Treatment of moderate-to-severe CFL with onabotulinumtoxinA was effective and well tolerated.

The concentrations of androstenedione, testosterone, oestrone and oestradiol-17beta were measured in peripheral and ovarian venous blood and follicular fluid of women at various stages of the menstrual cycle. The concentration of oestradiol was similar in small follicles (diameter less than 8 mm) at all stages of the menstrual cycle and in large follicles (diameter greater than or equal to 8 mm) except during the mid- and late follicular phase when the concentration reached a peak (approximately 1500 ng/ml). The concentration of androstenedione was lowest in large preovulatory follicles at midcycle at a time when the secretion into the ovarian vein was markedly increased. The concentration of testosterone in large follicles (greater than or equal to 8 mm) was unchanged during the follicular phase whereas in small follicles there was a peak at mid-cycle. The rise in the concentration of testosterone and androstenedione at mid-cycle in peripheral plasma may be due to increased secretion by the preovulatory follicle into the ovarian vein. It is suggested that the relatively low concentration of androstenedione in follicular fluid of the preovulatory follicle arises from increased aromatization by granulosa cells in the course of oestrogen synthesis.

Background:Uncontrolled complement activation plays a pivotal role in a variety of disorders such as paroxysmal nocturnal hemoglobinuria (PNH). Challenges to be addressed with eculizumab therapy include inter-individual variation in clearance of eculizumab, economic burden, and improvements in the current biweekly intravenous infusion maintenance schedule. ALN-CC5 is a subcutaneous (SC) investigational RNA interference (RNAi) therapeutic targeting hepatic complement C5 (C5) synthesis. Previously presented data from our ongoing Phase 1/2 study showed that ALN-CC5 was generally well tolerated and exhibited a clamped C5 knockdown and complement activity inhibition in healthy volunteers (Hill et al. Haematologica 2016; 101, Suppl 1). The aim of this abstract is to report updated tolerability and clinical activity of ALN-CC5 in patients with PNH. Methods: A phase 1/2 single-ascending dose (Part A) and multiple-ascending dose study (Part B) of ALN-CC5 was conducted in healthy adult volunteers and in patients with PNH (Part C). In Part C, patients with PNH received weekly doses of 200 mg or 400 mg of ALN-CC5 for 2 to 16 weeks; ALN-CC5 is administered subcutaneously at a concentration of 200 mg/mL. The primary endpoints are safety and tolerability and secondary endpoints include: pharmacokinetics (PK), reduction of circulating C5 and complement activity, as measured by CAP/CCP Wieslab ELISA assays and sheep erythrocyte hemolysis assay, as well as reduction in LDH. Results: Part C included 6 patients with PNH (treatment naïve n=3; patients receiving eculizumab n=3), including 1 patient who was experiencing breakthrough hemolysis despite receiving 1200mg eculizumab q2wk. ALN-CC5 was generally well tolerated in patients with PNH after multiple doses with the majority of adverse events (AEs) being mild or moderate in severity. There were no serious AEs or discontinuations due to AEs. One patient, who was also taking eculizumab, cyclosporine and anabolic steroids as concomitant medications, experienced a transient asymptomatic grade 3 elevation of liver transaminases that was deemed possibly related to study drug. In eculizumab naïve patients (n=3), ALN-CC5 monotherapy achieved a mean maximum C5 knockdown of 98.2% ± 0.3%, residual C5 levels of 0.9 mcg/mL and a mean maximum CCP inhibition of 94.2 ± 1.7%. During treatment with ALN-CC5, maximum reduction in LDH was 37% and 50% in 2 patients who received 17 doses of ALN-CC5 but remained above the goal of less than 1.5 times the ULN. In the remaining eculizumab naïve patient, LDH lowering was not observed following 8 doses of ALN-CC5. After completion of ALN-CC5 dosing and in the setting of ongoing >95% ALN-CC5-mediated KD of serum C5, treatment naïve patients received a single 600 mg dose of eculizumab (labeled induction dose is 600 mg weekly x 4) for the treatment of residual hemolysis followed by close clinical monitoring. An exploratory analysis was conducted to understand the potential for ALN-CC5 to reduce eculizumab dose and frequency. All 3 patients achieved sustained lowering of LDH <1.5 ULN for out to 4 weeks. In patients entering the study on a stable dose of eculizumab (n=3), ALN-CC5 was also able to achieve a robust C5 KD (mean max 86.7% ± 5.6%) with residual complement activity of <2% as measured by CCP assay from day 21 onward. The addition of ALN-CC5 resulted in LDH lowering to within reference range by day 35 post treatment (maintained out to Day 112) in an inadequate response patient who entered the study on higher than labeled dose of eculizumab. As a result, this patient's subsequent dosing of eculizumab was lowered from 1200mg q2wk to 900mg q2wk. Updated safety, pharmacodynamics (PD) and clinical activity for all 6 patients with PNH in Part C of this ongoing Phase 1/2 study will be presented. Conclusion: ALN-CC5 was shown to be generally well tolerated in patients with PNH. The PD effects of ALN-CC5 were found to be durable, with clamped C5 knockdown and complement activity inhibition. Collectively, the data suggest that clamped inhibition of hepatic C5 synthesis may provide the foundation to potentially reduce the dose and frequency of eculizumab administration for patients with PNH, and to improve disease control in patients with inadequate response to eculizumab. Disclosures Hill: Alnylam Pharmaceuticals: Consultancy, Honoraria. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference support. Munir:Alexion pharmaceuticals: Honoraria. Borodovsky:Alnylam Pharmaceuticals: Employment, Equity Ownership. Kawahata:Alnylam Pharmaceuticals: Employment, Equity Ownership. Mclean:Alnylam Pharmaceuticals: Employment, Equity Ownership. Shi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Partisano:Alnylam: Employment, Equity Ownership. Kim:Alnylam Pharmaceuticals: Employment, Equity Ownership. Najafian:Alnylam Pharmaceuticals: Employment, Equity Ownership.

