Combining Regulatory Pathways to Optimize Development Efficiency

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Multiple regulatory pathways exist during the drug development process.

Numerous distinct regulatory designations and pathways are made available to companies in the pharmaceutical and biotech industries for developing and commercializing drugs, with the end goal of creating or expanding upon treatment options for patients. There are therefore many pathways through the drug development landscape, that employ distinct combinations of regulatory elements to guide the journey.

Here we focus on the strategic use of the Orphan Drug Designation and the Accelerated Approval pathway being used by XORTX Therapeutics, of which I am CEO, as we seek to bring to patients a treatment for autosomal dominant polycystic kidney disease.

Orphan Drug Designation for Rare Diseases

For individuals afflicted with a rare disease, unmet medical needs are a burdensome fact of life. Efficacious treatments, or any treatment, may not exist. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) have made strides in recent decades by developing novel regulatory pathways and mechanisms allowing for more rapid access to potential therapeutics, which can have a meaningful effect on rare disease patients.

In order to encourage and facilitate testing of new therapeutic candidates for rare diseases, the U.S. Congress passed the Orphan Drug Act of 1983. This created the Orphan Drug Designation (ODD) to provide incentives for drug development for disorders affecting fewer than 200,000 individuals in the United States. These incentives include tax credits, user fee exemptions and the potential for up to seven years of market exclusivity for orphan drugs that are approved.

The result of this program is an expanded set of treatments for a number of rare diseases, driven by advances in experimental techniques extending scientific knowledge and leading to better understanding of disease mechanisms. New understanding has provided a rationale for investigating new compounds that may be of benefit to patients and expanded the pipeline of candidates for drug testing. The Orphan Drug Act has been a wellspring, with more than 5000 therapeutics receiving the designation, and 878 drug approvals as of 2019 with substantial contributions to oncology, neurology and infectious disease, in particular (Miller et al. 2021). One familiar example is Keytruda, which received orphan designation to treat Stage IIB through IV malignant melanoma in 2012. More recently, designation was given to Skyclarys for the inherited neurological disorder Friedrich’s Ataxia, where it is currently the only approved treatment.


Nephrology has lagged oncology and neurology in the use of the orphan drug designation, but not for lack of need. Autosomal dominant polycystic kidney disease, or ADPKD, is a rare genetic disorder that unfortunately leads to end-stage renal disease (ESRD) by age 60 in more than half of patients. It is estimated that because of the rapid rate of disease progression ADPKD accounts for ~4% of diagnosed chronic kidney disease and 10% of all dialysis patients. In the case of ADPKD, research has provided us with a better understanding of the tissue-specific role that the enzyme xanthine oxidase plays in the progression of this disease. Xanthine oxidase catalyzes key reactions in purine metabolism and produces uric acid as well as oxygen free radicals, which are elevated in many ADPKD patients. Recent evidence suggests that higher blood concentrations of uric acid may promote and accelerate formation of new cysts and accelerate disease progression.

Inhibition of xanthine oxidase may thus represent a useful treatment modality for ADPKD. One way in which this can be achieved is by purine-like molecules such as the active metabolite oxypurinol, which is the approach taken by XORTX Therapeutics. In preclinical rodent studies, using oxypurinol to attenuate xanthine oxidase function reduced total kidney volume (TKV) driven by hyperuricemia in a model of PKD. A clinical study of XORTX’s proprietary oxypurinol formulation, XORLOTM, showed high bioavailability and a favorable safety profile in human subjects.

The Accelerated Approval Process

Whether or not a therapeutic is aimed at orphan designation, the FDA provides four pathways to speed the availability of a drug to patients with a life-threatening illness: Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. The Food and Drug Administration provides guidelines for Accelerated Approval that make use of surrogate endpoints as measures for clinical benefit as a key element of the process. For example, the recent accelerated approval of Leqembi was based on its ability to reduce amyloid-β plaques in a subset of Alzheimer’s subjects exhibiting mild cognitive impairment or dementia, as evidence suggests a role for these plaques in the development of the clinical symptoms of the disease.

The choice of an appropriate surrogate endpoint is thus a vital component of the Accelerated Approval process, whether for drugs for more widespread conditions or for those with orphan designation. In ADPKD, diagnosis is typically via detection of bilaterally enlarged polycystic kidneys. As cysts grow and proliferate, TKV increases and the filtering capacity of the kidneys, as indicated by estimated glomerular filtration rate (eGFR), decreases. Given the linkage of these characteristics in ADPKD, TKV increase or eGFR decrease are reasonable proxies for disease progression, and attenuating or arresting these changes could be predictive of a clinical benefit for XORLO and serve as valuable surrogate endpoints in ADPKD.

XORTX recently held a Type D meeting with the FDA to verify the applicability of these surrogate endpoints for potential accelerated approval, and to discuss planned Phase 3 multicenter, double-blind, placebo-controlled, randomized clinical studies that will focus on these endpoints in hyperuricemic stage 2-4 ADPKD patients to confirm efficacy and safety. Our Phase 3 trial is expected to begin in the second half of 2023. It should be noted that in any accelerated approval process, it is a necessity to follow up the surrogate endpoint data with further trial data that confirms the clinical benefit, as a final step to full marketing approval.

Patients with rare diseases often have few options for treatment, but regulatory options such as the Orphan Drug Designation and Accelerated Approval pathways provided by the FDA have facilitated the process of drug development.This enables companies, including XORTX, to use a combination of pathways to bring new hope to sufferers of rare diseases.


Miller KL, Fermaglich LJ, Maynard J (2021) Using four decades of FDA orphan drug designations to describe trends in rare disease drug development: substantial growth seen in development of drugs for rare oncologic, neurologic, and pediatric-onset diseases. Orphanet Journal of Rare Diseases 16:265.