Pivotal efficacy and safety trial supporting the nAMD indication

“The efficacy of LYTENAVA for the treatment of neovascular (wet) age-related macular degeneration (nAMD) was demonstrated in a randomized, multi-center, masked, active-controlled study (NORSE TWO – NCT03834753).” (opens the prescribing information at this quote)

“This was a prospective multicenter, randomized, double-masked, active-controlled study, the aim of which was to demonstrate the efficacy and safety of intravitreal ONS-5010 (bevacizumab-vikg) in eyes with neovascular age-related macular degeneration (nAMD). This was a phase III trial on ONS-5010 (NORSE TWO).” (opens the source at this quote in a new tab)

Summary: number of trial sites

The company's own announcement of the 12-month NORSE TWO results described the trial as enrolling 228 subjects across 39 clinical trial sites in the United States.

NORSE TWO trial dates and location

Field	Quoted record
Study Start Date	“2019-06-25”
Primary Completion Date	“2021-06-07”
Study Completion Date	“2021-07-08”
Overall Status	“Completed”
Country	“United States”

NORSE TWO study design

“A Clinical Effectiveness, Multicenter, Randomized, Double-masked, Controlled Study of the Efficacy and Safety of ONS-5010 in Subjects With Subfoveal Choroidal Neovascularization (CNV) Secondary to Age-related Macular Degeneration” (opens the source at this quote in a new tab)

Field	Quoted record
Allocation	“Randomized”
Intervention Model	“Parallel Assignment”
Masking	“Double”
Who Masked	“Participant”, “Outcomes Assessor”
Primary Purpose	“Treatment”
Phase	“Phase 3”
Enrollment	“228”

“In NORSE TWO, adult patients with nAMD were randomized to LYTENAVA 1.25 mg (N=113) administered once monthly for 1 year or ranibizumab 0.5 mg (N=115) administered once monthly for 3 months (Days 0, 30, and 60) followed by once every 3 months for 1 year (Days 150 and 240). Patient ages ranged from 54 to 98 years, with a median age of 79 years.” (opens the prescribing information at this quote)

NORSE TWO eligibility criteria

“Active primary Subfoveal Choroidal Neovascularization lesions secondary to Age-related macular degeneration (AMD) in the study eye” (opens the source at this quote in a new tab)
“Best corrected visual acuity of 25-67 letters read (20/50 to 20/320 Snellen equivalent)” (opens the source at this quote in a new tab)
“Have active leakage on Fluorescein Angiogram involving the fovea” (opens the source at this quote in a new tab)
“Have edema involving the fovea” (opens the source at this quote in a new tab)
“Be free of scarring, fibrosis, or atrophy involving the central foveal zone” (opens the source at this quote in a new tab)
“Previous subfoveal focal laser photocoagulation in the study eye” (opens the source at this quote in a new tab)
“Active intraocular inflammation (grade trace or above) in the study eye” (opens the source at this quote in a new tab)
“Current vitreous haemorrhage in the study eye” (opens the source at this quote in a new tab)
“Polypoidal choroidal vasculopathy (PCV) in the study eye” (opens the source at this quote in a new tab)
“Uncontrolled glaucoma in the study eye (defined as intraocular pressure ≥30 mmHg despite treatment with anti-glaucoma medication)” (opens the source at this quote in a new tab)

“Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included.” (opens the source at this quote in a new tab)

NORSE TWO treatment regimens

“Patients randomized to ONS-5010 received monthly intravitreal doses of 1.25 mg of ONS-5010, bevacizumab-vikg (Outlook Therapeutics) for 12 months. Patients randomized to ranibizumab received 0.50 mg of ranibizumab on days 0, 30, 60, 150, and 240 based on the PIER study dosing regimen.” (opens the source at this quote in a new tab)

Field	Quoted record
Bevacizumab (ONS-5010) dose	“1.25 mg, intravitreal injection”
Ranibizumab dose	“0.5mg, intravitreal injection”

Primary endpoint statistical result

“Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052.” (opens the source at this quote in a new tab)

Primary endpoint: proportion gaining 15 or more ETDRS letters at 11 months

“Proportion of Subjects Who Gain 15 or More Letters in Best Corrected Visual Acuity (BCVA)” (opens the source at this quote in a new tab)
“BCVA to be assessed as letters read using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts. A positive change represents an improvement in visual acuity.” (opens the source at this quote in a new tab)

