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A 52 week multicenter, randomized, double masked, 2 arm parallel study to compare efficacy, safety and immunogenicity of SOK583A1 to Eylea, administered intravitreally, in patients with neovascular age related macular degeneration

Phase 3 study assessing the efficacy, safety and immunogenicity of SOK583A1 versus Eylea in patients with neovascular age related macular degeneration

485

A total of 723 subjects were screened. Of these, 485 subjects were randomized, and 484 subjects (99.8%) received study treatment (SOK583: 244 subjects, 99.6%; Eylea EU: 240 subjects, 100%). One subject was randomized by mistake into the SOK583 group and did not receive study treatment. The FAS comprised 483 subjects as 1 subject in the SOK583 group was excluded from the FAS because no post-baseline BCVA was available for the subject. The mean (standard deviation [SD]) age of 483 subjects (FAS) at the time of entry was 75.7 (7.76) years, 210 (43.5%) were male and 273 (56.5%) were female.

Four hundred and thirty-one of the 485 randomized subjects (88.9%) completed treatment, and 438 subjects (90.3%) completed the study. A total of 53 randomized subjects (10.9%) discontinued treatment early, and a total of 47 subjects (9.7%) discontinued the study early. Reasons for early study discontinuation included (but were not limited to) withdrawal by subject (19 subjects, 3.9%), adverse events (7 subjects, 1.4%), physician decision (7 subjects, 1.4%), and death (6 subjects, 1.2%).

No clinically relevant differences in safety and immunogenicity were observed between the SOK583 and Eylea EU groups. In summary, the overall safety profiles observed of SOK583 and Eylea EU in this study were comparable and in accordance with the established safety profile of Eylea. Overall, the TEAE profiles by SOC and PT of ocular TEAEs in the study eye and the fellow eye and of non-ocular TEAEs were comparable between the SOK583 and Eylea EU groups and in accordance with the established safety profile of Eylea. Most PTs were reported by 1 or 2 subjects, and no trends of TEAEs were observed in a treatment group or SOC. Most subjects reported TEAEs of mild or moderate severity (SOK583: 159 subjects, 65.2%; Eylea EU: 154 subjects, 64.2%), and most TEAEs resolved during the study. The proportions of subjects reporting TEAEs related to study treatment (SOK583: 6 subjects, 2.5%; Eylea EU: 7 subjects, 2.9%), ocular TEAEs in the study eye related to study procedure (SOK583: 28 subjects, 11.5%; Eylea EU: 26 subjects, 10.8%), or severe TEAEs (SOK583: 20 subjects, 8.2%; Eylea EU: 20 subjects, 8.3%) were comparable between both treatment groups. The proportions of subjects reporting ocular TEAEs in the study eye were comparable between the SOK583 group (84 subjects, 34.4%) and the Eylea EU group (78 subjects, 32.5%). Most frequently reported ocular TEAEs in the study eye were visual acuity reduced, retinal pigment epithelial tear, and conjunctival haemorrhage. The proportions of subjects reporting non-ocular TEAEs were comparable between the SOK583 group (141 subjects, 57.8%) and the Eylea EU group (141 subjects, 58.8%). Most frequently reported non-ocular TEAEs were COVID-19, hypertension, back pain, and nasopharyngitis. Six deaths occurred in the study, 5 in the SOK583 group and 1 in the Eylea EU. The deaths were considered not related to study treatment by the investigators, generally occurred several weeks after the last treatment received by the subjects and can be attributed to the subjects' medical conditions. There were no clinically relevant differences between the SOK583 and Eylea EU groups in SAEs: - The number and proportions of subjects reporting ocular SAEs in the study eye were comparable between the 2 treatment groups (SOK583: 4 subjects, 1.6%; Eylea EU: 2 subjects, 0.8%). PTs were reported only once except for retinal haemorrhage, which was reported for 2 subjects (0.8%) in the SOK583 group. - Ocular SAEs in the fellow eye (retinal haemorrhage and visual acuity reduced) were reported in the Eylea EU group only. - The number and proportions of subjects reporting non-ocular SAEs were comparable between the 2 treatment groups (SOK583: 35 subjects, 14.2%; Eylea EU: 27 subjects, 11.3%). Most frequently reported PTs were atrial fibrillation and death, all of which were not related to study treatment. There were no clinically relevant differences between the SOK583 and Eylea EU groups in TEAEs leading to discontinuation or in TEAEs according to the risks defined for Eylea in the EU RMP. No clinically relevant differences between the 2 treatment groups were observed for any of the laboratory parameters, the vital signs parameters or in intraocular pressure at any visit, or in changes from baseline in vital signs parameters. The numbers and proportions of subjects of the IAS with immune responses post-baseline were small and similar between the SOK583 group and the Eylea EU group at individual visits and overall up to Week 52 (SOK583: 2 subjects, 0.9%; Eylea EU: 6 subjects, 2.6%). Anti-drug antibodies that developed post-baseline were neutralizing. Anti-drug antibody and neutralizing antibody positive results were not associated with specific TEAEs such as hypersensitivity reactions in any subject.

