scholarly journals Patient Preferences for Hemophilia a Treatments: A Discrete Choice Experiment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-22
Author(s):  
Shawn X. Sun ◽  
Jing Zhao ◽  
Hongbo Yang ◽  
Eric Wu
Keyword(s):  
Gene Therapy ◽  
Pharmaceutical Company ◽  
Patient Preferences ◽  
Choice Experiment ◽  
Research Funding ◽  
Hemophilia A ◽  
Patient Treatment ◽  
Treatment Preferences ◽  
Emerging Treatments ◽  
Attribute Levels

Background: Gene therapy is being investigated as a potential new treatment for patients with hemophilia A. This is designed to provide functional copies of the factor VIII (FVIII) gene via a 1-time infusion to facilitate sustained endogenous production of therapeutic FVIII levels. As part of the patient-focused development of new hemophilia treatments, gene therapy is expected to have a number of different characteristics from current hemophilia A treatments, which are likely to influence patient treatment preferences. Aims: To assess patients' preferences for different hemophilia A treatments, including emerging treatments such as gene therapy. Methods: Male patients aged ≥18 years with moderate or severe hemophilia A and no history of FVIII inhibitors, who had been receiving prophylaxis in the previous month, were recruited in the US from December 2019 to January 2020. Patients who provided informed consent to participate in the online survey were screened and those eligible took part in a discrete choice experiment to quantify the relative importance of different treatment attributes on patient treatment preferences. Patients were presented with 14 choice cards and were asked to select the preferred treatment profile from 2 treatments with varying attribute levels on each card. Attributes and their levels to describe hemophilia A treatments were selected on the basis of a targeted literature review and feedback from 15 patients interviewed by telephone. One attribute level for out-of-pocket cost (a cost not covered by medical insurance) was hypothetical (1-time cost of $3000 for 5 years). Attributes focused on efficacy, safety, and administration-related measures. A conditional logit regression model was used to analyze patient preferences. Odds ratios quantified the impact of specific attribute levels on patients' treatment choices. Estimates of relative attribute importance (RAI) quantified the influence of each attribute on patients' decision making. Results: The survey was completed by 95 patients, 20 (21.1%) with moderate and 75 (78.9%) with severe hemophilia A, who had received prophylactic treatment for a mean (standard deviation [SD]) 14.0 (10.2) years. Most patients (75/95 [78.9%]) were receiving recombinant or plasma-derived FVIII prophylaxis administered once per month, once every 2 weeks, once per week, twice per week, or every other day (2, 3, 4, 33, and 33 patients, respectively). Twenty patients (21.1%) received nonfactor prophylaxis once per month, once every 2 weeks, once per week, twice per week, and with regular use of concomitant FVIII (2, 8, 7, 2, and 1 patient, respectively). Mean (SD) patient age at the survey date was 36.0 (11.3) years. Administration-related measures were the most important class of attributes for patients when selecting treatments (71.5% RAI): route and frequency of administration (30.3% RAI), out-of-pocket cost (24.1% RAI), and place of administration, eg, home versus clinic (17.1% RAI; Figure 1A). The risk of serious side effects was the least important attribute (2.2% RAI), lacking a significant impact on patient treatment choice. The directionality of odds ratios (ORs) for all attribute levels aligned with expectations. Patients exhibited a clear preference for infusion treatments administered with low versus high frequency (OR 3.3; P<0.001) and for treatments administered at home versus the clinic (OR 2.0; P<0.001; Figure 1B). Conclusions: Frequency, route, and place of administration and out-of-pocket costs were the treatment attributes found to have the greatest impact on patient preferences for hemophilia A treatment. Study limitations include potential for selection bias associated with the use of an online panel-based survey. Exclusion of patients with FVIII inhibitors also reduced generalizability, possibly leading to the reduced influence of safety-related treatment attributes. In future studies, design of efficacy attribute levels may better reflect the observed variability in FVIII expression between patients and over time with gene therapy. Insights from this study improve our understanding of preferred treatment regimens for patients with hemophilia A, and could help physicians, stakeholders, and decision makers to evaluate patient acceptance of emerging treatments for hemophilia A, such as gene therapies. Disclosures Sun: Takeda Pharmaceutical Company Ltd.: Current Employment. Zhao:Analysis Group Inc.: Current Employment; Takeda Pharmaceutical Company Ltd: Research Funding. Yang:Analysis Group Inc.: Current Employment; Takeda Pharmaceutical Company Ltd: Research Funding. Wu:Analysis Group Inc.: Current Employment; Takeda Pharmaceutical Company Ltd: Research Funding.

scholarly journals Patient preferences and priorities for haemophilia gene therapy in the US: A discrete choice experiment