“The primary efficacy endpoint was the proportion of patients who gained ≥ 15 Best Corrected Visual Acuity (BCVA) letters from baseline to Month 11 as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score. The difference observed between the study drug groups was significant, in favor of LYTENAVA (see Table 2).” (opens the prescribing information at this quote)

Secondary endpoints

“Mean Change in the Best Corrected Visual Acuity” (opens the source at this quote in a new tab)
“Proportion of Participants Who Gain at Least 10 Letters in the Best Corrected Visual Acuity” (opens the source at this quote in a new tab)
“Proportion of Participants Who Gain at Least 5 Letters in the Best Corrected Visual Acuity” (opens the source at this quote in a new tab)
“Proportion of Participants Who Lose Fewer Than 15 Letters in the Best Corrected Visual Acuity” (opens the source at this quote in a new tab)
“Proportion of Participants With Visual-acuity Snellen Equivalent of 20/200 or Worse” (opens the source at this quote in a new tab)

“The pre-specified secondary efficacy endpoint of mean change in BCVA from baseline to Month 11 favored LYTENAVA once monthly compared to ranibizumab administered once monthly for 3 months then every 3 months and is displayed over time in Figure 1.” (opens the prescribing information at this quote)

Summary: number of trial sites

The company's own announcement of the 12-month NORSE TWO results described the trial as enrolling 228 subjects across 39 clinical trial sites in the United States.

NORSE TWO participants analyzed by arm

Field	Ranibizumab 0.5 mg Once Monthly x 3 Months then every 3 Months (N = 115)	LYTENAVA 1.25 mg Once Monthly (N = 113)
Number of subjects, n/N (%)	“24/104 (23.1)”	“45/108 (41.7)”
Risk difference		“0.1859”
95% CI		“0.0442, 0.3086”

NORSE TWO statistical results summary

Field	Quoted record
Risk difference	“0.1859”
95% CI	“0.0442, 0.3086”

Summary: intent-to-treat and per-protocol analyses

The company's own 12-month results announcement described the primary endpoint as met in both an intent-to-treat (ITT) primary dataset (23% ranibizumab vs. 41% bevacizumab-vikg, p=0.0052) and a secondary per-protocol (PP) dataset (24% ranibizumab vs. 41% bevacizumab-vikg, p=0.04).

NORSE TWO analysis set composition

“One hundred thirteen participants were included in the ONS-5010 group and 115 participants were included in the ranibizumab group.” (opens the source at this quote in a new tab)
“All 228 randomized patients were included in the ITT and safety populations (113 patients in the ONS-5010 group and 115 patients in the ranibizumab group), and 163 patients were included in the PP population (85 and 78 patients in the ONS-5010 and ranibizumab groups, respectively).” (opens the source at this quote in a new tab)

NORSE TWO participants included in each arm

“One hundred thirteen participants were included in the ONS-5010 group and 115 participants were included in the ranibizumab group.” (opens the source at this quote in a new tab)

Field	Ranibizumab 0.5 mg Once Monthly x 3 Months then every 3 Months (N = 115)	LYTENAVA 1.25 mg Once Monthly (N = 113)
Number of subjects, n/N (%)	“24/104 (23.1)”	“45/108 (41.7)”

Completion and reasons for discontinuation

“A total of 228 patients were randomized at 39 study centers across the US. Of those, 198 (86.8%) completed the study. The three most frequently reported reasons for study discontinuation were withdrawal of consent (4.8%), AEs (3.5%), and other reasons (1.8%).” (opens the source at this quote in a new tab)
“In the ONS-5010 group, nine patients discontinued the treatment and withdrew from the study (five because of AEs, three lost to follow-up, and one withdrew voluntarily); one patient completed treatment but withdrew from the study; and two patients discontinued treatment but completed the study. In the ranibizumab group, 20 patients discontinued the treatment and withdrew from the study (10 due to voluntary withdrawal, five because of AEs, three because of lack of effectiveness, and three for other reasons); one patient discontinued treatment but completed the study.” (opens the source at this quote in a new tab)

NORSE TWO baseline age

“Patient ages ranged from 54 to 98 years, with a median age of 79 years.” (opens the prescribing information at this quote)

