Oral Diabetes-Related Eye Disease Drug Shows Mixed Results in Clinical Trial

An experimental pill for a vision-threatening complication of diabetes did not meet its main goal in a recent clinical trial. However, researchers say the drug still showed enough promise to warrant further study.

The medication, called tonabersat, was tested against a placebo in patients with diabetic macular edema (DME). DME is a condition where fluid builds up in the part of the eye responsible for sharp, straight-ahead vision (the macula). This swelling can lead to blurry vision and, if left untreated, permanent vision loss.

While the drug did not produce a statistically significant improvement in the primary measure of retinal swelling after six months, it did show encouraging trends in certain groups of patients. Experts presented these findings at the Association for Research in Vision and Ophthalmology (ARVO) meeting in Denver.

What the Study Found: The Main Result

The main goal of the study was to see if tonabersat could reduce retinal thickening. The key measurement was “central subfield thickness” (CST), which is the thickness of the macula.

– After six months, patients taking tonabersat saw their CST decrease by an average of 15 micrometers (µm).

• In contrast, patients taking a placebo saw their CST increase by an average of 5 µm.
• When researchers adjusted the numbers to account for other factors, the difference between the two groups was 16 µm.
• However, this difference did not reach statistical significance. The p-value was 0.08. In medical research, a p-value of less than 0.05 is typically considered statistically significant, meaning the result is unlikely to be due to chance alone.

Lead researcher Dr. Jennifer K. Sun, from the National Eye Institute in Bethesda, Maryland, presented the findings. “There was no statistically significant difference in central subfield thickness at 24 weeks between tonabersat- and placebo-treated patients,” she stated.

But she added an important note: “However, there were consistent modest anatomic trends that favored tonabersat across additional analyses.”

A Closer Look: Why Researchers Are Still Hopeful

Even though the main result was not a “home run,” as Dr. Sun put it, several secondary and “post-hoc” (done after the main analysis) findings kept the research team interested.

1. The “Thicker Eyes” Subgroup

One of the most striking findings came when researchers looked at patients who had the most severe swelling at the start of the study.

“Our subgroup analyses showed a dramatic difference in terms of greater CST reductions in thicker eyes compared to thinner eyes,” Dr. Sun explained.

This makes biological sense. If a drug works by reducing fluid leakage, patients with more fluid to drain would likely see a bigger change. The study originally planned to enroll equal numbers of patients with moderate and severe thickening, but they had trouble finding enough patients with very thick retinas who also had good vision.

2. The Anti-VEGF Factor

Many current treatments for DME involve injections of anti-VEGF medications, which block a protein that causes abnormal blood vessel growth and leakage. In this study, a “post-hoc” analysis excluded patients who had received any anti-VEGF therapy during the trial.

– In this group, the adjusted mean difference in CST between tonabersat and placebo jumped to 21 µm.

• This result was statistically significant, with a p-value of 0.02.

This suggests that tonabersat’s effects may be more visible in patients who are not also receiving other powerful anti-leakage treatments.

Discussion Among Experts: Is the Effect “Real”?

During a question-and-answer session after the presentation, other eye specialists weighed in on the data. Dr. Arshad Khanani of Sierra Eye Associates in Reno, Nevada, noted, “It seems like there is some sort of an efficacy signal here.”

Dr. Khanani raised a technical point about how the data was handled. When patients drop out of a study, researchers often use a method called “last observation carried forward” (LOCF) to fill in missing data. If patients drop out because the drug isn’t working, this method can sometimes make a drug look better than it really is. He asked whether the researchers had properly accounted for this.

Dr. Sun acknowledged the limitations but stood by her conclusion. “Although this was not a home run and we did not make the primary outcome, I think there is enough signal here that we can conclude there probably is good evidence for some sort of biological effect.”

Another co-moderator, Dr. Aude Couturier from the French Myopia Institute in Paris, suggested that future studies might use special imaging techniques (like fluorescein angiography) to better identify patients who are most likely to benefit.

Dr. Sun agreed: “If there was interest in doing a second, more focused phase II study, we might target it specifically for patients with thicker retinas.”

Why a Pill Matters: The Need for New DME Treatments

To understand why researchers are excited about a pill, it helps to know what current treatments look like. Diabetic macular edema is a leading cause of vision loss in working-age adults. It affects people with both type 1 and type 2 diabetes.

