Eloxx Pharmaceuticals Doses First Patients in Phase 2b EXACT Study of Exaluren for Alport Syndrome

Trial Begins to Test Exaluren in Nonsense Mutation Alport Syndrome

Eloxx Pharmaceuticals has dosed the first two patients in the EXACT study, a Phase 2b clinical trial evaluating exaluren in people with nonsense mutation Alport syndrome (NMAS).

The trial is designed to study whether exaluren can help address the genetic problem that causes this rare form of Alport syndrome.

Eloxx is developing exaluren as an investigational treatment for rare kidney diseases. The company expects to report topline results from the initial part of the EXACT study in mid-2027.

What Is Nonsense Mutation Alport Syndrome?

Alport syndrome is an inherited disease that damages the kidneys and can also affect hearing and vision.

Nonsense mutation Alport syndrome is a specific form of the disease caused by certain mutations in the COL4A3, COL4A4, or COL4A5 genes.

These genes provide instructions for making type IV collagen. This collagen is an important structural part of the kidney's filtration system.

In people with nonsense mutations, the genetic instructions contain a premature stop signal. This can prevent cells from producing a complete and functional collagen protein.

Without enough functional type IV collagen, the kidney's filtration barrier can become damaged over time.

The Disease Can Lead to Serious Kidney Damage

People with NMAS can develop progressive kidney damage.

The disease can cause blood in the urine, known as hematuria, as well as protein in the urine, known as proteinuria.

Damage can also occur to podocytes, specialized cells that help maintain the kidney's filtration barrier.

As the disease progresses, kidney function can decline and eventually lead to kidney failure.

According to Eloxx, approximately 7% of people with Alport syndrome carry nonsense mutations.

These mutations are associated with a more severe disease course than some other types of Alport mutations. The company states that the mean age of kidney failure in this population is approximately 20 years.

There Is Currently No FDA-Approved Treatment Targeting the Genetic Cause

There are treatments used to manage kidney damage in people with Alport syndrome, but Eloxx states that there is currently no FDA-approved therapy specifically addressing the underlying genetic cause of nonsense mutation Alport syndrome.

This is the problem that exaluren is being developed to target.

Instead of only treating the effects of kidney damage, the drug is designed to work at the genetic-protein production level.

How Does Exaluren Work?

Exaluren is an investigational small-molecule ribosomal modulator.

To understand how it works, it helps to look at what happens with a nonsense mutation.

Normally, cells read genetic instructions and use them to produce a complete protein. A nonsense mutation introduces a premature stop signal into those instructions.

The cell then stops making the protein too early, resulting in an incomplete protein that may not work properly.

Exaluren is designed to promote a process called readthrough.

In simple terms, the drug aims to help the cellular machinery continue reading through the premature stop signal so that production of the full-length protein can continue.

The goal is to restore production of a functional protein from a gene containing a nonsense mutation.

EXACT Is a Global Phase 2b Study

The EXACT study is a randomized, placebo-controlled, delayed-start Phase 2b clinical trial.

The global study is planned to include 24 patients with nonsense mutation Alport syndrome.

Participants must have disease-causing nonsense mutations in one of three genes: COL4A3, COL4A4, or COL4A5.

The initial part of the study will compare exaluren with placebo for 16 weeks.

The trial is designed to evaluate both the safety and effectiveness of exaluren in this patient population.

Researchers Will Look at Changes in Kidney Structure

For non-U.S. pediatric patients and all adult patients, the primary efficacy endpoint in the initial portion of the study will focus on structural changes in podocytes.

Podocytes are specialized cells in the kidney that help form and maintain the filtration barrier.

Researchers will examine kidney biopsy samples and measure changes in a feature called foot process effacement, or FPE.

The study will assess changes in foot process diameter, or FSD, as a measure of the effect of treatment on podocyte structure.

This approach allows researchers to look directly at changes in the kidney's filtration system rather than relying only on measurements such as protein levels in urine.

Topline Results Are Expected in 2027

Eloxx expects to report topline data from the initial 16-week portion of the EXACT study in mid-2027.

The company expects the final 32-week readout by the end of 2027.

These results will provide information about the safety of exaluren and whether the treatment produces measurable changes in kidney structure and other study assessments.

Why the Trial Matters for People With NMAS

Nonsense mutation Alport syndrome is caused by a clearly defined genetic problem.

The COL4A3, COL4A4, and COL4A5 genes are involved in producing type IV collagen, which is needed to maintain the kidney's filtration barrier.

Because exaluren is designed to promote readthrough of premature stop signals, the treatment is being studied as a way to potentially address the consequences of these specific mutations.

The Phase 2b study will provide clinical data on whether this approach can produce meaningful biological effects in people with NMAS.

Eloxx Plans to Study Exaluren in Other Kidney Diseases

Alport syndrome is not the only kidney disease being considered for exaluren.

Eloxx is also developing the drug for autosomal dominant polycystic kidney disease, or ADPKD.

The company plans to conduct a Phase 2 clinical trial of exaluren in ADPKD.

ADPKD is another inherited kidney disease, although it is caused by different genetic changes from those seen in nonsense mutation Alport syndrome.

The European Commission has granted orphan medicinal product designation to exaluren for ADPKD.

Exaluren Has Received Orphan Drug Designations

Exaluren has received regulatory orphan designations for its development in Alport syndrome.

The U.S. Food and Drug Administration and the European Commission have granted orphan drug designation to exaluren for the treatment of Alport syndrome.

These designations are intended for medicines being developed for rare diseases and can provide certain development and regulatory incentives.

The designations do not mean that exaluren has been approved as a treatment.

Eloxx Says the Trial Is an Important Step

Sumit Aggarwal, President and Chief Executive Officer of Eloxx Pharmaceuticals, said dosing the first patients in the EXACT study is an important step for the company and for the Alport syndrome community.

He said the company remains focused on developing exaluren for people with nonsense mutation Alport syndrome.

Eloxx expects the first topline data from the study in mid-2027.

Clinical Experts Highlight the Need for New Treatments

Professor Daniel Gale, Professor of Nephrology at University College London and Consultant Nephrologist at the Royal Free London NHS Foundation Trust, also commented on the beginning of the study.

He noted that people with nonsense mutation Alport syndrome can progress to kidney failure at a young age.

The disease can therefore create a significant need for treatments that target its underlying genetic cause.

The EXACT study will now provide clinical data on whether exaluren's genetic readthrough approach can translate into measurable effects in patients.

Eloxx Focuses on Ribosome-Modulating Medicines

Eloxx Pharmaceuticals is a clinical-stage biopharmaceutical company developing small-molecule medicines that are designed to modulate the ribosome.

The ribosome is the cellular machinery responsible for producing proteins.

The company's approach is focused on premature stop codons caused by nonsense mutations.

By promoting readthrough of these premature stop signals, Eloxx aims to enable cells to produce full-length proteins that may have been stopped early because of the mutation.

The company's current development work includes exaluren for nonsense mutation Alport syndrome and other rare kidney diseases.

What Happens Next for the EXACT Study?

The first two patients have now received treatment in the Phase 2b study.

The trial will continue enrolling patients with nonsense mutation Alport syndrome and will evaluate exaluren against placebo during its initial 16-week period.

Researchers will assess safety as well as changes in kidney and podocyte-related measures.

Eloxx expects topline results from the initial portion of the study in mid-2027, followed by a final 32-week readout expected by the end of 2027.

The results will help determine the next stage of clinical development for exaluren in nonsense mutation Alport syndrome.