KOLs eye the future of genetic engineering and cell transplantation

Did you miss last month’s Ophthalmology Technology Forum (OTF)? No need to worry, we’ve got you covered.

This latest industry rundown includes insight from the leading experts within the genetic engineering and cell transplantation sector of the ophthalmic field to the latest—and future—tech to keep in sight.

Let’s start with these experts.

The session’s participants included the following key opinion leaders (KOLs):

Marjan Farid, MD (co-moderator)
- Professor of Ophthalmology, Director of Cornea, Cataract, and Refractive Surgery: Gavin Herbert Eye Institute, University of California, Irvine
Baruch D. Kuppermann, MD, PhD (co-moderator)
- Steinert Endowed Professor, Chair, Department of Ophthalmology, Director: Gavin Herbert Eye Institute, University of California, Irvine
Greg Kunst
- CEO: Aurion Biotech
Jeffrey L. Goldberg, MD, PhD
- Co-Founder and Director, Board of Managers: Emmecell
- Professor and Chair of Ophthalmology: Byers Institute, Stanford University
John S. Pollack, MD
- CMO: jCyte, Inc.
Richard Small
- CEO and Board of Directors: Neurotech Pharmaceuticals, Inc.

Now the meat of this discussion.

Dr. Goldberg opened with a dive into the basis of Emmecell’s regenerative medicine leveraging cell therapies for the eye, stating that in almost all of the irreversible blindness in eye disease, some specific cells are lost.

“We have to figure out how to replace those cells—not just to slow down the course of vision loss, but to restore vision in our patients,” he said.

Enter in Emmecell’s technology: The proprietary Magnetic Cell Delivery (MCD) nanoparticle platform

What it is: The MCD platform uses magnetic nanoparticles to effectively localize and integrate cell therapies to the appropriate target tissue.

And how is this platform unique?

The MCD platform is designed to provide a safe and effective, microinvasive surgical approach to transplant corneal endothelial cells into the eye.

Its focus: Solving the current challenges associated with standard cell therapies via the delivery, retention, and integration of cell therapies.

Now compare this to other cell therapies: Those therapies are typically limited in their capacity to replace or enhance damaged tissue, Emmecell has noted—due, in part, to an inability to localize treatment to the site of injury or disease.

Gotcha. So what are the company’s lead assets targeting?

Emmecell currently has a lead investigational candidate in the pipeline and two others in the preclinical stage:

EO2002: Corneal endothelial disease (CED)
EO1301: Preclinical stage for geographic atrophy (GA)
EO0408: Preclinical stage for glaucoma

Give me the rundown on them.

First up: EO2002.

What it is: Formulated as a minimally-invasive cell therapy comprised of donor human corneal endothelial cells (HCECs) combined with magnetic nanoparticles
- How it works: Via the MCD platform, healthy corneal endothelial cells taken from donor corneas are injected into the anterior chamber
  - From there, the cells rapidly integrate into the patient's endothelial cell layer via a magnetic eye patch
- The intended result: To repopulate a patient’s diseased cornea with functional endothelial cells, potentially solving the underlying disease and eliminating the need for corneal transplantation.

What about patient access for this therapy?

Administered as an in-clinic injection—and with a standard reimbursement code opportunity via a new J-Code and existing Current Procedural Terminology (CPT) code—EO2002 has the potential to expand the patient and provider base, according to Dr. Goldberg.

“It allows us to think about treating the full spectrum of eye disease,” he said.

How about other surgical candidates?

Dr. Goldberg noted that the therapy isn't just for surgical patients already being treated for Descemet’s stripping endothelial keratoplasty (DSEK) or Descemet’s membrane endothelial keratoplasty (DMEK).

“Think about the 10, 20, to 30 times as many patients who have this disease but aren’t coming to surgery,” he said. “These are the patients that we can target with this cell therapy.”

Is there clinical data to support its efficacy?

That’s ongoing! In May 2024, Emmecell announced the final dosing of participants in a U.S.-based, multicenter, prospective, open-label, dose-escalation phase 1 study (NCT04894110).

Its purpose: To evaluate the safety, tolerability, and efficacy of EO2002 for treating corneal edema.

The participants: Per Dr. Goldberg, up to 21 patients (aged >21) with and without endothelial cell brushing (EB) or DSEK.
- Read more about this trial and its objectives

Any data yet?

