Opicapon (1) – Ongentys®

• Clinical trials
  • The pharmaceutical manufacturer cites the BIPARK-I study, including its open-label extension phase, as evidence of additional benefit. This is a randomised, actively controlled study with a parallel-group design, which was conducted at 106 centres in 19 European countries.

a) As an adjunct to levodopa/DOPA decarboxylase inhibitors (DDCI) in adult patients with Parkinson’s disease experiencing motor ‘end-of-dose’ fluctuations, in whom stabilisation cannot be achieved with these combinations

• Therefore, having weighed up the data submitted, the G-BA concludes that, for opicapon compared with entacapon in adult patients with idiopathic Parkinson’s syndrome and motor ‘end-of-dose’ fluctuations in whom stabilisation cannot be achieved with levodopa/DDCI.
• mortality
  • In the double-blind phase of the study, no deaths occurred and there was therefore no difference between the treatment arms.
• Morbidity – ON and OFF periods
  • The effect of the treatment on disease progression was demonstrated by the change in patients’ ON and OFF times (in minutes).
  • No superiority or inferiority of opicapon over entacapon could be demonstrated in either ON or OFF times.
• Morbidity – Symptoms (Unified Parkinson’s Disease Rating Scale, UPDRS)
  • The Unified Parkinson’s Disease Rating Scale (UPDRS) assesses cognitive functioning, behaviour and mood (Part I), activities of daily living (Part II), motor function (Part III) and complications during treatment (Part IV; the present analysis includes only the items relating to dyskinesias).
  • No statistically significant differences were observed between the opicapon and entacapon arms for any of the individual scales or for the total score of Parts I to III.
• Morbidity – Health Status (Patient’s Global Impression of Change, PGI-C)
  • In the Patient’s Global Impression of Change (PGI-C) assessment tool, the patient rates the change in their health status on a 7-point scale (from ‘much worse’ to ‘much better’).
  • Patients who reported an improvement (‘slightly better’, ‘much better’ or ‘very much better’) during the double-blind phase were classified as responders. Compared with entacapone, there was a significant benefit in favour of opicapone (72.2% vs. 52.5% with entacapone; p = 0.002).
  • An analysis considering only the top two categories (‘much better’ or ‘much, much better’), as was also used by the EMA in the authorisation process, shows no statistical significance.
  • However, the analysis is subject to methodological limitations, as there are no established standards for response criteria and clinically relevant differences. This is particularly significant with regard to the ‘slightly better’ category compared with the ‘no change’ category.
  • The robustness of the effect is questionable given that the significance threshold was not met in an alternative analysis, i.e. one considering only the categories ‘much better’ and ‘very much better’. Furthermore, this significant effect is not supported by advantages in other endpoints, particularly motor endpoints. Overall, there are uncertainties regarding both the methodology of the analysis and the relevance of the measured difference, meaning that no additional benefit can be established.
• Morbidity – Further endpoints (Clinician’s Global Impression of Change, CGI-C)
  • In addition, the pharmaceutical manufacturer also provides analyses of the Clinician’s Global Impression of Change (CGI-C), in which the change in the patient’s overall clinical impression is assessed in a similar manner on a 7-point scale by an investigator.
  • Self-assessment by the patient is generally possible for this indication and is considered more appropriate. An assessment by the investigator is not regarded here as sufficient or relevant to the patient.
• Morbidity – Additional endpoints (Parkinson’s Disease Sleeping Scale, PDSS, and Non-Motor Symptom Scale, NMSS)
  • The pharmaceutical manufacturer has submitted analyses of the Parkinson’s Disease Sleeping Scale (PDSS) and the Non-Motor Symptom Scale (NMSS).
  • However, there is a lack of evidence for the validity of these two instruments, which is why they are not taken into account in the assessment of additional benefit.
• Health-related quality of life (Parkinson’s Disease Questionnaire, PDQ-39)
  • The Parkinson’s Disease Questionnaire (PDQ-39) comprises 39 items across eight subscales (mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication and physical discomfort).
  • There is no significant difference in the total score between opicapon and entacapon.
• Side effects
  • As described, the results regarding adverse events must be considered in the context of the short study duration.
  • No significant differences were observed in the incidence of serious adverse events (3.5% with opicapon vs. 6.6% with entacapon; p = 0.293) or in therapy discontinuations due to adverse events (4.3% vs. 6.6%; p = 0.533).
  • Similarly, no statistical significance was observed for the numerically higher incidence of dyskinesias (15.7% with opicapon vs. 8.2% with entacapon; p = 0.080) and psychiatric disorders (MedDRA system organ class; 15.7% on opicapon vs. 8.2% on entacapon; p = 0.080) were numerically more frequent on opicapon, but no statistical significance was observed.

Courtesy translation only, please refer to the German original.