ONS-5010 did not demonstrate non-inferior BCVA gains compared to ranibizumab at week 8 in the Phase III NORSE EIGHT trial.
Outlook Therapeutics’ (New Jersey, United States) quest to bring an on-label bevacizumab formulation to neovascular AMD (nAMD) patients has hit a major stumbling block after the company reported disappointing topline data on Wednesday for ONS-5010 (bevacizumab-vikg).
Despite the setback, the company has stated that it still plans to resubmit a biologics licensing application (BLA) for the drug to the FDA in Q1 2025.
ONS-5010 failed to meet its primary non-inferiority endpoint in the Phase III NORSE EIGHT comparing it to ranibizumab. The mean best-corrected visual acuity (BCVA) difference between ONS-5010 and ranibizumab was reported at -2.257 BCVA letters (95% CI; -4.044, -0.470), falling short of the lower prespecified non-inferiority threshold (95% CI; -3.5) and failing to confirm non-inferiority (p>0.025).
Data analysis is ongoing, and the company is still collecting 3-month data from the trial. Complete results are expected in January 2025.
Following the announcement, the company’s stock (NASDAQ:OTLK) fell by as much as 81% in Wednesday trading, reaching a low of $0.87 compared to its Tuesday close of $5.00. Shares in OTLK rebounded by the end of trading Wednesday to close at $1.70.
Bevacizumab fails to match ranibizumab’s efficacy
The NORSE EIGHT Phase III trial compared bevacizumab to a current standard of care for nAMD, ranibizumab. The pre-specified non-inferiority endpoint at week 8 outlined in the Special Protocol Assessment (SPA) with the FDA was measured by the mean change in BCVA from baseline to week 8.
In the intent-to-treat (ITT) primary dataset, NORSE EIGHT demonstrated a mean +4.2 letter improvement in BCVA for bevacizumab and a +6.3 letter improvement in BCVA for ranibizumab. The company also reported the presence of biologic activity in its topline readout.
Though the data indicates an improvement in visual acuity at eight weeks, failure to demonstrate non-inferiority has raised questions about the drug’s viability as an alternative to current nAMD therapies like ranibizumab.
Safety profile of bevacizumab remains favorable
Although bevacizumab failed to meet its primary BCVA endpoint, the safety data from the NORSE EIGHT trial remained consistent with previous studies. The treatment was generally well-tolerated, with ocular adverse event rates comparable to ranibizumab.
Importantly, no cases of retinal vasculitis were reported in either treatment arm, aligning with the favorable safety profile demonstrated in earlier clinical trials, including NORSE ONE, NORSE TWO and NORSE THREE.
Outlook Therapeutics emphasized that additional safety and efficacy data, particularly from the 3-month data set expected in January 2025, will be critical for a more comprehensive assessment of bevacizumab’s potential.
What’s next for bevacizumab and Outlook Therapeutics?
Despite the setback in the NORSE EIGHT trial, Outlook Therapeutics plans to launch bevacizumab (branded as LYTENAVA™) in Germany and the United Kingdom in 2025. The drug has already received the European Commission and MHRA Marketing Authorization for the treatment of wet AMD.
Outlook Therapeutics remains committed to ONS-5010 as a potential treatment for wet AMD, noting that remediation of Chemistry, Manufacturing and Controls (CMC) issues identified in a previous FDA Complete Response Letter (CRL) has been successfully completed. However, the company’s plans to enter the U.S. market could be hampered by the trial’s BCVA results.
As Outlook Therapeutics awaits additional data from the NORSE EIGHT trial, all eyes will be on the upcoming 3-month results and the company’s strategy for securing approval in the U.S. market.
