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29 OCT 2015 BAY no. 73-4506 / IMPACT no. 15984 Page: 1 of 9 Synopsis Date of report: 29 OCT 2015 Study title: Sponsor s study number: NCT number: A combined Phase IIa / IIb study of the efficacy, safety, and tolerability of repeated topical doses of regorafenib eye drops, in treatment-naïve subjects with neovascular age-related macular degeneration. 15984 NCT02222207 EudraCT number: 2012-003763-22 Sponsor: Clinical phase: Bayer HealthCare IIa and IIb Study objectives: Part A: Primary objectives: Assess the effect of treatment with regorafenib eye drops on visual acuity at Study Week 4 and at Study Week 12 in subjects with subfoveal CNV due to AMD Secondary objectives: Part B: Evaluate the effect of treatment with regorafenib eye drops on ocular safety and tolerability Primary objectives: Explore an optimal dosing regimen Assess the effect of treatment with regorafenib eye drops on visual acuity at Study Week 4 and at Study Week 12 in subjects with subfoveal CNV due to AMD Secondary objectives: Evaluate the effect of different dosing regimens with regorafenib eye drops on visual acuity and ocular safety and tolerability Following evaluation of the efficacy and safety data from Part A of this study, the sponsor decided not to continue the study, because
29 OCT 2015 BAY no. 73-4506 / IMPACT no. 15984 Page: 2 of 9 Test drug: Name of active ingredient(s): Regorafenib Dose: Route of administration: Duration of treatment: the pre-specified success criteria for proof of concept (PoC) were not met in the full population or any of the subgroups investigated. Therefore, this study was prematurely terminated following completion of Part A. Regorafenib (BAY 73-4506) Part A: 30 mg/ml, 25µL, 1 drop (0.75 mg), 3 times daily. Part B: Dosing was planned to be determined following the analysis of data collected in Part A. Subjects who received regorafenib eye drops were also planned to receive sham IVT injections once every 4 weeks. The comparator drug, ranibizumab was to be injected IVT to the study eye once every 4 weeks for 3 treatments, as per label instructions. Subjects who received ranibizumab were also to receive placebo eye drops at frequencies that matched the active regorafenib eye drop treatment. Topical application to the eye Regorafenib was administered for 12 weeks in Part A and was planned to be administered for12 weeks for Part B Reference drug: Dose: Route of administration: Duration of treatment: Indication: Diagnosis and main criteria for inclusion: Part A: none Part B: Ranibizumab (Lucentis) Part A: none Part B: 0.5 mg, once every 4 weeks for 3 treatments, as per label instructions Intravitreal injection 12 weeks Neovascular age-related macular degeneration of all subtypes Eligible subjects received a diagnosis of neovascular age-related macular degeneration in one or both eyes; however, only one eye was enrolled in this study, the study eye. All ophthalmic eligibility criteria applied only to the study eye unless otherwise specified. The main criteria for inclusion in Part A and Part B are: Men and women 50 years of age
29 OCT 2015 BAY no. 73-4506 / IMPACT no. 15984 Page: 3 of 9 Active primary subfoveal choroidal neovascularization lesions secondary to age-related macular degeneration, including juxtafoveal lesions that affected the fovea as evidenced by fluorescein angiography in the study eye and reviewed by the central reading center The area of choroidal neovascularization occupied at least 50% of total lesion in the study eye, as determined by fluorescein angiography review at the central reading center Evidence of intraretinal and/or subretinal fluid on optical coherence tomography and reviewed by the central reading center Early Treatment Diabetic Retinopathy Study best corrected visual acuity of 73 to 25 letters (20/40 to 20/320 Snellen equivalent) in the study eye Willing, committed, and able to return for all clinic visits and complete all study-related procedures Study design: Methodology Part A: This part of the study had a multi-center, single-arm, open-label design. Part B: This part of the study was planned to be a multi-armed, randomized, double-masked, active-controlled, dose and dosing frequency finding. However, given the results