While the study isn’t slated to conclude until October 2024, Dr. Goldberg offered a sneak peak of positive data from one patient whose best-corrected visual acuity (BCVA) went from 20/50 at pre-treatment to 20/25 at 1-year follow-up.

Plus: Following an injection of EO2002 (per study protocol), the patient demonstrated a 460% improvement in corneal endothelial cell density (ECD).

Sounds promising! Any other details on those preclinical assets?

Emmecell’s next investigational asset target is evaluating geographic atrophy (GA).

What it does: This second candidate—EO1301— is intended to be administered using the MCD platform as a subretinal injection of suspension of magnetic retinal pigment endothelial (RPE) cells, with the intent to lay down a smooth layer of cells across the macula.

The result: By flattening these cells against the retina, the structural integrity could possibly restore the dysfunctional to absent RPE cells thereby resolving the GA lesions.

Note: This asset is still in preclinical development, estimated to be 9 months to a year away from human clinical testing.

Sounds exciting! Now let’s move on to Aurion Biotech.

The company’s focus: corneal edema secondary to corneal endothelial dysfunction (CED).

CEO Greg Kunst introduced Aurion’s basis for its regenerative cell therapy by noting the self-limiting area of corneal transplants’ standard of care: It’s estimated that for every 70 people with the disease around the world, only one transplant is provided.

Comparatively: Aurion’s cell therapy can make up to about 1,000 doses per donor, Kunst noted.

“That number will grow over time—we’ve demonstrated up to 3,000 (doses) and potentially even higher per dose,” he said. “More importantly, this can be done in a very minimally-invasive way.”

That’s incredible. Give me the full picture of this cell therapy process.

The process involves healthy cells that are taken from a donor cornea to regenerate in a multi-step, proprietary, open method by culturing the cells from a single donor.

The result: These cells are then manufactured to produce treatment for 100+ recipients' eyes.

The significance: The entire minimally-invasive procedure can be performed “relatively rapidly, with a recovery period of approximately 2-3 hours for patients,” per Aurion.
- See here for a visual.

Any details on the investigational asset for this process?

Indeed: AURN001 is the company’s first clinical candidate.

What it is: a combination cell therapy designed as a once-administered, intracameral injection comprised of:

Neltependocel (allogeneic human corneal endothelial cells)
Y-27632 (an inhibitor of Rho-associated, coiled-coil containing protein kinase [ROCK])

Regulatory note: AURN001 is already approved for use in Japan.

And its clinical status in the United States?

The candidate is currently being studied in the prospective, multicenter, randomized, double-masked, parallel-arm, dose-ranging phase 1/2 (ABA-1, CLARA) trial (NCT06041256).

The participants: 100 (estimated; aged 18-99)
- Diagnosed with corneal edema secondary to CE and requiring endothelial keratoplasty
The set up: Three varying doses of AURN001 + neltependocel + Y-27632 (ROCK)
- Randomized to receive a single injection of AURN001 vs contribution of each element in the experimental arms: cells alone, neltependocel alone, and ROCK alone
Expected end date: October 2025

See more study details.

Note: Patient dosing in Canada and the U.S. concluded in April 2024. Kunst reported that > 130 patients have been treated to date.

Didn’t it receive an FDA designation?

Yes! Kunst noted that the FDA recently granted both Breakthrough Therapy Designation (BTD) and Regenerative Medicine Advanced Therapy (RMAT) for AURN001, making it “one of the first (allogeneic cell therapy) drugs—ever—in our healthcare system to have that,” he said.

And the bigger picture?

With the CED market estimated at $9 billion—plus the approximately 8 million patients globally who are blind due to CED—“this is really a function of the FDA seeing this as an area of significant unmet need and disease burden around the world,” he said.

Thus: “What we have is an area of large opportunity.”

Nice! Who’s next?

Dr. Pollack provided a clinical update on jCyte’s famzeretcel (jCell) therapy for retinitis pigmentosa (RP), which is slated to be studied in an upcoming phase 2/3 clinical trial in September 2024.

The details: Famzeretcel cells represent millions of retinal progenitor cells (multipotent stem cells [MSCs}) that produce neurotrophic factors (NTFs) which, in turn, improve retinal cell function and reduce cell death.

