Phenylketonuria (PKU) is a rare genetic condition that affects how your body processes an amino acid called phenylalanine (Phe). People with PKU have low levels or missing activity of an enzyme called phenylalanine hydroxylase (PAH). Without enough PAH, Phe builds up in the blood, which can harm the brain and cause developmental problems. Managing PKU requires keeping blood Phe levels in a safe range, most often through a strict, Phe-restricted diet.
Sephience (sepiapterin) is a newer treatment option for certain people with PKU. It is approved for adults and children as young as 1 month old who have sepiapterin-responsive PKU.
How Does Sephience Treat Phenylketonuria?
Sephience is a PAH activator. Your body turns Sephience into a naturally occurring substance called tetrahydrobiopterin (BH4). BH4 is a helper molecule, or “cofactor,” that PAH needs to break Phe down into another amino acid called tyrosine. In people whose PKU responds to sepiapterin, boosting BH4 levels helps PAH work better, lowering Phe in the blood.
How Is Sephience Used?
Sephience is a powder you take by mouth once a day with food. Taking Sephience with food helps your body absorb the medicine. The dose is based on your age and weight. For example, the recommended starting dose is:
- Under 6 months old: 7.5 milligrams (mg) per kilogram (kg) of body weight
- 6 months to <1 year: 15 mg/kg
- 1 to <2 years: 30 mg/kg
- 2 years and older: 60 mg/kg (this is the maximum dose for anyone taking Sephience)
If your dose is under 1,000 milligrams, it is mixed with water or apple juice before taking. If it is 1,000 milligrams or more, it can also be mixed with soft foods like strawberry jam or applesauce. Your health care provider will give you exact mixing and dosing instructions. If a dose is missed, it should be taken as soon as possible, but you should never take two doses in one day. The regular dosing schedule should be resumed the next day.
How Do I Know if Sephience Is Working?
Your health care provider will likely check your blood Phe within two weeks after you start treatment.They may change your dose, pause your treatment, or stop it completely if you have certain side effects. If it has not dropped enough at the highest recommended dose (60 mg/kg/day), treatment will be stopped. If it is working, you will likely keep taking it long-term, with dose adjustments as needed to keep your Phe in the target range.
This medicine is always used along with a Phe-restricted diet that is based on blood Phe levels. They may also change your diet while you are on this medicine. Follow their directions and do not change your diet unless you talk to them first.
Are There Interactions With Sephience?
Several medicines can interact with Sephience. This may make Sephience less effective or increase your risk of side effects. Sephience may also affect other medicines.
Some medicines used for infections, cancer, or certain other conditions can block how your body processes Sephience. Examples include methotrexate (Trexall and others), pemetrexed (Alimta, Pemfexy), trimethoprim, and others. These medicines block folate production by inhibiting an enzyme called dihydrofolate reductase (DHFR) and can interfere with how Sephience is processed into its active form (BH4). Other medicines called sepiapterin reductase inhibitors, such as sulfamethoxazole and sulfasalazine (Azulfidine), can also lower how much Sephience is converted into its active form. If you need to take one of these medicines while on Sephience, your health care provider will likely check your blood Phe levels more often.
Sephience may also affect other medicines. It can increase the amount of tyrosine in your body, which may increase blood levels of levodopa (a medicine used for Parkinson’s disease), increasing your risk for side effects. If you take both, your health care provider will likely watch for changes in your nervous system, such as unusual movements, mood changes, or seizures.
Medicines called phosphodiesterase-5 (PDE-5) inhibitors used for erectile dysfunction or pulmonary arterial hypertension, such as sildenafil (Revatio, Viagra, and others), tadalafil (Cialis and others), and vardenafil (Levitra, Staxyn), can lower your blood pressure. Taking them with Sephience may lower your blood pressure too much. If you use both, you may experience dizziness, lightheadedness, or fainting.
How Was Sephience Studied for the Treatment of Phenylketonuria?
Sephience was studied in a major clinical trial called APHENITY, which included both adults and children with PKU who had high blood Phe levels despite following a Phe-restricted diet. People of any age with a confirmed diagnosis of phenylketonuria could join the study if their blood Phe level was 360 μmol/L (micromoles per liter) or higher at the start. People with high Phe caused by certain gene changes in GCH1, PTS, QDPR, SPR, or PCBD1, which indicate primary BH4 deficiency, were not allowed to participate.
The APHENITY trial had two parts. Part 1 was a 14-day study where everyone knew they were receiving Sephience, and the goal was to see how their blood Phe levels responded. In Part 2, which lasted six weeks, participants were randomly assigned to either keep taking Sephience or switch to a placebo, which contained no active medicine. Neither the participants nor the study team knew who was receiving which treatment during this phase.
A total of 157 people took part in the study. The average age of participants was 17, and 101 of the 157 participants (64%) were younger than 18. Among the 110 people who were randomly assigned to a treatment group in Part 2, 19 had classic PKU, 29 did not show a response to BH4, and 23 were taking Sephience when the study began. Most people followed instructions to keep a diet diary, maintain their pre-study diet, and track their dietary Phe intake. The mean baseline Phe concentration at screening for people included in the study was 712.2 μmol/L.
What Were the Results of the Study?
In Part 1, 114 (73%) participants had a meaningful drop (≥15%) in their blood Phe and were eligible to move on to Part 2. In Part 2, 98 people were a part of the efficacy analysis population (those who had more than or equal to 30% reduction in blood Phe concentration). People taking Sephience had an average drop in blood Phe of about 63% after six weeks of treatment, while people taking the placebo had almost no change in their Phe levels. The difference between the groups was nearly 400 μmol/L lower in the Sephience group.
Out of 44 people who started the study with higher-than-recommended Phe levels, 37 (about 84%) reached the target level recommended by the American College of Medical Genetics and Genomics of 360 µmol/L or lower within 6 weeks.
For children under 12 years old, 17 out of 19 (about 89%) reached the European guideline target of less than 360 µmol/L. For participants 12 years and older, 16 out of 17 (about 94%) reached the European guideline target of less than 600 µmol/L.
In total, 11 out of 49 people taking sepiapterin (about 22%) reached blood Phe levels in the normal healthy range of 35-120 µmol/L. None of the people taking the placebo reached this healthy range.
Sephience was effective and well-tolerated for people of all sexes and ages, including children, teenagers, and adults. There were no deaths, serious side effects, or severe treatment-related problems. The most common side effects were diarrhea and headache, each happening in about 7% of people taking Sephience compared to about 2% of those taking a placebo.
Along with the published results of the phase III APHENITY trial and previous phase I and phase II initial efficacy and safety studies, there is an ongoing continuation study, which includes both children and adults with PKU, will provide information beyond six weeks to help evaluate the long-term effectiveness and safety of the treatment.
Your results may differ from what was seen in clinical studies.
Are There Any Special Steps Required to Get Sephience?
Sephience is a “specialty” medicine. This means it is a high-cost medication that is taken for rare, complex, or chronic (long-term) diseases. It will require a different process than picking up a prescription at your local pharmacy. You will use a specialty pharmacy for getting this medicine. Your insurance may require approval for using Sephience, also called a prior authorization. The insurance company reviews the prescription from your health care provider to make sure it is covered and determines the process that needs to be followed. You may also be able to work with a representative from the drugmaker that can help you through the process of insurance coverage and with details around the specialty pharmacy shipping the medicine.
Is There Any Cost Assistance Available?
There are financial assistance options available from the drugmaker. Whether you are eligible depends on whether you have prescription insurance and what type of insurance you have. You can find out more at ptccares.com/pku or call 844-478-2227.
