WATCH: Experts react to the FDA approval of sepiapterin to treat PKU

On July 28, 2025, the FDA approved PTC Therapeutics' sepiapterin (Sephience) to treat adult and pediatric patients with phenylketonuria (PKU). Sepiapterin is now the third FDA-approved medication for lowering blood phenylalanine (Phe) levels and can be used alongside a Phe-restricted diet to expand protein tolerance in individuals with sepiapterin-responsive PKU.

"This is a really exciting time in PKU, with a new treatment coming out," said Suzanne Hollander, MS, RD, LDN, metabolic dietician, Boston Children’s Hospital. "Sepiapterin is an oral Phe-lowering medication just recently approved for PKU in individuals of all ages. For individuals with PKU, historically, standard of care treatment has included a protein-restricted diet with low phenylalanine formula. More recently, there have been two Phe-lowering medications available on the market. These previous two and the diet do not always sustainably work for everyone to keep their blood phenylalanine, or Phe, level within the target treatment range. That target treatment range is less than 360 µmol/L."

FDA approval follows the phase 3 APHENITY trial, in which sepiapterin demonstrated potential benefits such as increased dietary protein intake and reduced reliance on PKU-specific formula.

"Sepiapterin will become the third FDA-approved Phe-lowering medication. The approval is exciting because it offers an additional Phe-lowering option, and it may be appropriate for some people who have not achieved their treatment goals with the other two available medications and/or with the PKU diet," Hollander said.

For metabolic care teams, the approval introduces new considerations for treatment planning. "Many individuals will still require a phenylalanine-restricted diet alongside this therapy. However, sepiapterin does offer a Phe-lowering effect that could allow individuals to liberalize their diet and eat more dietary phenylalanine and more dietary protein. For some people, it may lower their blood phenylalanine level enough that they could receive all the dietary protein they need from food, allowing them to discontinue use of the phenylalanine-restricted PKU formula. Any time people on a restricted diet can liberalize their protein intake, it is a huge win."

Timothy Tramontana, MD, medical and biochemical geneticist, Cleveland Clinic Foundation, emphasized the broader impact. "The added benefit is that we currently have a drug called sapropterin, which we have been utilizing for a long time under the brand name Kuvan. Sepiapterin provides an alternative treatment to this, hopefully helping patients with extremely diminished levels of phenylalanine hydroxylase, the enzyme affected in this disorder. It is thought that patients even with null mutations, or mutations that may be leaky—meaning there may be minimal to almost no enzyme—may benefit from this treatment. The drug has a chaperone effect; it can help with the conformation of the enzyme, which may be affected. Those with almost no enzyme activity may actually see benefit from it in reducing their phenylalanine levels, as compared to a drug like sapropterin or Kuvan."

"It goes hand in hand; the approach has always centered around diet, with pharmacologic management as an adjunct to hopefully help liberalize diet. That approach has helped a number of people through the use of sapropterin and now with sepiapterin. The hope is to expand the number of patients who may be able to liberalize their diet and increase their protein intake. That is our goal for most of our patients—to help them live a more normal life in terms of intake. It may never be 100% protein unrestricted, but the hope is to liberalize it enough to allow increased intake," Tramontana added.

Both experts encouraged primary care providers to support continued specialty care. "For general practitioners working with individuals with PKU, we absolutely want you to encourage individuals with PKU in your practice to come to a PKU clinic, which may also be referred to as a metabolism or metabolic clinic. Even if someone has been away from clinic for many years, we always welcome people back so they can be made aware of these new treatment options," Hollander said.

"We are excited that there is another drug on the horizon that can help our patients live a more normal life and increase their protein intake," Tramontana added. "That is always exciting. General providers need to be aware that there are treatments available and should enlist the help of a biochemical geneticist. We work hand in hand with metabolic dietitians who are integral to the team and the management of these patients. Knowing that a new treatment may help patients further liberalize their protein intake is going to be important," Tramontana said.