A new agent for the treatment of noninfectious uveitis: rationale and design of three LUMINATE (Lux Uveitis Multicenter Investigation of a New Approach to Treatment) trials of steroid-sparing voclosporin

Figures & data

Figure 1 Comparison of structures of voclosporin (left) and cyclosporin A (right).

Figure 2 Comparison of calcineurin inhibition of voclosporin versus CsA.

Abbreviations: AIC, Akaike information criterion; CsA, cyclosporin A; E_max, maximal effect.

Figure 3 E_max versus reduction in PASI in phase 3 psoriasis study.

Abbreviations: CNi, calcineurin inhibition; E_max, maximal effect; PASI, Psoriasis Area and Severity Index.

Figure 4 Voclosporin therapeutic window for renal toxicity.

Abbreviations: AUC, area under the curve; CNi, calcineurin inhibitor; SCr, serum creative.

Table 1 Selected inclusion and exclusion criteria for the LUMINATE clinical trials program (Protocol 1, p. 22–24; Protocol 2, p. 22–25; Protocol 3, p. 20–23)

LUMINATE Active	LUMINATE Maintenance	LUMINATE Anterior
Selected inclusion criteria
Documented history of noninfectious intermediate-, anterior and intermediate-, posterior-, or pan-uveitis	Diagnosis of noninfectious intermediate-, anterior and intermediate-, posterior-, or pan-uveitis of at least 3 months duration prior to enrollment, requiring treatment during that period to control intraocular inflammatory disease and avoid sight-threatening complications due to inflammation	Documented history of noninfectious anterior-, anterior and intermediate-, or pan-uveitis
Uncontrolled uveitis, evidenced by Grade 2+ or higher vitreous haze in atleast one eye for ≥2 weeks prior to randomization	Minimum prescribed therapy upon enrollment is ≥1 of the following:	Uncontrolled uveitis, evidenced by Grade 2+ or higher anterior chamber cells in at least one eye for ≥2 weeks prior to randomization
Current uveitis therapy must conform to ≥1 of the following:	Systemic prednisone or equivalent averaging ≥10 mg/day	In subjects whose diagnosis is not exclusively anterior uveitis, the predominant manifestation of their condition at the time of enrollment must be anterior segment inflammation
Prednisone monotherapy at a dose of ≥10 mg/day (or equivalent) for ≥2 weeks prior to randomization	Received ≥2 intravitreal/periocular corticosteroid administrations for control of inflammatory disease within the past 8 months, but not within 6 weeks of randomization	Current uveitis therapy must conform to ≥1 of the following:
Received ≥2 injections of corticosteroid (intravitreal or periocular) for control of disease within the past 8 months, but not within 2 weeks of randomization; subjects may be receiving systemic corticosteroids	Note: Subjects may be receiving topical corticosteroids for control of anterior inflammation during study	Prednisone monotherapy at a dose of ≥10 mg/day (or equivalent) for ≥2 weeks prior to randomization
Subjects for whom corticosteroid therapy (oral or systemic) is medically inappropriate, or who refuse corticosteroid therapy	Subjects with clinically quiescent uveitis in both eyes at enrollment and who have been on a treatment regimen that has neither been intensified nor augmented for a minimum of 6 weeks	Received ≥2 injections of corticosteroid (intravitreal or periocular) for control of disease within the past 8 months, but not within 2 weeks of randomization; subjects may be receiving systemic corticosteroids
Subjects who do not plan to undergo elective ocular surgery (eg, cataract extraction) during study	Considered by the investigator to require immunomodulatory therapy	Subjects for whom corticosteroid therapy (oral or systemic) is medically inappropriate, or who refuse corticosteroid therapy
A minimum ability to count fingers at a distance of 1 meter, 30 centimeters using the study eye	Must have best corrected visual acuity (BCVA) in the worst involved eye of 20/400 or better (Early Treatment Diabetic Retinopathy Study [ETDRS] logMAR <1.34)	Subjects who do not plan to undergo elective ocular surgery (eg, cataract extraction) during study
Considered by the investigator to require immunomodulatory therapy	Subjects who do not plan to undergo elective ocular surgery (eg, cataract extraction) during study	A minimum ability to count fingers at a distance of 1 meter, 30 centimeters using the study eye
Must be ≥13 years of age and must weigh at least 38 kg (84 lbs) and no more than 110 kg (242 lbs)	Must be ≥13 years of age and must weigh at least 38 kg (84 lbs) and no more than 110 kg (242 lbs)	Considered by the investigator to require immunomodulatory therapy
		Must be ≥13 years of age and must weigh atleast 38 kg (84 lbs) and no more than 110 kg (242 lbs)

