Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for ultra-rare inherited bleeding disorders.

BACKGROUND: Ultra-rare inherited bleeding disorders (BDs) present important challenges for generating a strong evidence foundation for optimal diagnosis and management. Without disorder-appropriate treatment, affected individuals potentially face life-threatening bleeding, delayed diagnosis, suboptimal management of invasive procedures, psychosocial distress, pain, and decreased quality-of-life. RESEARCH DESIGN AND METHODS: The National Hemophilia Foundation (NHF) and the American Thrombosis and Hemostasis Network identified the priorities of people with inherited BDs and their caregivers, through extensive inclusive community consultations, to inform a blueprint for future decades of research. Multidisciplinary expert Working Group (WG) 3 distilled highly feasible transformative ultra-rare inherited BD research opportunities from the community-identified priorities. RESULTS: WG3 identified three focus areas with the potential to advance the needs of all people with ultra-rare inherited BDs and scored the feasibility, impact, and risk of priority initiatives, including 13 in systems biology and mechanistic science; 2 in clinical research, data collection, and research infrastructure; and 5 in the regulatory process for novel therapeutics and required data collection. CONCLUSIONS: Centralization and expansion of expertise and resources, flexible innovative research and regulatory approaches, and inclusion of all people with ultra-rare inherited BDs and their health care professionals will be essential to capitalize on the opportunities outlined herein.

Living with an ultra-rare inherited bleeding disorder is challenging. Patients can feel alone and unsure of where to find support because their disorder is so rare. In this paper, a group of ultra-rare bleeding disorder experts, including doctors, researchers, regulators, patient advocates, and patients, identify the research that could best improve the lives of people with these disorders. They propose a national network of specialists who can help doctors, who may never have seen these disorders before, to find the right diagnosis faster. A centralized laboratory specialized in ultra-rare bleeding disorders could also improve diagnosis and do research studies. This would help us learn, for example, how symptoms change throughout a patient's life, how effective different treatments are, and what it is like for patients to live with these disorders. A second research priority is to better understand each individual disorder so that the best treatments can be chosen or developed. A pathway showing doctors which treatment options to try, in which order, would help them help their patients. The third research priority is to make it easier to study new treatments for ultra-rare bleeding disorders. This requires designing studies with very small numbers of participants, identifying meaningful outcomes to measure, and convincing pharmaceutical companies to invest in these studies. International agreement on these requirements would allow more patients to participate and benefit from the research. These top-priority research goals should greatly improve knowledge about, and diagnosis and treatment of, ultra-rare inherited bleeding disorders.

Response to triheptanoin therapy in critically ill patients with LC-FAOD: Report of patients treated through an expanded access program.

Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of inborn errors of metabolism wherein patients are unable to process long-chain fatty acids into useable energy in the mitochondria. LC-FAOD commonly affects organ systems with high energy demand, manifesting as hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Collectively, LC-FAOD have a high mortality rate, especially in cases of early onset disease, and in the presence of cardiomyopathy. Triheptanoin is a synthetic medium-odd chain triglyceride, produced using a GMP-compliant process, which was designed to replenish mitochondrial metabolic deficits and restore energy homeostasis. Prior to its approval, triheptanoin was only available through clinical trials or to seriously ill patients as part of an expanded access program (EAP) following physician request. This retrospective study examined the impact of triheptanoin on cardiovascular parameters, in critically ill patients who participated in the EAP from February 2013 to January 2018. These patients persisted in critical condition despite receiving standard treatment in highly qualified centers by expert metabolic physicians and dietitians. Physician-completed questionnaires and narrative summaries were used to evaluate the disease presentation and management prior to the trigger event leading to triheptanoin request and use, and the response to triheptanoin treatment. Following triheptanoin initiation, most patients survived the initial trigger event (e.g., severe urinary tract infection, pneumonia) and demonstrated improvements in both short-term and long-term LC-FAOD manifestations. In patients with cardiomyopathy, stabilization or improvement from pretreatment levels was reported in left ventricular ejection fraction and left ventricular mass, in particular, all infants with cardiomyopathy showed improvement in cardiac function during triheptanoin therapy. Triheptanoin therapy was generally well tolerated. The study results are consistent with the existing positive benefit/risk profile of triheptanoin and reflect the effect of triheptanoin improving cardiac function in patients experiencing severe episodes of metabolic decompensation despite standard therapy.

Results from a 3-year Non-interventional, Observational Disease Monitoring Program in Adults with GNE Myopathy.

BACKGROUND: GNE myopathy is a rare, autosomal recessive, muscle disease caused by mutations in GNE and is characterized by rimmed vacuoles on muscle biopsy and progressive distal to proximal muscle weakness. OBJECTIVE: Investigate the clinical presentation and progression of GNE myopathy. METHODS: The GNE Myopathy Disease Monitoring Program was an international, prospective, observational study in subjects with GNE myopathy. Muscle strength was assessed with hand-held dynamometry (HHD), with upper extremity (UE) and lower extremity (LE) composite scores reflecting upper and lower extremity muscle groups, respectively. The GNE myopathy-Functional Activity Scale (GNEM-FAS) was used to further assess impairment in mobility, upper extremity function, and self-care. RESULTS: Eighty-seven of 101 enrolled subjects completed the trial until study closure by the sponsor; 60 completed 36 months. Mean (SD) HHD UE composite score decreased from 34.3 kg (32.0) at baseline to 29.4 kg (32.6) kg at month 36 (LS mean change [95%CI]: -3.8 kg [-5.9, -1.7]; P = 0.0005). Mean (SD) HHD LE composite score decreased from 32.0 kg (34.1) at baseline to 25.5 kg (31.2) at month 36 (LS mean change [95%CI]: -4.9 [-7.7, -2.2]; P = 0.0005). GNEM-FAS scores were more severe at baseline in subjects who walked <200 meters versus ≥200 meters in 6 minutes; in both groups, GNEM-FAS total, mobility, UE, and self-care scores decreased from baseline through month 36. CONCLUSIONS: These findings demonstrate progressive decline in muscle strength in GNE myopathy and provide insight into the appropriate tools to detect clinically meaningful changes in future GNE myopathy interventional trials.

Impact of newborn screening on the reported incidence and clinical outcomes associated with medium- and long-chain fatty acid oxidation disorders.

Fatty acid oxidation disorders (FAODs) are potentially fatal inherited disorders for which management focuses on early disease detection and dietary intervention to reduce the impact of metabolic crises and associated spectrum of clinical symptoms. They can be divided functionally into long-chain (LC-FAODs) and medium-chain disorders (almost exclusively deficiency of medium-chain acyl-coenzyme A dehydrogenase). Newborn screening (NBS) allows prompt identification and management. FAOD detection rates have increased following the addition of FAODs to NBS programs in the United States and many developed countries. NBS-identified neonates with FAODs may remain asymptomatic with dietary management. Evidence from numerous studies suggests that NBS-identified patients have improved outcomes compared with clinically diagnosed patients, including reduced rates of symptomatic manifestations, neurodevelopmental impairment, and death. The limitations of NBS include the potential for false-negative and false-positive results, and the need for confirmatory testing. Although NBS alone does not predict the consequences of disease, outcomes, or management needs, subsequent genetic analyses may have predictive value. Genotyping can provide valuable information on the nature and frequency of pathogenic variants involved with FAODs and their association with specific phenotypes. Long-term follow-up to fully understand the clinical spectrum of NBS-identified patients and the effect of different management strategies is needed.

Phase I study of samalizumab in chronic lymphocytic leukemia and multiple myeloma: blockade of the immune checkpoint CD200.

PURPOSE: Samalizumab is a novel recombinant humanized monoclonal antibody that targets CD200, an immunoregulatory cell surface member of the immunoglobulin superfamily that dampens excessive immune responses and maintains self-tolerance. This first-in-human study investigated the therapeutic use of samalizumab as a CD200 immune checkpoint inhibitor in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). EXPERIMENTAL DESIGN: Twenty-three patients with advanced CLL and 3 patients with MM were enrolled in an open-label phase 1 study (NCT00648739). Patients were assigned sequentially to one of 7 dose level cohorts (50 to 600 mg/m2) in a 3 + 3 study design, receiving a single dose of samalizumab intravenously once every 28 days. Primary endpoints were safety, identification of the maximum tolerated dose (MTD), and pharmacokinetics. Secondary endpoints were samalizumab binding to CD200, pharmacodynamic effects on circulating tumor cells and leukocyte subsets, and clinical responses. RESULTS: Twenty-one patients received > 1 treatment cycle. Adverse events (AEs) were generally mild to moderate in severity. Samalizumab produced dose-dependent decreases in CD200 expression on CLL cells and decreased frequencies of circulating CD200 + CD4+ T cells that were sustained at higher doses. The MTD was not reached. Decreased tumor burden was observed in 14 CLL patients. One CLL patient achieved a durable partial response and 16 patients had stable disease. All MM patients had disease progression. CONCLUSIONS: Samalizumab had a good safety profile and treatment was associated with reduced tumor burden in a majority of patients with advanced CLL. These preliminary positive results support further development of samalizumab as an immune checkpoint inhibitor. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00648739 registered April 1, 2008.

Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis.

Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based on long-term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient-years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy-six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit-risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab.

Clinical benefit of eculizumab in patients with no transfusion history in the International Paroxysmal Nocturnal Haemoglobinuria Registry.

BACKGROUND: Eculizumab reduces intravascular haemolysis and improves disease symptoms in patients with paroxysmal nocturnal haemoglobinuria (PNH). AIMS: To characterise, in a real-world setting, the effect of eculizumab in patients with haemolytic PNH (lactase dehydrogenase (LDH) ≥ 1.5 upper limit of normal) and no history of red blood cell transfusion, including those with high disease activity (HDA). METHODS: Three populations from the International PNH Registry were studied: (i) non-transfused, untreated; (ii) non-transfused, eculizumab-treated and (iii) transfused, eculizumab-treated (≥1 transfusions in 6 months prior to eculizumab initiation). Using multivariate linear regression, the primary outcome was mean absolute change from baseline to 6 months in LDH (U/L) in non-transfused patients who were treated with eculizumab versus those who remained untreated. Secondary outcomes were mean changes in functional assessment of chronic illness therapy (FACIT)-Fatigue and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ)-C30 Fatigue scores from baseline to last available assessment. RESULTS: The study population included (i) 144 non-transfused, untreated patients; (ii) 45 non-transfused, eculizumab-treated patients and (iii) 105 transfused, eculizumab-treated patients. Of these, 136/144, 43/45 and 99/105 had HDA respectively. Compared with untreated patients, non-transfused, treated patients had greater absolute reduction in LDH (-1318.8 vs -39.4; P < 0.001) and greater percentage reduction in LDH (-69.9 vs -1.6%; P < 0.001). Clinically meaningful improvements in FACIT-Fatigue (73.7 vs 24.6%, respectively) and in EORTC-QLQ-C30 (84.2 vs 33.3%, respectively) were observed. Non-transfused, treated patients with HDA had significantly reduced LDH levels (P < 0.001) and clinically meaningful improvements in FACIT-Fatigue (P = 0.003) and EORTC-QLQ-C30 (P = 0.020) versus untreated patients. CONCLUSION: Significant LDH reduction and clinically meaningful improvement in fatigue were observed in patients with PNH and HDA treated with eculizumab versus untreated patients, irrespective of transfusion history.

Terminal Complement Inhibitor Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome: A Single-Arm, Open-Label Trial.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Eculizumab, a terminal complement inhibitor approved for aHUS treatment, was reported to improve hematologic and renal parameters in 2 prior prospective phase 2 studies. This is the largest prospective study of eculizumab in aHUS to date, conducted in an adult population. STUDY DESIGN: Open-label single-arm phase 2 trial. SETTING & PARTICIPANTS: Patients 18 years or older with aHUS (platelet count <150 × 10(3)/µL, hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥1.5 × upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study. INTERVENTION: Intravenous eculizumab (900mg/wk for 4 weeks, 1,200mg at week 5 and then every 2 weeks) for 26 weeks. OUTCOMES & MEASUREMENTS: Primary end point was complete TMA response within 26 weeks, defined as hematologic normalization (platelet count ≥150 × 10(3)/µL, LDH ≤ ULN), and preservation of kidney function (<25% serum creatinine increase from baseline), confirmed by 2 or more consecutive measurements obtained 4 or more weeks apart. RESULTS: 41 patients were treated; 38 (93%) completed 26 weeks of treatment. 30 (73%) were included during their first TMA manifestation. 30 (73%) had complete TMA response. Platelet counts and estimated glomerular filtration rates increased from baseline (P<0.001). All 35 patients on baseline plasma exchange/plasma infusion discontinued by week 26. Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment. No patients lost existing transplants. Quality-of-life measures were significantly improved. Two patients developed meningococcal infections; both recovered, and 1 remained on eculizumab treatment. LIMITATIONS: Single-arm open-label design. CONCLUSIONS: Results highlight the benefits of eculizumab in adult patients with aHUS: improvement in hematologic, renal, and quality-of-life parameters; dialysis discontinuation; and transplant protection.

Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complement pathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Based on 2 prospective studies in mostly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS in an open-label phase II study. The primary end point was complete TMA response by 26 weeks. Twenty-two patients (aged 5 months-17 years) were treated; 16 were newly diagnosed, 12 had no prior plasma exchange/infusion during current TMA symptomatology, 11 received baseline dialysis and 2 had prior renal transplants. By week 26, 14 achieved a complete TMA response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. Plasma exchange/infusion was discontinued in all, and 9 of the 11 patients who required dialysis at baseline discontinued, whereas none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred. Bone marrow failure, wrist fracture, and acute respiratory failure were reported as unrelated severe adverse events. Thus, our findings establish the efficacy and safety of eculizumab for pediatric patients with aHUS and are consistent with proposed immediate eculizumab initiation following diagnosis in children.

Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS.

Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease characterized by uncontrolled complement activation, systemic thrombotic microangiopathy (TMA), and vital organ damage. We evaluated the effect of terminal complement blockade with the anti-C5 monoclonal antibody eculizumab on biomarkers of cellular processes involved in TMA in patients with aHUS longitudinally, during up to 1 year of treatment, compared with in healthy volunteers. Biomarker levels were elevated at baseline in most patients, regardless of mutational status, plasma exchange/infusion use, platelet count, or lactate dehydrogenase or haptoglobin levels. Eculizumab reduced terminal complement activation (C5a and sC5b-9) and renal injury markers (clusterin, cystatin-C, ß2-microglobulin, and liver fatty acid binding protein-1) to healthy volunteer levels and reduced inflammation (soluble tumor necrosis factor receptor-1), coagulation (prothrombin fragment F1+2 and d-dimer), and endothelial damage (thrombomodulin) markers to near-normal levels. Alternative pathway activation (Ba) and endothelial activation markers (soluble vascular cell adhesion molecule-1) decreased but remained elevated, reflecting ongoing complement activation in aHUS despite complete terminal complement blockade. These results highlight links between terminal complement activation and inflammation, endothelial damage, thrombosis, and renal injury and underscore ongoing risk for systemic TMA and progression to organ damage. Further research regarding underlying complement dysregulation is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01194973.

Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies.

Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m(2) or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.

Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is rare in children, but represents a similarly serious and chronic condition as in adults. Children with PNH frequently experience complications of chronic hemolysis, recurrent thrombosis, marrow failure, serious infections, abdominal pain, chronic fatigue, and decreased quality of life with reduced survival. The terminal complement inhibitor eculizumab is proven to be effective and safe in adults and approved by the FDA for treatment of PNH. PROCEDURE: This 12-week, open-label, multi-center phase I/II study evaluated pharmacokinetics, pharmacodynamics, efficacy, and safety in seven children with PNH 11-17 years of age. Eculizumab was intravenously administered at 600 mg weekly for 4 weeks, 900 mg in week 5, and 900 mg every 2 weeks thereafter (http://clinicaltrials.gov NCT00867932). RESULTS: Eculizumab therapy resulted in complete and sustained inhibition of hemolysis in all participants with a reduction of lactate dehydrogenase to normal levels. All hematological parameters stabilized. No definitive, study drug-related adverse events were observed. Only one severe SAE of hospitalization due to aplastic anemia occurred, which was not study drug-related. CONCLUSION: Eculizumab appears to be a safe and effective therapy for children with PNH.

Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry.

Paroxysmal nocturnal hemoglobinuria is a rare, acquired disease associated with hemolytic anemia, bone marrow failure, thrombosis, and, frequently, poor quality of life. The International PNH Registry is a worldwide, observational, non-interventional study collecting safety, effectiveness, and quality-of-life data from patients with a confirmed paroxysmal nocturnal hemoglobinuria diagnosis or detectable paroxysmal nocturnal hemoglobinuria clone, irrespective of treatment. In addition to evaluating the long-term safety and effectiveness of eculizumab in a global population, the registry aims to improve diagnosis, optimize patient management and outcomes, and enhance the understanding of the natural history of paroxysmal nocturnal hemoglobinuria. Here we report the characteristics of the first 1610 patients enrolled. Median disease duration was 4.6 years. Median granulocyte paroxysmal nocturnal hemoglobinuria clone size was 68.1% (range 0.01-100%). Overall, 16% of patients had a history of thrombotic events and 14% a history of impaired renal function. Therapies included anticoagulation (31%), immunosuppression (19%), and eculizumab (25%). Frequently reported symptoms included fatigue (80%), dyspnea (64%), hemoglobinuria (62%), abdominal pain (44%), and chest pain (33%). Patients suffered from poor quality of life; 23% of patients had been hospitalized due to paroxysmal nocturnal hemoglobinuria-related complications and 17% stated that paroxysmal nocturnal hemoglobinuria was the reason they were not working or were working less. This international registry will provide an ongoing, valuable resource to further the clinical understanding of paroxysmal nocturnal hemoglobinuria.