The standard of care today is anti-VEGF injections. While these are effective for many people, they come with significant downsides:

– Invasive: The medicine is injected directly into the eye (intravitreal injection).

• Frequent visits: Patients often need injections every 4 to 8 weeks, requiring constant trips to the doctor.
• Costly: The medications and procedures are expensive.
• Not for everyone: A substantial proportion of patients do not respond well to anti-VEGF therapy.

Dr. Sun highlighted this need in her introduction: “Current treatments for DME are effective, but a substantial proportion of patients do not benefit. Treatment can be costly, invasive, and require frequent office or clinic visits. A need exists for novel, VEGF-independent, well-tolerated, noninvasive treatments.”

A pill like tonabersat could potentially offer a convenient, at-home option. It could be used alone or in combination with injections to reduce the number of shots a patient needs.

How Tonabersat Works: A Different Approach

Tonabersat works by targeting a different biological pathway than anti-VEGF injections. It blocks something called “connexin 43 (Cx43) hemichannels.”

– In diabetic retinopathy, these channels are overexpressed (too many are made).

• They are linked to the activation of proinflammatory molecules that damage the retina.
• By blocking Cx43 hemichannels, tonabersat reduces the release of these inflammatory signals.

Importantly, in preclinical (animal) models, tonabersat blocked the release of key inflammatory cytokines, including VEGF itself. It also reduced vascular leakage and edema (swelling) from ischemic injury. This means it attacks the problem from a different angle than current drugs.

Previous studies of tonabersat for migraine headaches showed that the drug was generally well-tolerated and had no major safety issues.

Study Details: Who Was in the Trial?

The Phase II trial included 129 patients (15 of whom had both eyes treated). Key details about the participants:

– Diabetes type: 96% had type 2 diabetes.

• Vision: All patients had visual acuity of 20/32 or better.
• Treatment history: No DME treatment in the past year; no more than four injections in the prior three years.
• Baseline CST: Average CST was 359 µm in the tonabersat group and 362 µm in the placebo group.
• Baseline vision: Both groups averaged 20/25 vision.

It’s worth noting that the two groups were not perfectly matched at the start. Patients in the tonabersat group had:

• A longer duration of diabetes (19 years vs. 16 years)
• Higher rate of insulin use (69% vs. 54%)
• More kidney disease (23% vs. 9%)
• More heart failure (11% vs. 3%)

These differences could have affected the results.

Side Effects and Dropout Rates

The study also revealed some safety concerns that need further investigation:

– Discontinuation: More patients in the tonabersat arm stopped treatment before six months (13 vs. 6).

• Serious adverse events: These occurred more often in the tonabersat group (19% vs. 8%).
• Hospitalization: More patients taking tonabersat required hospitalization (16% vs. 3%).

These numbers are concerning and would need to be carefully weighed against any benefits in future, larger studies.

Practical Takeaways for Patients

If you or a loved one has diabetes and is concerned about eye health, here is what this news means for you right now:

– Tonabersat is not yet FDA-approved. It is an experimental drug that is still in clinical trials. Do not expect to see it in your pharmacy anytime soon.

• Current treatments remain the gold standard. Anti-VEGF injections are proven to help prevent vision loss in DME. Do not stop or delay your current treatment based on this early research.
• Talk to your eye doctor. If you have DME, ask about your CST (central subfield thickness). Knowing this number helps doctors track your condition.
• Control your diabetes. The single best way to prevent or slow diabetic eye disease is to keep your blood sugar, blood pressure, and cholesterol under control. Regular dilated eye exams are critical.
• Watch for future studies. If tonabersat moves into larger Phase III trials, you may hear about opportunities to participate through clinicaltrials.gov or your eye specialist.

What Comes Next?

The researchers believe the data justifies a second, more targeted Phase II study. They would likely focus on:

– Patients with the thickest retinas at baseline.

• Using advanced imaging to select patients with the most leakage.
• Possibly combining tonabersat with anti-VEGF therapy to see if it reduces the need for injections.

Dr. Sun summed up the cautious optimism: “I would love to see additional studies, kind of parsing out what it all means and what the role might be in our overall population of DME patients.”

For now, tonabersat remains a promising but unproven candidate. It has not yet hit the mark, but it has shown enough of a signal to keep researchers—and patients—watching closely. The search for a safe, effective, and convenient pill for diabetic eye disease continues.

Source: MedPage Today