In an exclusive interview, Cary O. Harding, MD, provides Rare Disease Report® with insight into pegvaliase-pqpz and its recent approval by the FDA to treat patients with PKU.
Last week, on May 24, 2018, the US Food and Drug Administration (FDA) approved Biomarin Pharmaceuticals’ pegvaliase-pqpz (Palynziq) to reduce blood phenylalanine (Phe) concentrations in adults with the rare inherited metabolic disorder, phenylketonuria (PKU).
In an exclusive interview with Cary O. Harding, MD, professor of Molecular and Medical Genetics, and Pediatrics, and medical director of Biochemical Genetics at Knight Diagnostic Laboratories at Oregon Health & Science University, Rare Disease Report ® gleaned additional insight on the treatment and implications of its approval.
Previous to this approval, PKU treatment has heavily relied upon “extreme restriction of dietary phenylalanine intake through a complicated, unpalatable protein-restricted diet that must be maintained for life,” Dr. Harding explained. Adherence to such a strict diet has proved challenging, if not impossible for most adults, and, as such, many individuals with PKU are unable to maintain blood phenylalanine concentrations within the recommended treatment range, which is 120 to 360 µM.
This range, according to Dr. Harding is “still significantly above the normal plasma phenylalanine range of 60 to 120 µM.” When the diet is not adhered to, blood phenylalanine levels increase, which results in several psychiatric symptoms and cognitive impairment. According to Dr. Harding, common issues include anxiety, inattention, and mood disorders, which could hinder relationship stability and interfere with their educational and employment potential. In pregnant women, nonadherence to the strict diet could result in maternal PKU syndrome.
“Simply put, in my opinion, although dietary Phe restriction is essential for the treatment of infants and young children with PKU, for many adults with PKU, dietary therapy does not work,” he stressed.
“Playnziq’s mechanism of treatment action, namely enzymatic degradation of phenylalanine into a readily excretable non-toxic metabolite, is a completely novel treatment approach for PKU,” Dr. Harding explained to RareDR®. “Its success is not dependent upon maintaining dietary phenylalanine restriction.” Pegvaliase-pqpz combined with a varied high-protein diet has been found in clinical trials to result in improvements in attention, mood, performance at school or work, and overall quality of life.
Of course, the road to developing pegvaliase-pqpz was not easy.
“The major challenge for the phase 3 trial, in my opinion, was related to the fact that PKU, although it is one of the most common inborn errors of metabolism, is still a rare disease, and 33 study centers were ultimately needed to recruit sufficient study subjects to adequately power the pivotal phase 3 randomized discontinuation trial,” Dr. Harding told RareDR®.
He added that since the 1950’s—when using dietary treatment for PKU had just been developed—the field has been stressing the need for a dietary therapy to combat a rare disorder that affects about 1 in 12,500 children annually in the United States.
“The shortcomings of dietary treatment have become readily apparent to patients, families, and providers within the field, but it has been a bit of a persistent educational process to reorient others, who are not so intimately involved with the PKU field, to understand the need for novel therapies,” he said. “It’s not about just being able to eat a hamburger; it’s the physical, neurologic and psychologic needs not being met by contemporary therapy that we are trying to address.”
He also shared that obtaining adequate measurements of the neurocognitive effects of elevated blood phenylalanine in a quantitative way also proved challenging, as single quantitative neuropsychological tests that are currently available may not capture deficits that patients with PKU often experience. “This often impairs our ability to measure a treatment effect upon any specific neuropsychological variable,” he said.
When asked what the implications of this approval are for health care providers and patients struggling with PKU, Dr. Harding stressed that pegvaliase-pqpz is a revolutionary treatment approach to the disorder. “I predict that it will potentially transform the quality of life for many patients who have not had success maintaining low blood phenylalanine levels through dietary therapy,” he said. “We have as a field never had the opportunity to study the long-term effects of maintaining low blood phenylalanine, often lower than can be achieved with the PKU diet, while consuming typical dietary protein intake.”
Dr. Harding expects to see the combination of low blood phenylalanine and normal dietary protein intake resulting in several unexpected benefits, as investigators continue to assess the long-term safety of the therapy. However, he admits that for some patients, this therapy might be satisfactory either due to intolerable hypersensitivity, inadequate response to available doses, or personal aversion to daily subcutaneous injections.
“For that reason, I am committed to continue efforts toward the development of further novel treatment approaches such as gene therapy, an approach I have studied in my research lab for nearly thirty years,” he stressed. “As a PKU clinician, I look forward to the day, when I might reach into my clinical toolbox, and have a variety of different effective therapeutic tools available to offer the patient with PKU.”
For more news from the rare disease community, subscribe to Rare Disease Report®’s e-newsletter.