One daily dose of either 5 mg or 10 mg cyproterone acetate (CA) was administered to 2 groups of 4 fertile men for 6 months. The medication was preceded by a 3 months placebo period and followed by a recovery phase of 5 to 8 months. During CA-treatment the sperm count/ml decreased and the percentage of abnormal spermatozoa increased slightly (0.001 < P < 0.05). Sperm penetration assessed by the Kremer test did not show any decrease during treatment. Serum levels of testosterone and FSH decreased, but those of LH remained unchanged during treatment. Two pregnancies occurred after 1¾ and 5½ months of CA-treatment. The serum-CA concentration in these 2 volonteers did not differ from that of the remainder. Three subjects who began the study were withdrawn because of depressive mood changes (2) and weakness combined with dizziness (1). Data from these subjects were not included. The results indicate that daily doses of 5 mg and 10 mg of cyproterone acetate are not effective as a male contraceptive.

Introduction: Uncontrolled complement activation plays a pivotal role in a variety of disorders such as PNH and aHUS. ALN-CC5 is a subcutaneous (SC) investigational RNAi therapeutic targeting complement C5 (C5). In preclinical studies, ALN-CC5 has demonstrated decreased terminal complement activity. Based on the literature, preventing the generation of the terminal complex protects against intravascular hemolysis and complement-mediated tissue damage. The purpose of this study is to evaluate the safety and tolerability of ALN-CC5 in normal healthy volunteers. Material and methods: A multi-centered, placebo controlled, double blind phase 1 clinical study in healthy volunteers is ongoing. Several cohorts of healthy volunteers in Part A, a single ascending dose study and Part B, a weekly multiple ascending dose study have been completed. Primary endpoints are safety and tolerability. Secondary endpoints are pharmacokinetics, reduction of circulating C5, reduction in hemolytic, CAP and CCP activity. Results: In Part A, 20 healthy volunteers were randomized (1:3) to placebo or single SC dose of 50, 200, 400, 600 or 900mg of ALN-CC5 and followed for at least 70 days. In Part B, 12 healthy volunteers were randomized (1:3) to placebo or 5 weekly doses of 100, 200 or 400mg of ALN-CC5. No SAEs or study discontinuations occurred and overall ALN-CC5 was considered safe and generally well tolerated. A dose dependent and 94% mean maximum C5 knockdown was achieved following weekly administration. Updated safety and tolerability data as well as C5 knockdown, and changes in CAP, CCP and hemolytic activity from the study will be presented. Conclusion: Collectively, these initial results suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement-mediated diseases. The subcutaneous route of administration and infrequent dosing make this a potentially encouraging therapy. Disclosures Hill: Alnylam: Consultancy. Off Label Use: ALN-CC5 is an investigational RNAi therapeutic targeting complement C5.. Borodovsky:Alnylam Pharmaceuticals: Employment, Equity Ownership. Kawahata:Alnylam Pharmaceuticals: Employment, Equity Ownership. Mclean:Alnylam Pharmaceuticals: Employment, Equity Ownership. Powell:Alnylam Pharmaceuticals: Employment, Equity Ownership. Chaturvedi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Warner:Alnylam Pharmaceuticals: Employment, Equity Ownership. Garg:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership.