adverse events.18 Additionally, sirolimus also proved to be very effective as a steroid-sparing agent in subjects receiving steroids at baseline. Reduction in vitreous haze scores was significant in both groups. (Table 1).

Table 1. Comparison of Results at Primary Endpoints of Clinical Trials Evaluating Sirolimus for the Management of Uveitis
SAVE SAVE-2* SAKURA 1
Groups IVT Sirolimus (352 µg q 2 months) Subconjunctival Sirolimus (1320 µg q 2 months) IVT Sirolimus (440 µg q 1 month) IVT Sirolimus (880 µg q 2 months) IVT Sirolimus (44 µg q 2 months) IVT Sirolimus (440 µg q 2 months) IVT Sirolimus (880 µg q 2 months)
Percentage of patients ≥2-step reduction in VH score 29 29 64 50 16 28 19
Percentage of patients with 1 or more line gain in VA 36 43 63 23
IVT, intravitreal; SAVE, Sirolimus As a therapeutic approach for uVEitis; SAVE-2, Sirolimus As a therapeutic approach for uVEitis — protocol 2; SAKURA, Sirolimus study Assessing double-masKed Uveitis tReAtment; VH, vitreous haze.
*The results from the SAVE-2 study were from the interim analysis of 24 enrolled subjects who completed the primary endpoint at month 5.

The 1-year outcomes of the SAVE study were similar to the primary results at month 6 and showed that repeated sirolimus injections were well tolerated.19 At month 12, 70% of the subjects demonstrated a ≥2-step reduction in VH score from baseline, and 30% of the subjects showed a 1-step reduction or no change in VH score. A gain of 1 or more lines in VA was shown by 36% of the subjects. Forty-three percent showed no change in VA, while 29% lost 1 or more lines at month 12. Subjects enrolled in the SAVE clinical trial also demonstrated an overall improvement in vision-related health and quality of life, as assessed by the Visual Function Questionnaire of the NEI.20

The favorable efficacy and safety results of the SAVE study led to initiation of the Sirolimus as a therapeutic Approach for uVEitis: Protocol 2 (SAVE-2) study.21 SAVE-2 is a phase 2, multicenter, randomized, open-label clinical trial evaluating the safety and efficacy of 2 doses of IVT sirolimus for NIU. Subjects randomized to a low dose (440 µg) received therapy at baseline followed by monthly treatment, while subjects receiving a high dose (880 µg) were treated at baseline and every 2 months thereafter until month 6.

Starting at month 6, subjects in both groups were treated on an as-needed basis with the dose assigned to them at baseline. Moreover, in the SAVE-2 study, the fellow eye with active disease could be treated with sirolimus at the investigators’ discretion with the dose opposite to that of the study eye, enabling assessments of bilateral injections of IVT sirolimus, which may resemble clinical practices more closely.

The interim analysis of the SAVE-2 study for 24 randomized subjects demonstrated a significant ≥2-step reduction in 63.6% and 50% of the subjects in the low- and high-dose groups, respectively (Table 1).21 Sixty-three percent of the subjects in group 1 and 23% of the subjects in group 2 demonstrated gains of 1 or more lines of VA (Table 1). Overall, both doses of sirolimus were well tolerated with no ocular or systemic serious adverse events, even in cases in which both eyes were treated on the same day. The SAVE-2 study is currently ongoing (NCT01280669).

Phase 3 Clinical Trial

Based on the results of the SAVE and SAVE-2 studies, two sequential phase-3, double-masked, multinational, controlled, randomized clinical trials were initiated.22 The Sirolimus study Assessing double-masKed Uveitis tReAtment (SAKURA 1) study involved 347 subjects who were randomized through March 2013 at 103 sites across Europe, India, Israel, Japan, Latin America, and the United States. Subjects were randomized into the SAKURA 2 study beginning in 2013, and data from SAKURA 2 were first reported in 2016. An NDA for intravitreal sirolimus is currently under review by the FDA.

In SAKURA 1, subjects were randomized into 3 groups at a 1:1:1 ratio to receive intravitreal sirolimus 44 (active control), 440, and 880 µg at baseline, month 2, and month 4, respectively. The primary and secondary endpoints were assessed at month 5. Starting at month 6, there was a 6-month open-label treatment period, followed by a 12-month retreatment period with 880 µg of sirolimus.

The primary endpoint (month 5) results of SAKURA 1 showed that 22.8% of the subjects in the 440-µg group, 16.4% in the 880-µg group, and 10.3% in the 44-µg group achieved the primary endpoint of a VH score of 0.22 The proportions of subjects with ≥2-step reductions in VH score were 28.1%, 19.0%, and 16.2% in the 440-, 880-, and 44-µg groups, respectively (Table 1).

