Solid Biosciences has acquired AavantiBio, a company whose lead program, AVB-202, is a gene therapy candidate in preclinical studies for 

The combined company will now focus on advancing Solid’s preclinical gene therapy program SGT-003 for the potential treatment of Duchenne muscular dystrophy (DMD) as well as AVB-202 under the leadership of AavantiBio’s current chief executive officer (CEO), Bo Cumbo. Aavanti’sadditional programs in development include AVB-401 for BAG3-mediated dilated cardiomyopathy and undisclosed programs for other cardiac indications.

“I created Solid with my wife, Annie, and our co-founders nearly 10 years ago, to bring meaningful treatment options to patients and families who, like ours, live with the devastating consequences of DMD,”

 Ilan Ganot, president, chief executive officer and co-founder, Solid Biosciences

 “This acquisition provides exciting opportunities to bring our potentially best-in-class Duchenne gene transfer candidate, SGT-003, to patients and to expand our portfolio with innovative gene therapies designed to address significant unmet need in additional, adjacent rare disease indications. Bo Cumbo will assume the role of president and CEO and is a seasoned biotech executive with extensive expertise in bringing products through development and commercialization. I look forward to helping Bo with the leadership transition following the acquisition, and I am grateful to the investors who continue to support Solid’s critical efforts.”

Solid Biosciences also announced that it has entered into a securities purchase agreement with investors for a $75 million private placement expected to close concurrently with the merger. With the funding, thecombined company is expected to have approximately $215 million to be able to fund it into 2025 and advance the gene therapy programs.

Craig M. McDonald, MD, on Developing Gene Therapy for Different Populations of DMD

“I am excited for the opportunity to lead Solid Biosciences and to help build a leading genetic medicine company with a focus on neuromuscular and cardiac rare diseases,” said Bo Cumbo, president and chief executive officer, AavantiBio, said in a statement.

 “The Solid team has done incredible work in advancing Duchenne gene therapy, and its commitment to the Duchenne community aligns with AavantiBio’s patient-centric mission of bringing new therapies that can positively improve the quality of life of rare disease patients and their families. I also look forward to advancing our library of next generation cardiac and skeletal muscle capsids to extend our opportunities to bring treatment options to more people in need.”

Solid previously announced in a company update that it would be pausing development on SGT-001, its previous lead candidate for DMD, in favor of SGT-003, its next-generation candidate.2 The company stated that it would be switching to a scaled transient transfection-based manufacturing process of SGT-001 and that its phase 1/2 IGNITE-DMD trial (NCT03368742) would continue dosing in mid-2023. Solid also plans to be able to submit an investigational new drug application for SGT-003 in mid-2023.

Prior to the reprioritization, Solid had presented positive 2-year data from the IGNITE-DMD study at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 13-16, in Nashville, Tennessee.

 These data, from the first 3 patients treated in the high-dose cohort (2E14vg/kg), were in line with previous data reported from the 12- and 18-month time points.

Participants exhibited improved motor function, with a mean 16-meter improvement (range, -12 to 39; mean difference from natural history, +100.6) in 6-Minute Walk Test from baseline and a –1.7 change (range, -3 to –1; mean difference from natural history, +4.3) in North Star Ambulatory Assessment from baseline. They also showed improvements from baseline differing from natural history in pulmonary function with a mean 9.2% improvement in forced vital capacity (range, -1.4 to 29.0; mean difference from natural history, +19.2) and a 6.5% improvement in peak expiratory flow (range, -5.8 to 14.8; mean difference from natural history, +16.5). Patient-reported outcomes also improved and the therapy was well-tolerated.

While Solid’s progress in the DMD space seems to have stalled for the time being, other competitors such as Sarepta, Dystrogen, and CRISPR Therapeutics, are racing ahead with their respective DMD programs in recent months. CRIPSR received

 for its CRISPR therapeutic CRD-TMH-001 in August 2022, and in September, Dystrogen 

 for SRP-9001 (delandistrogene moxeparvovec).

