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."
https://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersMDSInternationalCongress/pages/post.aspx?PostID=32
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]
Abstract
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.
See: https://news.ohsu.edu/2019/10/29/discovery-clears-way-for-clinical-trial-to-treat-devastating-neurologic-disorder
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