These MSCs modulate NTF secretion (up to 4x the production of NTFs, Dr. Pollack noted) as a response to signals from a dysfunctional retina.

Now about jCell…

A first-in-class allogeneic cell therapy, jCell is designed as a minimally-invasive intravitreal injection administered with a topical anesthetic.

Its mechanism of action: a sustained release of NTFs that could reduce photoreceptor cell death to promote function for surviving photoreceptors.

Note: Due to this, the approach is agnostic—it does not target a specific genotype
- A notable distinct difference from gene therapy

How has it performed in clinical trials?

Dr. Pollack stated that, based on phase 2b data, jCell’s durability extends to at least 12 months.

He also noted the three key findings from that data—all of which informed the design of the upcoming phase 2/3 study:

BCVA disparity between a patient’s eyes of ≤ 15 letters significantly reduced variability/test results of BCVA and contrast sensitivity
Central visual field (CVF) diameter of ≥ 8° appeared to optimize the rod-cone ratio
- Provided greater potential for improvements in BCVA and contrast sensitivity
Central subfield thickness (CST) of at least ≥ 130 µm may be a biomarker for sufficient cone survival and function, enabling potential rejuvenation via jCell

Any specific data points available from that study?

Yes, actually… Dr. Pollack gave a brief rundown on findings from a subset of RP patients with a CVF diameter of ≥ 8° and a BCVA disparity of ≤ 15 letters.

The 12-month data:

50% of those patients who received 6.0 million (M) jCell dose gained at least 15 letters (compared to 0% in the sham group)
For BCVA mean vision change, the 6.0M jCell dose group gained 18 letters (compared to 1 letter in the sham group)

So how are these findings being used in the upcoming phase 2/3 trial?

First, the phase 2/3 study design includes an estimated 120 to 180 participants enrolled in two stages with the following criteria:

Patients of all genotypes (aged 18-60)
BCVA of 20/80 – 20/800
Interocular disparity of ≤ 15 letters
CVF of ≥ 12°
Optical coherence tomography (OCT) CST ≥ 130 µm

Participant randomization will be divided into one of three groups (n = 40, estimated per each) to receive the following doses:

Single 6.0M jCell dose
Single 8.8M jCell dose
Placebo control

And what will be measured?

Dr. Pollack noted that, similar to the previous study, this adaptive design trial will feature a primary endpoint of BCVA ≥ 15 letters at 12 months (ie: the responder rate analysis).

Remind me… enrollment is pending?

Yes! It begins September 2024.

Alrighty, now what other innovations should we be aware of?

Next up: Neurotech Pharmaceuticals and its CEO Richard Small.

Fun fact: Ahead of OTF, the clinical-stage biotechnology company was granted FDA priority review for its Biologics License Application (BLA) of an encapsulated cell therapy (ECT) designed to treat macular telangiectasia type 2 (aka: MacTel), a rare, neurodegenerative retinal disease.

That therapy: NT-501

Explain this ECT.

To understand NT-501, you’ll need to know about Neurotech’s core platform technology: the ECT platform.

What it is: A small, semi-permeable capsule filled with customizable retinal epithelium (RPE) cells genetically modified to produce clinically-relevant levels of specific therapeutic proteins for targeted disease treatments

Note: These proteins have the potential to be delivered over an extended period of time—even years, Small noted.

And the process?

The encapsulated RPE cells are inserted into a patient’s vitreous and sutured to the sclera during an outpatient procedure

Once secured, the capsule’s semipermeable membrane allows the cells to diffuse to the back of the eye and for critical nutrients to enter/therapeutic proteins to exit into the vitreous.
- Note: During this process, the membrane provides protection to the encapsulated RPE cells from a patient’s immune system, enabling both functionality and long-term survival.

Now talk about this first product for the ECT platform.

Enter in: the NT-501 implant, designed to release ciliary neurotrophic factor (CNTF) directly into the retina and protect the health of photoreceptors.

Its purpose: Slow disease progression

Why its short half-life is important: This makes the implant an ideal candidate for the ECT platform because it would be difficult to continuously inject CNTF over a long period of time, according to Small.

“The release rates of CNTF are fairly consistent, anywhere between 1 to 3 nanograms (ng).” he said.

