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Page 8 of 14 Brooks et al. Rare Dis Orphan Drugs J 2024;3:15 https://dx.doi.org/10.20517/rdodj.2023.27

found that specific variants in the SORD gene resulted in the loss of function of the enzyme sorbitol
dehydrogenase (SORD), resulting in intracellular sorbitol accumulation. The result is a disorder that
presents in a manner similar to Charcot-Marie-Tooth disease. In fact, the individuals identified with the
[9]
variant had previously been diagnosed with Charcot-Marie-Tooth disease (CMT2) . The SORD variants
were previously not identified, as they were obscured by a “pseudogene” called SORDP2 that was not picked
up by software commonly used for analysis.

Building upon this finding, the INC team initiated a pilot study with AT-007 (NCT05397665), an aldose
reductase inhibitor, in patients with the specific variant in the SORD gene. The study demonstrated the
ability to reduce sorbitol levels by a mean of 66% . This promising finding led to Applied Therapeutics
[10]
initiating a registrational phase III study of AT-007. This occurred within three years of the initial discovery
of the variant.

The preliminary results from the 12-month Interim Analysis of Govorestat (AT-007) in the Ongoing
INSPIRE Phase 3 Trial in Sorbitol Dehydrogenase (SORD) Deficiency have been very encouraging. The
results demonstrate that: (1) Interim primary endpoints have been met; (2) Sustained, significant reduction
in sorbitol in govorestat-treated patients compared to placebo control; and (3) highly statistically significant
effects on a patient-reported outcome measure, the CMT Health Index (CMT-HI), with a particular benefit
of govorestat on measures of lower limb function, fatigue, pain, mobility, sensory function, and upper limb
function .
[11]

• Opportunities for strengthened collaborations and working together across different organizations and
regions.

The RDCRN emphasizes the FAIR principles of research. These include data that are (1) Findable - rich
metadata; (2) Accessible - can be easily downloaded with standard protocols; (3) Interoperable - Metadata
that uses an accessible protocol; and (4) Reusable - data that are well described and provide clear usage
information. To achieve this goal, the RDCRN reaches out to other data gathering and data standards
organizations (e.g., C-Path, C-Disc) and confirms that the data from the RDCRN will be interoperable with
other systems.

• Global involvement to identify additional individuals with rare diseases.

Many of the consortia within the RDCRN collaborate with clinical sites around the world. The RDCRN has
collaborators in eleven countries including Australia, Belgium, Canada, England, Germany, India, Ireland,
Italy, The Netherlands, South Africa, and Switzerland.

• Collaboration with international organizations on data standards and operability.

The RDCRN, via the NCATS program, has been involved in international data standards and operability
discussions including the conference organized by the International Rare Diseases Research Consortium
(IRDiRC) and the European Joint Programme on Rare Diseases (EJP RD), focusing on rare disease clinical
research networks (CRNs). The conference brought together experts from different countries and programs
to share experiences and knowledge related to clinical research center structure and activities. Efforts to
establish collaboration and ensure interoperability across networks were identified as important goals for
the organizations.