1. Solid Biosciences announces acquisition of AavantiBio and concurrent $75 million private placement. News release. Solid Biosciences. September 30, 2022. https://www.solidbio.com/about/media/press-releases/solid-biosciences-announces-acquisition-of-aavantibio-and-concurrent-75-million-private-placement
2. Solid Biosciences provides second quarter 2022 business update and financial results. News release. Solid Biosciences. August 11, 2022. 

https://www.solidbio.com/about/media/press-releases/solid-biosciences-provides-second-quarter-2022-business-update-and-financial-results


3. Dreghici R, Redican S, Lawrence J, et al. Ignite DMD phase I/II study of SGT-001 microdystrophin gene therapy for DMD: 2-year outcomes update. Presented at MDA Clinical and Scientific Conference; March 13-16. Poster 46.
4. Cure Rare Disease Receives FDA Approval to Administer First-in-Human CRISPR Therapeutic. News release. Cure Rare Disease. August 10, 2022. 

https://www.biospace.com/article/releases/cure-rare-disease-receives-fda-approval-to-administer-first-in-human-crispr-therapeutic/


5. Sarepta Therapeutics submits biologics license application for SRP-9001 for the treatment of ambulant patients with Duchenne muscular dystrophy. News release. Sarepta Therapeutics. Septemebr 29, 2022. 

https://www.globenewswire.com/news-release/2022/09/29/2525189/36419/en/Sarepta-Therapeutics-Submits-Biologics-License-Application-for-SRP-9001-for-the-Treatment-of-Ambulant-Patients-with-Duchenne-Muscular-Dystrophy.html


6. Dystrogen Therapeutics investigational chimeric cell therapy DT-DEC01 for Duchenne muscular dystrophy demonstrates clinically significant functional and biomarker improvements. News release. Dystrogen Therapeutics, Corp. September 26, 2022. https://www.prnewswire.com/news-releases/dystrogen-therapeutics-investigational-chimeric-cell-therapy-dt-dec01-for-duchenne-muscular-dystrophy-demonstrates-clinically-significant-functional-and-biomarker-improvements-301633161.html

Articles

Solid has also pivoted from developing SGT-001 to SGT-003 for treating Duchene muscular dystrophy. 

Solid Bio Adds Friedreich Ataxia to Pipeline With Aavanti Acquisition

RGX-314, REGENXBIO’s investigational gene therapy for 

wet age-related macular degeneration (AMD)

, was well-tolerated and reduced treatment burden in participants treated in the phase 2 AAVIATE trial (NCT04514653).

These data were presented at the American Academy of Ophthalmology (AAO) annual meeting taking place September 30 – October 1 in Chicago, Illinois. Participants experienced no treatment-related serious adverse events (TEAEs) and REGENXBIO is adding a sixth cohort to the AAVIATE trial to evaluate a prophylactic ocular steroid regimen.

"Today's announcements come nearly a year into our collaboration with AbbVie to advance RGX-314 in wet AMD and other retinal diseases. These new subretinal and suprachoroidal data highlight the potential impact of RGX-314 for the millions of patients facing vision loss from wet AMD," Kenneth T. Mills, president and chief executive officer, REGENXBIO, said in a statement. "I am pleased with the continued progress on and momentum for these programs. We remain on track to submit a BLA for RGX-314 in 2024, and we expect to provide an update on the ALTITUDE trial of RGX-314 for the treatment of diabetic retinopathy using suprachoroidal delivery at the upcoming Retina Society Meeting in November."

Investigators have reported that as of August 1, 2022, suprachoroidal delivery of RGX-314 has been well-tolerated across 5 cohorts of participants with wet AMD enrolled in AAVIATE. No TEAEs have been reported although there were 15 serious AEs (SAEs) unrelated to treatment. Common TEAEs included conjunctival hemorrhage, increased intraocular pressure, episcleritis, and conjunctival hyperemia in 65 patients in cohorts 1 through 4 and these were mild or moderate. Participants treated at the first or second dose level had similar incidences of mild intraocular inflammation while those treated at the third dose level (cohort 4; 1x10

 GC/eye) had increased incidence of mild to moderate inflammation, all of which resolved with topical corticosteroids.