	LUMINATE Active	LUMINATE Maintenance	LUMINATE Anterior
Selected exclusion criteria
Uveitis of infectious etiology	✓	✓	✓
Clinically suspected or confirmed central nervous system or ocular lymphoma	✓	✓	✓
Primary diagnosis of anterior uveitis	✓	✓
Uncontrolled glaucoma, evidenced by an intraocular pressure of >21 mmHg while on medical therapy, and chronic hypotony (<6 mmHg)	✓	✓	✓
Presence of an ocular toxoplasmosis scar	✓	✓	✓
Any implantable corticosteroid-eluting device (eg, Retisert^™, Posurdex^®, Medidur^™, I-vation^™ TA intravitreal implant)	✓	✓	✓
Treatment with an immune suppression regimen that includes an alkylating agent within the previous 90 days	✓	✓	✓
Treatment with a monoclonal antibody or any other biologic therapy within the previous 30 days, or with alemtuzumab within the previous 12 months	✓	✓	✓
Use of any drugs or substances known to be strong inhibitors of CYP 3A4/5 enzymes within 7 days of the first dose, or grapefruit juice and star fruit within 24 hours of the first dose	✓	✓	✓
Lens opacities or obscured ocular media upon enrollment such that reliable evaluations and grading of the posterior segment cannot be performed	✓	✓
Evidence of active, uncontrolled noninfectious uveitis		✓
History or diagnosis of Behçet’s disease		✓
Local (periocular/intravitreal) administration of corticosteroids within the previous 6 weeks		✓

Table 2 Primary, secondary, and additional endpoints of the LUMINATE clinical trial program* (Protocol 1, p. 18; Protocol 2, p. 18; Protocol 3, p. 17)

LUMINATE Active	LUMINATE Maintenance	LUMINATE Anterior
Primary endpoints
Mean change from baseline in graded vitreous haze after 16 weeks of therapy or at time of rescue, if earlier Mean change from baseline in graded vitreous haze after 24 weeks of therapy or at time of rescue, if earlier	The proportion of subjects experiencing inflammatory exacerbation during 26 weeks of treatment, as defined by a clinically significant deterioration in either eye for one or more of the following: Vitreous haze: increase of ≥2 grades from baseline AC cells: increase of ≥2 grades from baseline Visual acuity: change of ≥ +0.3 logMAR from baseline in BCVA	Mean change from baseline in graded AC cells after 16 weeks of therapy or at time of rescue, if earlier Mean change from baseline in graded AC cells after 24 weeks of therapy or at time of rescue, if earlier
Secondary and additional endpoints
Proportion of subjects tapered to ≤5 mg/day of prednisone (or equivalent) by Week 16, and who do not require intensification or augmentation of therapy through Week 24	Change from baseline in dose of oral corticosteroid at week 26 or at time of rescue, if earlier	Proportion of subjects tapered to ≤5 mg/day of prednisone (or equivalent) by Week 16, and who do not require intensification or augmentation of therapy through Week 24
Mean change from baseline in BCVA using the ETDRS method at week 24 or subject’s last visit, if earlier	Change from baseline in BCVA at week 26 or at time of rescue, if earlier	Mean change from baseline in graded vitreous haze after 16 and 24 weeks of therapy or at time of rescue, if earlier, in the subset of subjects entering the study with a diagnosis of either panuveitis or anterior and intermediate uveitis
Mean change from baseline in thickness of the macula, as measured by OCT, at Week 24 or at subject’s last visit, if earlier	Change from baseline in QoL, NEI VFQ-25, EQ-5D, and SF-36, at week 26 or at time of rescue, if earlier	Mean change from baseline in BCVA using the ETDRS method at 24 weeks of therapy or at time of rescue, if earlier
Mean change from baseline in graded AC cells after 16 weeks of therapy or at time of rescue, if earlier, in the subset of subjects entering the study with a diagnosis of either panuveitis or anterior and intermediate uveitis	Time to occurrence of deterioration from baseline of ≥2 grades of vitreous haze during 26 weeks of therapy	Change from baseline in QoL, NEI VFQ-25, EQ-5D, and SF-36
Mean change from baseline in graded AC cells after 24 weeks of therapy or at time of rescue, if earlier, in the subset of subjects entering the study with a diagnosis of either panuveitis or anterior and intermediate uveitis	Time to occurrence of deterioration from baseline in graded AC cells during 26 weeks of therapy in the subset of patients entering the study with a diagnosis of either panuveitis or anterior and intermediate uveitis	Change from baseline in thickness of macula at 24 weeks of therapy or at time of rescue, if earlier, as confirmed by OCT
Mean change from baseline in daily prednisone dose at 24 weeks or at time of rescue, if earlier	Time to occurrence of inflammatory exacerbation during 26 weeks of therapy	Mean change from baseline in graded AC flare at 16 and 24 weeks of therapy or at time of rescue, if earlier
Mean change from baseline in thickness of the macula, as measured by OCT, at Week 16	Extension of an existing lesion and/or occurrence of new lesions requiring treatment
Change from baseline in area of macular hyperfluorescence as measured by FA
Change from baseline in QoL, NEI VFQ-25, EQ-5D, and SF-36
Change from baseline in presence and/or severity of ocular exam inflammatory abnormalities

* Note: All relevant measures in each study will be analyzed for the other eye.

Abbreviations: AC, anterior chamber; BCVA, best corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; EQ-5D, EuroQoL-5 domains; FA, fluorescein angiography; NEI VFQ-25, National Eye Institute Visual Functioning Questionnaire; OCT, optical coherence tomography; QoL, quality of life; SF-36, 36-Item Short Form Health Survey.