Haemophilia ◽  
2021 ◽  
Author(s):  
Michelle Witkop ◽  
George Morgan ◽  
Jamie O'Hara ◽  
Michael Recht ◽  
Tyler W. Buckner ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Discrete Choice Experiment ◽  
Discrete Choice ◽  
Patient Preferences ◽  
Choice Experiment ◽  
The Us

Assessing Patient Experiences with Prophylactic Treatments for Hemophilia a: Concept Elicitation for Gene Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Shawn X. Sun ◽  
Oyebimpe Olayinka-Amao ◽  
Dana DiBenedetti
Keyword(s):  
Gene Therapy ◽  
Physical Health ◽  
Pharmaceutical Company ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Current Therapy ◽  
Specific Patient ◽  
Hypothetical Scenario ◽  
The Impact

Background: Gene therapy for hemophilia A is designed to be a one-time infusion to deliver functional copies of the defective factor VIII (FVIII) gene, to facilitate the endogenous production of therapeutic FVIII levels. The aim is to achieve long-term protection from bleeds without the burden of regular infusions. Aims: To better understand patients' experiences of living with hemophilia A, the impact of traditional hemophilia A treatments, and patients' perceptions of the potential value of gene therapy versus traditional prophylactic treatments. Methods: Patients were identified from the database of a US rare diseases patient organization, who also recruited and screened patients for the study using materials developed by the outcomes research organization (RTI-HS) and Takeda. Adult males aged ≥18 years with a self-reported diagnosis of moderate or severe hemophilia A, who reported using factor or nonfactor prophylactic treatment and were not currently receiving treatment for inhibitors, were eligible for the study. Eligible patients provided verbal informed consent to participate in a semi-structured, 60-minute telephone interview conducted in English by 2 members of RTI-HS who did not have access to any patient-identifying information at any time during the study. Targeted questions probed perceptions of treatment burden, impact of hemophilia A on daily life, and time spent on treatment. Additionally, questions were posed to assess patients' perceptions of the impact of traditional treatments and the potential benefits they anticipate from gene therapy. Results: Nineteen patients aged 19-55 years with moderate (n = 1) or severe (n = 18) hemophilia A were interviewed. Most (16/19, 89.5%) received prophylactic FVIII therapy, (3/19, 15.8%) were receiving nonfactor prophylactic treatment, of which 1 patient also used FVIII treatment. The aspects of current or past treatments most frequently disliked by patients were lack of efficacy, frequency of infusions, intravenous administration, vein health/scar tissue, and dosing volume. Most patients expressed satisfaction with their current treatment (18/19; 94.7%), though all listed ≥1 negative treatment impact, most frequently related to difficulties with travel (13/19; 68.4%), mood/emotions (12/19; 63.2%), day-to-day activities (10/19; 52.6%), and physical health/activities (7/19; 36.8%), including having to give up or reduce particular activities because of their treatment and needing to be more cautious, especially on nontreatment days. When presented with a hypothetical scenario for gene therapy - a one-time long-acting intravenous infusion to provide a constant level of FVIII that could reduce future bleeds - all patients stated they would choose gene therapy over their current therapy, although several said they would have initial questions regarding safety, efficacy, and duration of protection. Commonly expressed reasons for preferring gene therapy (Figure 1) included fewer infusions and less worry about the need to infuse. All 19 patients said they expected to be highly satisfied with this treatment, largely because of the long-term protection from bleeds, fewer infusions, and less concern about inhibitors. The most commonly anticipated improvements were in mood/emotions (15/19; 78.9%), specifically related to reduced concern about infusions and bleed protection. Other commonly anticipated improvements included gain in time usually spent infusing (13/19; 68.4%), easier travel (12/19; 63.2%), and improved physical health and ability to perform activities (10/19; 52.6%). Conclusions: This study identified specific patient priorities, including treatment convenience, long-lasting bleed protection, frequency of intravenous infusions, and infusion volumes. The results suggest that gene therapy clinical trials should consider evaluating patient concerns in relation to the level of patient confidence in bleed protection. A study limitation is that, at the time of the survey, data on the efficacy and safety of gene therapy were limited. In the future, the study will be expanded to include a larger population of patients with hemophilia. Disclosures Sun: Takeda Pharmaceutical Company Ltd.: Current Employment. Olayinka-Amao:Takeda Pharmaceutical Company Ltd: Other: RTI-HS was contracted by Takeda Pharmaceutical Company Ltd to conduct this work; RTI Health Solutions: Current Employment. DiBenedetti:RTI Health Solutions: Current Employment; Takeda Pharmaceutical Company Ltd: Other: RTI-HS was contracted by Takeda Pharmaceutical Company Ltd to conduct this work.