First Patient Treated in Dry AMD iPSC Therapy Clinical Trial

The multicenter, open-label, randomized, dose-escalation AAVIATE trial is evaluating the safety and efficacy of suprachoroidal delivery of RGX-314. The trial is primarily evaluating mean change in vision at week 40 from baseline via Best Corrected Visual Acuity (BCVA) compared to patients receiving monthly injections of ranibizumab. The trial is also evaluating mean change in central retinal thickness (CRT) and the number of anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections received after treatment with RGX-314.

Participants in the RGX-314 arm had a meaningful reduction in anti-VEGF treatment burden (range, -63.8% to –84.7%) compared to mean annualized injection rate during the 12 months prior to administration. Participants treated at the third dose level had the highest reduction in treatment burden, with a mean 1.3 injections over 6 months after RGX-314 treatment – an 84.7% reduction in anti-VEGDF treatment burden. Ten of these patients (67%) had no anti-VEGF injections in this time period while maintaining visual acuity and CRT. Data from the second dose level (cohorts 2 and 3) additionally suggest that there is no meaningful difference in safety and vision outcomes for patients who are neutralizing antibody (NAb) positive.

An additional cohort, cohort 6, will be enrolled at the third dose levelwith a short course of prophylactic ocular steroids to evaluate the effect on intraocular inflammation. Participants will be enrolled regardless of NAb status.

"We are pleased to share updated data from the AAVIATE trial, including new 6-month data from Cohorts 1-4 which provides continued evidence of the emerging clinical profile of RGX-314 for the treatment of wet AMD using suprachoroidal delivery," Steve Pakola, MD, chief medical officer, REGENXBIO, added to the statement. "RGX-314 continues to be well tolerated, with emerging evidence of treatment effect, including meaningful reduction in anti-VEGF treatment burden at all dose levels. We look forward to expanding this trial to further explore the third dose level."

REGENXBIO also presented data from a long-term follow-up (LTFU) study(NCT03999801) that evaluated subretinal delivery of RGX-314 in 37 patients with wet AMD. Investigators observed dose-dependent increases in treatment effect and 16 patients in cohorts 3 and 4 have continued to tolerate the treatment and have experienced a durable treatment effect for up to 4 years. Stable to improved visual acuity was observed, with a mean BCVA of +12 letters from baseline at four years for Cohort 3 patients and -5 letters from baseline at three years for Cohort 4 patients following RGX-314 administration.

Nine SAEs, none related to treatment, were reported. One participant, in cohort 5, had a significant decrease of vision during the LTFU study who had macular pigmentary changes after a superior bleb in the phase 1/2a trial.

The LTFU study also revealed a meaningful reduction in anti-VEGF treatment burden, with a decrease in mean annualized rate from 6.8 injections to 2.4 injection in cohort 3 (67% reduction) and from 10.2 injections to 4.4 injections in cohort 4 (58.4%). Altogether, these data are expected to support the anticipated biologic license application filing for RGX-314 in 2024.

"These positive interim data from the long-term follow-up and AAVIATE trials continue to reinforce the potential clinical benefit of a one-time administration of RGX-314 in the overall management of patients with neovascular AMD," Arshad M. Khanani, MD, MA, FASRS, director, clinical research, Sierra Eye Associates, Reno, Nevada, added to the statement. "I am extremely encouraged by this long-term data up to four years showing durable treatment effect and the potential of RGX-314 to meaningfully reduce injection burden for patients while maintaining vision outcomes. I look forward to the further investigation of RGX-314 in Cohort 6 of the AAVIATE trial, as in-office suprachoroidal delivery has the potential to be an important treatment option for patients."

