Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Holostem Terapie Avanzate s.r.l., Via Glauco Gottardi 100, 41125 Modena, Italy Telephone: +39 059 2058070 Telefax: +39 059 2058115
Pharmacotherapeutic group: Ophthalmologicals, other ophthalmologicals
ATC code: S01XA19
The mechanism of action of Holoclar is the replacement of corneal epithelium and lost limbal stem cells in patients in which the limbus has been destroyed by ocular burns. During the corneal repair process, the administered stem cells are intended to partially multiply, differentiate and migrate to regenerate corneal epithelium, as well as maintaining a reservoir of stem cells that can continually regenerate the corneal epithelium.
Conventional pharmacodynamic studies for Holoclar have not been performed.
The efficacy of the medicinal product was evaluated in a multi-centre, case-series, non-controlled, retrospective cohort study in 106 patients (HLSTM01 study) of both genders, treated for the presence of a moderate to severe limbal stem cell deficiency (LSCD). Moderate to severe LSCD was defined according to an invasion of at least two quadrants of the corneal surface by superficial neo vessels. A total of 104 patients, aged between 13 and 79 years (mean 46.8 years) were included in the primary efficacy analysis. At the time of product administration, the mean duration of the condition since the injury was 18 years (median 10 years), 99% of patients had corneal opacity and 90% of them had a severe impairment in visus (1/10th or less at Snellen chart). Success of the procedure was evaluated based on the presence of a stable corneal epithelium (i.e. absence of epithelial defects) without significant recurrence of neovascularisation (no more than one quadrant without central corneal involvement) at 12 months post-intervention. A total of 75 (72.1%) treatments were reported with a successful outcome. These results were confirmed in a sensitivity analysis where superficial neovascularisation was evaluated by an independent assessor from blinded photos of patients' eyes taken before and after Holoclar implantation.
Additional clinically-relevant parameters were evaluated as secondary efficacy assessments.
The proportion of patients with symptoms (pain, burning or photophobia) significantly decreased from pre-surgery (40 patients with at least one symptom; 38.5%) to one year after the procedure (12 patients; 11.5%).
Fifty-one patients (49.0%) had an improvement in visual acuity of at least one full line on a Snellen chart (or one category for the severely impaired cases). The proportion of patients with improvement in visual acuity was higher among those without a scar of the corneal stroma (15/18 patients, 83.3%) than in those with scarring (36/81 patients, 44.4%). When categorical values for visual acuity were converted into the Logarithm of the Minimum Angle of Resolution (LogMAR), 47% of cases (40 over 85 with non-missing values) experienced an improvement equal or greater than 3 Snellen line equivalents.
Fifty-seven patients underwent a keratoplasty after the use of the product with a success rate of 42.1% (N=24) one year after the corneal transplantation (i.e. with a stable corneal epithelium without significant recurrence of neovascularisation).
The HLSTM01 study enrolled a total of seven patients (6.7% of the study population) with an age at baseline of 65 years or above, and seven additional patients (24.1%) were included in HLSTM02. Although limited with regard to the number of subjects, data from both studies showed a success rate around 70% of treated cases in the elderly population. This level of efficacy is similar to that observed in the treated patients overall.
The European Medicines Agency has deferred the obligation to submit the results of studies with Holoclar in one or more subsets of the paediatric population in the treatment of limbal stem cell deficiency due to ocular burns (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
The product is implanted locally.
The nature and intended clinical use of Holoclar are such that conventional pharmacokinetic studies on absorption, biotransformation and elimination are not applicable. Immunohistochemical analysis of cornea taken from patients receiving keratoplasty after Holoclar treatment demonstrated that the transplanted stem cells establish a normal layer of stratified corneal epithelium, which do not migrate or invade basal ocular structures.
Non-clinical safety data were limited to in vitro testing of tumorigenicity of the human autologous cell cultures. These tests included cell karyotype, cell growth in soft agar and growth factor-dependent proliferation. In vitro studies have revealed no evidence of anchorage-independent growth indicative of tumorigenic potential.
The safety of Holoclar is demonstrated in the results obtained from the two retrospective clinical studies.
Conventional non-clinical reproductive and developmental toxicity studies are not considered relevant, given the nature and the intended clinical use of the autologous product.
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