BAX 335 / Takeda, Bayer - LARVOL DELTA

Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B (clinicaltrials.gov) - P1/2 | N=30 | Active, not recruiting | Sponsor: Baxalta now part of Shire | Trial completion date: Oct 2030 ➔ Jan 2030 | Trial primary completion date: Oct 2030 ➔ Jan 2030

Gene therapy • Trial completion date • Trial primary completion date • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

BAX 335 Hemophilia B Gene Therapy Phase 1/2 Clinical Trial: Long-Term Safety and Efficacy Follow-up (ASH 2022) - P1/2 | "No additional BAX 335-related AEs, malignancy or thrombosis were reported in this long-term follow-up analysis of a phase 1/2 study. One participant achieved persistent FIX transgene activity in the circulation for 7.2 years and remains free from bleeding and the need for FIX replacement therapy. This is the longest duration of FIX R338L expression reported."

Clinical • P1/2 data • Cardiovascular • Gene Therapies • Hematological Disorders • Hemophilia • Immunology • Oncology • Rare Diseases • Rheumatology • Thrombosis • IL6R

Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B (clinicaltrials.gov) - P1/2 | N=30 | Active, not recruiting | Sponsor: Baxalta now part of Shire | Trial completion date: Jul 2022 ➔ Oct 2030 | Trial primary completion date: Jul 2022 ➔ Oct 2030

Trial completion date • Trial primary completion date • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B (clinicaltrials.gov) - P1/2 | N=30 | Active, not recruiting | Sponsor: Baxalta now part of Shire | Trial completion date: Nov 2021 ➔ Jul 2022 | Trial primary completion date: Nov 2021 ➔ Jul 2022

Trial completion date • Trial primary completion date • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B (clinicaltrials.gov) - P1/2; N=30; Active, not recruiting; Sponsor: Baxalta now part of Shire; Trial completion date: Aug 2021 ➔ Nov 2021; Trial primary completion date: Aug 2021 ➔ Nov 2021

Clinical • Trial completion date • Trial primary completion date • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B (clinicaltrials.gov) - P1/2; N=30; Active, not recruiting; Sponsor: Baxalta now part of Shire; Trial completion date: Dec 2020 ➔ Aug 2021; Trial primary completion date: Dec 2020 ➔ Aug 2021

Clinical • Trial completion date • Trial primary completion date • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B (clinicaltrials.gov) - P1/2; N=30; Active, not recruiting; Sponsor: Baxalta now part of Shire; Trial completion date: Oct 2030 ➔ Dec 2020; Trial primary completion date: Oct 2030 ➔ Dec 2020

Clinical • Trial completion date • Trial primary completion date • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases

BAX 335 hemophilia B gene therapy clinical trial results - potential impact of CpG sequences on gene expression. (PubMed, Blood) - P1/2 | "We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization. Registered at www.clinicaltrials.gov as NCT01687608."

Clinical • Journal • Cardiovascular • Gene Therapies • Hematological Disorders • Hemophilia • Rare Diseases • Thrombosis

Baxter: ISTH Congress (Baxter) - "The ongoing BAX 335 Phase 1/2 study has escalated to 3rd dose cohort. An additional 5 patients will be dosed"; "Sustained expression of 20-25% for 1 year was observed in cohort 2"; "Peak FIX activity level >50% achieved in Cohort 3 but persistent, stable expression was not achieved in the first two patients in this cohort"; "Dose-dependent immune responses were observed in two patients in cohort 3 and treated with corticosteroid. FIX expression has subsequently declined in both subjects, likely due to delayed start of corticosteroid"; "No inhibitors observed in any of the subjects treated to date"; "Conclusion: Hemostatically effective plasma FIX activity levels were achieved in cohort 2 and 3 with sustained high level expression in one patient (20-25%)"

P1/2 data • Hemophilia

Shire's discontinuation of BAX 335 program positive for uniQure (QURE) - Leerink (Streetinsider.com) - "...SHPG (OP) announced on their 2Q16 earnings call today that they are discontinuing dev't of clinical stage hemophilia B gene therapy program BAX-335 and are focusing on advancing a different preclinical program instead given the inconsistent results seen to date. This is incrementally positive for QURE, since competition in hemophilia B has formed a major overhang on the stock....Next updates from QURE's high dose cohort of the AMT-060 trial are expected by YE16."

Anticipated clinical data • Discontinued • Gene Therapies • Hemophilia

Gene therapy’s roller coaster ride (Pink Sheet - Informa) - "Baxter AG is expected to file a BLA in 2017-2018 for its hemophilia B candidate AskBio009 (scAAV2/8-LP1-hFIXco), a recombinant adeno-associated virus (rAAV) based gene therapy, which corrects a defect in the gene encoding coagulation Factor IX."

Anticipated BLA • Hemophilia

Adeno-associated virus 8 (AAV8) vector genome biodistribution into body fluids following single intravenous administration of BAX 335 gene therapy for hemophilia B (ASH 2015) - P=P1/2, N=16; NCT01687608; Sponsor: Baxalta US Inc.; "The remaining 3 subjects (S5-S7) have not yet achieved a negative result in blood (S5) or have not yet reached the month 9 visit (S6 and S7) at the time of this abstract and are still being followed (Table). BAX 335 genomes were also identified at lower levels in saliva (n=7), semen (n=5), stool (n=7), and urine (n=4), with peak values achieved between 1 day and 2 weeks and persisting for 1-5 weeks. The safety profile for all subjects enrolled to date was acceptable, including no inhibitors to factor IX (FIX)."