Human-Cl Rhfviii Effectively and Safely Prevents Bleeding Episodes in Previously Treated Adult Patients with Severe Haemophilia A

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1132-1132
Author(s):  
Sigurd Knaub ◽  
Toshko Lissitchkov ◽  
Kingsley Hampton ◽  
Mario Von Depka ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Research Funding ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Open Label ◽  
Bleeding Rate ◽  
Previously Treated

Abstract Abstract 1132 The main purpose of this prospective, multi-center, open-label phase 3 study was to assess the efficacy of prophylactic treatment with Human-cl rhFVIII, the first human cell-line derived recombinant FVIII, in previously treated patients (PTPs) with severe haemophilia A. Patients were to receive 30–40 international units (IU) FVIII of Human-cl rhFVIII per kg every other day for 6 months. Efficacy of preventing and treating bleeds were judged using objective criteria taking the monthly bleeding rate and the number of infusions needed to manage a break-through bleed into account. In-vivo recovery (IVR) was determined at the beginning of the study and after 3 and 6 months. FVIII:C was measured by validated chromogenic (CHR) and one-stage (OS) assays in a central laboratory, which also assigned drug potencies. Inhibitor activity was determined using the Nijmegen modification of the Bethesda assay before the first administration and at defined intervals thereafter. Thirty-two patients between 18 and 75 years of age were enrolled from 11 centres in Europe and treated prophylactically for 6.0±0.9 months (mean ± SD) with a mean prophylactic dose of 32.8 IU/kg. Sixteen patients never bled, 11 patients bled once and 5 more than once. The mean total and spontaneous monthly bleeding rate was 0.188±0.307 and 0.095±0.211, respectively. Efficacy of the prophylactic treatment was “excellent” in all patients for spontaneous BEs and “excellent” or “good” in all patients but one for all types of bleeds. All treatments of bleeds were rated as “excellent” (71.4%) or “good” (28.6%). The IVR at baseline was 2.6±0.5 % per IU/kg for the CHR and 2.2±0.5 % per IU/kg for the OS assay and remained stable during the study. A total of 2921 infusions were given in the study. Human-cl rhFVIII was well tolerated and no patient experienced a related serious adverse event. No FVIII inhibitors were detected. Conclusion: The data indicate that Human-cl rh FVIII is safe and efficacious in preventing and treating bleeds in PTPs with severe haemophlia A. Disclosures: Knaub: Octapharma AG: Employment. Lissitchkov:Octapharma AG: PI Other. Tuddenham:College London: Consultancy, Employment, Gene therapy for hemophilia A, Gene therapy for hemophilia A Patents & Royalties, Research Funding. Collins:Octapharma AG: Consultancy. Oldenburg:d and e: Baxter, Bayer, Biotest, CSL-Behring, Grifols, Inspiration, NovoNordisk, Octapharma, Pfizer e: Biogen IDec, Swedish Orphan Biovitrum: Honoraria, Research Funding. Bichler:Octapharma AG: Employment.

scholarly journals Gene Therapy in Hemophilia: An Assessment of Hematologists' Knowledge Gaps and Attitudes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3485-3485 ◽  
Author(s):  
Simi Hurst ◽  
Charlotte Warren ◽  
K. John Pasi
Keyword(s):  
Gene Therapy ◽  
Research Funding ◽  
Hemophilia A ◽  
Viral Vector ◽  
Healthcare Providers ◽  
Factor Ix ◽  
Educational Activity ◽  
Knowledge Gaps ◽  
Endogenous Expression ◽  
Therapy Strategies

