Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera.

BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).

Rusfertide for the treatment of iron overload in HFE-related haemochromatosis: an open-label, multicentre, proof-of-concept phase 2 trial.

BACKGROUND: Hereditary haemochromatosis protein (HFE)-related haemochromatosis, an inherited iron overload disorder caused by insufficient hepcidin production, results in excessive iron absorption and tissue and organ injury, and is treated with first-line therapeutic phlebotomy. We aimed to investigate the efficacy and safety of rusfertide, a peptidic mimetic of hepcidin, in patients with HFE-related haemochromatosis. METHODS: This open-label, multicentre, proof-of-concept phase 2 trial was done across nine academic and community centres in the USA and Canada. Adults (aged ≥18 years) with HFE-related haemochromatosis on a stable therapeutic phlebotomy regimen (maintenance phase) for at least 6 months before screening and who had a phlebotomy frequency of at least 0·25 per month (eg, at least three phlebotomies in 12 months or at least four phlebotomies in 15 months) and less than one phlebotomy per month, with serum ferritin of less than 300 ng/mL and haemoglobin of more than 11·5 g/dL, were eligible. Patients initiated 24 weeks of subcutaneous rusfertide treatment within 7 days of a scheduled phlebotomy at 10 mg once weekly. Rusfertide doses and dosing schedules could be adjusted to maintain serum transferrin iron saturation (TSAT) at less than 40%. During rusfertide treatment, investigators were to consider the need for phlebotomy when the serum ferritin and TSAT values exceeded the patient's individual pre-phlebotomy serum ferritin and TSAT values. No primary endpoint or testing hierarchy was prespecified. Prespecified efficacy endpoints included the change in the frequency of phlebotomies; the proportion of patients achieving phlebotomy independence; change in serum iron, TSAT, serum transferrin, serum ferritin, and liver iron concentration (LIC) as measured by MRI; and treatment-emergent adverse events (TEAEs). The key efficacy analyses for phlebotomy rate and LIC were conducted by use of paired t tests in the intention-to-treat population, defined as all patients who received any study drug and who had pretreatment and at least one post-dose measurement. We included all participants who received at least one dose of rusfertide in the safety analyses. This trial is closed and completed and is registered with ClinicalTrials.gov, NCT04202965. FINDINGS: Between March 11, 2020, and April 23, 2021, 28 patients were screened and 16 (ten [63%] men and six [38%] women) were enrolled. 16 were included in analyses of phlebotomy endpoints and 14 for the LIC endpoint. 12 (75%) patients completed 24 weeks of treatment. The mean number of phlebotomies was significantly reduced during the 24-week rusfertide treatment (0·06 phlebotomies [95% CI -0·07 to 0·20]) compared with 24 weeks pre-study (2·31 phlebotomies [95% CI 1·77 to 2·85]; p<0·0001). 15 (94%) of 16 patients were phlebotomy-free during the treatment period. Mean LIC in the 14 patients in the intention-to-treat population was 1·4 mg iron per g dry liver weight (95% CI 1·0 to 1·8) at screening and 1·1 mg iron per g dry liver weight (95% CI 0·9 to 1·3) at the end of treatment (p=0·068). Mean TSAT was 45·3% (95% CI 33·2 to 57·3) at screening, 36·7% (24·2 to 49·2) after the pretreatment phlebotomy, 21·8% (15·8 to 27·9) 24 h after the first dose of rusfertide, 40·4% (27·1 to 53·8) at the end of treatment, and 32·6% (25·0 to 40·1) over the treatment duration. Mean serum iron was 24·6 µmol/L (95% CI 18·6 to 30·6), 20·1 µmol/L (14·8 to 25·3), 11·9 µmol/L (9·2 to 14·7), 22·5 µmol/L (15·9 to 29·1), and 19·0 µmol/L (15·3 to 22·6) at these same timepoints, respectively. Mean serum ferritin was 83·3 µg/L (52·2 to 114.4), 65·5 µg/L (32·1 to 98·9), 62·8 µg/L (33·8 to 91·9), 150·0 µg/L (86·6 to 213.3), and 94·3 µg/L (54·9 to 133.6) at these same timepoints, respectively. There were only minor changes in serum transferrin concentration. 12 (75%) patients had at least one TEAE, the most common of which was injection site pain (five [31%] patients). All TEAEs were mild or moderate in severity, except for a serious adverse event of pancreatic adenocarcinoma, which was considered severe and unrelated to treatment and was pre-existing and diagnosed 21 days after starting rusfertide treatment. INTERPRETATION: Rusfertide prevents iron re-accumulation in the absence of phlebotomies and could be a viable therapeutic option for selected patients with haemochromatosis. FUNDING: Protagonist Therapeutics.