The study fulfilled its primary objective to demonstrate similar efficacy of SOK583 and Eylea EU in terms of changes from baseline in BCVA score at Week 8. The difference between SOK583 and Eylea EU in the LS mean changes from baseline in BCVA score was -0.3 letters for the PPS; the 95% CI: (-1.8, 1.3) letters and 90% CI: (-1.5, 1.0) letters were contained within the prespecified intervals [-3.5, +3.5] (EMA and PMDA requirement) and [-3.0, +3.0] (FDA requirement). Therefore, therapeutic equivalence in terms of change from baseline in BCVA score was concluded for EMA, PMDA, and FDA requirements. Results from the sensitivity and supplementary analyses of the primary endpoint (differences in LS means of BCVA change from baseline at Week 8 using MMRM model for the PPS and using last observation carried forward (LOCF) methodology and mixed-model repeated measures (MMRM) model for the FAS) corroborate the result of the primary endpoint. Mean changes from baseline in CSFT at Weeks 1, 4, 8, 24, and 52, CNV lesions size at Weeks 8 and 52, and BCVA score at Weeks 24 and 52 were similar between SOK583 and Eylea EU. The results of the secondary efficacy endpoint analyses therefore support the objective to show similar efficacy between the 2 study treatments.

The study met its primary objective, and similar efficacy between SOK583 and Eylea EU was shown. No clinically relevant differences in PK, safety, and immunogenicity were observed between the SOK583 and Eylea EU groups. Overall, the observed safety profile of SOK583 was in line with the established safety profile of Eylea.

Jan. 31, 2024

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210120

Kobayashi Takeshi

Syneos Health Clinical K.K.

27F Shinagawa Season Terrace, 1-2-70 Konan, Minato-ku, Tokyo

takeshi.kobayashi@syneoshealth.com

Kobayashi Takeshi

Syneos Health Clinical K.K.

27F Shinagawa Season Terrace, 1-2-70 Konan, Minato-ku, Tokyo

+81-80-7032-1082

takeshi.kobayashi@syneoshealth.com

Complete

May. 28, 2021

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

1. Signed informed consent must be obtained prior to participation in the study
2. Participants must be 50 years of age or older at Screening
3. Anti VEGF treatment naive patients for either eye and systemically
4. Study eye diagnosed with active CNV lesions (type 1 and/ or type 2) secondary to AMD and/or Retinal Angiomatous Proliferation lesions (type 3), affecting the central subfield. Active CNV lesion is defined by the presence of leakage as evidenced by fluorescein angiography, and intra or subretinal fluid as evidenced by optical coherence tomography, both confirmed by the CRC at Screening
5. Total area of CNV (including both classic and occult components) must comprise > 50% of the total lesion area in the study eye, confirmed by the CRC at Screening
6. BCVA between 73 and 38 letters, both inclusive, in the study eye at Screening and Baseline using ETDRS testing charts
7. Willing and able to comply with all study procedures, and be likely to complete the study
8. Clear ocular media and adequate pupil dilatation in both eyes to permit good quality photographic imaging