Abstract BACKGROUND: Currently available treatments for hemophilia A and B require frequent intravenous infusions. Gene therapy, by contrast, offers the hope of a functional cure through endogenous expression of the factor VIII or factor IX genes. To identify and address practice gaps among healthcare providers who manage patients with hemophilia, a collaboration between the National Hemophilia Foundation (NHF), European Haemophilia Consortium (EHC), World Federation of Hemophilia (WFH), and Medscape Education was established. The objective of the current study is to assess clinicians' needs with regard to understanding the science and mechanism for gene therapy, the different technologies being proposed, identifying candidates for gene therapy, disease areas for which gene therapy is being explored, and the latest data on the potential role of gene therapy in hemophilia A and B. METHODS: A continuing medical education (CME)-certified clinical practice assessment comprising 25 multiple choice questions that measured knowledge, attitudes, and perspectives about gene therapy was developed. The survey instrument was made available online to physicians without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. The activity launched on March 03, 2018; data through July 27, 2018 are presented, but data collection is ongoing. RESULTS: At the time of this analysis, 194 physician participants indicated that they actively manage patients with hemophilia. Demographics are presented in Table 1; confidence and attitudes about gene therapy in Table 2. Among hematologists/oncologists (n=54; hem/onc), identified knowledge gaps include, 46% could not identify the liver as the tissue/cell type that is the primary target for gene therapy in hemophilia46% thought that current approaches to gene therapy in hemophilia involved some form of host gene editing39% did not realize that gene therapy strategies only affect somatic cells and not the germline22% thought current gene therapy strategies would prevent or reduce the severity of hemophilia in subsequent generations of patients33% were unable to correctly identify adeno-associated virus (AAV) as the viral vector that is the current basis for the majority of gene therapy trials in hemophilia81% had misconceptions regarding the key characteristics of the AAV vector56% did not recognize that the AAV vector does not routinely integrate into the host genome19% were unfamiliar with the maximum gene cassette capacity of AAV57% were unfamiliar with the results from the pivotal University College London (UCL)/St Jude trial of scAAV2/8-LP1-hFIXcovector in patients with hemophilia B63% were unfamiliar with the clinical trial data for SPK-8011 in hemophilia A67% were unfamiliar with the results at the 12 month time-point for valoctocogene roxaparvovec in hemophilia A trials57% had misconceptions with regard to the causes for and treatment of ALT elevations seen in hemophilia AAV gene therapy trials CONCLUSIONS: Gene therapy has the potential to fundamentally alter the management of hemophilia. This educational activity identified clear deficits about - and attitudes toward - gene therapy among healthcare providers who currently care for patients with hemophilia. Furthermore, the great majority of healthcare providers lacked confidence in their understanding of gene therapy for hemophilia A. These findings will be used to inform the development of educational programs and to prepare providers for anticipated changes to the hemophilia treatment landscape. Disclosures Pasi: Catalyst Bio: Honoraria; Octapharma: Honoraria; NovoNordisk: Speakers Bureau; Bioverativ: Honoraria, Research Funding; Apcintex: Honoraria; Shire: Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Speakers Bureau; Sobi: Honoraria; Biomarin: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding.

scholarly journals Updated Follow-up of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (SB-525) Gene Therapy in Adults with Severe Hemophilia a

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-12
Author(s):  
Andrew D. Leavitt ◽  
Barbara A. Konkle ◽  
Kimo Stine ◽  
Nathan Visweshwar ◽  
Thomas J. Harrington ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Stock Options ◽  
Research Funding ◽  
Hemophilia A ◽  
Phase 1 ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Dose Cohort ◽  
Fviii Activity

Introduction: Hemophilia A is a rare bleeding disorder caused by pathogenic variants in the F8 gene, resulting in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)-mediated gene transfer enables the delivery of a modified functional F8 gene to hepatocytes that subsequently synthesize FVIII at levels that may prevent bleeding events in the absence of exogenous FVIII. Updated results and follow-up from the Alta study, an ongoing gene therapy study in patients with severe hemophilia A, are presented. Methods: The Alta study is a phase 1/2 dose-ranging, single-dose study of giroctocogene fitelparvovec (also known as SB-525 and PF-07055480), a recombinant AAV serotype 6 (rAAV6) vector encoding a modified F8 gene. Adults aged ≥18 years with severe hemophilia A were eligible for inclusion. Giroctocogene fitelparvovec was infused into patients in 4 cohorts of 2 patients each across 4 ascending doses (9e11, 2e12, 1e13, and 3e13 vg/kg). The 3e13 vg/kg dose cohort was expanded with 3 additional patients. Key end points included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events. Presented data are from the ongoing Alta study (NCT#03061201; data cutoff date, 26 May 2020; database not locked; data reflect those at time of data cutoff, have not undergone standard quality checks, and may be subject to change). Results: Eleven male patients participated in the study (mean [SD] age, 30.3 [7.8] years; white, 81.8%). As of the cutoff date, patients have been followed for 35 to 144 weeks; one patient in the 1e13 vg/kg cohort discontinued from the study. Overall, the most commonly reported adverse events (AEs; n) included increased alanine aminotransferase (ALT; 8 [72.7%]), increased aspartate aminotransferase (AST; 5 [45.5%]), upper respiratory tract infection (4 [36.4%]), and pyrexia (4 [36.4%]). Treatment-related serious AEs were reported in 1 patient (in the 3e13 vg/kg cohort) who experienced hypotension and fever ≈6 hours after giroctocogene fitelparvovec infusion; the events fully resolved with treatment and did not delay post-infusion discharge. In the 3 lower-dose cohorts, no ALT elevation requiring more than 7 days of corticosteroid treatment was observed. Of the 5 patients in the 3e13 vg/kg cohort, 4 had elevations in ALT that were managed with a tapering course of corticosteroids (ranging from 10-134 days) without loss of clinically relevant FVIII activity through 40 weeks, as evidenced by a lack of bleeding events before and after treatment with corticosteroids. Increases in FVIII activity from baseline were generally dose-dependent. Patients in the 3e13 vg/kg cohort achieved a mean normal-range of FVIII activity within 5 weeks post-infusion, with mean FVIII activity maintained through week 40, which is the last time point with data for all 5 patients in this cohort (Table). Following the initial prophylactic period of up to ≈3 weeks after giroctocogene fitelparvovec administration, no bleeding events occurred in any patient treated in the 3e13 vg/kg cohort. Use of FVIII replacement therapy ≥3 weeks after giroctocogene fitelparvovec administration was reported in 5/6 patients in the lower-dose cohorts (range: 9-115 infusions); none of the patients in the 3e13 vg/kg cohort required FVIII replacement beyond initial use of prophylactic factor for up to ≈3 weeks (prophylactic coverage stopped 3 weeks and 2 days after giroctocogene fitelparvovec administration in 1 patient in the 3e13 vg/kg cohort). Conclusions: To date, a single infusion of giroctocogene fitelparvovec gene therapy in patients with severe hemophilia A resulted in dose-dependent and sustained increases in FVIII levels without administration of exogenous FVIII, bleeding episodes or sustained adverse events in the highest-dose cohort (3e13 vg/kg). Additionally, patients treated in the highest-dose cohort achieved a mean FVIII activity in the normal range within 5 weeks, which was maintained through week 40. Data on all patients with more than 1 year of follow-up will also be presented. The study is ongoing, and these interim results support further development of giroctocogene fitelparvovec for the treatment of patients with severe hemophilia A. Disclosures Leavitt: BioMarin: Membership on an entity's Board of Directors or advisory committees. Konkle:Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; BioMarin: Consultancy; Baxalta: Research Funding; Spark: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sigilon: Consultancy, Research Funding; Roche: Consultancy. Stine:Biomarin: Consultancy; Applied Stem Cell Therapeutics: Consultancy. Visweshwar:Biogen Idec: Membership on an entity's Board of Directors or advisory committees. Giermasz:uniQure: Consultancy, Research Funding; Sangamo Therapeutics: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau. Arkin:Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: own stock/options in the company. Fang:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Plonski:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Smith:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Tseng:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Di Russo:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Cockroft:Sangamo Therapeutics: Current Employment, Other: Shareholder of Sangamo Therapeutics. Rupon:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Rouy:Sangamo Therapeutics: Current Employment, Other: Shareholder of Sangamo Therapeutics.

