Opthea Limited released topline data from the pivotal phase 3 COAST trial evaluating sozinibercept (OPT-302) for the treatment of wet age-related macular degeneration (AMD).
Word to the wise: It’s less-than-stellar news for the company’s lead investigational candidate.
First thing’s first: sozinibercept.
Referred to as an anti-vascular endothelial growth factor (VEGF) “trap” agent, sozinibercept is specifically designed to be used in combination with standard-of-care anti-VEGF therapies.
What it does: The candidate blocks and sequesters VEGF-C and VEGF-D (which are both activated during wet AMD) to, in turn, prevent the activation of VEGF receptors 2 and 3.
How it does this: Sozinibercept is used in combination with a VEGF-A inhibitor
- Why this is important: When activated, VEGF receptors 2 and 3 play key roles in wet AMD development via abnormal growth (choroidal neovascularization) and leakage of blood vessels.
And how does this mechanism of action differ from current wet AMD therapies?
The main difference: Current wet AMD therapeutics on the market—including ranibizumab (Lucentis; Genentech) and aflibercept (Eylea; Regeneron Pharmaceuticals)—block the effects of VEGF-A.
- Conversely (and as we mentioned above): Sozinibercept uses these VEGF-A inhibitors to block the signaling pathways of VEGF-C and VEGF-D.
Even further: Opthea has noted the candidate is “the first and only drug with strong clinical evidence demonstrating visual acuity (VA) superiority” when used in combo with an anti-VEGF-A therapy for wet AMD—while also presenting with a well tolerated safety profile.
Speaking of clinical data … what else have investigations found so far?
Phase 2b trial data (NCT03345082) reported in February 2023 was based on an evaluation of two varying doses of sozinibercept (0.5 mg and 2.0 mg) + ranibizumab administered via intravitreal (IVT) injection once every month (EM) versus ranibizumab alone for 6 months.
The findings: The study met its primary endpoint, with the sozinibercept + ranibizumab combo demonstrating superiority in VA at 24 weeks over ranibizumab.
- Specifically: Vision gains of 10+ letters and anatomical improvements in reducing vascular leakage and improved retinal drying.
Sounds promising…now to this phase 3 trial.
The multicenter, double-masked, sham-controlled Combination OPT-302 with Aflibercept Study Trial (COAST) study (NCT04757636) evaluated sozinibercept (2 mg) + aflibercept (2 mg) versus aflibercept (2 mg) alone.
- The participants: Approximately 990 wet AMD patients (aged 50+; see criteria here)
And the setup?
Three cohorts received varying combination dosings:
- 2.0 mg aflibercept + sozinibercept 2.0 mg
- Aflibercept administered at 4 weekly intervals for three treatments (12 weeks), then at 8 weekly intervals (40 weeks)
- Sozinibercept 2.0 mg administered at 4 weekly intervals (52 weeks)
- 2.0 mg aflibercept + extended dosing of sozinibercept 2.0 mg
- Aflibercept + sozinibercept administered at 4 weekly intervals for three treatments (12 weeks), then at 8 weekly intervals (40 weeks)
- Sham + aflibercept combination administered at visits when sozinibercept was not
- 2.0 mg aflibercept with sham
- Aflibercept administered at 4 weekly intervals for three treatments (12 weeks), then at 8 weekly intervals (40 weeks)
- Sham administered at 4 weekly intervals
The primary endpoint: Mean change in Early Treatment Diabetic Retinopathy Scale (ETDRS) best-corrected visual acuity (BCVA) letters, measured at baseline to Week 52.
- See here for secondary outcomes.
At long last: the findings.
We’ll just cut straight to the chase: The study failed to meet its primary endpoint.
As for “why” this was the case … a few reasons were given. First, we’ll look at wet AMD patients with minimally classic and occult lesions:
- Participants receiving sozinibercept + aflibercept every 4 (n = 296) or 8 weeks (n = 297) achieved a mean change in BCVA of 13.2 or 13.2 letters from baseline to week 52, respectively (p-value = 0.59)
- Comparatively: Patients receiving aflibercept alone (n = 299) achieved 13.8 letters from baseline to week 52 (p-value = 0.62 )
And for the overall population?
In all, patients receiving sozinibercept + aflibercept—dosing regimen of every 4 weeks (n = 333) or 8 weeks (n = 330)—achieved a mean change BCVA of 13.5 and 12.8 letters from baseline to week 52 (respectively; p-value = 0.86).
- As for the aflibercept-alone group: Patients achieved 13.7 letters (n = 330; p-value = 0.42)
And take note: No differences were observed for the key secondary endpoints (with sozinibercept + aflibercept being well tolerated).
So…what has the company determined based on this data?
To start: Opthea reported it has been assessing its rights and obligations based on its development funding agreement (DFA; a contract that dictates the terms and conditions for financing a development project) with investors of sozinibercept’s clinical development.
- A potential outcome: The company could be required to pay these investors (as compensation for their funding) enough to have “a material adverse impact on the (company’s) solvency.”
And if that were to happen?
Opthea would need to pay its investors up to “four multiples of the amounts paid to the company” under its DFA.
Yikes. What would necessitate the DFA to be terminated?
A few factors could trigger the move (along with their corresponding amounts Opthea would need to repay):
- An inability for Opthea to fund its sozinibercept development costs
- Repayment amount: $229.5 million
- Opthea’s failure to continue to use “commercially reasonable efforts” to develop the therapeutic
- Repayment amount: $467.5 million
- A disagreement between the company and its DFA investors
- Repayment amount: $680 million
Double yikes … so what has Opthea decided to do?
In a nutshell: Nothing yet.
While the company and its DFA investors are reportedly “in active discussions” to explore potential options and next steps following the COAST study’s lackluster data, no decision has been made.
- Also: Opthea did offer a few options for what could happen (see here).
Got it. And what happens in the meantime?
Keeping with the theme … the company stated that “no decision has yet been taken with respect to either trial, including whether to discontinue activities for the COAST trial or accelerate and unmask the ShORe trial.”
Refresh: The ShORe (Study of OPT-302 in combination with Ranibizumab [NCT04757610]) trial is the second of Opthea’s two phase 3 studies (the other being COAST, obviously) on sozinibercept.
- Unlike COAST (which analyzed sozinibercept + aflibercept), ShORe is evaluating sozinibercept + ranibizumab.
Is data expected to be released from that trial soon?
Indeed! As Opthea previously reported, the company expects to release ShORe findings mid-year.