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Animal models have predicted the dosage of Brineura enzyme replacement therapy (cerliponase alfa) for patients with late infantile Batten disease, also known as CLN2 disease, according to a study.

Scientists said this approach could also be applied to predict the cross-species dosage for other similar drugs.

“Overall, the approach described here provides an example of how non-clinical data can be leveraged to streamline clinical development in rare diseases,” the researchers wrote.

The monkeys were used in the study in part because, according to the researchers, they have a semi-vertical posture which yields data “more likely to be representative” of humans.

“Dogs and monkeys were chosen as non-clinical test species because their CNS [central nervous system] and CSF [cerebral spinal fluid] parameters are more similar to humans than rodents, including a larger, more complex brain and a similar rate of CSF turnover, ”the team wrote. Note that the central nervous system is made up of the brain and spinal cord, and cerebrospinal fluid is the clear fluid that surrounds the CNS.

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The study, “Dose selection for intracerebroventricular cerliponase alfa in children with CLN2 disease, animal to human translation in a rare genetic disorder, ”Was published in the journal Clinical and translational science.

CLN2 disease, which usually occurs in children between the ages of 2 and 4, is caused by mutations in the TPP1 uncomfortable.

These mutations lead to a deficiency of the enzyme TPP1, which is involved in the breakdown of protein waste in cells. In the absence of this enzyme, wastes accumulate to toxic levels inside cells, causing their death and characteristic symptoms of the disease such as seizures, vision loss, and progressive cognitive and motor difficulties.

Brineura is an approved CLN2 enzyme replacement therapy developed by BioMarin, which helps slow disease progression in patients with late childhood Batten disease. The therapy consists of a form of the enzyme TPP1 which is used to replace the missing enzyme in patients by injecting it directly into the fluid in the brain – a procedure known as an intraventricular infusion.

Clinical trials supporting approval of the therapy have shown that it slows the gradual loss of the ability to walk in children with the inherited disease.

Due to the progressive nature and severity of CLN2, animal models have been used to inform dose selection for human patients. In a process known as allometric scaling, pharmacokinetic data – information about how the drug enters, through, and out of the animal’s body – is used to predict human exposure and the dosage.

There is, however, a lack of models in the current literature on how to tailor assay parameters to different species for direct delivery to the brain of enzyme replacement therapies.

Now, working with the University of Missouri School of Medicine, BioMarin scientists have described how two allometric scaling approaches – using monkeys and a canine model of CLN2 disease – could predict exposure. to Brineura to inform the selection of the human dose.

To confirm the predictions, the scientists used human pharmacokinetic data from a phase 1/2 open label dose escalation trial (NCT01907087) who evaluated Brineura in 24 children with this type of Batten disease.

“This approach to translating dose and predicting human exposure for [Brineura] may apply to others [brain and spinal cord-] therapies given in development, ”the team wrote.

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Concentration and time data for Brineura in cerebrospinal fluid, or CSF, were obtained from cynomolgus monkeys (macaques). Brineura was administered in increasing doses (5, 14 or 20 mg) to individual monkeys, followed by CSF samples taken during and after the infusion for a period of up to 14 days.

CSF concentration samples were also taken from dachshund dogs for seven days, including normal and TPP1 deficient animals, after 4 and 16 mg Brineura infusions.

Exposure of Brineura in CSF after the 16 mg dose in dogs was similar to that observed after the 20 mg dose in monkeys.

The mean C-max, the maximum Brineura concentration in CSF, was 1460 micrograms per mL (mcg / mL) for dogs and 1580 mcg / mL for monkeys. At these doses, the area under the curve (AUC), a measure of total exposure over time, was 6450 mcg-hour / mL for dogs and 8670 mcg-hour / mL for monkeys. .

Two independent pharmacokinetic models have been developed, one for each species. The data best matches a two-compartment model, which refers to a central tissue compartment with fast exposure and a peripheral tissue compartment with slower exposure.

The model parameters were then scaled in dogs, monkeys and humans based on brain mass. The average size of the young human brain has been assumed to be 1000 g, due to the progressive shrinkage of the brain (atrophy) in CLN2 patients. In turn, the average brain size for dogs was set at 50g, and for monkeys – 65g.

The 16 mg dose of Brineura in the TTP1 dog was the best dose based on the preservation of cognitive function and brain structure observed after treatment. This dose in dogs resulted in a dose of 320 mg in humans, while a dose of 20 mg in monkeys resulted in a dose of 300 mg in humans.

At the dog level, the predicted C-max in human CSF at a dose of 300 mg was 1,090 mcg / mL and an AUC of 11,200 mcg-hour / mL. In monkeys, the predicted human C-max was 1,100 mcg / mL and AUC of 13,000 mcg-hour / mL.

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Brineura awarded by Popular Science

Compared to the pharmacokinetic data from the phase 1/2 dose escalation trial, the human equivalent dose of 300 mg was twice the exposure observed in CSF in both animal models. After scaling by dose, the mean absolute percent error or MAPE, a measure of the accuracy of predictions, was 21%, with values ​​below 20% considered good predictors.

“The PK [pharmacokinetic] the models developed in this study are empirical in nature and rely on allometric scaling from a large animal model of disease with pharmacologically translatable endpoints for translation of therapeutic dose and exposure to humans The researchers wrote.

Scientists said the approach used here provides an example of how, with rare diseases, non-clinical data can be used to streamline clinical development.

This is “a method for translating dose and predicting human exposure to CSF ​​which may be applicable to other [brain and spinal cord-] therapies given during development, ”they wrote.

“These data will be invaluable for other therapies delivered by the central nervous system under development”, concluded the scientists.

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