Long-Awaited Drug for Alkaptonuria (AKU), the First “Inborn Error,” On the Way to Approval in Europe

The European Medicines Agency has just recommended extending use of an existing drug, nitisinone (Orfadin), to treat alkaptonuria (AKU). AKU holds a special place in the history of genetics as the first “inborn error of metabolism” described. It affects one in 250,000 to one in a million people.

The route to impending approval took two decades, illustrating factors that make the quest to discover, develop, and deliver a treatment for a very rare disease so challenging. There’s no “Operation Warp Speed” for the rare disease community. Sometimes there aren’t even enough participants to carry out a clinical trial that is controlled, relying instead on comparisons to the natural history of a disease, or enrolling one patient at a time in an “N+1” study.

I last wrote about AKU in 2014, calling it “black pee disease.” I’m happy to report now on the progress in Europe, but won’t use that attention-grabbing descriptor, because it minimizes the severity.

A Peculiar Condition and an Astute Physician

Twenty years ago, Nick and Sonya Sireau, who live in the UK, noted the odd urine of their two-week old son, Julien. A few moments after being exposed to air, it turned a deep, reddish-black. After a physician suggested that Sonya refrain from eating red cabbage, a second consult, with blood and urine analysis, brought the diagnosis of AKU with the telltale high concentration of homogentisic acid. Their second son Daniel has AKU too. This excellent article in Nature tells their story in detail.

If dark urine was the only feature of AKU, it would be merely an oddity. But after age 30, cartilage begins to darken and degrade, especially in the large joints and in the spine, and the ear tips too. Painkillers and joint replacement are used to minimize the arthritis. Kidney stones, heart valve damage, tendon and muscle rupture, and fractures may follow.

In genetic diseases, a collection of strange symptoms often points to a deficiency of a single enzyme. That’s the case with AKU. It is, literally, a classic disease.

Sir Archibald Garrod (1857-1936) was a physician at St. Bartholomew’s in London when he investigated the puzzling condition. His initial description in The Lancet in 1902 noted that when one child had black urine, a sibling sometimes did too, noting that 19 of 32 cases were from 7 families. And parents of affected children were more often first cousins than expected for such a rare condition. That pointed to a recessive mutation, pairing up in the unfortunate family members who inherited AKU.

Most importantly, Sir Garrod nailed the molecular origin of the disease: excess excretion of homogentisic acid, a breakdown product of the amino acid tyrosine. That’s what darkened urine.

Sir Garrod, in describing AKU as an “alternative mode of metabolism,” was way ahead of his time in realizing that people vary in their biochemistry. Perhaps the recent rediscovery of Mendel’s laws had inspired his insight into the preponderance of cousin-cousin parental pairings and familial clustering. He coined the phrase “inborn error of metabolism” in 1908 in a lecture to the Royal College of Physicians, where he referenced “Garrod’s tetrad” of four such conditions: alkaptonuria, cystinuria, pentosuria, and albinism.

The enzyme behind alkaptonuria was discovered in 1958, the gene in 1996. The drug Orfadin was originally developed for a related inborn error due to a glitch in the same pathway that dismantles tyrosine.

A Kinked Metabolic Garden Hose

An inborn error blocks synthesis of an enzyme that is part of a metabolic pathway. Precursors build up as products wane, like the effect of a kinked garden hose on water flow.

Metabolic pathways are sequences of linked biochemical reactions. The product of one is the starting material of another, an enzyme catalyzing each step.

Interference in the breakdown of tyrosine affects health because the intermediate biochemicals normally provide starting materials for production of thyroid and other hormones, the pigment melanin, and parts of the energy pathways. Block any step and a specific inborn error results.

The drug was initially used to treat hereditary tyrosinemia type 1 (HT-1), which arises from a block in the first step of the five-step pathway and severely damages the liver. AKU is due to a block in the second step. In both diseases, homogentisic acid builds up in blood and urine.

