Search

Background: About two-thirds of AML patients harbor mutations in signaling and kinase pathways (e.g., FLT3, KRAS, NRAS, PTPN11, NF1, KIT), which utilize the growth factor receptor bound protein-2 (Grb2) to induce AML progression. Prexigebersen (BP1001), a liposome-incorporated Grb2 antisense oligonucleotide that inhibits Grb2 expression, suppresses cancer growth and survival. A Phase I/IB single center study (Ohanian, Lancet Haematol 2018) in relapsed/refractory AML patients demonstrated BP1001 safety up to 90 mg/m 2 and demonstrated CR/CRi in 3 of 6 relapsed/refractory AML patients treated with BP1001 + low dose cytarabine combination in the Phase IB portion. Preclinical studies indicated that BP1001 enhanced the inhibitory effects of decitabine (DAC), or DAC + venetoclax (VEN) against AML cells. Thus, we designed a clinical trial with three treatment arms: (1) BP1001 + DAC + VEN for newly diagnosed AML, (2) BP1001 + DAC + VEN for relapsed/refractory AML, (3) BP1001 + DAC for relapsed/refractory AML patients who are VEN-resistant or -intolerant [ClinicalTrials.gov Identifier: NCT02781883]. The study was amended to obtain safety run-in data for patients treated with BP1001 + DAC first before proceeding to safety run-in for patients treated with BP1001 + DAC + VEN. Here we report the safety run-in and efficacy data of AML patients treated with BP1001 + DAC or BP1001 + DAC + VEN. Methods: This is a multi-center open-label, Phase II study in newly diagnosed and relapsed/refractory AML patients to determine the safety and preliminary efficacy of BP1001 (given at 60 mg/m 2 over 2-3 h twice weekly for a total of 8 doses over a 28-day cycle) in combination with DAC (20 mg/m 2, once daily for 5 days) or in combination with DAC and VEN (400 mg, once daily). Eligible patients were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Patients treated with at least 1 cycle of therapy were evaluable for safety run-in. Results: Between April 2018 and May 2020, 6 patients (4 male: 67%) with median age 72 years (range, 51 - 76) were treated with at least 1 cycle of BP1001 + DAC combination therapy. Four patients (67%) had de novo AML and two (33%) had secondary AML. All patients in this cohort were considered high risk due to having either adverse risk status by ELN (n=5) or treated secondary AML (n=1) (transformed from myelodysplastic syndrome/myeloproliferative neoplasm after failing 4 lines of prior therapy). Adverse events (AEs) were generally consistent with those expected with DAC and/or AML and included diarrhea (67%), fatigue (50%), constipation (50%), nausea (50%), dyspnea (50%), hypoxia (50%), hypotension (50%) and pain in extremity (50%). The most frequent serious AE (SAE) was bacteremia (33%). Two de novo patients (33%) achieved a CRi and 1 treated secondary AML patient (17%) achieved a PR. Patients received a median of 2.5 cycles of therapy (range, 1 - 6); median duration of follow-up was 140 days (range, 72 - 678). Since May 2020, 6 patients (2 male: 33%) with median age 61 years (range, 44 - 81) were treated with at least 1 cycle of BP1001 + DAC + VEN combination therapy. Two (33%) had de novo AML, and four (67%) were relapsed/refractory. All patients in this cohort were adverse-risk by ELN (n=2) or relapsed/refractory (n=4). AEs were generally as expected with DAC, VEN and/or AML, including fatigue (67%), diarrhea (67%), constipation (67%), decreased appetite (67%), hypokalemia (67%), hypocalcemia (50%), edema peripheral (50%), asthenia (50%), nausea (50%), abdominal pain (50%), dysphagia (50%), hypotension (50%) and febrile neutropenia (50%). The most frequent SAEs were sepsis (33%) and febrile neutropenia (50%). Four patients (67%) achieved a CR/CRi/MLFS (n=1/2/1) and 1 (17%) achieved a PR. Of these patients, 3 were relapsed/refractory (1 CR/1 CRi/1 MLFS) and two were de novo (1 CRi/1 PR). Patients received a median of 4 cycles of therapy (range, 1 - 9); median duration of follow-up was 177 days (range, 113 - 318). Conclusions: BP1001-based combination therapy has been safely administered to high-risk and relapsed/refractory AML patients who were considered unsuitable for standard chemotherapy. Preliminary data showed the combination treatment of BP1001 + DAC or BP1001 + DAC + VEN was well-tolerated, with encouraging efficacy signals. The study will continue enrollment across all three cohorts. Drug dosing for the study will proceed as planned. Figure 1 Figure 