“Treatment-naïve nAMD patients aged 50 years and older with a best-corrected distance visual acuity (BCVA) of 25 to 67 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and evidence of disease activity were included.” (opens the source at this quote in a new tab)

“In the three completed Phase 3 clinical studies, approximately 70% (238/341) of patients treated with LYTENAVA were ≥ 65 years of age and approximately 47 % (160/341) were ≥ 75 years of age. No overall differences in efficacy or safety were seen with increasing age in these studies [see Clinical Studies (14)].” (opens the prescribing information at this quote)

NORSE TWO baseline demographics and disease characteristics

Parameter	Ranibizumab (n = 115)	ONS-5010 (n = 113)
Male, n (%)	“46 (40.0%)”	“46 (40.7%)”
Female, n (%)	“69 (60.0%)”	“67 (59.3%)”
Age, mean ± SD	“79.1 ± 8.49”	“78.8 ± 8.30”
White, n (%)	“113 (98.3%)”	“110 (97.3%)”
Asian, n (%)	“1 (0.9%)”	“1 (0.9%)”
Right study eye, n (%)	“51 (44.3%)”	“49 (43.4%)”
Left study eye, n (%)	“64 (55.7%)”	“64 (56.6%)”
Prior anti-VEGF, n (%)	“5 (4.3%)”	“4 (3.5%)”
Baseline BCVA, mean ± SD	“51.1 ± 12.96”	“52.1 ± 12.16”
Baseline CFT (μm), mean ± SD	“423.7 ± 114.77”	“430.0 ± 150.85”

Summary: mean change in best corrected visual acuity from baseline to Month 11

The company's own 12-month results announcement reported that the secondary endpoint of mean BCVA change from baseline to Month 11 was also statistically significant, at p=0.0043 in the intent-to-treat dataset.

NORSE TWO primary endpoint result

Field	Ranibizumab 0.5 mg Once Monthly x 3 Months then every 3 Months (N = 115)	LYTENAVA 1.25 mg Once Monthly (N = 113)
Number of subjects, n/N (%)	“24/104 (23.1)”	“45/108 (41.7)”
Risk difference		“0.1859”
95% CI		“0.0442, 0.3086”

“Respectively, 41.7% and 23.1% of patients gained ≥ 15 letters (3 lines) of visual acuity, with a risk difference of 0.1859 [95% CI = 0.0442, 0.3086]; P = 0.0052. The change in BCVA from baseline to 11 months was found to be 11.2 ± 12.19 and 5.8 ± 14.80 ETDRS letters, respectively. The number of patients gaining ≥ 5 and ≥ 10 letters and patients losing < 15 letters was significantly higher in the ONS-5010 group. Similarly, patients with a Snellen visual acuity equivalent of 20/200 (35 ETDRS letters) or worse at 11 months were significantly fewer in the ONS-5010 group.” (opens the source at this quote in a new tab)

NORSE TWO secondary endpoint responder analysis

Parameter, n/N (%)	Ranibizumab (n = 115)	ONS-5010 (n = 113)
Subjects gaining ≥5 letters from baseline at 11 months	“53/104 (51.0)”	“74/108 (68.5)”
Subjects gaining ≥10 letters from baseline at 11 months	“36/104 (34.6)”	“61/108 (56.5)”
Subjects losing <15 letters from baseline at 11 months	“86/104 (82.7)”	“101/108 (93.5)”
Subjects with a visual acuity Snellen equivalent of 20/200 or worse at 11 months	“25/104 (24.0)”	“14/108 (13.0)”

NORSE TWO mean BCVA change by complementary analysis

“When calculated using the trimmed means fixed approach, the least squares (LS) mean change in BCVA from baseline to 11 months was 19.310 letters in the ONS-5010 group and 14.575 letters in the ranibizumab group (LS mean difference of 4.735 [95% CI = 1.306, 8.163]; P = 0.0035). When calculated using the trimmed means adaptive approach, the LS mean change in BCVA from baseline to 11 months was 13.640 letters in the ONS-5010 group and 5.770 letters in the ranibizumab group. The difference observed between study treatment groups was significant, with an LS mean difference of 7.870 (95% CI = 4.536, 12.599; P = 0.0001).” (opens the source at this quote in a new tab)

Summary: ocular adverse events and inflammation

The company's own 12-month results announcement reported only one subject with an ocular inflammation adverse event following exposure to bevacizumab-vikg, one related ocular serious adverse event in the bevacizumab-vikg arm (which resolved), and conjunctival hemorrhage as the most common ocular adverse event, and described the safety database as consistent with previously published bevacizumab safety results.

