He was busy with his work on diabetes and obesity, and he knew that US physicians were planning a clinical trial for a promising drug. That trial was of a drug called nitisinone, which was originally developed as a weedkiller in the s but was found to have toxic effects in fish and rats. Its development as a weedkiller was halted, but the company that owned it, Zeneca Agrochemicals, asked some specialists in the United Kingdom to investigate how it worked.
The researchers discovered that it kills plants in an unexpected way: it chokes off their supply of chlorophyll by disabling an enzyme called HPPD. His response astonished them: he wanted to give nitisinone to children. Lindstedt was searching for a way to inhibit the enzyme in order to save the lives of babies and children with a condition called type-1 hereditary tyrosinaemia HT1 , which results from a disruption to the same metabolic pathway affected in AKU. Although the weedkiller was toxic, the effects of HT1 were so devastating and deadly that it was considered worth a shot.
Lindstedt described the results in a paper in The Lancet : the treatment worked better than anyone had hoped 4. Under laws that popped up around the world in the s, companies could reap financial incentives — such as extended patent protection — to commercialize treatments for rare diseases such as HT1. So, the Stockholm-based company Swedish Orphan Biovitrum acquired the license for nitisinone and marketed it as Orfadin.
And all without a randomized controlled trial. HT1 was considered so serious that the drug was first given under a compassionate-use exemption, and later under an agreement that the company would gather the necessary data on safety and efficacy afterwards. Alkaptonuria AKU has been known about for more than a century and has been a prominent disease in the course of modern medical genetics. Nitisinone is made available to residents as part of an observational study.
It includes surrogate endpoints and no placebo, but should satisfy European regulators. Disabling HPPD halts the breakdown of the amino acid tyrosine. Patients knew this, too, and many were desperate to get their hands on the drug. To get it covered required approval, and that meant a trial.click here
Short Mystery Stories For Middle School
The US government stepped in. This was the trial that Ranga had hoped would report positive results. With hindsight, however, the study was doomed from the start: just 40 patients were recruited, half of whom were not given the drug. And success of the treatment — the clinical endpoint — was defined in a very narrow way. Introne speculates that this was because all trial participants received regular physical therapy as part of the study.
The failure of the trial was especially frustrating, she says, because nitisinone worked exactly as expected from a biochemical perspective: HGA levels plummeted in the participants receiving treatment 5. Still, without meeting its endpoint goals, nitisinone was not going to win approval in the United States. For a clinical trial to succeed, and to convince regulators, the Liverpool team would have to find a more-reliable endpoint.
That meant tracking how the disease progressed, both in animals and in people. This would require more research, and that meant money. In , he ran a sponsored half marathon to raise the money needed to transport the dead body of a year-old with AKU from Nottingham to Liverpool. This suggested a complicated mechanism by which the damaging deposits build up.
This went to James Gallagher, a musculoskeletal researcher at the University of Liverpool, to develop a mouse model of the condition. Constitution numbers.
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Short Mystery Stories For Middle School
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