SAKURA Results Support the Efficacy and Safety of Sirolimus in Noninfectious Uveitis

PAULINE T. MERRILL, MD

The SAKURA (Sirolimus study Assessing double-masKed Uveitis tReAtment) study is the largest trial in noninfectious uveitis of the posterior segment (NIU-PS) conducted to date. It included 2 phase 3 multinational, randomized, double-masked studies that evaluated the comparative safety and efficacy of intravitreal (IVT) sirolimus, administered every other month, in patients with active intermediate, posterior or panuveitis. SAKURA 1 and SAKURA 2 included an active control dose (44 μg) and 2 higher doses (440 μg and 880 μg) of IVT sirolimus. After the final unmasked analysis of SAKURA 1, the 880-μg dose was phased out of SAKURA 2, and eligible subjects were randomized (1:1) to receive 44 μg or 440 μg. The primary endpoint of both studies was achieving a vitreous haze (VH) score of 0 in the study eye at month 5, with VH measured on a modified Standardization of Uveitis Nomenclature (SUN) Working Group scale. The key secondary endpoint was achieving 0 to trace (0 or 0.5+) VH at month 5.

At the annual meeting of the Association for Research in Vision and Ophthalmology, we reported results from the integrated intent-to-treat (ITT) population, comparing the 440-μg dose to the 44-μg active control dose, with 208 subjects in each group. All subjects had a VH score of at least 1.5+ in the study eye at baseline. Noncorticosteroid systemic immunosuppressants (IMTs) and topical corticosteroids (CSTs) were discontinued before the baseline evaluation. The primary efficacy measures were collected at month 5 and safety data through month 24.

Serious adverse events were similar between the 2 groups. The most frequently reported serious ocular adverse event category was worsening uveitis (7.8%), with the incidence of all others, including increases in IOP, at or less than 2%.

The efficacy analysis of the integrated ITT population showed that 21.2% of subjects in the 440-μg cohort and 13.5% in the 44-μg cohort (P=.038) met the primary endpoint of zero VH. Half of the patients (50%) in the 440-μg arm and 40.4% in the 44-μg group (P=.049) met the secondary endpoint of 0 or trace VH. The integrated analysis of the SAKURA program supports the 440-μg dose of IVT sirolimus as having a more favorable benefit-to-risk profile than the 44-μg dose.

A post-hoc analysis was performed on patients with multiple measures of inflammation (MMI), which is based on patients having VH of at least 1.5+ and 1 or more of the following: systemic CSTs at an overall prednisone-equivalent dose greater than 5 mg/day; impaired vision (BCVA of 75 ETDRS letters — Snellen equivalent: 20/32 — or less); and/or macular edema (central retinal thickness ≥300 μm on OCT).

Most patients (80.7%) in the integrated ITT population presented with MMI at baseline (n=171, 440 μg; n=163, 44 μg). In this group, 21.1% in the 440-μg dose cohort achieved VH=0 at month 5 without the use of rescue therapy, while only 8.0% in the 44-μg dose group did so (P=.0007). Against the secondary endpoint, 48.0% of patients with MMI in the 440-μg dose group reached 0 or trace VH at month 5 without the use of rescue therapy, compared to 37.4% in the active control group (P=.052).

This integrated post-hoc analysis reinforces the favorable benefit-to-risk profile demonstrated by the 440-μg dose of IVT sirolimus. The 440-μg dose is now under FDA review, with the possibility of a novel treatment option becoming available for NIU-PS in the near future.

REFERENCE

  1. Nguyen QD, Merrill PT, Clark L. Efficacy and safety results from the SAKURA program: Two phase III studies of intravitreal sirolimus every other month for non-infectious uveitis of the posterior segment. Poster presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; May 6-11, 2017; Baltimore, MD.

The improvement in inflammatory indices in the 440-µg group were significant compared to the 44-µg group, while the improvement in the 880-µg group was not statistically significant compared to the 44-µg group. Visual acuity was maintained or improved in 80%, 80%, and 79% of the subjects in the 440-, 880-, and 44-µg groups, respectively. The study demonstrated that all of the doses of intravitreally administered sirolimus were well tolerated with serious adverse event profiles that were similar across all of the groups and to those reported in previous studies. Additionally, the steroid-sparing effect was prominently noted in the 440-µg dose group. Eligible subjects from the SAKURA 1 study are currently being treated and followed in the SPRING study, an extension protocol with 440 µg of sirolimus.

CONCLUSION

Sirolimus has a unique mechanism of action with the blockade of multiple modulators of inflammation. Its favorable safety profile and promising clinical efficacy, as demonstrated by phase 1, phase 2, and phase 3 clinical trials, indicate that sirolimus may be a feasible, effective therapeutic option in the management of uveitis and ocular inflammatory diseases, especially as a corticosteroid-sparing agent. RP

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