Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic Group: cenegermin (recombinant human nerve growth factor), ATC code: S01XA24.


Mechanism of action

OXERVATE contains cenegermin, a recombinant form of human nerve growth factor.

Nerve growth factor is an endogenous protein involved in the differentiation and maintenance of neurons, which acts through specific high-affinity (i.e., TrkA) and low-affinity (i.e. p75NTR) nerve growth factor receptors. Nerve growth factor receptors are expressed in the anterior segment of the eye (cornea, conjunctiva, iris, ciliary body, and lens), by the lacrimal gland, and by posterior segment intraocular tissues. The treatment with cenegermin, administered as eye drops, is intended to allow restoration of corneal integrity.

Clinical efficacy and safety

The efficacy and safety of OXERVATE were evaluated in two multicentre, randomised, double-masked, vehicle-controlled clinical studies (NGF0212 and NGF0214) in patients with moderate (persisted epithelial defect) or severe (corneal ulcer) neurotropic keratitis refractory to non-surgical treatments. In both studies patients received OXERVATE or vehicle 6 times daily in the affected eye(s) for 8 weeks, and underwent a follow-up period.

Study NGF0214 enrolled 48 patients (mean age 65±14 years, range 33-94 years) treated with OXERVATE 20 µg/ml or vehicle (24 patients per arm). Study NGF0212 enrolled a total of 174 patients (mean age
61±16 years, range 18-95 years), who have been exposed to OXERVATE and vehicle without the L- methionine excipient; 156 patients were assessed independently for efficacy, comparing two different dosages of the medicinal product with 20 and 10 µg/ml cenegermin to vehicle (52 patients per arm).
The table below summarizes the results for complete corneal healing of the persistent epithelial defect or corneal ulcer (the primary endpoint, defined as the greatest diameter of corneal fluorescein staining <0.5 mm) after 4 and 8 weeks of treatment for patients who received OXERVATE 20 µg/ml or vehicle in the two studies.

Study NGF0214              Study NGF0212
Results after 4 and 8 weeks of treatment                Week 4    Week 8           Week 4    Week 8 OXERVATE            56.5 %     69.6 %          58.0 %     74.0 %
Complete corneal healing rate            vehicle        37.5 %     29.2 %          19.6 %     43.1 % (p value)        (0.191)   (0.006)          (0.001)   (0.002)

The percentage of patients experiencing complete corneal clearing (grade 0 on the modified Oxford scale), the least squares mean change in best corrected distance visual acuity score (Early Treatment Diabetic Retinopathy Study letters) from baseline and any improvement in corneal sensitivity as measured in millimetres by Cochet-Bonnet aesthesiometry (difference compared to baseline >0) was also measured after 8 weeks of treatment in both studies, and summarized in the table below.

Results after 8 weeks of treatment                             Study NGF0214          Study NGF0212 OXERVATE             22.7 %                 21.4 %
Complete corneal clearing                         Vehicle           4.2 %                 10.0 % (p value)         (0.062)                (0.157)
OXERVATE               6.11                   11.9
Best corrected distance visual acuity             Vehicle            3.53                   6.9 (p value)         (0.143)                (0.213)
OXERVATE             72.2 %                 76.3 %
Corneal sensitivity inside lesion                 Vehicle          60.0 %                 68.4 % (p value)         (0.458)                (0.442)

Patients considered completely healed at the end of 8 weeks of treatment with OXERVATE did not tend to have recurrences within the 12 months follow-up period of study NGF0212. Specifically, more than 80 % 

of the 31 patients who were healed after initial OXERVATE 20 µg/ml treatment and for whom a response was available, remained completely healed at the end of the 12 months follow up period.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption

Cenegermin is mostly removed from the eye with the tear production and through the naso-lacrimal duct; the minor portion that is absorbed occurs mostly in the conjunctiva and peri-orbital tissue and to a minor extent through the cornea following ocular administration.
Pharmacokinetic profiling of patients included in studies found no accumulation effect of cenegermin. In general, the systemic absorption of OXERVATE is negligible.

Distribution

After eye drop administration, cenegermin is distributed particularly in the anterior portion of the eye, although a study with radiolabelled cenegermin in rats has shown that it also reaches the retina and other posterior parts of the eye at doses significantly higher than those administered by eye drops in humans to treat neurotrophic keratitis. At the ocular doses, cenegermin is not distributed throughout body tissues as there is no systemic absorption above the natural baseline levels.

Biotransformation

Ocular administered cenegermin is mainly eliminated by tear secretion and the remainder mostly biotransformed by local tissue proteases.

Elimination

Cenegermin administered by eye drops is mostly eliminated with the tear secretion.