Alnylam's approach is to knock down ALAS-1, an enzyme upstream of porphobilinogen deaminase , the defective gene in AIP. RNAi-mediated silencing of hepatocyte ALAS-1 could reduce the abnormal creation of the toxic heme intermediates, particularly aminolevulinic acid and porphobilinogen , which mediate the symptoms and disease pathology in AIP individuals. Alnylam believes that a subcutaneously administered RNAi therapeutic targeting ALAS-1 has the potential to be utilized as a prophylactic method of prevent attacks and also as a therapy for acute episodes. Specifically, multi-dose administration of a GalNAc-siRNA targeting ALAS-1 led to rapid, dose-dependent, and long-lasting knockdown of the ALAS-1 mRNA in non-human primates, with an ED50 of around 1.25 mg/kg.Serum creatinine levels improved from baseline by 33 percent or more in 37 of 373 patients who received 5 mg of tofacitinib and in 38 of 397 patients who received 10 mg of tofacitinib , as compared with 5 of 186 individuals who received methotrexate . An increase in serum creatinine degrees of more than 50 percent from baseline was confirmed by means of two consecutive exams in 6 patients in the 5-mg tofacitinib group and 11 patients in the 10-mg tofacitinib group, in comparison with no patients in the methotrexate group.