Fosmetpantotenate, a drug tested to help restore coenzyme A levels in pantothenate kinase-associated neurodegeneration (PKAN), failed in clinical trials, researchers told attendees here at the International Congress of Parkinson's Disease and Movement Disorders. And they are sifting through the data to try to understand why the trial delivered disappointing results.
PKAN, a rare genetic disease, usually strikes in early childhood causing motor and cognitive problems, with no approved treatments. The disappointing results still leave the genetic disease, which usually strikes in early childhood causing motor and cognitive problems, with no approved treatments.
In PKAN, genetic variants in the PANK2 gene cause a defective PanK2 enzyme, leading to an error in vitamin B5, or pantothenate, metabolism. This disrupts the production of coenzyme A, a vital cofactor in central metabolic reactions, and leads to an accumulation of iron in the brain, and ultimately neurodegeneration.
Fosmetpantotenate is a phosphopantothenate precursor intended to help restore coenzyme A levels.
In the trial, known as FORT, patients ranged widely in age from 6 to 65, disease duration, and baseline function scores. Researchers enrolled 41 patients in the treatment group and 43 in the placebo group.
At 24 weeks, however, researchers found no difference between the treatment and placebo groups in either PKAN-Activities of Daily Living scores (p = 0.9115) or United Parkinson's Disease Rating Scale Part 3 (p = 0.1421).
Feriandas Greblikas, MD, senior medical director at Retrophin, which funded the study and makes the drug, said researchers are trying to glean guidance from the data.
"We are not totally stopping, we are still looking—we have all the detailed data set in our hands," he said. "We are still going through the data."
Ashley Bush, MBBS, PhD, director of the Melbourne Dementia Research Center in Australia, said the results were disappointing because the approach made sense, and the pre-clinical primate data were promising.
"There was certainly hope in the field that this trial would succeed in slowing down disease progression," he said. "For this particular trial, the disease severity inclusion was highly variable and so the outcome measures may not have had the dynamic range of sensitivity needed to appreciate effects over such a broad range. However, there is very little even in the way of a hint that fosmetpantotenate was beneficial."
He said it is not known whether the dose given was enough for a sustained and effective concentration in the brain because there no biomarker to measure for this.
"It is also possible that the treatment was administered to patients with too advanced disease, and possibly early intervention would demonstrate benefit," Dr. Bush said.
After a recent clinical trial of iron-chelator deferiprone in PKAN showed a trend toward disease modification, Dr. Bush and his colleagues noted that mutations to the PANK2 gene lead to a drop in coenzyme A as well as an increase in cysteine, which together can protect cells against iron-dependent cell death. By increasing coenzyme A with fosmetpantotenate, this protection could actually be disrupted, negating benefits, he said.
"If this is true," Dr. Bush said, "the combination therapy of fosmetpantotenate and deferiprone"—or a ferroptosis inhibitor—"could be worth testing in a clinical trial."
Jeong SY, Hogarth P, Placzek A, Gregory AM, Fox R, Zhen D, Hamada J, van der Zwaag M, Lambrechts R, Jin H, Nilsen A, Cobb J, Pham T, Gray N, Ralle M, Duffy M, Schwanemann L, Rai P, Freed A, Wakeman K, Woltjer RL, Sibon OC, Hayflick SJ. 4'-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN. EMBO Mol Med. 2019 Oct 29:e10489. doi:10.15252/emmm.201910489. [Epub ahead of print]
Pantothenate kinase‐associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease‐vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4′‐phosphopantetheine, normalized levels of the CoA‐, iron‐, and dopamine‐related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4′‐phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron–sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4′‐phosphopantetheine as a candidate therapeutic for PKAN.