ALBERT

Beschreibung: Patients with sickle cell disease have an increased number of circulating activated iNKT cells while murine SCD models report increased number and activation state of iNKT cells in target organs. Furthermore, the use of a murine iNKT cell-depleting antibody in murine SCD models prevents inflammation driven end-organ damage. NKTT120 is a humanized monoclonal antibody directed to the unique invariant TCR of iNKT cells that depletes these cells by ADCC. In preclinical studies, NKTT120 has demonstrated a safe and specific dose and time dependent depletion/recovery of iNKT cells. The preclinical efficacy and safety data supported a clinical development program to show that NKTT120 demonstrates the same safety and specificity for iNKT cell depletion from the peripheral circulation in SCD patients. In this first in human phase 1 dose-escalation study, we have examined the safety of NKTT120 in adults with steady state SCD. Future studies will explore the ability of NKTT120 prevent painful vaso-occlusive crises. Objective: To determine the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of NKTT120 in adults with steady state SCD. The optimal dose for a phase 2 study of NKTT120 will deplete iNKT for approximately 3 months allowing for periodic dosing. Methods: A first-in-humanphase 1 study utilizing a 3+3 design to evaluate single doses escalating over a range of 7 doses from 0.001 mg/kg to 1.0 mg/kg. The primary outcome measure is safety. Secondary outcomes include blood iNKT cell depletion and recovery, pain, analgesic use, quality of life (QoL), and pulmonary function. During a screening run-in period and after dosing of NKTT120, subjects maintained a daily smartphone eDiary (eSCaPe) to report pain, respiratory symptoms and analgesic use. ASCQ-Me and PROMIS QoL questionnaires were administered at clinic visits. The screening run-in outcomes will be used as baseline comparison for values obtained post-dosing. Results: A total of 21 patients were enrolled into the 7 cohorts of the completed and closed study. The drug was delivered as a 10-minute IV push in all cohorts. No MTD was defined, as no DLTs were reported. Three subjects each were dosed at 0.001, 0.003, 0.01, 0.03, 0.1, 0.3 or 1.0 mg/kg. At leastone month of follow-up data on circulating iNKT cell numbers are available for all of the patients dosed in the study. Only iNKT cell counts were affected by NKTT120 dosing, no change in other hematologic parameters was observed in peripheral blood. No acute elevation in circulating inflammatory cytokines was seen after antibody administration. All doses of NKTT120 resulted in maximum depletion of iNKT cells at the first time point (6 hours) monitored in all patients. During the recovery period, all patients had detectable iNKT cells in their peripheral blood. In all cohorts, the time to recovery of iNKT cells correlates with the starting circulating levels, with a longer recovery time for patients with lower baseline cell numbers. T1/2 is approximately 11 days. As observed in the pre-clinical safety studies, iNKT cell depletion and recovery was dose and time dependent. At the recommended Phase 2 dose (0.3 mg/kg) no iNKT cells were detectable in the peripheral circulation for a period of several months, suggesting near complete tissue depletion at these doses requiring recovery from T cell precursors that are not targeted by NKTT120. Conclusions: In adults with SCD,NKTT120 administered up to a dose of 1.0 mg/kg specifically reduces iNKT cells without NKTT120 dose limiting toxicity. Patients at the higher dose cohorts of NKTT120 illustrate temporal pattern for iNKT cell depletion and recovery in the circulation that inform the dosing strategy for phase 2 studies. The recommended Phase 2 dose is 0.3 mg/kg administered at a 3 month interval. The Phase 2 study will highlight the reduction of iNKT cells in the suppression of the inflammatory stimuli that promote many of the pathophysiologic sequelae seen in SCD. Disclosures Eaton: NKT Therapeutics: Employment. Mazanet:NKT Therapeutics: Consultancy, Equity Ownership. Nathan:NKT Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Beschreibung: Background: von Willebrand disease (VWD) is the most common congenital bleeding disorder. In affected women, menorrhagia is the most common bleeding symptom. Combined oral contraceptives (COCs), the first choice therapy recommended by NHLBI 2007 guidelines, reduce menstrual loss by increasing coagulation factor levels, but at least 30% are unresponsive or intolerant. Non-hormonal options include the antifibrinolytic tranexamic acid (TA), reduces menstrual bleeding by 30-50%, but requires dosing three times a day. Intranasal desmopressin (Stimate) is simpler to use, but ineffective in ~20%. Effective treatment for menorrhagia, thus, remains the greatest unmet health need in women with VWD. Von Willebrand factor (VWF) is used typically when first-line and second-line treatments fail, but few data exist regarding its