P1/2 data • Hemophilia

Baxter provides progress update on gene therapy program, including phase I/II clinical trial of BAX 355, investigational gene therapy for hemophilia B (Baxter Press Release) - P1/2, N=16; NCT01687608; "Baxter International...today provided an update on its gene therapy program, including progress on the Phase I/II open-label clinical trial assessing the safety and optimal dosing level of BAX 335...As of the end of 2014, a total of six patients in three dosing cohorts have been treated in the trial with evidence of a dose-related response. No patients have developed FIX inhibitors to date. In the two highest dose cohorts, FIX activity levels around 10 percent or above have been observed in two patients, who also experienced no bleeding events."

P1/2 data • Hemophilia

Update on a phase 1/2 open-label trial of BAX335, an adeno-associated virus 8 (AAV8) vector-based gene therapy program for hemophilia B (ISTH 2015) - Abstract #LB010; P1/2, N=16; Sponsor: Baxter; NCT01687608; "Therapeutic FIX levels of 3% were achieved in Cohort 1, sustained levels of 0.5 to 20% were observed 6 months post dosing in Cohort 2, and sustained levels above 25% were observed in Cohort 3.  BAX335 appears to be well-tolerated in the 6 subjects dosed to date and hemostatically effective plasma FIX levels were achieved in two dosing cohorts."

P1/2 data • Hemophilia

Expression of a gain of function factor IX variant from adeno-associated virus (AAV) serotype 8 in a human clinical trial of gene therapy (WFH 2014) - P1/2, N=NA; NCT01687608; "The lowest dose cohort, which has completed enrollment, received a vector dose 10-fold lower than the dose associated with hepatic inflammation in two prior trials. At this dose (2 x 1011 vg/kg) there were no drug-related safety concerns. Sustained FIX expression has been observed at >4 months after dosing."

P1/2 data • Hemophilia

Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B (clinicaltrials.gov) - P1/2; N=30; Active, not recruiting; Sponsor: Baxalta US Inc.; Trial primary completion date: Nov 2019 ➔ Nov 2030

Trial primary completion date • Biosimilar • Gene Therapies • Hematological Malignancies • Hemophilia

Baxalta: Q3 2015 Results (Baxalta) - Anticipated launch in US for hemophilia during 2018-2020

Anticipated launch US • Hemophilia

Baxalta: Q4 & FY 2015 Results (Baxalta) - Anticipated dosing of last patient in P2 trial (NCT01687608) for hemophilia in 2016

Anticipated enrollment status • Hemophilia

Development of an In Vitro Biopotency Assay for an AAV8 Hemophilia B Gene Therapy Vector Suitable for Clinical Product Release. (PubMed, Mol Ther Methods Clin Dev) - "To compare the performance of the in vitro and in vivo biopotency assay, we applied statistical analyses including regression techniques and variation decomposition to the results obtained for 25 AAV8-FIX vector lots (BAX 335). These showed a highly significant correlation, with the cell culture-based assay demonstrating less variation than the in vivo test. The in vitro assay thus constitutes a viable alternative to using animals for lot release testing."

Journal

Preclinical studies provide a rationale for TAK‐748 dosing in humans (EAHAD 2020) - P1/2; "Introduction: Gene therapy using adeno-associated virus (AAV) vectors has the potential to manage factor IX (FIX) deficiency and provide clinical benefit to patients with hemophilia B. Based on FIX expression data from preclinical and phase 1/2 studies (NCT01687608) using a previous gene therapy candidate (BAX 335), liver transduction efficiency was 30-fold higher in mice than in humans... Based on the previously estimated 30-fold liver transduction efficiency factor between mice and humans, and the observed FIX activity after TAK-748 administration to mice, these studies helped determine a clinical starting dose of 4 × 1011 vg/kg. This dose is anticipated to achieve approximately 20% FIX activity in patients with hemophilia B."

Preclinical

Whole Exome Sequencing of Patients Treated with Adeno-associated Virus Serotype 8-factor IX (AAV8-FIX) Gene Therapy Reveals Potential Determinants of Persistent Transgene Expression (ISTH 2019) - "Two important parameters required for successful liver-targeting gene therapy are implicated: (i) design of robust expression cassette resistant to gene silencing by heterochromatinization and (ii) protection of targeted hepatocytes from inflammatory stress induced by viral load."

Clinical

Influence of Obesity on Gene Therapy Mediated Factor IX (FIX) Expression in Mice (ISTH 2019) - "...Aims: The presented study investigated FIX expression in normal-weight and adipose hemophilia B mice after gene therapy using a recombinant AAV8 vector and a human FIX transgene under the control of a liver-specific transthyretin promoter (BAX335)... Body weight-based dosing to normal-weight mice produced mean plasma FIX levels slightly lower than in mice exhibiting an obese phenotype suggesting feasibility of that approach also for individuals with a high body mass index."

Evaluation of Gene Therapy Mediated Factor IX Activity in Selected in vivo Test Systems (ISTH 2019) - "Treatment of FIX KO mice with BAX335 resulted in about 10-fold higher FIX activity levels when compared with BAX335 treated rhesus monkeys. When compared to non-human primate the FIX activity levels were more closely matched in BAX335 treated humanized FRG mice and only about 2-fold higher when adjusted for dose. [1] Lisowski L, et al."

Preclinical

Comparative Integration Site Analysis of Two Factor IX (FIX) Gene Therapy Vectors with Different Vector Design in Mice (ISTH 2019) - "For both vectors, there were no signs for potential adverse effects, as neither clonal outgrowth nor preferred integration in cancer-associated genes were observed . In comparison to BAX335 however, the next generation vector TAK-748/SHP648 showed a lower integration frequency, suggesting that vectors with a self-complementary design exhibit a higher tendency to integrate."

Preclinical