1. Disclosures Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Ritchie: Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Speakers Bureau; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; NS Pharma: Research Funding; Protaganist: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Pemmaraju: Clearview Healthcare Partners: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; Springer Science + Business Media: Other; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; LFB Biotechnologies: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Affymetrix: Consultancy, Research Funding; Blueprint Medicines: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Aptitude Health: Consultancy; CareDx, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Borthakur: Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; Protagonist: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees. Tari Ashizawa: Bio-Path Holdings, Inc.: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Kantarjian: Immunogen: Research Funding; Ipsen Pharmaceuticals: Honoraria; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Aptitude Health: Honoraria; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria; NOVA Research: Honoraria; Astra Zeneca: Honoraria; Ascentage: Research Funding; BMS: Research Funding; Astellas Health: Honoraria; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; KAHR Medical Ltd: Honoraria. Cortes: Novartis: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding. Roboz: Amgen: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Blueprint Medicines: Consultancy; Glaxo SmithKline: Consultancy; Agios: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Astex: Consultancy; Bristol Myers Squibb: Consultancy; Actinium: Consultancy; Jasper Therapeutics: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Mesoblast: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.

TPS7561 Background: The growth factor receptor bound protein-2 (Grb2) is vital to oncogene signaling and tumor progression. BP1001 is a liposome-incorporated Grb2 antisense oligonucleotide that inhibits Grb2 expression. Grb2 inhibition suppresses cancer growth and survival. A Phase I/Ib single center study in patients with refractory/relapsed leukemias demonstrated the safety of BP1001 up to 90 mg/m2 dose and the efficacy of BP1001 in combination with low dose cytarabine (LDAC) in refractory/relapsed acute myeloid leukemia (AML) patients (Ohanian, Lancet Haematol 2018). Based on pharmacokinetic (PK) considerations, the recommended Phase II dose was 60 mg/m2. A phase II study was initiated to explore the clinical impact of BP1001 in combination with LDAC in untreated AML patients. Interim safety and efficacy of BP1001 + LDAC in untreated AML patients was presented at the 2018 Annual ASH Meeting. BP1001 was safely administered to 25 patients with untreated AML, who were considered unfit for standard chemotherapy. Efficacy data compared favorably to what has been reported with available options for unfit patients largely with secondary AML or adverse-risk AML. Since the Interim Data presentation, the study was amended to investigate BP1001 + decitabine combination and include myelodysplastic syndrome (MDS) patients. This is because BP1001 enhanced decitabine anti-leukemic effects in preclinical studies. Methods: This is a multi-center, open-label study with 2 parallel cohorts of BP1001 + decitabine treatment in untreated AML/high risk MDS patients and refractory/relapsed AML/high risk MDS patients who are considered by the investigator unsuitable for or refused intensive chemotherapy. BP1001 is given intravenously (IV) at 60 mg/m2 twice weekly. Decitabine is given 20 mg/m2 IV daily for 5 consecutive days. Each cycle is 28 days. Each cohort can enroll 19 patients, with a decision to stop or proceed to 54 patients. The primary objective of this study is to assess whether BP1001 + decitabine provides higher complete remission rates than decitabine alone (by historical comparison) in AML/high risk MDS patients. The secondary objectives of this study are to assess: Safety of BP1001 + decitabine; partial remissions and blast count reductions; overall survival, time to response and duration of response; minimal residual disease status in patients who achieve complete remission; and plasma PK profile of BP1001. The exploratory objective of this study is to evaluate the association of treatment response with cytogenetic and molecular characteristics. Clinical trial information: NCT02781883 .