effectiveness in reducing menorrhagia. Methods: We therefore conducted a survey of U.S. hemophilia treatment centers (HTCs) of current therapy for menorrhagia in VWD, utilizing Centers for Disease Control (CDC) website https://www2a.cdc.gov/ncbddd/htcweb/Main.asp, and the Hemostasis and Research Society (HTRS) site http://htrs.org. To specifically assess the use of VWF concentrate for menorrhagia, we also performed a literature review using medical subject heading (MeSH) search terms "von Willebrand factor," "menorrhagia," and "von Willebrand disease." Statistical analysis was by descriptive statistics. Results: Of 83 surveys distributed to hemophilia treatment centers (HTCs) caring for adult patients, 35 HTC MDs responded (42.2%) but only 20 HTC MDs (24.1%) provided sufficient data for analysis. These 20 HTC MDs reported a total of 1,321 women with VWD age 18-45 years seen during the 3-year period 2011-2014, of whom 816 (61.8%) had menorrhagia. Among these women, the most common first-line therapy was COCs, reported by 50.0% of the 20 HTC MDs, TA in 30.0% and desmopressin (DDAVP) in 20.0%. Overall, including all therapies (first-, second-, third-line), DDAVP was prescribed by 90.0% of the 20 HTC MDs, TA in 80.0%, COCs in 70.0%, aminocaproic acid (amicar) in 25.0%, and the levonorgestrel-releasing intrauterine system (Mirena IUD) in 15.0%. Only 4 HTC MDs (20.0%) prescribed VWF concentrate (VWF) for menorrhagia: all used VWF as third-line therapy after first-line and second-line treatments had failed. In the 13 women with type 1, 2, or 3 VWD and menorrhagia treated with intravenous VWF by these 4 HTC MDs, there was reduction in menorrhagia in all 13 (100%), with no adverse effects. These patients learned intravenous technique and infused VWF at 40-50 IU/kg at home for up to 5 days of menstrual bleeding each cycle, with good acceptability. In the literature search, we identified six published studies, including two prospective clinical trials, two retrospective observational trials, and two observational network studies. A total of 455 subjects with VWD reported in these six studies were treated with either plasma-derived (pdVWF) or recombinant (rVWF) VWF for bleeds. Of these, nearly one-third or 138 (30.3%) were women with type 1, 2, or 3 VWD and menorrhagia who were treated with pdVWF or rVWF at a dose of 36-50 IU/kg for 1-6 days of menstrual cycle bleeding. In these studies, 95-100% of these women reported reduction in menorrhagia, with no reported adverse events. Discussion: This survey and literature review of 151 women with VWD and menorrhagia represent the largest treatment experience to date. DDAVP, TA, and COCs are the most common first-line therapies. VWF is a third-line therapy but safely and effectively reduces menorrhagia in at least 95% of women with VWD. Prospective clinical trials of VWF are needed to establish the minimal dose required for menorrhagia, to determine patient acceptability of this intravenous therapy, and to compare safety and efficacy with standard therapy. Disclosures Off Label Use: recombinant VWF and plasma-derived VWF for treatment of menorrhagia in VWD. Ragni:Bristol Myers Squibb: Research Funding; Biogen: Research Funding; Bayer: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Dimension Therapeutics: Research Funding; CSL Behring: Research Funding; Foundation Women Girls Blood Disorders: Membership on an entity's Board of Directors or advisory committees; Genentech Roche: Research Funding; Medscape, Web MD: Honoraria; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; SPARK: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Ferring Pharmceuticals: Research Funding; Biomarin: Research Funding; Vascular Medicine Institute: Research Funding. Malec:Baxalta: Research Funding; Biogen: Research Funding. Coyle:Bayer: Membership on an entity's Board of Directors or advisory committees. Drygalski:Biogen: Consultancy; Baxalta: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Hematherix Inc: Equity Ownership; Biogen: Research Funding; Baxalta: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; CSL Behring: Speakers Bureau; Hematherix Inc: Membership on an entity's Board of Directors or advisory committees. James:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees. Jobe:Biogen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Konkle:Octapharma: Research Funding; Baxalta: Consultancy; CSL Behring: Consultancy; Baxalta: Research Funding. Kouides:CSL Behring: Membership on an entity's Board of Directors or advisory committees. Kuriakose:Kedrion: Speakers Bureau. Ma:Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Nance:Patient Services, Inc.: Membership on an entity's Board of Directors or advisory committees. Neff:Alexion: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novonordisk: Membership on an entity's Board of Directors or advisory committees. Philipp:Baxter: Research Funding. Yaish:Agios: Membership on an entity's Board of Directors or advisory committees.