Phase 2 studies of oral hypoxia-inducible factor prolyl hydroxylase inhibitor FG-4592 for treatment of anemia in China.

BACKGROUND: FG-4592 (roxadustat) is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) promoting coordinated erythropoiesis through the transcription factor HIF. Two Phase 2 studies were conducted in China to explore the safety and efficacy of FG-4592 (USAN name: roxadustat, CDAN name: ), a HIF-PHI, in patients with anemia of chronic kidney disease (CKD), both patients who were dialysis-dependent (DD) and patients who were not dialysis-dependent (NDD). METHODS: In the NDD study, 91 participants were randomized to low (1.1-1.75 mg/kg) or high (1.50-2.25 mg/kg) FG-4592 starting doses or to placebo. In the DD study, 87 were enrolled to low (1.1-1.8 mg/kg), medium (1.5-2.3 mg/kg) and high (1.7-2.3 mg/kg) starting FG-4592 doses or to continuation of epoetin alfa. In both studies, only oral iron supplementation was allowed. RESULTS: In the NDD study, hemoglobin (Hb) increase ≥1 g/dL from baseline was achieved in 80.0% of subjects in the low-dose cohort and 87.1% in the high-dose cohort, versus 23.3% in the placebo arm (P < 0.0001, both). In the DD study, 59.1%, 88.9% (P = 0.008) and 100% (P = 0.0003) of the low-, medium- and high-dose subjects maintained their Hb levels after 5- and 6-weeks versus 50% of the epoetin alfa-treated subjects. In both studies, significant reductions in cholesterol were noted in FG-4592-treated subjects, with stability or increases in serum iron, total iron-binding capacity (TIBC) and transferrin (without intravenous iron administration). In the NDD study, hepcidin levels were significantly reduced across all FG-4592-treated arms as compared with no change in the placebo arm. In the DD study, hepcidin levels were also reduced in a statistically significant dose-dependent manner in the highest dose group as compared with the epoetin alfa-treated group. Adverse events were similar for FG-4592-treated and control subjects. CONCLUSIONS: FG-4592 may prove an effective alternative for managing anemia of CKD. It is currently being investigated in a pivotal global Phase 3 program.

Outcomes and effectiveness of posterior occipitocervical fusion for suboccipital spinal metastases.

OBJECTIVE The incidence of suboccipital spinal metastases is rare but has increased given cancer patients' longer life expectancies. Operative treatment in this region is often challenging because of limited fixation points due to tumor lysis, as well as adjacent neural and vascular anatomy. Few studies have reported on this population of cancer patients. The purpose of this study was to evaluate clinical outcomes and complications of patients with suboccipital spinal metastases who had undergone posterior occipitocervical fixation. METHODS A single-institution database was reviewed to identify patients with suboccipital metastases who had undergone posterior-only instrumented fusion between 1999 and 2014. Clinical presentation, perioperative complications, and postoperative results were analyzed. Pain was assessed using the visual analog scale. Survival analysis was performed using a Kaplan-Meier curve. The revised Tokuhashi and the Tomita scoring systems were used for prognosis prediction. RESULTS Fifteen patients were identified, 10 men and 5 women with mean age of 64.8 ± 11.8 years (range 48-80 years). Severe neck pain without neurological deficit was the most common presentation. Primary tumors included lung, breast, bladder, myeloma, melanoma, and renal cell cancers. All tumors occurred in the axis vertebra. Preoperative Tokuhashi and Tomita scores ranged from 5 to 13 and 3 to 7, respectively. All patients had undergone occipitocervical fusion of a mean of 4.6 levels (range 2-7 levels). Median survival was 10.3 months. In all cases, neck pain markedly improved and patients were able to resume activities of daily living. The average postoperative pain score was significantly improved as compared with the average preoperative score (1.90 ± 2.56 and 5.50 ± 2.99, respectively, p = 0.01). Three patients experienced postoperative medical complications including urinary tract infection, deep vein thrombosis, myocardial infarction, and cardiac arrhythmia. In the follow-up period, no wound infections or reoperations occurred and no patients experienced spinal cord deficits from tumor recurrence. CONCLUSIONS Posterior-only occipitocervical stabilization was highly effective at relieving patients' neck pain. No instrumentation failures were noted, and no neurological complications or tumor progression causing spinal cord deficits was noted in the follow-up period.