of Part A, Part B was not initiated. Part A: During the screening period potential study subjects were identified and informed consent obtained prior to the initiation of any study-related procedures. Subjects were then evaluated for eligibility against the study-specific inclusion and exclusion criteria. It was estimated that approximately 70 subjects would be screened to obtain 50 eligible subjects. During the 12-week treatment period, subjects self-administered topical regorafenib to the study eye (30 mg/ml, 25µL, 1 drop, 3 times daily [TID]). Subjects returned to the study clinic for efficacy and safety assessments weekly for 4 weeks followed by bi-weekly visits through Study Week 12. Subjects were assessed at each study visit for BCVA using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Optical coherence tomography was performed at each study visit and FP and FA examinations were performed at screening, Study Week 4 and Study Week 12 (and other treatment visits as needed at the discretion of the investigator). Pharmacokinetic sampling was performed pre- and post-
29 OCT 2015 BAY no. 73-4506 / IMPACT no. 15984 Page: 4 of 9 administration of study eye drops at each clinic visit. Ongoing safety assessments included ophthalmic examinations including inspection of periocular skin, eye lids, and hands; the recording and evaluation of clinical AEs; safety laboratory measurements; ECGs; and vital signs. Clinic visit safety procedures also included observation of the subjects 30-60 minutes post administration of eye drops followed by a re-measurement of intraocular pressure (IOP) and the collection of the second PK sample towards the end of this observation period. Rescue treatment with ranibizumab IVT (administered as per drug label) was initiated as early as Visit 5 (end of Study Week 3) through the end-of-treatment (EOT) visit, if both of the following rescue criteria were met at the same visit: A loss of vision by >5 ETDRS letters (from best previous measurement since baseline, and actual BCVA below baseline values) and Persistence, i.e., no decrease since baseline, or recurrence of subretinal or intraretinal fluid from baseline The final treatment with regorafenib eye drops occurred on the last day before the EOT visit at Study Week 12. After 12 weeks of treatment, subjects entered a 4-week follow-up period. At the start of this period, at the EOT visit, subjects were eligible for treatment with ranibizumab IVT unless the investigator decided that this treatment was not in the best interest of the subject. Subjects returned 4 weeks later, at Study Week 16 for the end-of-study (EOS) visit to undergo final efficacy and safety assessments. Interim evaluation period: The Steering Committee was tasked with the review of safety and efficacy data from Part A and to make a recommendation on (1) whether to continue the study by proceeding to Part B and (2) which doses / dosing regimens to test in Part B. Based on the results and the recommendation, the sponsor made the decision to prematurely terminate the study after Part A as the pre-defined PoC criteria were not met and the available data did not justify going into the dose finding part of the study (Part B). Part B: This part of the study was not started following evaluation of the efficacy and safety data from Part A. The Steering committee decided not to recommend initiation of Part B of the study and the sponsor decided not to continue the study because the pre-defined PoC criteria were not met.
29 OCT 2015 BAY no. 73-4506 / IMPACT no. 15984 Page: 5 of 9 Study center(s): Publication(s) based on the study (references): 27 study centers in 7 countries: 1 site in Switzerland, 4 sites in the Czech Republic, 2 sites in Germany, 7 sites in Spain, 3 sites in France, 5 sites in Hungary and 5 sites in Israel. None at the time of report creation. Study period: First subject, first visit: 10 OCT 2014 Last subject, last visit: 17 JUN 2015 Early termination Yes. The pre-defined PoC criteria were not met in Part A. Number of subjects: Planned: Part A: Approximately 50 subjects were to receive treatment Analyzed: Part B: Approximately 70 subjects per treatment arm (number of treatment arms were to be determined following the analysis of data collected in Part A) Part