ABBV-951, Levodopa as Infusion, Seen as Similar to Intestinal Gel

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by Steve Bryson, PhD |

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ABBV-951, a continuous infusion formulation of levodopa/carbidopa, brought comparable levels of levodopa into the bloodstream of healthy volunteers as surgically implanted levodopa-carbidopa intestinal gel (LCIG), a Phase 1 study confirmed.

Because the delivery of doses can be tailored to a patient’s needs, this alternative form of delivery — a portable pump allowing 24-hour, under-the-skin infusion of the medicine — may be an effective option for controlling Parkinson’s symptoms and motor fluctuations in people with advanced disease, the researchers wrote.

The study, “Foslevodopa/foscarbidopa subcutaneous infusion maintains equivalent levodopa exposure to levodopa-carbidopa intestinal gel delivered to the jejunum,” was published in the journal Parkinsonism & Related Disorders.

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Levodopa, a standard treatment, is a precursor of dopamine, the nerve signaling molecule that is abnormally low in Parkinson’s patients. Levodopa is usually taken orally alongside carbidopa, a medicine that prevents the breakdown of levodopa before it reaches the brain.

But as Parkinson’s progresses, the absorption of oral levodopa in the gut can vary, leading to fluctuations in the levels of levodopa in the bloodstream that reduce its effectiveness.

LCIG, sold as Duodopa or Duopa, is a formulation of levodopa and carbidopa developed by AbbVie and administered via a tube surgically inserted into the small intestines to minimize bloodstream fluctuations. LCIG is typically delivered over 16 hours during the day, and patients often take additional oral tablets of levodopa/carbidopa or other Parkinson’s medications for symptoms that emerge during the night and in the morning.

ABBV-951, being developed by AbbVie, is a subcutaneous (under-the-skin) formulation of foslevodopa and foscarbidopa, two prodrugs metabolized into levodopa and carbidopa, that is administered through a continuous subcutaneous infusion via a portable pump. This delivery method has the potential to be as effective as LCIG without the need for surgery.

“Foslevodopa/foscarbidopa is intended for 24-h[our] continuous infusion to help manage night-time motor symptoms of [Parkinson’s disease] as well as minimize morning ‘off’ symptoms,” the researchers wrote.

In this Phase 1 study, scientists at AbbVie compared the therapeutic absorption of 24-hour foslevodopa/foscarbidopa delivery to 16-hour LCIG, plus two oral levodopa/carbidopa doses, in 25 healthy adults, ages 45 to 75. Participants were randomly assigned in equal numbers to either form of treatment delivery, then switched to the other delivery form.

Blood samples were collected before infusion and throughout each treatment regimen, with blood measured for levels of levodopa, carbidopa, foslevodopa, foscarbidopa, and 3-OMD, a metabolite of levodopa.

Analysis revealed that the difference in levodopa exposure was less than 8% between the two regimens, “well contained within the defined equivalence range,” the scientists wrote. The two regimens differed little concerning short-term (up to 16 hours) or overall levodopa exposure.

The maximum level of levodopa achieved within a 16-hour window (hours 0 to 16) was lower for the foslevodopa/foscarbidopa regimen than LCIG (605.6 vs. 656.4 nanograms/mL), a ratio of 0.923.

Estimates for the overall maximum levodopa level were 658 nanograms/mL for the foslevodopa/foscarbidopa regimen and 1874 nanograms/mL for LGIG plus two oral levodopa/carbidopa doses. The time to reach the maximum levels of 3-OMD was similar between the two regimens.

Between two and 16 hours, when both infusions were ongoing, bloodstream fluctuations in levodopa levels were lower for the foslevodopa/foscarbidopa regimen compared with LCIG. From two to 24 hours, in comparison, the levodopa fluctuation was “considerably lower” than the LCIG plus two oral levodopa/carbidopa doses.

Continuous 24-hour infusion of foslevodopa/foscarbidopa provided similar levodopa levels to LCIG infusion over the 16-hour interval, which were maintained throughout the night, the study noted.

Of the 25 adults that started the study, 20 completed both treatment regimens. Five left the study.

More treatment-related side effects were reported following foslevodopa/foscarbidopa infusion (79%) than LCIG delivery (20%), mainly driven by infusion-site reactions that included redness, swelling, and, less frequently, pain at the injection site. All were reported to be mild and to not cause anyone to discontinue the study.

“Foslevodopa/foscarbidopa subcutaneous infusion provides levodopa exposures comparable to LCIG throughout the day,” the scientists concluded, with study findings showing that a continuous infusion of “foslevodopa/foscarbidopa achieves stable therapeutically relevant [levodopa] exposures without the need for surgery or concerns of a food effect on [levodopa] absorption.”

While no new safety concerns were evident, “the importance of education in aseptic techniques and in the right application of the infusion set is crucial to guarantee an overall positive patient experience and minimize skin reactions,” they added.