近日，美国FDA内分泌及代谢药物咨询委员会以12票赞成，0票反对的投票结果肯定了意大利Recordati公司血液疾病治疗药Carbaglu，该药用于治疗高氨血症——罕见的常染色体遗传性疾病，可导致N-乙酰谷氨酸合成酶（NAGS）缺乏。而NAGS的缺乏会导致患者体内血氨水平升高，进而会永久性损害其中枢神经系统，具有长期性和致命性的特点。

FDA官员曾就该药的实验设计表示担忧，但同时又表示所有受试患者用药之后未发现严重的安全性问题。总体而言，FDA仍认为由于Carbaglu相关的实验数据在数量和质量上都存在严重不足，因此还不能对药物的疗效下定论。

但内分泌及代谢药物咨询委员并未受到上述观点的影响，他们认为药物相关的临床实验数据可有力论证其疗效，特别是证实该药可以针对治疗血氨水平。相关专业人士表示，这种产品疗效较为显著，为那些患有先天性NAGS缺乏症的儿童带来了希望。

Recordati公司罕见病药事业部欧洲分部也表示，已“充分证实”Carbaglu的疗效。目前NAGS缺乏症新生儿发病率大约为1/30000。Carbaglu的安全性也已得到认可，该公司未被要求就此展开后续工作，但FDA建议应建立相关的监测系统。

N-carbamylglutamate

N-carbamylglutamate can potentially improve hyperammonemia inpatients with propionic and methylmalonic acidemia   N-acetylglutamate (NAG) is achemicalproducedintheliverthatisessentialfornormal function of the urea cycle; without it, the cycle does not do its job ofdetoxifying ammonia.  Patients who are deficient in NAG intheliverdevelophyperammonemia. There are several causes for NAG deficiency. The most obvious isageneticdefect in N-acetylglutamate synthase (NAGS), the enzyme that produces NAG.  Other causes involve secondary NAG deficiency due to interference with its production by NAGS.  The most known cause for secondary NAG deficiency is propionic acidemia (PA) where the accumulation of propionyl-CoA in liver mitochondriainterfereswithNAGproduction. Methylmalonic acidemia (MMA)presumablymanifests the sameproblem. Similarly, patientstreated with valproic acidmayalsodeveloplowliverNAGduetointerferencewithNAGproductionbyvalproic acid metabolites.  All latter conditions are associated with hyperammonemia presumably due toNAG deficiency.  Since we have recently shown that the drug Carbaglu® (N-carbamylglutamate) restores to normal urea cycle functions and eliminates the hyperammonemia in patients with NAGS deficiency, we further hypothesize that patients with PA and MMA who have hyperammonemia may also benefit from this drug.  In order to investigate this hypothesis, wehavelaunched a study in patients with severe PA and MMA (those who presented with neonatal hyperammonemia).  The study is open to patients with severe PA or MMA who are 5 years and older and consists of oral administration of a stable isotope [13C]sodium acetate before, and following 3 days of Carbaglu treatment, comparing the amount of [13C] that ends up in urea as an indication of urea production rate.  One patient with PA who was studied showed a marked increase of urea production on Carbaglu as well as decrease in glutamine and glycine levels.  If this finding can be reproduced in additional patients with PA or MMA, it will suggest that Carbaglu could effectively treat hyperammonemia episodesinpatientswiththemostcommonorganicacidemias.Althoughhyperammonemia is only one of the several mechanisms of metabolic derangement in PA or MMA, alleviation of hyperammonemia could facilitate the management of these patients. If you are interested in being part of this study, please contact paf@pafoundation.com