The ATMOSPHERE (NCT04704921) and ASCENT (NCT05407636) pivotal trials are active and enrolling patients with wet AMD. REGENXBIO is also expecting to present new interim data on RGX-314 in diabetic retinopathy from ALTITUDE (NCT04567550) at the Retina Society 55th Annual Scientific Meeting in November 2022.

REGENXBIO announces additional positive interim data from trials of RGX-314 for the treatment of wet AMD. News release. REGENXBIO. October 3, 2022. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-additional-positive-interim-data-trials-rgx

Participants in the AAVIATE trial had up to an 85% decrease in treatment burden 6 months after treatment with RGX-314. 

Wet AMD Gene Therapy Reduces Anti-VEGF Treatment Burden 

 at Monash University in Melbourne, Australia, is a world leader in the research and translation of cell therapies for newborn health conditions. The group consist of clinicians, scientists, research staff and students working together to find innovative cell therapy solutions for complications associated with preterm and high-risk birth.

Their specific interest is in stem cells and stem cell like cells derived from gestational tissues. These tissues are generally discarded after birth. Gestational tissues including placenta, its membranes (amnion and chorion), umbilical cord blood and cord tissue (wharton jelly) are rich sources of cells that have many potentially beneficial properties, including regenerative properties and cells with pluripotent potential. Some of these cell therapies are already in clinical use for a variety of hematological and oncological conditions (cord blood derived hematopoietic stem cells), but we are now evaluating their use for regenerative medicine purposes especially for conditions related to preterm and other high-risk births. 

The cells display a number of paracrine and trophic effects (effects away from the site of cell administration) on injured and vulnerable cells of vital organs like the brain, heart and lungs in preclinical models of newborn health conditions. The premise is that similar effects may be seen when these therapies translated in babies born after preterm and other causes of high-risk birth. Translation requires carefully stepping through early phase trials (establishing safety) to large trials evaluating efficacy, before these therapies could be considered therapeutic for newborn infants.

The group has a very strong track record of human translation already. Monash Newborn clinicians, along with colleagues from 

The Ritchie Centre, Hudson Institute of Medical Research, 

 of allogeneic (cells from a healthy donor) placental amnion epithelial cells for infants with the preterm lung disease bronchopulmonary dysplasia. They are now involved in a 

 of human amnion epithelial cells for the prevention of bronchopulmonary disease.

Cord blood derived cell therapies is a special interest of the group with a number of pre-clinical studies conducted by the group showing benefit in perinatal brain injury models. 

Cord blood and cord tissue derived therapies

 are increasingly being evaluated in early phase studies for newborn health conditions. The group is conducting two world–first studies using cord blood derived cells. These include autologous (babies own cord blood derived cells) safety and feasibility studies in extremely preterm infants (

). While these trials are at an early phase of investigation, the group is confident that they will be able to progress a number of these therapies to larger trials (randomised controlled trials) evaluating efficacy in the near future.

The group prides itself with strong consumer engagement in the design of all its studies. The involvement of parents with lived experiences of preterm or high-risk birth is critical to ensure that studies planned are going to be acceptable to parents of these vulnerable babies with meaningful outcomes being assessed after cell therapy administration.

Newborn Cell Therapies group’s work is supported by funding from a number of national bodies and philanthropic organisations including National Health and Medical Research Council of Australia, Cerebral Palsy Alliance Research Foundation, Inner Wheel Australia, Lions Cord Blood Foundation, and Monash Health Foundation.

The group most recently announced a $50,000 grant from Lions Cord Blood Foundation in August 2022. The group will receive the money over 2 years to support the neonatal cell therapy research.

The group is excited to announce the First Ever 

, which be held later this year in Melbourne, Australia. You can follow the Newborn Cell Therapies group’s activities on Social Media via their Twitter account, @Neo_CellTherapy.

Lions Foundation provides support to neonatal cell therapy research. News release. Monash Unviersity. August 25, 2022. https://www.monash.edu/medicine/news/latest/2022-articles/lions-foundation-provides-support-to-neonatal-cell-therapy-research

Newborn Cell Therapies Group at Monash University has received a $50,000 grant from Lions Cord Blood foundation.

