Hyperion Therapeutics' first drug, approved in February by the US Food and Drug Administration, has been welcomed by clinicians as a step forward for people with rare genetic conditions known as urea cycle disorders (UCDs). Ravicti (glycerol phenylbutyrate), an orphan drug from S. San Francisco, California–based Hyperion, got the agency's nod based on a 44-patient phase 3 trial showing that it was as effective in controlling blood ammonia levels as the standard-of-care Buphenyl (sodium phenylbutyrate) from Valeant Pharmaceuticals, of Montreal.

Up to 40 pills a day might be taken by individuals with urea cycle disorder to keep blood ammonia levels under control. Credit: Thinkstock

Individuals with UCDs have deficiencies in enzymes involved in the urea cycle, the body's main mechanism for removing ammonia from blood. Ammonia is a potent neurotoxin, resulting from the natural breakdown of protein and nucleic acids. Normally, in a series of enzymatic steps, the urea cycle transforms this neurotoxic nitrogen waste into urea, which is excreted as urine by the kidneys. In people with UCDs, if left untreated, ammonia levels will increase, resulting in brain damage and death. Hyperion estimates the prevalence of UCD deficiencies in the US is about 2,000.

Both Buphenyl and Ravicti provide an alternative sink to the urea cycle, acting as nitrogen scavenger drugs. The drugs are both metabolized to the same active substance, phenylacetic acid (PAA). This metabolite is conjugated with the amino acid glutamine (a temporary storage form of ammonia) to form phenylacetylglutamine, which is then eliminated by the kidneys. Buphenyl is a pro-drug of PAA, whereas Ravicti is a pre-pro-drug of PAA.

Although the two drugs operate through a similar mechanism, Ravicti represents an “evolutionary step forward in the management of UCDs,” says Marshall Summar, director of clinical research at the Children's National Medical Center (CNMC) in Washington, DC, because of side effects associated with Buphenyl. The latter drug is not well tolerated, mainly due to its unpleasant taste and gastrointestinal side effects, high sodium content and high pill burden (up to 40 pills, administered three to six times a day). In contrast, Ravicti is almost tasteless and is formulated as a concentrated liquid: about one teaspoon three times a day is equivalent to 40 tablets of Buphenyl. Ravicti also helps prevent some of the gastrointestinal side effects associated with Buphenyl as it is a slow-release formulation broken down by pancreatic enzymes in the intestine rather than in the stomach.

All this means that clinicians expect better compliance with Ravicti than Buphenyl, and this may be crucial, says CNMC executive vice president and chief academic officer Mark Batshaw, especially for young children in whom UCDs are often diagnosed. “Missing doses can be life threatening, so adherence is important in terms of outcome,” agrees Brendan Lee of Baylor College of Medicine in Houston, who served as the lead investigator of Ravicti's phase 3 trial.

If cost were not a consideration, most physicians say they would give Ravicti to all eligible patients. But Ravicti is priced at $250,000–$290,000/year, much higher than Buphenyl, which analysts at Needham in New York estimate as $40,000–50,000/year for children under 20 kg and $100,000–130,000/year for adults (prices are difficult to calculate because dosing is based on weight). Hyperion has until the end of April to decide whether to exercise an option to purchase Buphenyl from Valeant, which analysts expect it to do. Buphenyl is also now an off-patent drug opening opportunities for generics. For now, though, most doctors are likely to continue to start affected infants on Buphenyl (so far, Ravicti has not been approved for children under 2).

Payors are likely to reimburse Ravicti for those who opt for it over Buphenyl, says analyst Joseph Schwartz at Leerink Swann in Boston. Needham analyst Alan Carr agrees, citing the tolerability advantage and “relatively limited cost to payors overall,” given the small patient population. Annual peak sales of Ravicti in UCD are predicted to be at least $100 million. Hyperion is also planning a phase 3 trial of Ravicti in hepatic encephalopathy, a condition where ammonia is also a major toxin.