How to Evaluate a Medicine for the Treatment of an Ultra-rare Disease Such as PH1

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How to Evaluate a Medicine for the Treatment of an Ultra-rare Disease Such as PH1

August 3, 2020

Alnylam Pharmaceuticals

For a new medicine to become available, it needs to undergo stringent testing in clinical trials to evaluate its safety and, importantly, its efficacy (how well it works to improve the patients’ condition and the symptoms that come along with it). But before such testing can take place, physicians, drug makers and regulatory authorities, such as the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA), must come to a consensus on which parameters to test that would signal an improvement in the patients’ condition. These parameters are known as “clinical endpoints” – effects or outcomes that can be measured objectively to determine whether the medicine is impacting the disease.

In recent years, the voice and perspectives of the patient community have become more and more integrated in helping to evaluate what constitutes a clinical benefit or a quality of life improvement, particularly in the case of conditions with high unmet medical need. An example of such a condition is an ultra-rare liver disease called primary hyperoxaluria, or PH. There are currently no FDA or EMA-approved pharmacologic therapies for this life-threatening disease that typically presents in early childhood.

Recently, the community of PH patients and caregivers joined forces with the Oxalosis and Hyperoxaluria Foundation (OHF) – the leading patient advocacy group that supports this community in the U.S. – physicians, regulators and the biopharmaceutical industry, including Alnylam, to identify clinical trial endpoints that could be used in evaluating the safety and efficacy of investigational medicines for the treatment of PH. This undertaking was conducted in collaboration with the “Kidney Health Initiative” or KHI – a public-private partnership between the American Society of Nephrology (ASN), the US FDA, and more than 100 member organizations and companies – to enhance patient safety and foster innovation in chronic kidney disease, an effort to which Alnylam has been proud to contribute.

Patients living with primary hyperoxaluria type 1 (PH1) - the most common (70-80% of all PH cases) and severe form of PH – experience recurrent kidney stones and progressive kidney failure as a result of overproduction of a liver metabolite called oxalate that, when in excess, tends to accumulate and damage the kidneys and ultimately other organs in the body, such as the eyes, bones and heart, causing vision loss, bone fractures and heart failure. Once the disease advances, patients require an intensive dialysis regimen as a bridge to a dual or sequential liver/kidney transplant, profoundly impacting patients’ quality of life.

"My baby girl was on dialysis for about 15 hours a day for 2 years. She didn’t eat for the first 4 years of her life." – Caregiver of three pediatric patients diagnosed with PH1

Being on dialysis and waiting for a transplant, then having life-long immune issues and potential rejection...I hate that all I can do is sit and watch it happen. It goes against everything in my being to not be able to protect my children. – Caregiver of two pediatric patients diagnosed with PH1

"The hardest part of watching my brother go through the transplant process was seeing him in pain, seeing him get his freedom taken away, his ability to do small things that I take for granted." – Caregiver of an adult patient diagnosed with PH1

With organ transplants being associated with life-long immunosuppression and other potential complications, there is an urgent need for alternative treatment options.

In evaluating which clinical endpoints to study when researching potential new medicines for PH, the PH community and KHI stakeholders identified kidney stones, changes in estimated glomerular filtration rate or eGFR (a measure of kidney health), and oxalate levels in urine and plasma as the strongest candidate endpoints. However, while kidney stones affect how patients with primary hyperoxaluria feel and function, standards for measurement and monitoring of stones are lacking. With regard to kidney function, eGFR decline in most patients is gradual, but can be unpredictable. Taking those factors into consideration, urine and plasma oxalate levels in patients with moderate and severe kidney impairment, respectively, were determined as more robust endpoints. The KHI initiative and the ongoing research in PH would not have been possible without the participation of a dedicated community of patients, caregivers and advocates like the OHF.

To learn more about the output of this collaborative effort between the community of patients and advocates, US regulators, physicians, and the KHI on identifying clinical trial endpoints for PH, Read Article ‘Endpoints for Clinical Trials in Primary Hyperoxaluria’ (Subscription Required).

For the accompanying article on patient and caregiver perspectives, Click Here.