Advancing Neonatal Cell Therapy Research

Bioheng Biotech’s RD13-01, an investigational allogeneic CD7-targeted chimeric antigen receptor T-cell (CAR-T) product with genetic modifications to resist fratricide, graft versus host disease (GvHD), and rejection, demonstrated promising safety and efficacy data in a phase 1 clinical trial (NCT04538599) for patients with CD7

 hematological malignancies, according to results published in 

Among the 11 patients evaluated for efficacy, 9 patients (81.8%) had objective responses at 28 days after treatment and 7 patients (63.6%) had complete responses (CR). Four patients remained in complete remission at a median follow-up of 10.5 months. At 28 days after treatment, 6 of the 8 patients with leukemia demonstrated either a CR or a CR with incomplete hematological recovery, and these 6 patients showed negative minimal residual disease. In terms of safety, there were no dose-limiting toxicities and no cases of GvHD or immune effector cell-associated neurotoxicity (ICANS) reported. All cases of cytokine release syndrome (CRS) were grade 2 or lower. However, several patients experienced cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) reactivation, and 1 patient death resulted from a case of EBV-associated diffuse large B-cell lymphoma (DLBCL). In addition, all treated patients experienced grade 4 neutropenia and 1 patient died of sepsis 24 days after administration of RD13-01.

"T-cell malignancies are highly aggressive hematological tumors which are generally associated with poor prognosis,” He Huang, MD, PhD, Professor of hematology, President of The First Affiliated Hospital, Zhejiang University School of Medicine, and principal investigator of the study, said in a statement.

 “In particular relapsed or refractory (r/r) disease has dismal outcomes with a 5-year overall survival (OS) rate lower than 20%, there is an urgent medical need to develop novel therapies for this type of disease. Besides the marked attenuated CRS safety profile and impressive efficacy enhancement, I am also impressed with the availability and accessibility of RD13-01 for these patients with uncommon aggressive malignancies. The interval between enrollment and infusion was no more than 7 days, and no patients enrolled failed to receive RD13-01 infusion due to disease progression, leukapheresis or manufacture failure. It is expected that allogeneic CAR-T cell products provide more choices to address the unmet medical needs."

Of the 12 patients enrolled in the study who received treatment with RD13-01, there were 7 patients with T-cell acute lymphoblastic leukemia (T-ALL), 4 patients with 

 The ages of the patients ranged from 8 years to 66 years (median, 34) and the patients had previously been treated with between 2 and 7 lines of therapy (median, 4). All 12 patients had at least 2 lines of prior treatment with chemotherapy, and 2 patients had previously received allogeneic hemopoietic stem cell transplant (HSCT) and 1 patient had received autologous HSCT. The 12 patients were divided into 3 dose level groups for administration of RD13-01, with 3 patients receiving 1x10

 cells/kg. Dose level 2 was selected as the dose to be used in potential future studies due to all patients at this dose level achieving a response, and 5 achieving a CR.

“One patient with [peripheral T-cell lymphoma-not otherwise specified] had a CR to CAR-T cell therapy, but later developed EBV-associated B-cell lymphoproliferation (EBV-LPD) which was further progressed to DLBCL,” Huang and colleagues noted.

 “EBV-LPD occurs frequently in patients with primary or secondary immunodeficiency disorders and can be a complication of chemotherapy, HSCT or solid organ transplantation. Our results suggest that prior EBV infection might be considered as a risk factor or exclusion criteria for CAR-T cell therapies targeting T-cell malignancies.”

