Development of BRM-203

The Aim:
Continuous Dopaminergic Stimulation (CDS) helps to alleviate motor dysfunctions (on/off, L-Dopa induced dyskinesias) in PD patients.
The Situation
Oral sustained release L-Dopa-formulations failed to generate steady-state plasma levels.
Duo-DOPA®- although meeting the CDS aim with large variances – is cumbersome and unpleasant and even
severely diseased patients shy away from the surgical intervention.
New Developments using sc-Infusions
Neuroderm´s (ND-0612H) subcutaneous infusion shows the narrow limitations of LD-solubility. Treatment with 2 infusion sites hardly reach 800 ngLD/ml, which needs oral add-on treatments. ND-0612H not only misses the CDS aim but also shows significant local side effects. The mass ratio of LD to CD is 8:1.
AbbVie´s Pro-Duodopa® seems to be able to generate sufficiently high LD plasma levels but practically works without inhibition of AADC. The mass ratio of FLD to FCD is 20:1. Probably, FCD was made a part of the preparation mainly because only the mixture was patentable.
BRM-203 achieves a breakthrough by reducing the LD dose, that needs to be given by sc-infusion. As shown by PhaseI studies LD plasma levels were increased up to threefold by continuous and higher dosed AADC inhibitors. By this (patented) invention, the daily LD-dose given by sc-infusion was reduced to a level that is locally well tolerated with only one infusion site.

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.

Contact us

Phone: +49(0)30 288 69 878
Fax: +49(0)30 288 69 696

Berlirem GmbH

Breite 1
15806 Zossen

REDAXO 5 rocks!