Cenegermin (1) – Oxervate®

• Clinical trials
  • The NGF0212 study is a double-blind, randomised, controlled trial in which Cenegermin was investigated at two concentrations (10 μg/ml and 20 μg/ml) in comparison with a vehicle control.
  • The NGF0214 study is a double-blind, randomised, controlled trial in which Cenegermin at a potency of 20 μg/ml was compared with a vehicle control.

Adult patients with moderate or severe neurotrophic keratitis

• For adult patients with moderate or severe neurotrophic keratitis, there is a non-quantifiable additional benefit.
• In the overall assessment, a non-quantifiable added benefit has been identified for Cenegermin in the treatment of adult patients with moderate or severe neurotrophic keratitis, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective, a non-quantifiable additional benefit has been established.
• mortality
  • No statistically significant differences between the study arms were observed in any of the studies.
• Morbidity – Complete healing of the corneal epithelium
  • Complete healing of the corneal epithelium was assessed using imaging methods (fluorescein staining of the cornea).
  • For both operationalisations, the meta-analyses showed a statistically significant advantage for Cenegermin across all studies (EMA operationalisation: RR 1.7 [95% CI 1.2; 2.3], I=0%), FDA operationalisation: RR 1.9 [95% CI 1.3; 2.6], I=0%).
  • In the studies NGF0212 and NGF0214, treatment with the vehicle – which is approximately comparable in composition to artificial tears – resulted in healing of the corneal epithelium (as defined by the FDA) was achieved in 29–50% of patients. With Cenegermin, this was achieved in 58–71% of patients.
  • Against this background, the use of fluorescein staining to operationalise the endpoint ‘complete healing of the corneal epithelium’ is considered appropriate for this indication.
  • Given that no comparative data covering a sufficiently long period are available, no conclusions can be drawn regarding the sustainability of the effect.
• Morbidity – Improvement in best-corrected visual acuity by ≥ 15 ETDRS letters
  • With regard to the improvement in best-corrected visual acuity by ≥ 15 ETDRS letters, no statistically significant differences were observed between the study arms in the NGF0212 trial.
• Morbidity – Progression of lesion depth to corneal melting or perforation and corneal infection
  • With regard to disease progression, measured as the proportion of patients with progression of lesion depth to corneal melting or perforation, or as the proportion of patients with a cornealinfection after 8 weeks, no statistically significant differences were observed between the treatment groups at study level or in the meta-analysis (RR 1.2 [95% CI 0.3; 4.3], I=0% and RR 0.8 [95% CI 0.3; 2.1], I=0%, respectively).
• Morbidity – EQ-5D VAS
  • In the NGF0212 Phase 2 trial, no statistically significant difference in the change in the EQ-5D VAS at 8 weeks compared with baseline was observed between cenegermin and the vehicle.
  • Due to the low response rate, the results of NGF0214 and the Phase 1 study NGF0212 can be considered invalid.
• quality of life
  • The results on health-related quality of life are based on the NEI-VFQ-25 at 8 weeks.
  • After 8 weeks, both groups showed, on average, minor improvements in the NEI-VFQ-25 compared with baseline. The difference between the groups was not statistically significant.
  • The validity of the quality of life results is limited due to the high dropout rate and the associated low response rates.
• Side effects – adverse events (AEs), serious adverse events, vision-threatening events
  • Although numerically more patients in the cenegermine groups were affected, there was no statistically significant difference in Grade 3 AEs or serious adverse events, either at the individual study level or across studies.
  • In the summary analysis of vision-threatening events, which were defined as AEs of particular interest, no statistically significant differences were observed between the treatment groups.
  • As some of the reported adverse events are characteristic symptoms of this clinical condition – such as reduced visual acuity, eye pain, corneal epithelial defect and ocular inflammation, the interpretation of the results regarding adverse events is subject to uncertainty.
• Side effects – ocular tolerability
  • With regard to the change from baseline, no statistically significant result was observed for the total score.
  • For two subscales (burning or stinging and eye pain), there was indeed a statistically significant effect to the detriment of Cenegermin; however, the effect remained below the irrelevance threshold of 0.2.
• Side effects – therapy discontinuation due to AEs
  • Overall, the meta-analysis showed no statistically significant differences between the treatment arms for the endpoint of therapy discontinuation due to AEs.
• Overall assessment
  • To assess the extent of the additional benefit of Cenegermin for the treatment of moderate or severe neurotrophic keratitis in adult patients, the studies NGF0212 and NGF0214 provide results on mortality (overall survival), morbidity (symptoms), quality of life and side effects.
  • With the exception of the endpoint ‘complete healing of the corneal epithelium’ in the morbidity category, no clinically relevant differences between the treatment groups were identified for the other endpoints.
  • The endpoint ‘complete healing of the corneal epithelium’ is classified as patient-relevant and is used to determine the extent of the additional benefit.
  • However, the results for this endpoint are subject to uncertainty. The comparative treatment duration of 8 weeks was too short to assess the sustainability of the effect with regard to the recurrence of corneal defects and to demonstrate the prevention of secondary damage.
  • With regard to side effects, it should be noted that the reported adverse events could equally be symptoms of the disease itself. No statistically significant differences were observed between patients treated with Cenegermin and those treated with the vehicle.
  • In light of the uncertainties mentioned, it is not possible to validly quantify the additional benefit as ‘minor’, ‘considerable’ or ‘major’ on the basis of the data provided.

Courtesy translation only, please refer to the German original.