scholarly journals Development of an Optimized rAAV2/6 Human Factor 8 cDNA Vector Cassette for Hemophilia a Gene Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1173-1173
Author(s):  
Brigit E. Riley ◽  
Jeff Boonsripisal ◽  
Alicia Goodwin ◽  
Dominique Cartier ◽  
Eudean Garces ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Manufacturing Process ◽  
Research Funding ◽  
Human Factor ◽  
Hemophilia A ◽  
Mrna Levels ◽  
Clinical Scale ◽  
Wild Type ◽  
Dose Ranging ◽  
The Impact

Abstract Hemophilia A, which is caused by a mutation in the Factor 8 (F8) gene resulting in a deficiency or lack of the Factor VIII (FVIII) protein, is the most common inherited bleeding disorder in humans with an estimated worldwide incidence of half a million people. The disorder is X-linked and occurs in approximately 1 in 5,000 males; however there is also a growing appreciation of the impact on carrier females having a single mutant allele, with at least 10% of hemophilia A female carriers having less than normal clotting activity. Even modest increases in Factor V III activity (>1% of normal) can have a positive impact on patient lives, thus making the disease an ideal candidate for liver-directed gene therapy. Recombinant AAV (rAAV) has been used extensively for nearly 20 years as a gene therapy vector in preclinical and clinical studies where rAAV delivery to non-dividing tissues such as liver, brain and muscle affords stable, long-term transgene expression. However, there has been a lag in the clinical translation of a rAAV gene therapy approach for Hemophilia A/human F8 (hF8) compared to Hemophilia B/human Factor 9 due to poor yields of rAAV encoding a F8 transgene at clinical scale, and a requirement for large doses of rAAV F8 vector to achieve therapeutically relevant levels of circulating human FVIII (hFVIII), with the attendant risk of inducing an AAV-directed immune response requiring transient immunosuppression. To address these issues we optimized a rAAV F8 cDNA vector cassette to improve both virus yields and liver-specific hFVIII expression. The rAAV F8 cDNA vector cassette optimization required multi-factorial modifications to the liver-specific promoter module, hF8 transgene, synthetic polyadenylation signal and vector backbone sequence. This iterative process resulted in improved vector yields at research scale and greater than five-fold improvement in vector yields at clinical scale using our proven manufacturing process. Administration of the optimized rAAV hF8 cDNA packaged in serotype AAV2/6 at a dose of ~7.2E+12 vg/kg to both wild type and Hemophilia A mice resulted in robust circulating hFVIII levels and activity (levels in wild type mice were 241.6% of normal, and activity in Hemophilia A mice were 330.9% of normal). An analysis of hF8 mRNA levels in different tissues following dosage with our optimized vector demonstrated that hF8 expression from the modified promoter module was restricted to the liver. Notably there was a striking impact on hemostasis in the Hemophilia A mice treated with the optimized rAAV hF8 cDNA, with a reduction in bleeding time from 38.3 minutes to 2.5 minutes in treated mice (n = 12, p-value < 0.0001), which is in line with bleeding times in wild type mice. Initial studies in non-human primates (NHPs) resulted in supraphysiological levels of circulating hFVIII with mean peak values of 400-600% of normal levels. A follow up dose-ranging study was performed in NHPs with a rAAV2/6 F8 cDNA vector manufactured using our GMP clinical manufacturing process. Administration of vector doses ranging from 6E+11 vg/kg to 6E+12 vg/kg resulted in therapeutic circulating levels of hFVIII that were 5% - 229% of normal levels. The peak circulating hFVIII levels achieved in this dose-ranging study using GMP clinical-scale vector exceeds the levels previously reported in NHPs by several fold on an AAV vector dose basis. The high potency of this enhanced rAAV F8 cDNA cassette could significantly reduce the dose required to achieve therapeutically relevant levels in human subjects and reduce the potential of developing immune responses to AAV capsid requiring immunosuppression. Disclosures Riley: Sangamo BioSciences Inc: Employment. Boonsripisal:Sangamo BioSciences Inc: Employment. Goodwin:Sangamo BioSciences Inc: Employment. Garces:Sangamo BioSciences Inc: Employment. Ballaron:Sangamo BioSciences Inc: Employment. Tran:Sangamo BioSciences Inc: Employment. Kang:Sangamo BioSciences Inc: Employment. Zhang:Sangamo BioSciences Inc: Employment. Meyer:Sangamo BioSciences Inc: Employment. Greengard:Sangamo BioSciences Inc: Employment. Surosky:Sangamo BioSciences Inc: Employment. Ando:Sangamo BioSciences Inc: Employment. Lillicrap:bayer: Research Funding; biogen: Research Funding; CSL: Research Funding; Octapharma: Research Funding; Sangamo Biosciences Inc: Research Funding. Nichol:Sangamo BioSciences Inc: Employment. Holmes:Sangamo BioSciences Inc: Employment.

