While there are many incentives to invest in rare diseases, well designed clinical trials are critical to getting the new therapies conceived by pharmaceutical companies to the people who need them.  

Primary hyperoxaluria (PH) is a rare genetic kidney disease impacting fewer than 1000 people in the US. While many people with kidney disease are asymptomatic until they progress to kidney failure and can rely on dialysis or a transplant to replace their kidney function, the unique characteristics of PH cause severe symptoms early in life and make common kidney replacement therapies ineffective.

The genes altered by PH cause an overproduction of oxalate in the liver. Excess oxalate is not effectively removed by the kidneys and causes kidney damage and the development of kidney stones. The disease progresses quickly, with kidney failure occurring in 50% of people with PH by the age of 33. Dialysis and transplantation do not address the underlying issue of oxalate production causing transplant failure and ineffective dialysis.

There are no US Food and Drug Administration (FDA) approved therapies for this condition.

Fortunately, the pharmaceutical industry is incentivized to invest in rare diseases and several drug companies include PH in their drug development pipeline. Identifying and agreeing with regulators on clinical trial endpoints is critical to getting novel therapies through the development pipeline and to the people who need them.

Reliable clinical trial end points are often a barrier to innovation in the kidney community. The Kidney Health Initiative (KHI), a public-private partnership between the American Society of Nephrology (ASN) and the FDA, recognized this obstacle, and along with the Oxalosis and Hyperoxaluria Foundation (OHF) convened a workgroup to identify clinical trial end points for PH.

Kidney stones, worsening kidney function, urine oxalate, and plasma oxalate were identified as potential PH end points in a recent publication of the workgroup’s findings in the Clinical Journal of the American Society of Nephrology.

A substantial change in urine oxalate and plasma oxalate could support accelerated approval as a surrogate end point in specific PH populations and are the most feasible end points identified. Kidney stones is a clinical outcome that impacts how PH patients feel and function but does not have sufficient standards for measurement and monitoring. Worsening kidney function could be considered the equivalent of a clinically meaningful end point by accelerated approval standards but is difficult to measure in the PH population.

It is the workgroup’s hope that the outcomes of this project will facilitate discussions between industry and the FDA that will catalyze the development of new therapies for people with PH.

Several companies are already conducting clinical trials for PH:

- Allena Pharmaceuticals

• Reloxaliase has received the FDA’s Orphan Drug Designation and is in phase 2 clinical trials for primary hyperoxaluria and pediatric hyperoxaluria indications.

- Alnylam Pharmaceuticals

• Lumasiran has received FDA’s Breakthrough Drug Designation and is in phase 3 clinical trials for primary hyperoxaluria type 1.

- Dicerna Pharmaceuticals

• People with all three types of primary hyperoxaluria can now register for Nedosiran clinical trials.

- OxThera

• People with primary hyperoxaluria over the age of 2 can now register for Oxabact clinical trials.

Consensus clinical trial end points will make it easier for even more companies to develop therapies for PH and conduct successful trials.