The FDA and Opus Genetics, Inc. have agreed to a special protocol assessment (SPA) for the company’s phase 3 clinical trial evaluating its lead retinal investigational candidate targeting nonproliferative diabetic retinopathy (NPDR): APX3300.
Before we get to this SPA … refresh me on the latest Opus Genetics developments.
First and foremost: The company was most recently (October 2024) relaunched as a combined entity following the (now former) Ocuphire Pharma purchasing the Raleigh, North Carolina-headquartered, clinical-stage gene therapy company.
- The merger combined the former Opus Genetics’ therapeutic inherited retinal disease (IRD) pipeline with Ocuphire’s product pipeline of phentolamine for presbyopia and night vision disturbances (and we can’t forget its already-FDA-approved RYZUMVI for the reversal of mydriasis).
- Of interest: APX3300 (our topic interest) was originally developed by Ocuphire.
Interesting indeed. Now explain this SPA.
As dictated by the FDA, SPA is a process in which companies develop a specific investigational candidate (in this case: APX3300) and request a meeting with the federal agency to come to an agreement on the design / size specifications of certain clinical trials (in this case: that aforementioned phase 3 study).
- The purpose behind this: Essentially, an SPA is established in order to determine whether a company’s planned clinical trial “adequately addresses scientific and regulatory requirements that could support market approval.”
An important note: An SPA agreement doesn’t necessarily guarantee the FDA will accept the filing of a new drug application (NDA) or biologics license application (BLA), or that the respective trial results will support regulatory approval.
Next: Talk about APX3300.
APX3300 is a twice-daily, small-molecule inhibitor of reduction oxidation effector factor-1 protein (Ref-1) administered as an oral supplement.
- Refresh: Ref-1 has a key role in repairing DNA as well as reduction-oxidation activities.
Take note: Via a multimodal mechanism of action (MOA), APX3300 is able to block Ref-1 and, as a result, manage the downstream pathways regulated by Ref-1:
- Angiogenesis (vascular endothelial growth factor [VEGF])
- Oxidative stress (Nrf2)
- Inflammation (NFkB)
And by doing this: The candidate aims to restore homeostatic levels of these three pathway factors, all of which are involved in such ocular diseases as:
- DR
- Diabetic macular edema (DME)
- Age-related macular degeneration (AMD)
What else should we know about this candidate?
In its Q3 2024 financial results report, Opus Genetics stated that it intends to seek out a strategic partner to further advance APX3300’s late-stage development.
No word since then on how that search is going—although the company reiterated its intent in this latest announcement—so stay tuned for more information later this year (we hope).
Interesting … so how has it performed in clinical trials so far?
Prior to this upcoming phase 3 study (which we’ll discuss in a moment), the candidate’s most recent clinical data was reported last year from the ZETA-1 study, a randomized, double-masked, placebo-controlled phase 2 trial (NCT04692688).
- Its participants: A total of 103 patients diagnosed with moderately severe to severe NPDR or mild proliferative DR (MPDR) were randomized into two groups to receive either daily APX3300 or a placebo.
The data:
- Reported in January 2023 (by the then-Ocuphire): The study failed to meet its primary endpoint (% of patients with a ≥ 2-step improvement in Diabetic Retinopathy Severity Scale (DRSS) at Week 24 in the study eye)
- However: APX3330 achieved a statistically significant reduction in disease progression at 24 weeks (see more data here).
- Reported in May 2024: A post-hoc analysis found no participants in the APX3330 group “had a ≥ 4-step worsening at Week 24 compared to 15.2% in the placebo group, representing a 100% reduction between groups (p=0.07) (see here for more data).
- Plus: APX3300 demonstrated a favorable safety profile
Sounds promising … now what do we know about this phase 3 study?
Not much, to be honest. Similar to the phase 2 ZETA-1 trial, this study will be evaluating the use of oral APX3300 for treating moderate-to-severe NPDR.
- Its agreed upon primary endpoint: A reduction in 3-step or greater worsening on the binocular DRSS score compared to placebo.
No word yet on the number of NPDR participants, study design (although we know it was approved by the FDA), or the dosing initiation and target completion date.
And what’s the potential significance?
If successful, the phase 3 trial would support an eventual new drug application (NDA) submission of APX3300 for market approval—becoming a "transformative treatment option for patients with NPDR,” according to Opus Genetics CEO George Magrath, MD.
As always, stay tuned for further updates!
Gotcha. Now talk about this NORSE EIGHT trial.
The trial is designed as a randomized, controlled, parallel-group, masked, non-inferiority study that has set a target enrollment of an estimated 400 newly diagnosed wet AMD patients.
Participants will be randomized 1:1 to receive either of the following, administered via intravitreal injections:
- 1.25 mg ONS-5010
- 0.5 mg ranibizumab
Injections will be administered at Day 1, Week 4, and Week 8 visits.
What’s being measured?
Per Outlook, the primary endpoint, measured from baseline to Week 8, will be the mean change in best-corrected visual acuity (BCVA).
So what’s the intended endgame for this?
Pending the trial’s success, it would meet the FDA’s requirement as the second clinical trial to “address fully the clinical deficiency outlined in the [CRL],” according to the company.
And when can we expect a data readout?
Topline results—as well as a potential resubmission of ONS-5010’s BLA—are anticipated by the end of 2024.
Any other updates to know about?
Just this…
Outlook also revealed it has entered into a definitive securities purchase agreement with both institutional and accredited investors to secure up to $172 million in gross proceeds.
Why is that important?
“We believe that the funds we expect to receive in this financing will position Outlook Therapeutics to support the ONS-5010 development pathway through potential FDA approval and launch,” stated Russell Trenary, president and CEO.