A: 51 subjects (52 assigned to treatment) Part B: Not applicable due to early termination of the study. More details are given in the section on study subjects below. Criteria for evaluation Efficacy Primary The primary efficacy variable was the change from baseline in best corrected visual acuity (BCVA) as measured by Early Treatment Diabetic Retinopathy Study (ETDRS) letter score at Study Week 4 and Study Week 12. Secondary The proportion of subjects with individual changes in BCVA of 0 letters of vision from Study Week 4 to Study Week 12. The proportion of subjects with a loss of 10 letters from Baseline to Study Week 12. Exploratory The number and proportion of subjects with categorized gains and losses (0, 5, 10, 15 letters of vision) at Study Week 4 and Study Week 12
29 OCT 2015 BAY no. 73-4506 / IMPACT no. 15984 Page: 6 of 9 Clinical pharmacology: Safety: Other: Statistical methods: Change in BCVA from baseline to Study Week 16 The percentage of subjects who achieved complete fluid reduction in the retina (dry retina) as assessed by OCT at Study Week 4 Change in central retinal thickness (CRT) from baseline to Study Week 4 and to Study Week 12 and to Study Week 16 Change from baseline in CNV area at Study Week 4 The effect on BCVA and OCT / FA / FP parameters at Study Week 12 compared to Study Week 4 Time to rescue treatment The number of subjects requiring rescue treatment for the study eye up to Study Week 4 and Study Week 12 Pharmacokinetics Plasma concentrations of regorafenib (BAY 73-4506) and its metabolites M-2 (BAY 75-7495) and M-5 (BAY 81-8752) were determined at the times given in the schedule of procedures using a validated liquid chromatography-mass spectrography (LC-MS / MS) method. Safety assessments included the recording and evaluation of clinical AEs, as well as ophthalmic examinations, ECGs, safety laboratory measurements and vital signs. Not applicable due to the early termination of the study. All efficacy variables captured during the study were analyzed descriptively or displayed in patient listings. All analyses were conducted on the full analysis set (FAS) (primary) and the per protocol set (PPS). The analysis of safety variables will be conducted on the safety analysis set (SAF) population. Frequency tables will be used for subject counts to analyze adverse events. The frequency tables will be based on data that have been classified using the MedDRA coding system.
29 OCT 2015 BAY no. 73-4506 / IMPACT no. 15984 Page: 7 of 9 Substantial protocol changes: Protocol Amendment 1, dated 18 FEB 2015 was amended to reflect the following changes in the study clinical procedures and data handling: Addition of subfoveal fibrosis in exclusion criteria Clarification of the exclusion of subjects requiring steroid treatment Deletion of controlled glaucoma as an exclusion criteria Implementation of a satisfaction and tolerability questionnaire Inclusion of a description of how ranibizumab will be used (according to the label) Clarification of flow chart description of timing of pharmacokinetic sampling Implementation of additional pregnancy testing in Part B at baseline, Week 4, Week 8, EOT (or early termination), and EOS Clarification of timing of database closures Local Protocol Amendment 2 for Japan, dated 24 APR 2015 made the following changes to the study to adhere to the requirements and advice of the Pharmaceutical and Medical Devices Agency (PMDA): Modification of the following exclusion criteria: o Exclusion criteria 19, to add hypothyroidism as an example of excluded metabolic dysfunctions o Exclusion criteria 27, to specify that women could only be considered as not being of child-bearing potential if they were amenorrheic for at least 12 months with no other medical reason for amenorrhea except for being postmenopausal. Addition of a definition for the AE intensity classifications (ie, mild, moderate, severe). Study subjects A total of 89 subjects were enrolled after signing the informed consent form. There were 37 subjects who failed screening; 52 subjects completed screening and were assigned to treatment, however, 1 subject was excluded from the primary analysis sets due to protocol deviations which indicated GCP non-compliance leaving 51 subjects in the FAS and the SAF.