Current trends in rotator cuff repair: surgical technique, setting, and cost.

PURPOSE: The purpose of this study was to evaluate national trends in the surgical setting and hospital costs of shoulder arthroscopy and rotator cuff repair (RCR) using the Florida State surgical database and national inpatient database. METHODS: In part I we analyzed population-adjusted shifts in RCR technique (arthroscopic v open) in the Florida surgical database from 2000-2007 and quantified the procedural codes associated with arthroscopic and open RCR. In part II we analyzed the Nationwide Inpatient Sample database from 2001-2009 for the total number of inpatient RCRs, the inpatient hospital type (rural, urban non-teaching, or urban teaching), and the cost. RESULTS: Part I showed a 163% increase in outpatient procedures in Florida, with a 353% increase in arthroscopic RCRs. There was a concurrent decrease in open RCRs; however, the overall trend was a 2-fold increase in total RCRs. Associated procedures such as subacromial decompression, distal clavicle resection, and extensive glenohumeral debridement increased by 440%, 589%, and 1,253%, respectively. Part II showed an overall 58.8% decrease in inpatient RCRs that was similar across all hospital settings, with an increase in RCR-associated hospital charges by 144.9%, whereas hospital costs only increased by 85.2%. CONCLUSIONS: The study confirms a shift toward arthroscopic RCR and associated procedures in the outpatient setting. The increased financial cost partly explains the shift; nevertheless, future studies are needed to further examine national trends. CLINICAL RELEVANCE: This study examining RCR trends by hospital type, cost, and setting further elucidates how orthopaedic surgery practice is evolving with the implementation of arthroscopic RCR in the past decade.

Trends in hip arthroscopy utilization in the United States.

INTRODUCTION: The purpose of this study was to evaluate the changing incidence of hip arthroscopy procedures among newly trained surgeons in the United States, the indications for hip arthroscopy, and the reported rate of post-operative complications. METHODS: The ABOS database was used to evaluate the annual incidence of hip arthroscopy procedures between 2006-2010. Procedures were categorized by indication and type of procedure. The rate of surgical complications was calculated and compared between the published literature and hip arthroscopy procedures performed for femoroacetabular impingement (FAI)/osteoarthritis (OA) and for labral tears among the newly trained surgeon cohort taking the ABOS Part II Board exam. RESULTS: The overall incidence of hip arthroscopy procedures performed by ABOS Part II examinees increased by over 600% during the 5-year period under study from approximately 83 in 2006 to 636 in 2010. The incidence of hip arthroscopy for FAI/OA increased steadily over the time period under study, while the incidence of hip arthroscopy for labral tears was variable over time. The rate of surgical complications was 5.9% for hip arthroscopy procedures for a diagnosis of FAI/OA vs. 4.4% for a diagnosis of labral tear (P=0.36). CONCLUSIONS: The incidence of hip arthroscopy has increased dramatically over the past 5 years, particularly for the indication of FAI/OA. Reported surgical complication rates are relatively low, but appear higher than those rates reported in previously published series. Appropriate indications for hip arthroscopy remain unclear.

Stereotactic lesions for the treatment of psychiatric disorders.

OBJECT: The use of deep brain stimulation (DBS) has recently been expanded to the investigational treatment of specific psychiatric disorders. Much like movement disorders, the targets selected for DBS are based on past experience with stereotactic lesions. A literature review of past studies incorporating stereotactic lesions for psychiatric disorders was performed to provide historical context and possible guidance for current and future attempts at treating psychiatric disorders with DBS. METHODS: Original copies of the proceedings of the second, third, fourth, and fifth World Congresses of Psychiatric Surgery meetings were reviewed, and a Medline search was conducted for studies with the word "psychosurgery" and each of 14 highly prevalent psychiatric conditions identified by the National Institute of Mental Health. Postoperative results for 1145 patients with stereotactic brain lesions targeting various anatomical foci were standardized using a 5-point scale (3 [free of symptoms] to -1 [worse]). Each patient was entered into a database as a unique data point and used for this literature review. RESULTS: General anxiety disorder and obsessive-compulsive disorder had the greatest reported improvements from anterior capsulotomy, and bipolar disorder, depression, and schizoaffective disorder had the greatest reported improvements from anterior cingulotomy, supporting these areas for DBS investigation. Addiction and schizophrenia showed the least improvement from surgery. Therefore, pursuing the treatment of these disorders with DBS using the targets in these studies may be ineffective. CONCLUSIONS: This study provides retrospective data that suggest which anatomical focus may be effective to lesion or stimulate for the treatment of each of several psychiatric disorders.

Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer.

PURPOSE: Sipuleucel-T (APC8015) is an investigational immunotherapy product designed to stimulate T-cell immunity against prostatic acid phosphatase. A phase III study was undertaken to evaluate the safety and efficacy of sipuleucel-T in a placebo-controlled study. PATIENTS AND METHODS: A total of 127 patients with asymptomatic metastatic hormone refractory prostate cancer (HRPC) were randomly assigned in a 2:1 ratio to receive three infusions of sipuleucel-T (n = 82) or placebo (n = 45) every 2 weeks. On disease progression, placebo patients could receive APC8015F, a product made with frozen leukapheresis cells. RESULTS: Of the 127 patients, 115 patients had progressive disease at the time of data analysis, and all patients were followed for survival for 36 months. The median for time to disease progression (TTP) for sipuleucel-T was 11.7 weeks compared with 10.0 weeks for placebo (P = .052, log-rank; hazard ratio [HR], 1.45; 95%CI, 0.99 to 2.11). Median survival was 25.9 months for sipuleucel-T and 21.4 months for placebo (P = .01, log-rank; HR, 1.70; 95%CI, 1.13 to 2.56). Treatment remained a strong independent predictor of overall survival after adjusting for prognostic factors using a Cox multivariable regression model (P = .002, Wald test; HR, 2.12; 95%CI, 1.31 to 3.44). The median ratio of T-cell stimulation at 8 weeks to pretreatment was eight-fold higher in sipuleucel-T-treated patients (16.9 v 1.99; P < .001). Sipuleucel-T therapy was well tolerated. CONCLUSION: While the improvement in the primary end point TTP did not achieve statistical significance, this study suggests that sipuleucel-T may provide a survival advantage to asymptomatic HRPC patients. Supportive studies are underway.

Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a Phase 2 trial.

BACKGROUND: Prostate cancer is the most commonly diagnosed malignancy in American men, yet treatment of its metastatic androgen-independent form remains inadequate. This mandates development of new therapies such as immunotherapy. In this Phase 2 trial, we determined the efficacy of antigen presenting cells (APCs) loaded with PA2024, a recombinant fusion protein containing prostatic acid phosphatase (PAP) and GM-CSF. METHODS: We enrolled 21 patients with histologically documented androgen-independent prostate carcinoma that could be evaluated by radionuclide bone scan or computed tomography scan. APC8015 was prepared from a leukapheresis product; it contained autologous CD54-positive PA2024-loaded APCs with admixtures of monocytes, macrophages, B and T cells. APC8015 was infused intravenously twice, 2 weeks apart. Two weeks after the second infusion, patients received three subcutaneous injections of 1.0 mg of PA2024 1 month apart. We monitored patients' physical condition, immune response, and laboratory parameters. RESULTS: Nineteen patients could be evaluated for response to treatment. The median time to progression was 118 days. Treatment was tolerated reasonably well; most adverse effects were secondary to APC8015 and were NCI Common Toxicity Criteria Grade 1-2. Four of the 21 patients reported Grade 3-4 adverse events. Two patients exhibited a transient 25-50% decrease in prostate-specific antigen (PSA). For a third patient, PSA dropped from 221 ng/ml at baseline to undetectable levels by week 24 and has remained so for more than 4 years. In addition, this patient's metastatic retroperitoneal and pelvic adenopathy has resolved. PBMC collected from patients for at least 16 weeks proliferated upon in vitro stimulation by PA2024. For the patient with responsive disease, PBMC could be stimulated for 96 weeks. CONCLUSIONS: This study demonstrates a definite clinical response of androgen-independent prostate cancer to APC immunotherapy. Currently we are studying this mode of therapy in Phase 3 trials.

A phase I study of pivaloyloxymethyl butyrate, a prodrug of the differentiating agent butyric acid, in patients with advanced solid malignancies.

Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological, pharmacological, and pharmaceutical properties than BA in preclinical studies. The principal objective of this study was to determine the feasibility of administering AN-9 as a 6-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced solid malignancies. The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation. None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m(2)/day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation, hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely on this schedule, resulting in a maximum deliverable dose of 3.3 g/m(2)/day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent.