|Exclusion Criteria:||1) Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception (confirmed by a positive hCG laboratory test ;> 5 mIU/mL) and until the termination of gestation.|
2) Women of child bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method. A) adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. B) Hormonal contraceptives include any marketed contraceptive agaent that includes an estrogen and/or progestational agent. C) Reliable contraception should be maintained throughout the study and for 5 half lives of study drug after study tertment discontinuation. Cont. on #3
3) Cont. from #2: D) Women considered port- menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg. Age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL and estradiol < 20 pg/mL or have had surgical bilateral oopherectomy (with or without hysterectomy) at least six weeks ago. In the case of oopherectomy alone, only when the reproductive status of the women has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. E) Sexually active males must use a condom during intercourse while taking the drug for five half lives after stopping treatment and should not father a child in this period. A condom is require d to be used also be vastectomized men in order to prevent delivery of the drug via seminal fluid.
4) Subjects with inadequate liver or renal function at Screening as demonstrated by: a. Encephalopathy Grade 2 or more as per Child-Pugh System. b. Known hepatocellular disease (for example, hepatitis B or C, cirrhosis or other hepatocellular disease) c. Direct bilirubin equal to or more than 2 X upper limit of laboratory normal (ULN). d. Alanine aminotransferase (ALT) > 2.5x ULN. e. MDRD-eGFR < 30 mL/min/1.73m2 or on dialysis.
5) Subjects with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
6) Subjects with clinically significant bacterial, fungal, parasitic or viral infection which requires therapy: • Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed. • Subjects with known active hepatitis A, B or C at Screening or with known HIV positivity.
7) Subjects with diagnosed primary immunodeficiency syndromes such as X-Linked Agammaglobulinemia and Common Variable Immune Deficiency
8) Subjects with an active malignancy over the previous 5 years except treated cervical intraepithelial neoplasia, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin, with no evidence for recurrence in the past 3 years.
9) Subjects with clinically significant cardiac disease (NYHA Class III or IV).
10) Subjects receiving PEG-IFN-alpha-2a within 5 weeks of Screening or having a prior history of 32P therapy.
11) Subjects being treated concurrently with a potent systemic inhibitor of CYP3A4 at the time of Screening (ketoconazole, clarithromycin, itraconazole, nefazodone or telithromycin).
12) Subjects being treated concurrently with any prohibited medications
13) Subjects who have previously received treatment with a JAK inhibitor.
14) Subjects being treated concurrently with any investigational agent or prior participation in an investigational study within 30 days prior to enrollment or within 5-half lives of the investigational product, whichever is longer.
15) Subjects who are unable to comprehend or are unwilling to sign an informed consent form (ICF)
16) Subjects with active alcohol or drug addiction that would interfere with their ability to comply with the study requirements.
17) Subjects with an uncontrolled intercurrent illness or any concurrent condition that, in the investigator's opinion, would jeopardize the safety of the subject or compliance with the protocol.