This case report describes how eculizumab reversed neurologic impairment and improved renal damage in severe atypical hemolytic uremic syndrome. A 50-year-old female, after presenting with diarrhea and abdominal pain, developed pancolitis, acute renal failure, and thrombocytopenia. The patient underwent total abdominal colectomy. Pathology confirmed ischemic colitis with scattered mesenteric microthrombi. Due to mental and respiratory decline, she remained intubated. Continuous venovenous hemodialysis was initiated. Renal failure, neurologic changes, hemolysis, thrombotic microangiopathy, and low complement levels all suggested atypical hemolytic uremic syndrome. Eculizumab 900 mg was administered intravenously on hospital day 6 and continued weekly for four doses followed by maintenance therapy. She recovered neurologically and renally after the third dose, and hematologically by the sixth dose. Her recovery has been sustained on long-term eculizumab treatment. In severe atypical hemolytic uremic syndrome, eculizumab safely reverses neurologic impairment and eliminates the need for dialysis. The optimal duration of treatment with eculizumab remains to be determined.

Background: We have previously shown that a single intravenous administration of a self-complementary adeno-associated virus (scAAV) vector containing a codon-optimised factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid, (scAAV2/8-LP1-hFIXco) resulted in a dose-dependent increase in plasma FIX levels in all 10 enrolled severe hemophilia B (HB) patients (ClinicalTrials.gov:NCT00979238; Nathwani et al 2011). FIX activity was stably maintained for at least 3 years (Nathwani et al 2014) but concerns over FIX expression declining over time remain. This is because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural hepatocyte turn-over. The only vector-associated adverse event was an asymptomatic rise in liver enzymes associated with a decline in FIX levels, occurring within 3 months of gene transfer in two-thirds of the patients treated at a dose of 2x1012 vector genomes(vg)/kg. Liver enzymes normalized with corticosteroids without complete loss of transgene expression. There was no long-lasting toxicity over a period of 3 years but further follow-up is required. The vector preparation used contained an excess of empty capsids, which lacked a full-length viral genome, and are therefore, non-functional but capable of provoking an immune response against transduced hepatocytes. Therefore, a new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured from which most of the empty particles were removed by caesium chloride density centrifugation in the hope that this would reduce the risk of hepatotoxicity. We report on the evaluation of this new vector preparation in severe HB patients and provide an update on up to 8 years follow-up of our original cohort of patients. Methods: Ten subjects were recruited in 2010-2012 to the initial dose-escalation/extension study arm, which entailed a single intravenous infusion of scAAV2/8-LP1-hFIXco (full: empty capsid ratio ~1:10) at a dose of either 2x1011vg/kg, 6x1011vg/kg or 2x1012vg/kg. Two severe HB patients (FIX Results: Transgenic FIX activity levels have remained stable in all 10 subjects treated in the initial dose escalation/extension arm over a median follow-up of 6.7±1.0 years with mean levels in the three dose cohorts at the time of reporting of 1.9±0.6, 2.3±0.3 and 5.1±1.4 IU/l respectively. Over this period, annual FIX concentrate usage has dropped by 66% and annual bleed rate has declined by 82% when compared to pre-gene therapy levels. No late toxicity was observed. Neutralising antibodies to FIX were not detected in any patient but anti-AAV8 capsid-specific antibody levels persisted at high titres in 9 of 10 patients. In patients treated with the new preparation of scAAV2/8-LP1-hFIXco (median follow up = 2.1±1.4 years), mean FIX activity in the 2x1012vg/kg dose cohort was 2.6±0.7 IU/l. This is lower than observed previously at this dose level, but the difference is not statistically significant. Mean steady state FIX levels in the 5x1012vg/kg cohort were 17±5 IU/l. FIX antigen to activity ratio was 1:1. Elevation of serum alanine aminotransferase was observed in 3 of 4 patients treated with the new vector preparation, requiring treatment with corticosteroids. Conclusion: This is the first report to demonstrate stable therapeutic expression of FIX in patients with severe HB over a period of 8 years following systemic administration of scAAV2/8-LP1-hFIXco without late toxicities. We show for the first time that reducing the capsid load by removing empty AAV capsids does not appear to reduce the incidence of hepatotoxicity in patients with severe HB suggesting that other factors are involved in the aetiology of this process. Disclosures Nathwani: Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BioMarin: Consultancy, Patents & Royalties; UniQure: Patents & Royalties. Tuddenham:BioMarin: Consultancy, Patents & Royalties; Freeline: Consultancy. Chowdary:Freeline: Consultancy; Baxalta (Shire): Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum AB (Sobi): Honoraria. McIntosh:Freeline: Consultancy. Recht:Biogen: Research Funding; Shire: Research Funding; Novo Nordisk: 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.