The story of the drug’s approval for one condition, but not the other, reveals some of the detours that can arise in clinical trials. Choosing how to measure or assess an effect is of utmost importance.

Once a Weedkiller

The Nature article details how Nick Sireau met Bob Gregory, who had AKU and lived in Liverpool. They learned of physician Lakshminarayan Ranganath from the University of Liverpool, who was interested in AKU. “Ranga” knew about a drug being looked at in the US, at the NIH, since 2000: nitisinone.

The origin of the drug goes back to the 1980s, when it was originally destined to be a weedkiller, but was sidelined when it poisoned rats and fish. The agrichemical company continued to investigate the compound, and discovering how it kills plants revealed a possible therapeutic use.

The weedkiller interferes with synthesis of chlorophyll by disabling an enzyme, HPPD, that is part of the pathway that breaks down tyrosine. Block that enzyme, and homogentisic acid levels should fall.

Researchers at the ag company contacted the world’s expert on HPPD, Swedish doctor Sven Lindstedt. Surprisingly, he suggested trying the toxic weedkiller on young children who had HT1. The kids were so sick, the disease so rare, that risks seemed justified. Children with HT1 have difficulty gaining and maintaining weight due to frequent vomiting, jaundice, bleeding, kidney failure, rickets, and high risk of liver cancer. Without treatment the disease is typically fatal before age 10.

So Dr. Lindstedt and four colleagues gave three children the enzyme inhibitor, reporting on the encouraging results in The Lancet in 1992. The drug could provide an alternative to liver transplantation, they concluded.

The once-weedkiller became Orfadin to treat HT1, cleared for marketing without the gold-standard randomized controlled clinical trial. Instead, it was granted compassionate-use status with the proviso that the company report on safety and efficacy going forward.

Things weren’t so straightforward for using the same drug to treat AKU. In the US, insurers wouldn’t support off-label prescribing without evidence from a controlled clinical trial.

The NIH conducted the trial, from 2005 to 2008, but it was flawed. The study enrolled only 40 patients with AKU, who either received the drug or didn’t. The design wasn’t blinded; the controls had black urine.

The problem was that success was defined as hip flexibility, and the two groups didn’t differ much. In retrospect, that might have been because people in the control group hadn’t declined enough to see a difference because everyone in the trial received physical therapy! Homogentisic acid levels indeed fell precipitously in the treated patients, but technically, the trial hadn’t shown efficacy as it had been defined.

Meanwhile, across the pond, Nick Sireau and Bob Gregory had started a nonprofit organization and brought Ranga aboard. Fundraising and clinical trial planning began.

First, a mouse model in 2014 showed decline in homogentisic acid with the drug. Then Ranga recruited 81 patients in the UK to be in the trial. A natural history study of the patients led to development of a severity score, a critical tool in objectively evaluating new treatments.

In 2012 it seemed all was in place to begin a large clinical trial in the UK, but an unexpected good news/bad news situation arose: the National Health Service began providing the drug for free to all AKU patients, calling it an “observational study.” After that, why would anyone participate in a clinical trial and risk being in the control group?

Still, the trial began anew in 2015 with 138 patients recruited from beyond the UK, called Suitability of Nitisinone in Alkaptonuria 1 (SONIA 1). An organization called DevelopAKUre was instrumental in continuing the project.

The new trial set a more measurable endpoint: homogentisic acid level, as well as improved symptoms. No placebo needed – it’s difficult to ignore black urine.

And that trial, reporting both a 99.7% drop in homogentisic acid level and a slowing of disease progression, led the EMA to recommend extension of use of the drug to AKU, on September 18, 2020.

Julien Sireau and his brother Daniel are taking nitisinone. “It’s too early to tell if it’s stopping the joint problems, but it’s definitely reduced the homogentisic acid considerably,” Nick told me. He is Chair and CEO of the AKU Society.

I hope that the drug comes to the US soon!