scholarly journals First-in-human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4630-4630
Author(s):  
Steven Pipe ◽  
Michael Becka ◽  
Elke Detering ◽  
Konstantina Vanevski ◽  
Toshko Lissitchkov
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Care Providers ◽  
Dose Cohort ◽  
Fviii Activity ◽  
Equity Ownership ◽  
Hemostatic Efficacy

Background: Gene therapy for hemophilia A has the potential to reduce the treatment burden for care-providers and patients, by eliminating the need for regular factor VIII (FVIII) prophylaxis through the long-term expression of endogenous FVIII at levels sufficient to provide bleed protection. BAY 2599023 (AAVhu37FVIII) is a non-replicating adeno-associated virus (AAV) vector, based on the AAV serotype hu37, which contains a single-stranded DNA genome encoding a B-domain deleted FVIII, under the control of a liver-specific promotor/enhancer combination optimized for transgenic expression. The AAVhu37 capsid is a member of the hepatotropic Clade E family and has been selected based on nonclinical studies demonstrating efficient liver-directed FVIII gene transfer, favorable biodistribution as well as durable FVIII expression. BAY 2599023 is the first clinical-stage AAV gene therapy vector based on the AAVhu37 serotype. This analysis reports safety and FVIII activity following a single intravenous infusion of BAY 2599023 in the first-dose cohort of a phase I/II open-label, first time in human dose-finding study (NCT03588299) of previously treated, severe hemophilia A patients. Patients/Methods: Two participants were enrolled sequentially; each received a single infusion of AAVhu37 (0.5 x 1013 GC/kg). Patients were males ≥18 years with no history of FVIII inhibitor development, no detectable immunity to the AAVhu37 capsid, and >150 exposure days to FVIII products. Primary endpoints were adverse events (AEs), serious AEs and AEs/SAEs of special interest (S/AESI); the secondary endpoint was change in FVIII activity from baseline. Informed patient consent, and ethics committee approval at each local site, were obtained. Results: Following more than 15 weeks of safety observation, no SAEs, AEs related to study drug, nor S/AESI were reported. Liver enzymes (alanine aminotransferase and aspartate aminotransferase) remained <1.5 of baseline. Corticosteroids were not used in either patient. Clear evidence of FVIII expression was observed in both patients with stable values of ~5% and ~17% in the first and second patient, respectively. An early read-out also indicated hemostatic efficacy in both; the first patient had successfully halted prophylaxis for 6 weeks, while the second one, treated on-demand with 99 bleeds recorded in the 12 months prior to gene transfer, has been bleed free for over 5.5 months to date. Conclusions: BAY 2599023 was previously shown in non-clinical studies to have a good safety profile, with the potential to achieve endogenous expression of FVIII at therapeutic levels, over an extended period of time. In this first-in-human clinical study with BAY 2599023, two patients have been treated with BAY 2599023 at the starting dose of 0.5 x 1013 GC/kg and no safety concerns have been reported to date. Measurable expression of endogenous FVIII and an early read-out of hemostatic efficacy have been demonstrated in both patients. Overall, data generated from this first dose cohort demonstrate that successful translation from pre-clinical to clinical development and proof-of-mechanism for BAY 2599023 was achieved. Disclosures Pipe: HEMA Biologics: Consultancy; Shire: Consultancy; Roche/Genentech: Consultancy; Sanofi: Consultancy; Freeline: Consultancy; Apcintex: Consultancy; Novo Nordisk: Consultancy; Catalyst Bioscience: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; uniQure: Consultancy; BioMarin: Consultancy; Pfizer: Consultancy; Spark Therapeutics: Consultancy. Becka:Bayer: Employment. Detering:Bayer: Employment. Vanevski:Bayer: Employment. Lissitchkov:Octapharma: Equity Ownership, Research Funding; Bayer: Consultancy, Equity Ownership, Honoraria, Other: Principal investigator for clinical trials, Research Funding; Sobi: Consultancy, Equity Ownership, Honoraria; Sanofi: Equity Ownership, Research Funding; Roche: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Shire: Consultancy, Equity Ownership, Honoraria, Speakers Bureau. OffLabel Disclosure: Gene therapy for haemophilia treatment.

