NORSE EIGHT

18 evidence topics · 5 sources

Objective

Second pivotal trial supporting the NORSE TWO efficacy finding

“In a multicenter, randomized, masked, controlled study (NORSE EIGHT – NCT06190093), 400 adult patients with nAMD were randomized (1:1) to LYTENAVA 1.25 mg or ranibizumab 0.5 mg, administered every 4 weeks for 3 total doses (Day 0, Week 4, and Week 8). The primary efficacy endpoint was the mean change in baseline BCVA as measured by ETDRS score at Week 8 using a non-inferiority (NI) margin of -3.5 letters.” (opens the prescribing information at this quote)

“Safety and Effectiveness of ONS-5010 Compared to Lucentis® in Subjects With Neovascular Age-related Macular Degeneration; NORSE EIGHT” (opens the source at this quote in a new tab)

Location and study date

NORSE EIGHT trial dates and location

Field	Quoted record
Study Start Date	“2024-01-24”
Primary Completion Date	“2024-11-07”
Study Completion Date	“2024-12-05”
Overall Status	“Completed”
Country	“United States”

Study design

NORSE EIGHT study design

Field	Quoted record
Allocation	“N/A”
Intervention Model	“Parallel Assignment”
Masking	“Triple”
Who Masked	“Participant”, “Investigator”, “Outcomes Assessor”
Primary Purpose	“Treatment”
Phase	“Phase 3”
Enrollment	“400”

Eligibility criteria

NORSE EIGHT 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 35-75 letters read (20/32 to 20/200 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)
“Current vitreous hemorrhage 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

NORSE EIGHT treatment regimens

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

“In a multicenter, randomized, masked, controlled study (NORSE EIGHT – NCT06190093), 400 adult patients with nAMD were randomized (1:1) to LYTENAVA 1.25 mg or ranibizumab 0.5 mg, administered every 4 weeks for 3 total doses (Day 0, Week 4, and Week 8).” (opens the prescribing information at this quote)

Study outcomes

Rationale for using mean change in ETDRS best corrected visual acuity as the primary endpoint

Primary endpoint design as a non-inferiority comparison

“The primary efficacy endpoint was the mean change in baseline BCVA as measured by ETDRS score at Week 8 using a non-inferiority (NI) margin of -3.5 letters.” (opens the prescribing information at this quote)

Primary endpoint: mean change in ETDRS BCVA from baseline at Week 8

“Evaluate the Effectiveness of Intravitreal Injections of ONS-5010 Compared to Ranibizumab in Preventing Vision Loss, as Measured by the Mean Change in Baseline Best Correct Visual Acuity (BCVA) at Week 8” (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 mean change in baseline BCVA as measured by ETDRS score at Week 8 using a non-inferiority (NI) margin of -3.5 letters.” (opens the prescribing information at this quote)

Anatomic (pharmacodynamic) outcome: central retinal/foveal thickness

“Changes in CFT were assessed using optical coherence tomography in NORSE TWO and NORSE EIGHT [see Clinical Studies (14)]. Increasingly greater reductions in CFT were observed at Weeks 4, 8, and 12 across both treatment arms. Anatomic data were not used to influence LYTENAVA treatment decisions.” (opens the prescribing information at this quote)

Statistical analysis description

Number of participants (Planned and analyzed)

NORSE EIGHT enrollment and randomization

“In a multicenter, randomized, masked, controlled study (NORSE EIGHT – NCT06190093), 400 adult patients with nAMD were randomized (1:1) to LYTENAVA 1.25 mg or ranibizumab 0.5 mg” (opens the prescribing information at this quote)

NORSE EIGHT non-inferiority result

“NORSE EIGHT did not meet its pre-specified NI margin of -3.5 letters in mean change from baseline BCVA at Week 8 compared to ranibizumab.” (opens the prescribing information at this quote)

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

Summary: baseline visual acuity

The LYTENAVA arm had a mean baseline BCVA of 58.8 ETDRS letters.

Efficacy results

Summary: preliminary topline Week 8 result (November 2024 announcement)

Before the label's final analysis, the company's preliminary topline announcement reported a mean BCVA increase of “+4.2 letters” for ONS-5010 versus “+6.3 letters” for ranibizumab at Week 8, a difference it described as “-2.257 BCVA letters” (95% CI -4.044, -0.470); these preliminary figures differ slightly from the final Week 8 result in the approved label (Section 3.1.2.8.3 above).

Summary: BCVA gains over time and anatomic response

Mean BCVA improved progressively from baseline for the LYTENAVA arm: approximately +3.3 letters at month 1 (week 4), +4.2 letters at month 2 (week 8), and +5.5 letters at month 3 (week 12). Central retinal thickness decreased by approximately 123.9 microns in the LYTENAVA arm and 127.3 microns in the ranibizumab arm at week 12, an anatomic response the companies described as comparable between arms.

NORSE EIGHT week 8 BCVA result

“At Week 8, the LYTENAVA group had a mean increase in BCVA of 3.3 compared to a mean increase of 4.5 in the ranibizumab group. The LS mean difference and 95% CI was -2.3 (-4.0, -0.5). LYTENAVA showed an increase from baseline in BCVA at Week 12 consistent with NORSE TWO.” (opens the prescribing information at this quote)

“At Week 8, the LYTENAVA group had a mean increase in BCVA of 3.3 compared to a mean increase of 4.5 in the ranibizumab group.” (opens the prescribing information at this quote)

Week 12 visual acuity (non-primary timepoint)

“The difference in mean BCVA between ONS-5010 and ranibizumab was -1.009 letters (95% confidence interval, -2.865, 0.848), meeting the noninferiority margin at Month 3 (p=0.0043)” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

NORSE EIGHT ocular adverse events

“ONS-5010 was generally well-tolerated with overall ocular adverse event rates comparable to ranibizumab.” (opens the source at this quote in a new tab)
“no cases of retinal vasculitis reported in either study arm” (opens the source at this quote in a new tab)

“consistent with previously reported safety results from the NORSE ONE, NORSE TWO, and NORSE THREE clinical trials” (opens the source at this quote in a new tab)

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

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%”

Study limitations

Summary: primary endpoint not met at the pre-specified timepoint

NORSE EIGHT did not meet its pre-specified non-inferiority margin of -3.5 letters for the primary endpoint of mean change in BCVA at Week 8, although the LS mean difference at Week 12 (a secondary, non-primary timepoint) was within the non-inferiority margin.