NORSE TWO serious ocular adverse event and most common adverse event by arm

“Only one patient in the ONS-5010 group had a study-related serious ocular adverse event (SAE), namely, elevated intraocular pressure. The most common adverse event in the ONS-5010 group was conjunctival hemorrhage (8.8%), and reduced visual acuity in the ranibizumab group (12.2%).” (opens the source at this quote in a new tab)

NORSE TWO treatment-emergent adverse event summary

Criteria	Ranibizumab (n = 115), n (%)	ONS-5010 (n = 113), n (%)
At least 1 TEAE	“85 (73.9%)”	“85 (75.2%)”
At least 1 TEAE related to study drug/study procedure	“9 (7.8%)”	“21 (18.6%)”
At least 1 ocular TEAE	“61 (53.0%)”	“59 (52.2%)”
At least 1 serious TEAE	“16 (13.9%)”	“14 (12.4%)”
At least 1 TEAE leading to discontinuation	“5 (4.3%)”	“2 (1.8%)”

NORSE TWO deaths during the study

“A total of five patients died, including three in the ONS-5010 group and two in the ranibizumab group. The events that resulted in death were COVID-19 and respiratory failure (both occurring in the same patient of the ONS-5010 group), myocardial infarction and death due to COVID-19 (each occurring in different patients of the ONS-5010 group), and cardiac arrest and cardiac death (each occurring in different patients in the ranibizumab group). These events were not considered by the investigators to be related to the study treatment/study procedure.” (opens the source at this quote in a new tab)

Pooled ocular adverse reactions across the LYTENAVA clinical development program (five trials)

“The data described below reflect exposure to LYTENAVA in 601 patients, in five clinical trials [see Clinical Studies (14)].” (opens the prescribing information at this quote)
“Table 1 shows the most common ocular adverse reactions in LYTENAVA treated patients compared with ranibizumab 0.5 mg.” (opens the prescribing information at this quote)

Adverse Reactions	LYTENAVA 1.25 mg (N = 601)	Ranibizumab 0.5 mg (N = 345)
Conjunctival hemorrhage	“4%”	“3%”
Eye pain	“2%”	“1%”
Vitreous floaters	“2%”	“1%”

“Less common ocular adverse reactions reported in the study eye in <1% of patients treated with LYTENAVA were corneal abrasion, dry eye, eye irritation, and intraocular pressure increased.” (opens the prescribing information at this quote)

Summary: comparator dosing regimen

NORSE TWO compared monthly LYTENAVA dosing for one year against a ranibizumab regimen of three monthly loading doses followed by quarterly dosing, rather than against monthly ranibizumab throughout the study.

Authors' rationale for the unequal dosing regimens

“The different dosing regimen between the two groups is not considered a limitation of the study given that the aim of the study was to demonstrate the effect of bevacizumab. One reason for spacing doses in the ranibizumab group was to replicate a more realistic clinical dosing schedule. Furthermore, according to both the IVAN and CATT study, spaced dosing of ranibizumab was shown to be as effective as monthly dosing.” (opens the source at this quote in a new tab)
“While clinicians often treat nAMD with greater frequency than the ranibizumab arm of the NORSE TWO study, the study was designed to meet a regulatory endpoint of comparison to a previously approved treatment dosing regimen in order to demonstrate the existence of a treatment effect for ONS-5010.” (opens the source at this quote in a new tab)

Greater injection frequency as a possible driver of the higher treatment-related adverse event rate

“The frequency of TEAEs considered by the investigators to be related to the study treatment/study procedure was greater in the ONS-5010 group compared with the ranibizumab group (18.6% [21 patients] vs 7.8% [9 patients]). Hypothetically, this may be due to a greater number of injections in the ONS-5010 group (12 injections in the ONS-5010 group versus five injections in the ranibizumab group).” (opens the source at this quote in a new tab)