scholarly journals Patient Treatment Preferences for Relapsed/Refractory Multiple Myeloma: Are Patients Willing to Trade Off Efficacy for Tolerability?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 614-614 ◽  
Author(s):  
Daniel Auclair ◽  
Carol Mansfield ◽  
Ajai Chari ◽  
Craig E. Cole ◽  
Mark A. Fiala ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Latent Class Analysis ◽  
Pharmaceutical Company ◽  
Board Of Directors ◽  
Research Funding ◽  
Latent Class ◽  
Nerve Damage ◽  
Treatment Preferences ◽  
Relative Importance ◽  
Advisory Committees

Abstract OBJECTIVES: Several agents have recently been approved for relapsed/refractory multiple myeloma (RRMM), providing patients and providers with more treatment options. The existing literature on patient preferences for MM treatments is limited. This study aims to quantify these preferences using a discrete-choice experiment (DCE) survey coupled with a best-worst scaling (BWS) exercise to elicit treatment priorities and unmet needs. METHODS: The survey design utilized both a DCE and a BWS exercise that included attributes and levels that overlapped between the two types of patient preference questions (DCE and BWS) to provide multiple sources of information on treatment preferences. The attributes for the DCE and BWS exercise were informed by patient focus groups. The final DCE included six attributes with varying levels: progression-free survival (PFS, 6-24 months); risk of heart failure (0%-5%); peripheral neuropathy (none, mild-to-moderate, severe); risk of low blood counts, combining thrombocytopenia and neutropenia (0%-70%); gastrointestinal (GI) problems (none, nausea and vomiting, diarrhea, constipation); and mode and frequency of administration (daily and weekly pill, weekly injection, intravenous [IV] infusion 4 hours per week, IV 1 hour twice a week). The BWS exercise included 18 items (the modes and frequency of administration included in the DCE, additional treatment convenience items, mild and serious adverse events, and treatment side-effects). The final survey was administered online to patients recruited from the Multiple Myeloma Research Foundation CoMMpass study (NCT01454297). For the DCE data, latent-class analysis was used to identify patient subgroups with systematically different preferences. The relative strength of preference for each attribute level (i.e., relative preference weights) was estimated for all subgroups and was used to calculate the relative importance of attributes. For each item in the BWS exercise, a relative score was calculated by subtracting the number of times a feature was chosen as least bothersome from the number of times it was chosen as most bothersome, then dividing by the total number of times appeared in the design. RESULTS: The final sample consisted of 94 patient respondents with RRMM. Patients had an average age of 65 years, and 59% were male. The latent-class analysis identified two subgroups of respondents with systematically different preferences (Figure 1). Both subgroups expressed a willingness to trade PFS for less treatment toxicity. Members of subgroup 1 placed the greatest relative importance on toxicities (nerve damage, risk of low blood counts, GI problems). A change in nerve damage from none to severe was the most important attribute to subgroup 1, approximately 1.8 times more important than the relative importance of a change in the risk of low blood counts from 0% to 70%, and 2.7 times more than the relative importance of a change in PFS from 6 months to 1 year. Members of the second subgroup considered PFS the most important attribute, followed by nerve damage and mode of administration. Subgroup 2 considered the relative importance of a change in PFS from 6 months to 2 years to be more than two times as important as the relative importance of changes in all other attributes. In the BWS exercise, respondents evaluated kidney complications and low white blood cell count as the most bothersome medicine characteristics, while taking pills once a week for 3 weeks per month or pill taken daily were the least bothersome (most favorable) characteristics. CONCLUSIONS: Patients with RRMM place importance on PFS and nerve toxicity when considering treatment features and modes of administration. Results from the preference study indicate that there are subgroups of patients with systematically different treatment preferences. Understanding how different patients value treatment attributes may help decision makers improve the quality of patient-centered care. Figure 1. Figure 1. Disclosures Mansfield: Takeda Pharmaceuticals International Co: Consultancy; Genentech: Consultancy. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy. Cole:Cancer Support Community myeloma advisory board: Membership on an entity's Board of Directors or advisory committees; University of Michigan: Employment. Kaufman:Karyopharm: Other: data monitoring committee; Roche: Consultancy; BMS: Consultancy; Janssen: Consultancy; Abbvie: Consultancy. Siegel:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zonder:Takeda: Honoraria; Alnylam: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Coelum: Honoraria; BMS: Research Funding; Pharmacyclics: Other: DSMC. Mange:Takeda Pharmaceutical Company: Consultancy. Dalal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Employment, Equity Ownership. Mikhael:Onyx, Celgene, Sanofi, AbbVie: Research Funding.