And how durable is this platform?

Small reported that, following NT-501 explant, clinical data indicated continuous CNTF delivery, stable cell health, as well as device integrity from 6 months to up to 14.5 years.

Small presented a microscopic evaluation on the company's longest implant (clocking in at 14.5 years).

With no adherent tissue and still structurally intact, he noted the lack of fibrosis around it. Looking at the RPE cells in it: “The cells are actually viable and healthy—it’s quite remarkable,” he stated.

What’s the clinical data to support it?

Neurotech’s phase 3 program consisted of two clinical studies conducted at 47 clinical sites.

The details: Two randomized, multicenter, sham-controlled phase 3 studies evaluating the safety and efficacy of NT-501 for MacTel Type 2:

Protocol A: NCT03316300
Protocol B: NCT03319849

Primary endpoint for both: Rate of change in ellipsoid zone (EZ) area loss from baseline to 24 months

And those findings?

In all, positive topline data demonstrated statistical significance for the primary endpoint.

Further: The implant was determined to be safe, durable, and well-tolerated in both studies.

Small reported the following positive data:

56.4% rate of reduction in Protocol A (p<0.0001)
29.2% rate of reduction in Protocol B (p=0.021)

Note: This data was originally reported in November 2022.

Let’s circle back to that BLA priority review… what’s the timeline?

The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date of Dec. 17, 2024.

That’s fast approaching… let’s look at the bigger picture of this cell therapy “niche.”

Co-moderator Dr. Marjan Farid asked two bigger questions:

How can cell therapy companies such as Emmecell and Aurion Biotech ensure the environment for such cells is healthy enough to support new cells?
In regards to the gap between stem cell regeneration and the ocular surface, how are these cells able to reach this area and survive?

Kunst noted that, for Aurion, the company’s science involves using a polish in the eye—particularly important for patients with significant pathology, such as those with Fuch's endothelial cell dystrophy (FECD).

“You need to get the surface ‘roughed up’ a bit so that the cells actually do adhere and connect together,” he said, noting that Aurion has used this approach during its clinical trials.

For Emmecell’s cell therapy-based process, Dr. Goldberg noted that the niche for corneal epithelium stem cells at the limbus are not as complex as others.

“This is a very minimally-invasive procedure,” he said. “So this could be repeated if the patient needs another booster shot in a couple years.”

And in the case of jCyte and Neurotech?

As Dr. Kupperman noted, the companies are not integrating cells; instead, “your cells are sophisticated drug delivery vehicles,” he said.

He asked Dr. Goldberg: What makes your cells stay alive as they're injected into the eye?

“We’re injecting millions of cells, 6 to 9 million,” Goldberg said. “This produces nine different NTFs that diffuse through the retina and into the retinal tissue to have that impact.”

The cells aggregate and stay alive by scaling down, traveling through different passages, and being revived from cryopreservation. “Then there’s attrition, because the nutrition in the eye isn’t enough to keep them alive or replicate over time,” he added.

And for Neurotech?

“The cell line is very key here—it actually stays alive,” Small said. “The nutrient environment keeps on replicating those cells, so it’s the combination of those two.”

Lastly, why is ophthalmology so well-suited for cell therapy?

Dr. Pollack noted the industry’s ease of accessibility, use of minimally-invasive procedures (injection, implant, and even subretinal surgery), and the vast number of cell types in the eye that can be addressed.

“There’s just a lot of potential in ophthalmology alone,” he said.

In regards to minimally-invasive surgery, Small added that “we find, once a surgeon gets familiar with the procedure, it’s very well-tolerated.”

This advantage can also be seen when compared to other therapeutic areas. “Ophthalmology is really leading in the cell therapy space because we don't have to deal with the rejection problems that other parts of the body do,” Kunst said.

“That’s the immune privilege,” agreed Dr. Kupperman.

And the significance for ophthalmology’s future?

Dr. Goldberg noted that cell therapy is taking the ophthalmic field in a new direction for so many diseases “because it’s really about vision restoration.”

“It’s remarkable to think that we’re not just going to have a way to slow down patients’ vision,” he said, “but we’re going to be able to counsel patients and give them a shot that’s going to actually bring back their vision in these diseases that—until now—have meant absolute blindness.”