RESUMO
Choroideremia, an incurable, progressive retinal degeneration primarily affecting young men, leads to sight loss. GEMINI was a multicenter, open-label, prospective, two-period, interventional Phase II study assessing the safety of bilateral sequential administration of timrepigene emparvovec, a gene therapy, in adult males with genetically confirmed choroideremia (NCT03507686, ClinicalTrials.gov). Timrepigene emparvovec is an adeno-associated virus 2 (AAV2) vector encoding the cDNA of Rab escort protein 1 (REP1), augmented by a downstream woodchuck hepatitis virus post-transcriptional regulatory element (WPRE). Up to 0.1 mL of timrepigene emparvovec, containing 1×1011 vector genomes, was administered by subretinal injection following vitrectomy and retinal detachment. The second eye was treated after an intra-surgery window of <6, 6-12, or >12 months. Each eye was followed at up to nine visits over 12 months. Overall, 66 participants received timrepigene emparvovec and 53 completed the study. Visual acuity was generally maintained in both eyes, independent of intra-surgery window duration, even after bilateral retinal detachment and subretinal injection. Bilateral treatment was well tolerated, with predominantly mild or moderate treatment-emergent adverse events (TEAEs) and a low rate of serious surgical complications (7.6%). Retinal inflammation TEAEs were reported in 45.5% of participants, with similar rates in both eyes; post-hoc analyses found these were not associated with clinically significant vision loss at Month 12 versus baseline. Two participants (3.0%) reported serious noninfective retinitis. Prior timrepigene emparvovec exposure did not increase the risk of serious TEAEs or serious ocular TEAEs upon injection of the second eye; furthermore, no systemic immune reaction or inoculation effect was observed. Presence of anti-vector neutralizing antibodies at baseline was potentially associated with a higher percentage of TEAEs related to ocular inflammation or reduced visual acuity after injection of the first eye. The GEMINI study results may inform decisions regarding bilateral sequential administration of other gene therapies for retinal diseases.
RESUMO
INTRODUCTION: Approved in 1994 and assigned the International Nonproprietary Name (INN) imiglucerase by the World Health Organization, Cerezyme® (Sanofi Genzyme) is an enzyme replacement therapy used to treat Gaucher disease in > 90 countries. At least two therapies approved outside the USA and the European Union, Abcertin® and Asbroder®, have adopted the identical INN imiglucerase. Both drugs were approved via regulatory pathways not aligned with World Health Organization Similar Biotherapeutic Product guidelines. OBJECTIVE: We analyzed whether the use of the identical INN "imiglucerase" for these drugs impacts adverse event (AE) reporting in the Sanofi Global Safety Database. METHODS: First, we reviewed all imiglucerase individual case safety reports (referred to as cases) including AE data reported between January 2012 and March 2018 that contained Abcertin or Asbroder in the narrative. In a second analysis, we examined cases from Mexico reported between May 2013 and March 2018 to assess changes in imiglucerase reporting following the 2015 approval of Asbroder in Mexico. RESULTS: Fifty-six cases mentioning Asbroder and none mentioning Abcertin were retrieved in the first analysis. Upon close review, the AEs of 45 cases (80.4%) were attributed to Asbroder, one (1.8%) to Cerezyme; the specific drug attribution for the AEs of ten cases (17.9%) could not be determined. In the second analysis, a substantial increase in cases and AEs was observed in the period after Asbroder approval (73 cases with 150 AEs pre-approval vs 132 cases with 333 AEs post-approval). Twenty-three of 132 (17.4%) post-approval cases reported discontinuation of treatment (19 related to Asbroder AEs, and four related to Cerezyme AEs). Infusion-associated reactions occurred in 25/132 cases (17 Asbroder related, six Cerezyme related, two indeterminate). CONCLUSIONS: This analysis demonstrates two potential consequences of identical INN use between Cerezyme and Asbroder: (1) an aggregate safety profile for Cerezyme that includes other products using the identical INN leading to inaccurate pharmacovigilance data and (2) healthcare providers switching, substituting, or potentially assuming interchangeability between the products. Identical INN use without the brand name differentiator may compromise pharmacovigilance data, potentially masking differences in safety profiles between products.
The objective of this study was to assess the consequences of multiple drugs using the identical International Nonproprietary Name (INN) "imiglucerase" on adverse event reporting in the Sanofi Genzyme Global Safety Database. The World Health Organization established the INN system to identify drugs that are made of the same pharmaceutical substance and recommends that different products have distinct INN names. The INN imiglucerase was assigned in 1994 to Cerezyme® (Sanofi Genzyme), an orphan drug for the treatment of a rare disease known as Gaucher disease. In 2015, Asbroder® (ISU Abxis) was approved for Gaucher disease in Mexico and has adopted the INN imiglucerase. It was not approved as a biosimilar to Cerezyme. Most importantly, in a significant proportion of the adverse event cases reported, patients received a combination therapy of Asbroder and Cerezyme or Asbroder and "imiglucerase", suggesting that the shared INN may have led to misconceived interchangeability of these products. Such confusion among healthcare providers poses a potentially serious risk to patient safety and health. These results are especially worrisome because they relate to products sharing an INN that were not approved as biosimilars. The findings from this study are also consistent with the view that Cerezyme and Asbroder may have different safety profiles. The implications of drug products having the same INN are discussed in the article as well as recommended solutions. To our knowledge, this is one of the first reports on real-world safety experience with biologics sharing the same INN name.