scholarly journals A Dedifferentiated Sinusoidal Endothelium Impacts Liver-Directed Gene Transfer in Hemophilia-a Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3981-3981
Author(s):  
Shweta Gudapati ◽  
Tomasz W. Kaminski ◽  
Ravi Vats ◽  
Prithu Sundd ◽  
Tirthadipa Pradhan-Sundd
Keyword(s):  
Gene Therapy ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Gene Transfer ◽  
Intravenous Infusion ◽  
Research Funding ◽  
Hemophilia A ◽  
Null Mouse ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells

Abstract Hemophilia A is an X-linked recessive bleeding disorder that affects 1 in 5000 males and is caused by procoagulant factor VIII deficiency. Affected people are at danger of spontaneous bleeding into organs, which can be fatal and lead to persistent damage. Current therapy includes intravenous infusion of FVIII protein concentrate which carries the danger of transmitting blood-borne diseases. As a result of recent advancements in liver-directed gene transfer, gene therapy based innovative strategy for treating hemophilia has emerged. In patients with severe hemophilia B, intravenous infusion of an adeno-associated viral (AAV) vector encoding factor IX (FIX) under the control of a liver-directed promoter resulted in expression of FIX for a considerable period of time. In hemophilia-A patients, gene treatment utilizing AAV vectors has demonstrated to be less effective than Hemophilia B due to the size of the F8 coding sequence and the decreased release of FVIII protein. Among other concerns high immunogenicity of FVIII with 25-30% of hemophilia A patients forming inhibitors and overexpression of FVIII in hepatocytes triggering a cellular stress response are significantly challenging. A phase 1 clinical trial is now being conducted to examine the AAV8 induced liver directed gene expression strategy to circumvent these challenges. The Factor VIII null mouse has been effective in understanding the disease pathogenesis as well as the development of liver directed novel gene therapy techniques to treat hemophilia. FVIII is predominantly produced in the liver. Thus, liver directed adenoviral and retroviral vectors have been studied by several groups to understand the gene delivery method in hemophilia. A few of these studies have shown limited effectiveness in hemophilia animal models. Although the coagulation anomaly seen in hemophilia murine model was completely repaired immediately after liver directed adenovirus-mediated treatment, the effect was transient. Additionally, adeno associated virus (AAV8)-FVIII overexpression has been associated with increased cellular stress. In this study we evaluated the stability and efficacy of liver driven gene transfer mechanism in FVIII null mouse using recombinant AAV8 vector. Recombinant AAV8 vector delivered through the systemic circulation successfully transduces to target tissues via passing through the permeable barrier of sinusoidal endothelial cell. The bidirectional passage through sinusoidal endothelial cell is mainly supported by the presence of discontinuous fenestrated endothelium. Remarkably, we found that liver directed gene transfer was significantly delayed in FVIII null mice. Using quantitative liver intravital imaging we found that upon AAV8-GFP administration liver sinusoidal endothelial cells shows increased apoptosis. Moreover, structural analysis of the liver sinusoidal endothelial cells using intravital and electron micrograph imaging showed significant structural functional difference in liver sinusoidal endothelial cells of FVIII KO mouse. Work is currently underway to understand how absence of FVIII can affect the LSECs. In conclusion, detailed molecular characterization of LSEC-mediated liver directed gene transfer in a hemophilia mouse model is critical for understanding the efficacy and stability of gene-based hemophilia treatment. Disclosures Sundd: Bayer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Research Funding.

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