Background: The growth factor receptor bound protein-2 (Grb2) is vital to tumor progression. Prexigebersen (BP1001) is a liposome-incorporated Grb2 antisense oligonucleotide that inhibits Grb2 expression. Grb2 inhibition suppresses cancer growth and survival. A Phase I/IB single center study (Ohanian, Lancet Haematol 2018) in relapsed/refractory AML patients (pts) demonstrated BP1001 safety up to 90 mg/m2 and demonstrated CR/CRi in 3/6 relapsed/refractory AML pts treated with BP1001 + low dose cytarabine (LDAC) in the Phase IB portion. Based on PK considerations, the recommended Phase II dose was 60 mg/m2. A phase II study was initiated to explore the clinical impact of BP1001 in untreated AML pts considered unsuitable for standard chemotherapy. Methods: This is a multi-center open-label, Phase II study in untreated AML pts to determine the safety and preliminary efficacy of BP1001 (given at 60 mg/m2 over 1-3 h twice weekly for a total of 8 doses over a 28-day cycle) in combination with LDAC (starting after the Day 4 dose, 20 mg twice daily for 10 days). Eligible pts were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Blood samples were taken on Days 1 and 11 to determine BP1001 plasma pharmacokinetics (PK). Results: A total of 25 pts (16 male: 64%) with a median age of 74 years (range, 51-86 years) was treated with at least 1 cycle of BP1001 + LDAC. Sixty-eight percent (17/25) had secondary AML evolved from MDS (n=13) or MPN (n=3) or prior chemotherapy/radiotherapy (n=1). The majority (64%) had adverse-risk (ELN classification); 36% were intermediate-risk. Infusional reactions (IR) (rigors, fevers, or chills) were observed in 20% of pts when the infusion rate was 1 h. IR were mild, controlled with supportive measures, and were not observed when the infusion rate was 2 h. Other AE's were generally consistent with those expected with LDAC and/or AML, including fatigue (64%), diarrhea (24%), neutropenic fever (24%), and pneumonia (20%). The most frequent SAEs were pneumonia (20%) and neutropenic fever (24%). Four pts died within 30 days of treatment (between days 20-27), all of AML-related complications (including intracranial hemorrhage, pneumonia, septic shock, and splenic rupture). Ten pts had documented progressive disease. Two pts withdrew consent after 1 cycle of treatment. Evaluability of efficacy was defined as: receipt of at least 4 cycles of therapy, PD, or CR/CRi prior to 4 cycles. PK data revealed that the Time of maximal observed concentration (Tmax), the mean terminal elimination half-life (t1/2), and the area under the curve from zero to the last quantifiable concentration (AUC(last)) for BP1001 were similar between Days 1 and 11. Tmax of BP1001 was 1.9 vs 2.3 h (day 1 vs 11); t1/2 was 5.2 vs 5.7 h; AUC(last) was 308 vs 275 h*ng/mL. Response: Among 17 fully evaluable pts, 7 pts (41%) demonstrated bone marrow blast reduction, including 5 (29%) who achieved a CR (n=3), CRi (n=1), or morphologic leukemia free state (n=1). Two additional pts demonstrated a ≥50% reduction of bone marrow blasts (from 20% to 9% and from 71% to 8%), including 1 with hematologic improvement of the absolute neutrophil count. The median overall survival (OS) was 5.2 months (range, 0.6-15.2) for all patients. For evaluable patients, the median OS was 6.3 months (0.8-15.2 months). The CRs included: a 74-year old female who achieved CR after 2 cycles of therapy and then received 2 additional cycles followed by a matched-sibling allogeneic transplant. She remained in CR for 10 months before first relapse. A 73-year old female, with AML transformed from MDS, benefited from therapy despite refusal of blood products due to religious objections. Her hemoglobin declined to 4.0 g/dL during therapy but recovered to as high as 9.9 g/dL once in CR after 4 cycles. An 86-year old male achieved CR after 4 cycles of therapy and maintained CR for 3 months before relapse. Conclusions: BP1001 has been safely administered to 25 pts with untreated AML, who were considered unsuitable for standard chemotherapy. Efficacy data are encouraging in a challenging population in which the majority of pts had secondary AML or adverse-risk AML, and compares favorably to the reported CR/CRi/CRp rate with LDAC of 7-13% (Heiblig, Mediterr J Hematol 2016; Kantarjian, J Clin Oncol 2012; Döhner, Blood 2014). A protocol amendment made to optimize BP1001 administration with LDAC and to add a decitabine combination arm is in place. Disclosures Lin: Jazz Pharmaceuticals: Honoraria. Ritchie:Incyte: Consultancy, Speakers Bureau; Astellas Pharma: Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Craig:Celgene: Research Funding; Novartis: Research Funding; Actinium Pharmaceuticals: Research Funding. Agrawal:Incyte: Speakers Bureau. Pemmaraju:Affymetrix: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; SagerStrong Foundation: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Tari Ashizawa:Bio-Path Holdings, Inc.: Employment, Equity Ownership, Patents & Royalties. Hahne:Bio-Path Holdings, Inc.: Employment. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding. Roboz:Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Cellectis: Research Funding; Roche/Genentech: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; Celltrion: Consultancy; Otsuka: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Astex Pharmaceuticals: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Eisai: Consultancy; Eisai: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy.

International audience; BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2x10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (+/-SD) of 5.1+/-1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.).

This case report presents a newly diagnosed congenital factor VII deficiency treated with recombinant activated factor VII (rFVIIa). Congenital factor VII deficiency is a rare autosomal-recessive bleeding disorder that occurs in fewer than 1/500,000 persons. Its presentation can vary from epistaxis to hemarthroses and severe central nervous system bleeding, and correlates poorly with factor VII levels. Our patient had not had a significant hemostatic challenge prior to his presentation and therefore never had any symptomatology suggestive of this disease. He was treated with rFVIIa, and was able to undergo repair of his fractures without bleeding. Case report A 19-year-old African-American male presented to the emergency room after an altercation that resulted in significant trauma. He sustained bilateral mandibular angle fractures and orbital floor fractures, requiring urgent surgical correction. On initial evaluation, he was noted to have a prolonged prothrombin time of 40.1 seconds, with an International Normalized Ratio of 4.0, a normal activated partial thromboplastin time of 29.9 seconds, and a platelet count of 241. After receiving vitamin K and fresh frozen plasma, he was taken to the operating room for a temporary rigid maxillomandibular fixation. A 1:1 mixing study with normal plasma corrected the prothrombin time (decreasing from 40.7 to 14.7 seconds) and a factor VII assay revealed 5% of the normal factor VII level. The patient was diagnosed with congenital factor VII deficiency. Due to his coagulopathy and the extensive surgical correction needed, rFVIIa was administered and surgery was accomplished without hemorrhagic sequelae. Conclusion This case report and review describes a rare congenital disease, the history of rFVIIa use, and its mechanism. rFVIIA use in our patient provided a treatment option that allowed the necessary surgical correction, but further prospective studies on dose optimization would ensure adequate dosing with minimal risk of severe side effects.

Objective To describe how maintenance eculizumab sustains improved renal function in severe atypical hemolytic uremic syndrome (aHUS). Case report A previously described 50-year-old woman with aHUS had a remarkable recovery with eculizumab, which safely reversed profound neurologic damage and eliminated the need for dialysis. Her recovery has been sustained on long-term eculizumab treatment. She initially received eculizumab 900 mg weekly for four doses. On week 5 she commenced maintenance therapy starting at 1200 mg every 2 weeks. Due to nausea and vomiting at that dose, the maintenance dosing was reduced to 600 mg weekly, beginning on dose seven. After receiving 600 mg weekly for nine doses, eculizumab was then reduced to 600 mg every 2 weeks, with continued improvement in renal function. This dosing is lower than the usual 1200 mg every 2 weeks described in the adult literature and used in current clinical trials of aHUS. Conclusion Six months after the initial diagnosis, our patient continues to have improved renal function on maintenance doses of eculizumab as low as 600 mg every 2 weeks.