肌萎罕藥申請健保給付 家屬籲政府速通過 2016-04-0921:06 〔記者洪定宏／高雄報導〕由美國生物製藥公司PTC研發的罕藥Translarna，已取得歐洲藥物管理局（EMA）的上市授權，可用於無意義突變導致的裘馨型肌萎縮症患者（nmDMD），但因所費不貲，且須終生服藥，藥商已向衛福部提出健保給付申請，中華民國肌萎縮症病友協會理事長林榮祥呼籲政府儘速核准通過，減輕病友及家屬負擔，對未來充滿希望。肌萎縮症是基因缺損造成的罕見疾病，有很多類型，全台約500人，其中以裘馨型最常見也最嚴重，該藥物使用條件必須為裘馨型、年滿5歲且能行走，經過協會與藥商篩選，目前符合者僅6人。 台南市永康區的10歲李小弟是其中之一，他於7歲確診為裘馨型，雖然逐漸萎縮，但尚能行走及打球運動；李媽媽強調，若藥商能先免費提供，她願意讓孩子嘗試，只希望病症不再惡化。 中華民國肌萎縮症病友協會舉辦創會20週年活動，邀請台中榮總兒童醫學部主治醫師李秀芬與近300名肌萎病友及家屬，分享國外罕藥研究的重大突破與進展。 李秀芬表示，罕藥Translarna是蛋白質重建療法，能在患者身上形成功能性蛋白質，有效減緩肌肉功能惡化。代理藥商吉帝藥品公司營運處長江政起指出，法國及瑞士等國已核准為健保用藥，公司去年4月向衛福部提出申請，目前尚在補件，若有患者願意自費，可透過醫師向醫院、衛福部提出專案申請。
Translarna : Ataluren, formerly known as PTC124, is a pharmaceutical drug for the treatment of Duchenne muscular dystrophy and potentially other genetic disorders. It was designed by PTC Therapeutics and is sold under the trade name Translarna in the European Union. Medical uses Ataluren has been tested on healthy humans and humans carrying genetic disorders caused by nonsense mutations,[1][2] such as some people with cystic fibrosis and Duchenne muscular dystrophy. It is approved for the use in Duchenne in the European Union. Mechanism of action Ataluren makes ribosomes less sensitive to premature stop codons (referred to as "read-through"). This may be beneficial in diseases such as Duchenne muscular dystrophy where the mRNA contains a mutation causing premature stop codons or nonsense codons. There is ongoing debate over whether Ataluren is truly a functional drug (inducing codon read-through), or if it is nonfunctional, and the result was a false-positive hit from a biochemical screen based on luciferase.[3] In cystic fibrosis, early studies of ataluren show that it improves nasal potential difference.[4] Ataluren appears to be most effective for the stop codon 'UGA'.[1] Clinical trials In 2010, PTC Therapeutics released preliminary results of its phase 2b clinical trial for Duchenne muscular dystrophy, with participants not showing a significant improvement in the six minute walk distance after the 48 weeks of the trial.[5] This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug. Phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.[6] Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.[7] Approval On 23 May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).[8] Translarna was first available in Germany, the first EU country to launch the new medicine.[9] In August 2014, ataluren received market authorization from the European Commission to treat patients with nonsense mutation Duchenne muscular dystrophy. A confirmatory phase III clinical trial is ongoing.[9] The drug does not yet have approval by the US Food and Drug Administration. In October 2015, NICE asked for further evidence of benefit to justify the "very high cost".[10] NICE estimated that for a typical patient, treatment would cost £220,256 per year. In February 2016, FDA declined to approve ore even discuss PTC Therapeutics application for ataluren because it deemed the data presented by the developer "insufficient to warrant a review".[11]
Translational read-through of the RP2 Arg120stop mutation in patient iPSC-derived retinal pigment epithelium cells. Hum Mol Genet. 2015 Feb 15;24(4):972-86. Mutations in the RP2 gene lead to a severe form of X-linked retinitis pigmentosa. RP2 patients frequently present with nonsense mutations and no treatments are currently available to restore RP2 function. In this study, we reprogrammed fibroblasts from an RP2 patient carrying the nonsense mutation c.519C>T (p.R120X) into induced pluripotent stem cells (iPSC), and differentiated these cells into retinal pigment epithelial cells (RPE) to study the mechanisms of disease and test potential therapies. RP2 protein was undetectable in the RP2 R120X patient cells, suggesting a disease mechanism caused by complete lack of RP2 protein. The RP2 patient fibroblasts and iPSC-derived RPE cells showed phenotypic defects in IFT20 localization, Golgi cohesion and Gβ1 trafficking. These phenotypes were corrected by over-expressing GFP-tagged RP2. Using the translational read-through inducing drugs (TRIDs) G418 and PTC124 (Ataluren), we were able to restore up to 20% of endogenous, full-length RP2 protein in R120X cells. This level of restored RP2 was sufficient to reverse the cellular phenotypic defects observed in both the R120X patient fibroblasts and iPSC-RPE cells. This is the first proof-of-concept study to demonstrate successful read-through and restoration of RP2 function for the R120X nonsense mutation. The ability of the restored RP2 protein level to reverse the observed cellular phenotypes in cells lacking RP2 indicates that translational read-through could be clinically beneficial for patients.
G418 is an aminoglycoside that is proposed to suppress NMD by inhibiting translationally active ribosomes and thereby lowering the efficiency of the cellular proof-reading machinery (60). G418 has successfully suppressed PTCs in cellular models (61), as well as in patients with Duchenne muscular dystrophy and cystic fibrosis (62–66). However, the clinical disadvantages of G418 treatment are the high level of toxicity for long-term use, such as nephron- and ototoxicity, as well as the requirement for intramuscular or intravenous drug delivery (67). In contrast, PTC124 has an excellent preliminary safety and tolerability profile and can be taken orally (47,68). PTC124 has been successfully used in treatment of arylsulfatase B (ARSB associated mucopolysaccharidosis) (69) and PTC124 is currently in clinical trials for the treatment of cystic fibrosis (70) and Duchenne muscular dystrophy (46); however, the clinical findings of these studies are not conclusive. In a Phase 3 clinical trial of PTC124 treatment for cystic fibrosis, patients did not have an increased lung function following treatment (70). In contrast, the majority of patients in a Phase 2a clinical trial for Duchenne muscular dystrophy showed a PTC124 mediated increase in dystrophin levels (46). The mechanism of action for PTC124 is still controversial. It has been suggested that the activity of PTC124 in luciferase-based in vitro experiments is due to PTC124′s post-translational stabilization of the luciferase reporter and not a genuine read-through effect (71). However, PTC124 treatment restored 20–25% of dystrophin protein levels in the mdx-mouse, a model for Duchenne muscular dystrophy, in vitro and in vivo (47). In addition, a recent study using a GFP reporter plasmid showed that PCT124 was effective in inducing full-length protein expression of GFP containing a stop codon. Computational modelling of the supramolecular interaction of PTC124 and an mRNA fragment containing a stop codon confirmed that PTC124 interacts specifically with the stop codon (72). These findings and our data suggest that PTC124 is indeed able to promote translational read-through of premature stop codons.
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