1. Previous treatment with any anti VEGF therapy in either eye or investigational drugs in study eye or fellow eye, at any time prior to Baseline
2. Participant has received any approved treatment for nAMD (other than vitamin and dietary supplements) in the study eye and at any time prior the Baseline
3. Presence of other causes of CNV, including pathologic myopia (spherical equivalent of 8 diopters or more negative, or axial length of 25 mm or more), ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, or multifocal choroiditis in the study eye
4. Any active or suspected intraocular or periocular infection or active or suspected intraocular inflammation (e.g. infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) in either eye at Screening or Baseline
5. Subfoveal fibrosis, atrophy, or scarring extending > 50% of total lesion area in the study eye as assessed by the Investigator at Screening and confirmed by the CRC prior to randomization
6. Subretinal hemorrhage that is >= 50% of the total lesion area in the study eye, or if the subretinal hemorrhage involving the fovea is 1 or more disc areas (>= 2.54 mm2) in size in the study eye, as assessed by FA and confirmed by the CRC
7. Retinal pigment epithelium (RPE) rip/tear in the study eye at Screening or Baseline
8. Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 weeks prior to Baseline
9. History or evidence of the following, in the study eye
1)Intraocular (including cataract surgery) or refractive surgery within the 90 day periodprior to Baseline. The yttrium aluminum garnet (YAG) posterior capsulotomy is allowed no later than 4 weeks prior to Baseline
2)Previous penetrating keratoplasty or vitrectomy
3)Previous panretinal photocoagulation
4)Previous photodynamic therapy
5)Previous submacular surgery or other surgical intervention for AMD
6)Retinal detachment or treatment or surgery for retinal detachment
7)Any history of macular hole of stage 2 and above
8)Prior trabeculectomy or other filtration surgery
9)Ocular trauma within 6 months prior to Baseline
10. History of hypersensitivity to any of the study treatments or its excipients, or clinically relevant sensitivity to fluorescein dye, as assessed by the Investigator
11. Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg on medication or according to Investigator judgment at Screening or Baseline
12. Aphakia and/or absence of the posterior capsule in the study eye at Screening or Baseline, unless it occurred as a result of a YAG posterior capsulotomy in association with prior posterior chamber intraocular lens implantation
13. Intra or periocular use of corticosteroids in the study eye within a 6 month period prior to Baseline
14. Use of topical ocular corticosteroids in the study eye for 30 or more consecutive days within the 90 days period prior to Baseline
15. Previous therapeutic radiation near the region of the study eye
16. Concomitant conditions or ocular disorders in the study eye, including media opacities, cataract and diabetic macular edema, at Screening or Baseline which could, in the opinion of the Investigator, prevent response to study treatment or may confound interpretation of study results (efficacy and safety), compromise visual acuity or require medical or surgical intervention during the course of the study
17. Presence of amblyopia, amaurosis or ocular disorders with BCVA <38 letters (ETDRS testing charts) in the fellow eye at Screening (except when due to conditions whose surgery may improve VA, e.g. cataract)
18. Presence of Scleromalacia in either eye
19. Participants requiring anti VEGF treatment of the fellow eye at Baseline will not be eligible for the PK substudy Systemic conditions and treatments
20. Previous systemic treatment with any anti VEGF therapy
21. Use of systemic corticosteroids for 30 or more consecutive days within the 90 days prior to Baseline, with the exception of low stable doses of corticosteroids (defined as <= 10 mg prednisolone or equivalent dose used for 90 days or more prior to Baseline).
22. Uncontrolled blood pressure defined as a systolic value >= 160 mmHg or diastolic value >= 100 mmHg at Screening
23. Stroke or myocardial infarction during the 6 month period prior to Baseline
24. Participation in an investigational systemic drug, biologic, or device study within 30 days or duration of 5 half lives of the investigational product (whichever is longer) prior to Baseline. Note: observational clinical studies solely involving over the counter vitamins, supplements, or diets are not exclusionary
25. Presence of infection at Screening or active infection within 2 weeks before Screening
26. Underlying advanced, severe and uncontrolled concomitant condition (including, but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, inflammatory, infectious or gastrointestinal), physical examination finding, or clinical laboratory finding which in the opinion of the Investigator place the participant at unacceptable risk from participation in the study
27. History of a medical condition (including, but not limited to chronic disease, immunosuppression, metabolic dysfunction, prior exposure to other drugs that may pose risk of infection or allergic reactions) that, in the judgment of the Investigator, would preclude scheduled study visits, completion of the study, or a safe administration of investigational product, or that might affect participant safety or interpretation of the study results.
28. Pregnant or nursing (lactating) women and women of child bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 3 months after stopping the medication. Highly effective contraception methods include
1)Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
2)Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
3)Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant.
4)Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS).

Both

neovascular age-related macular degeneration

SOK583A1 2mg or Eylea EU 2mg, IVT administration

1 Mean change from baseline in BCVA score
using ETDRS testing charts at Week 8
2 Spectral Domain Optical Coherence Tomography (SD-OCT)
3 Color fundus photography and fluorescein angiography

+81-29-887-1161

Nov. 16, 2020

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