The Development of BRM-203

Starting Observation
During our clinical research with LD prodrugs and LD we noticed that Gly-DOPA was not completely split in vivo but Penta-DOPA was. So, we defined Penta-Dopa as development candidate. However, when we studied the effect of different doses and administration intervals of oral AADC inhibitors on the plasma LD levels of sc-infused Penta-Dopa, we recognized sharp LD level increases shortly after the oral inhibitor was taken. This observation emphasized the need for more frequent oral carbidopa/benserazide dosing regimens (or effective modified release formulations) to achieve a constant inhibitor plasma level as a must for optimal inhibition of L-DOPA metabolism.
Dose dependent effects of Benserazide (BZ) and Carbidopa (CD)
In order to always have standard conditions, we studied the effects of 12.5, 25, and 50mg/hour of BZ and CD and compared respective AUC data with sc-infused LD without AADC inhibitor. Results are shown in the Figure 1 below.

Figure 1: The dependency of total mean AUC (ng*h/ml) of LD following either no AADC inhibition or during 12.5, 25, or 50 mg Benserazide (filled circles) or Carbidopa/h (squares) in volunteers; the total LD dose was 50 mg either as a bolus i.v. injection or as sc-infusion over 4 hours (12.5mg/h);

Obviously, the AADC inhibition increased total systemic LD availability 3.1 fold (benserazide) or 2.4 fold (carbidopa) at the 50mg/h dose levels.
The Invention
This finding was very surprising, since all marketed L-DOPA/carbidopa or benserazide products (cf. package inserts) limit the total daily carbidopa/benserazide dose to 200mg, translating to an hourly dose limit of roughly 8 mg/h.
The conclusion was, that all clinically used L-DOPA/CD (BZ) dose regimens clearly underdose the inhibitors resulting in an incomplete inhibition of LD decarboxylation.
While this may not pose a significant concern in oral therapy, when LD dose adjustments is easily done, the situation takes a critical turn in subcutaneous formulations, where the skin’s tolerance to elevated L-DOPA doses is severely constrained.
Berlirem decided to postpone the development of Penta-Dopa and to develop the combination sc-LD/oral CD instead. Reasons were:
• the use of oral carbidopa is of proven safety; high CD doses are given in the intraintestinal formulations (LCIG), in which 1000 mg and more carbidopa are applied per day
• L-DOPA plasma levels under high, optimised carbidopa dosing (BRM-203) were almost three times higher at equivalent infusion doses than of the (approved) formulation from competitors (ABBV-951; ND-0612).
• As an example, Figure 2 demonstrates what was filed for a patent

Figure 2 shows the development of the LD plasma level (ng/ml) during a sc infusion of 18.75 mg/h LD (equivalent to a daily dose of 450 mg LD) under almost complete inhibition of LD metabolism by CD (600 mg/day) and opicapone in standard dose. After 14 h, LD plasma levels of almost 1.600 ng/ml were reached.

Therefore, this innovative principle (BRM-203) was filed with the patent office.
In 2023, the patent for BER-203 was granted, entering the PCT-phase.