Beschreibung: Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting 1% of the population, and characterized by deficient or defective von Willebrand factor (VWF). Among women with VWD, up to 80% have heavy menstrual bleeding (HMB), many of whom have depleted iron stores and iron deficiency anemia with reduced physical functioning, anxiety, depression, and poor quality of life. HMB is a serious problem causing significant health burden for those affected. The lack of effective therapies for menorrhagia is a major unmet healthcare need in women with VWD: in up to 30% desmopressin (DDAVP), combined oral contraceptives (COCs) hormones, or the recommended non-hormonal agent, tranexamic acid (Lysteda®, TA) may be ineffective or poorly tolerated. VWF concentrates, including plasma-derived VWF (pdVWF, Humate-P®) and recombinant VWF (rVWF, Vonvendi®) safely reduce bleeds in VWD, but few data exist on VWF use in menorrhagia, and no prospective trials are available to guide treatment. As rVWF has higher purity, potency, and a longer half-life than pdVWF, this phase III trial will compare rVWF with TA in reducing menorrhagia in women with type 1 VWD. Methods: This is an NHLBI-funded U01 phase III multicenter, prospective, randomized, crossover trial in to compare IV rVWF vs. po TA in reducing menorrhagia in type 1 VWD, clinicaltrials.gov, NCT02606045. Women with type 1 VWD, VWF:RCo100 in at least one of the last two cycles, are eligible. Exclusions include hypothyroidism, past thrombosis, and renal disease. Subjects are randomized to rVWF 40 IU/kg IV day 1 vs. TA 1300 mg po three times daily days 1-5 in each of two consecutive cycles. The order of treatment is determined by randomization: in Group 1, rVWF is given in cycles 1 and 2, and TA in cycles 3 and 4; while in Group 2, TA is given in cycles 1 and 2, and rVWF in cycles 3 and 4. A rescue dose day of rVWF 40 IU/kg may be given day 2 of cycles in which rVWF is given. The primary endpoint is a 40-point reduction in PBAC, a validated measure of menstrual loss, after 2 cycles. As rVWF is a greater burden (IV, cost), to show it is superior to TA, it should improve PBAC 40 points more from baseline than TA. Secondary endpoints are cycle severity, cycle length, QoL (SF-36, Ruta, CDC-HRQ0L-14, CES-D), and satisfaction survey. Treatment response will also be compared with VWF assays and VWF genotype. Safety is assessed by number of rescue doses, other bleeding, thrombosis, and allergic reaction. Our research hypothesis is that rVWF will be superior, producing a greater improvement, by at least 40 points, in PBAC, than TA. We also hypothesize that rVWF will be as safe, tolerable, and acceptable as TA, and that VWF assays and VWF genotype will predict response to treatment. A sample size of 60 (inflated to 66 for 5% attrition) will provide 84% power to detect a difference in improvement of 40 points between rVWF and TA. Analysis will be by intent-to-treat analyses, with a two-tailed alternative hypothesis with type 1 error rate of 0.05, a 4-period 2-group (AABB/BBAA) crossover design, and an estimated between-subject standard deviation (SD) of 63 points and within subject SD of 100 points. Results: A total of 442 potential subjects have been identified at 19 participating HTCs, of whom 33 (7.5%) are eligible, and 2 enrolled. The most common reason for ineligibility is use of an IUD (15.6%), COCs (9.4%), age