For patients living with Fabry disease, progressive kidney damage can lead to dialysis, transplantation and serious long-term complications. Idorsia is developing lucerastat, an investigational oral therapy designed to address the underlying disease process and potentially offer an alternative to existing treatments. BioPharma Boardroom speaks with Amer Joseph, MD, Chief Medical Officer and Head of Global Clinical Development at Idorsia Pharmaceuticals Ltd, about the Phase 3 FAB-KLEAR and planned FAB-SWITCH studies, the partnership with Nxera Pharma, and the company's development strategy ahead of a potential regulatory filing as early as 2029.

Q. Idorsia has started the Phase 3 FAB-KLEAR study of lucerastat for Fabry disease. What makes this an important milestone for the company, and what are the main objectives of the study?

The initiation of FAB-KLEAR is an important milestone because it marks the start of the pivotal phase of development for lucerastat in Fabry disease. It follows many years of research and extensive clinical experience generated through the Phase 3 MODIFY study and its long-term extension. 

FAB-KLEAR is designed to provide the baseline-controlled data required by regulatory authorities to assess the effect of lucerastat on kidney disease in Fabry patients. Specifically, the study will evaluate whether lucerastat can reduce the accumulation of globotriaosylceramide, or Gb3, in the kidney. Gb3 accumulation is a hallmark of Fabry disease and an important driver of progressive kidney damage. This study forms is a key component of our registration strategy and could support a regulatory filing as early as 2029. 

Q. Lucerastat is being developed as a potential oral treatment for Fabry disease. How could this treatment benefit patients, particularly those experiencing kidney-related complications?

Fabry disease is a progressive disorder that affects multiple organs, including the kidneys, heart, and nervous system. Kidney disease is one of the most serious manifestations as progressive loss of kidney function can lead to kidney failure requiring chronic dialysis or transplantation and is associated with an increased risk of cardiovascular complications. 

Lucerastat is an investigational oral substrate reduction therapy designed to act independently of enzyme activity, mutation type, or prior treatment history. Our goal is to address the underlying disease biology by reducing the production of the lipid substrates that accumulate in patients with Fabry disease. 

In addition to the potential clinical benefits, an oral therapy could offer greater convenience compared with treatments that require regular time-consuming intravenous infusions under medical supervision. We believe this combination of potential disease modification and ease of administration could represent a meaningful advance for patients if confirmed in Phase 3 studies.

Q. The FAB-KLEAR study will focus on reducing the buildup of Gb3 in the kidneys. Why was kidney health chosen as the main focus of this trial, and what results are you hoping to achieve?

Kidney health was chosen because progressive kidney disease remains a major cause of long-term morbidity in Fabry disease and is a significant contributor to premature death and reduced life expectancy. Preserving kidney function is therefore one of the most important treatment objectives for patients and physicians. By focusing on the kidney and evaluating tissue histology, we can also directly assess whether the treatment is improving the underlying disease pathology. 

The rationale for FAB-KLEAR is grounded in observations from the lucerastat development program. Long-term clinical data demonstrated sustained reductions in circulating Gb3 levels accompanied by encouraging findings related to kidney function. In addition, kidney biopsy analyses from patients who received long-term lucerastat treatment showed very low levels of kidney Gb3 accumulation than would be expected in untreated individuals.

With FAB-KLEAR, we hope to demonstrate that lucerastat can meaningfully reduce kidney Gb3 accumulation compared with baseline. Demonstrating such a histological effect would provide important evidence that the therapy is addressing a key driver of Fabry-related kidney disease and reducing the underlying disease burden.

Q. Idorsia has also announced a co-development and commercialization partnership with Nxera Pharma. What are the key benefits of this collaboration, and how will it help bring lucerastat to patients in Japan and other Asia Pacific markets?

The collaboration with Nxera brings several important benefits for the continued development of lucerastat.

Under the agreement, Nxera will contribute to the global Phase 3 development program while receiving exclusive rights to develop and commercialize lucerastat in Japan and selected Asia Pacific territories. Beyond strengthening the program operationally, the collaboration provides access to clinical sites and patients in Japan, allowing Japanese patients to participate directly in the global development program.

This is particularly important from a regulatory perspective because it supports a more globally integrated development strategy and may help avoid the need for separate regional development activities following completion of the Phase 3 program. 

Nxera also brings significant expertise and commercial capabilities in Japan and the broader Asia Pacific region. By combining our scientific and clinical experience with Nxera's regional presence, we are well positioned to advance lucerastat efficiently and, if approved, make it available to patients across multiple territories.

Most importantly, both companies share the same objective: generating the evidence needed to determine whether lucerastat can become a new treatment option for people living with Fabry disease worldwide. 

Q. Alongside FAB-KLEAR, Idorsia is planning the FAB-SWITCH study to compare lucerastat with existing enzyme replacement therapies. What do you hope to learn from this comparison, and how could it influence future treatment options for Fabry disease? 

The two Phase 3 studies are designed to answer complementary questions.

FAB-KLEAR focuses on demonstrating an effect on kidney Gb3 accumulation, while FAB-SWITCH is intended to evaluate renal function outcomes in patients switching from standard-of-care enzyme replacement therapy to lucerastat. 

The study will help us better understand how lucerastat performs relative to current treatment approaches in a real-world treatment population. It is designed to provide evidence regarding kidney function outcomes as well as the broader role lucerastat could play across the Fabry patient population. 

If successful, the study could help establish lucerastat as an important new treatment option for patients and physicians seeking alternatives to existing therapies. 

Q. Idorsia is targeting a potential regulatory filing as early as 2029. What are the major milestones ahead for lucerastat, and what are the company's priorities as it moves through the final stages of clinical development?

Our immediate priority is the successful execution of the Phase 3 program, including both FAB-KLEAR and FAB-SWITCH. 

That means enrolling patients efficiently, generating robust, high-quality clinical data, and continuing to work closely with investigators, patient communities, and regulatory authorities. We are fortunate to be building on a substantial body of existing clinical experience and long-term follow-up data, but the critical next step is generating the controlled evidence required for registration.

Beyond the studies themselves, we will continue preparing for potential future regulatory submissions and working with partners such as Nxera to support a global development and commercialization strategy.

Ultimately, our focus is clear: to bring a new treatment option to people living with Fabry disease. If the Phase 3 program confirms the promise we have seen so far, we believe lucerastat can address an important unmet need and make a meaningful difference for patients and their families.