C3 glomerulopathy: consensus report.

C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.

Long-term efficacy and safety of eculizumab in Japanese patients with PNH: AEGIS trial.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive hematopoietic stem cell disorder characterized by chronic complement-mediated hemolysis leading to life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody, inhibits terminal complement activation, reduces hemolysis, decreases the risk of thrombosis, and improves renal function and quality of life in PNH patients. The long-term efficacy and safety of eculizumab in Japanese patients were assessed in a 2-year extension to a 12-week, open-label study (AEGIS). Eculizumab treatment led to an immediate and sustained reduction in intravascular hemolysis (P < 0.001) and red blood cell transfusions (P = 0.0016) compared with baseline levels. There were no reports of thromboembolism during eculizumab treatment. The majority of patients had stable (56 %) or improved (41 %) renal function and an improved quality of life (P = 0.015), with sustained reductions in fatigue and dyspnea. Eculizumab was well tolerated; no deaths or serious hemolytic events were reported, and the rate of infections declined over time. There were no significant differences in the response to eculizumab in patients with or without bone marrow dysfunction. These results demonstrate that eculizumab is an effective, well-tolerated long-term treatment for Japanese PNH patients and leads to continued amelioration of some hemolytic complications.

Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial.

PURPOSE: As part of a phase 1 dose-escalation trial, the pharmacodynamic activity of the mammalian target of rapamycin (mTOR) inhibitor ridaforolimus was assessed in multiple tissues by measuring levels of phosphorylated 4E binding protein-1 (p-4E-BP1) or S6, two downstream markers of mTOR activity. METHODS: 32 patients (pts) were dosed intravenously with ridaforolimus once daily for 5 consecutive days (QD × 5) every 2 weeks. The pharmacodynamic activity of ridaforolimus was assessed in peripheral blood mononuclear cells (PBMCs; 32 pts), skin (28 pts), and tumor specimens (3 pts) collected before and after dosing by measuring levels of p-4E-BP1 by immunoblot analysis or pS6 by immunohistochemistry. Levels of these markers were assessed in up to 19, 5, and 2 pre- and post-dose time points in PBMC, skin, and tumor specimens, respectively. RESULTS: In preclinical models, ridaforolimus induced a dose-dependent inhibition of p-4E-BP1 in PBMCs that was associated with antitumor activity. Rapid and potent inhibition of mTOR was observed in PBMCs from all 32 pts dosed, with a median level of inhibition of 96% observed within 1 h after the first dose. Inhibition of mTOR (>90%) was sustained during the entire QD × 5 dosing period, and substantial inhibition was still observed after the 9-day holiday between dosing courses. Evidence of mTOR inhibition was also obtained in skin in pts from all dose cohorts, although it did not persist through the break between courses. After two to three doses of ridaforolimus, inhibition of mTOR was detected in the tumor from one of three pts analyzed. CONCLUSIONS: Ridaforolimus was shown to inhibit its intended target, mTOR, in PBMCs, skin, and tumors. In PBMCs and skin, inhibition was observed at all dose levels tested, thus supporting but not driving the selection of a recommended phase 2 dose.

Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial.

Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive and life-threatening disease characterized by complement-mediated chronic hemolysis, resulting in serious life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation, has been shown to reduce hemolysis in PNH patients. The pivotal open-label, 12-week phase II registration study (AEGIS) was designed to evaluate the efficacy and safety of eculizumab in Japanese patients with PNH. This trial achieved its primary endpoint of reducing intravascular hemolysis with high statistical significance. Twenty-seven of the 29 patients responded to eculizumab treatment, resulting in an 87% reduction in hemolysis (P < 0.0001) and subsequent improvement in anemia (P = 0.0003) despite reduction in transfusion requirements (P = 0.006). Fatigue and dyspnea significantly improved within 1-2 weeks of eculizumab treatment and the improvement was independent of changes in hemoglobin. Chronic kidney disease (CKD) was common (66%) and eculizumab treatment improved CKD in 41% of patients at 12 weeks (P < 0.001). Elevated thrombotic risk was evident in Japanese PNH patients and eculizumab treatment normalized D: -dimer levels in 45% of patients with elevated D: -dimers at baseline (P < 0.001). The AEGIS results demonstrate that eculizumab is effective, safe and well tolerated in Japanese patients with PNH.

A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies.

PURPOSE: This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. EXPERIMENTAL DESIGN: Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities. RESULTS: Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P=0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r=-0.38; P=0.029). CONCLUSIONS: Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.