29 OCT 2015 BAY no. 73-4506 / IMPACT no. 15984 Page: 8 of 9 There were slightly more females in the study than males (29 females vs. 22 males). The subjects were aged between 58 and 90 with a mean age of 75.0 years (median 76.0). A total of 27 subjects (51.9%) completed the treatment, 48 subjects (92.3%) completed the study and 4 subjects (7.7%) did not complete the study. Efficacy evaluation The efficacy of the study drug was not considered sufficient to proceed to Part B of the study because the efficacy evaluation did not meet pre-defined PoC criteria. Administration of study drug showed no beneficial effects on BCVA or on OCT/CRT. For primary efficacy, the data shows a decrease in the mean ETDRS letter score from Study Week 4 through Study Week 12 and a slight increase to Study Week 16 following IVT injection of rescue medication, with similar results for the OC analysis, repeated measurements model and multiple imputations analysis. In the primary analysis set, FAS (LOCF), the baseline mean ETDRS letter score was 59.04(±12.04) letters with a slight increase to Study Week 4 to 60.22(±12.80) letters and a decrease at Study Week 12 to 56.68(±13.54) letters. The mean change from baseline in letter score was increased by 1.18 ± 7.55 letters at Study Week 4 and at Study Week 12 was decreased by -2.36 ± 7.68 letters. For the mean change in letter score, the sensitivity analyses (ie, observed case analysis, repeated measurements model and multiple imputations analysis) showed similar results. The proportion of subjects with individual changes in BCVA of 0 letters of vision decreased during treatment. From Study Week 4 to Study Week 12 for the FAS (LOCF) set, the proportion of subjects with individual changes in BCVA of 0 letters was 21 of 50 subjects, 42.0% (90% CI: 30.1%, 54.6%). The proportion of subjects with a loss in BCVA 10 letters from baseline increased from Study Week 4 to Study Week 12. From Study Week 4 to Study Week 12, the proportion of subjects with a loss in BCVA 10 letters from baseline was 8 of 50 subjects, 16.0% (90% CI: 8.2%, 27.0%). There was no indication that the lack of efficacy was due to compliance issues based on plasma levels which increased within one week of treatment with regorafenib eye drops to geometric mean values of 3.4 µg/l with considerable variability (coefficient of variation about 90%) and remained virtually at that level over the entire study period. Following the administration of ranibizumab via IVT injection, which is approved for this indication, the subjects showed the expected improvement in their conditions. Safety evaluation There were no concerns with the safety profile of the study drug. Of the 51 subjects in the SAF analysis set, a total of 34 subjects (66.7%) had a treatment emergent adverse event. Twenty-three subjects (45.1%) experienced any ocular TEAEs, 21 subjects (41.2%) in the study eye and 8 subjects (15.7%) in the fellow eye. Eighteen subjects (35.3%) had any nonocular TEAE. A total of 9 subjects (17.6%) had any drug related TEAE, with 8 subjects
29 OCT 2015 BAY no. 73-4506 / IMPACT no. 15984 Page: 9 of 9 (15.7%) experiencing a drug related ocular TEAE, all in the study eye and 2 subjects (3.9%) experiencing a drug related non-ocular TEAE. Only one subject (2.0%) experienced an injection procedure related TEAE; an ocular TEAE in the study eye. Six subjects (11.8%) experienced a protocol required procedure related TEAE of which 3 subjects (5.9%) had protocol required procedure related ocular TEAEs occurring in the study eye and 3 subjects (5.9%) had a protocol required procedure related non-ocular treatment-emergent AE. Most subjects experienced TEAEs with a maximum intensity of mild; 13 subjects (25.5%) who experienced any ocular TEAEs; 12 subjects in the study eye and 6 subjects in the fellow eye. Thirteen (25.5%) subjects experienced any non-ocular TEAEs of mild intensity. Nine subjects (17.6%) experienced ocular TEAEs of moderate intensity; 8 subjects in the study eye and 2 subjects in the fellow eye. Four subjects (7.8%) experienced non-ocular TEAEs of moderate intensity. One subject (2.0%) experienced an ocular TEAE in the study eye and 1 subject (2.0%) a non-ocular TEAE of severe intensity. There were 3 subjects (5.9%) with treatment-emergent serious adverse events (SAEs). One subject (2.0%) experienced an ocular treatment-emergent SAE occurring in the study eye and 2 subjects (3.9%) experienced a non-ocular treatment-emergent SAE. There were no drug related SAEs, injection procedure related SAEs, or protocol required procedure related SAEs. Eight subjects (15.7%) had AEs leading to discontinuation of the study drug and 1 subject (2.0%) died due to an SAE in the study. In regards to the ophthalmic examination (indirect ophthalmoscopy, refraction, slit lamp biomicroscopy, IOP) and ECG evaluation, there were no significant pathological findings. Overall conclusions Following evaluation of the efficacy and safety data from Part A of this study by the Steering Committee as specified in the protocol, the committee decided not to recommend initiation of Part B of the study. The sponsor decided not to continue the study, because the pre-specified success criteria for proof of concept were not met and the efficacy was considered insufficient to proceed to Part B. Therefore, this study was prematurely terminated following completion of Part A. The positive results of the preclinical studies did not translate into similar results when the drug was administered to humans. PK assessments indicated that compliance was not an issue in the study. Although subjects included in the study showed higher lesion sizes compared to published studies, this did not appear to impede the response to the IVT injection rescue treatment approved for this indication. Administration of study drug showed no beneficial effects on BCVA or on OCT/CRT.