Overall, Huang and colleagues concluded that the study provides support for using CD7 as a target for CAR-T therapies and for the potential of allogeneic approaches in treating patients with T-cell leukemia or lymphoma and CD7

 AML. The investigators additionally stated that phase 2 studies for RD13-01 are warranted to gather more information about safety and efficacy. They also identified several additional areas of interest for future research, including whether the genetic modifications on RD13-01 reduce cytokine production; whether the less intense lymphodepletion helped reduce rates of severe CRS; whether bridging to HSCT after an initial response to CAR-T therapy could assist disease control and long-term survival; a closer look at the potential risks of clonal expansion of RD13-01 and of allo-rejection by host CD8

 T-cells in allogeneic CD7-CAR-T cell therapy; and ways to prolong CAR-T cell persistence without negatively impacting expansion of CD7

1. Hu Y, Zhou Y, Zhang M, et al. Genetically modified CD7-targeting allogeneic CAR-T cell therapy with enhanced efficacy for relapsed/refractory CD7-positive hematological malignancies: a phase I clinical study. Cell Res. Published online September 23, 2022. Doi: doi.org/10.1038/s41422-022-00721-y

2. BiohengBiotech announces publication of impressive results with CD7-targeted allogeneic CAR-T cell therapy for relapsed or refractory T cell malignancies. News release. Nanjing Bioheng Biotech Co., Ltd. September 27, 2022. 

https://firstwordpharma.com/story/5656849

Among the 11 patients evaluated for efficacy, 9 patients (81.8%) had objective responses at 28 days. 

Allogeneic Anti-CD7 CAR-T Demonstrates Promising Results in Hematological Malignancies 

The umbilical cord blood (UCB) cell therapy omidubicel (NiCord; 

) improved survival in patients with hematological malignancies receiving allogeneic hematopoietic stem cell transplantation (HSCT).

These data, from a phase 3 trial (NCT02730299) were presented at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO), taking place September 28- October 1 in Houston, Texas, by Chenyu Lin, MD, hematology/oncology fellow, malignant hematologist, Duke University.

“These data reinforce our commitment to advance transformational cell therapy research and underscore the potential of our NAM technology platform. Our lead stem cell therapy candidate, omidubicel, addresses the unmet need for patients with hematologic malignancies, demonstrated by the robust and growing body of encouraging clinical evidence, including the long-term follow up data and quality of life improvement,” Ronit Simantov, MD, chief medical officer, Gamida Cell, said in a statement.

“As we approach the PDUFA date of January 30, 2023, and upon potential FDA approval, we are prepared to execute our plan that ensures access to those patients who can benefit from omidubicel as quickly as possible.”

Lin and colleagues analyzed data from 105 participants across 2 academic transplant centers worldwide from the phase 3 study either as a standalone unit (n = 92) or together with an unmanipulated UCB (n = 24).

Eleven participants were excluded from an initial pool of 116. Most patients (n = 97; 93%) engrafted fully, 2 (2%) had mixed chimerism between omidubicel and UCB, 5 (5%) had primary graft failure, and 1 patient was not evaluable. All patients received myeloablative conditioning regimens and standard graft versus host disease (GVHD) prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. There were no late cases of secondary graft failure reported after the 5 patients reported in the primary analysis.

Omidubicel BLA Accepted With Priority Review in Hematological Malignancies

Median follow-up was 22 months (range, 0.3-122.5) overall and 35.7 months (range, 11.7-122.5) among survivors.Treated participants had an overall survival of 63% (95% CI, 53%-73%) and disease-free survival of 56% (95% CI, 47%-67%). Quality of life assessments revealed that overall well-being scores were higher in these patients when compared to standard of care.

In terms of safety, most chronic GVHD cases were mild (54%), with 33% moderate and 13% severe cases. No deaths were primarily attributed to chronic GVHD. One participant developed donor-derived MDS which is consistent with previous reports of donor-derived myeloid neoplasms after cord blood transplants (0.6–2%). A case of donor-derived AML was also observed in the phase 3 control group.

Omidubicel has demonstrated fast engraftment, few infections, and short durations of hospitalization in previous trials. It is an ex vivo expanded stem cell therapy derived from UCB.

“In addition to the known early benefits, omidubicel demonstrated long-term graft durability, with preserved trilineage hematopoiesis and immune competence at up to 10 years of follow-up,” Lin and colleagues wrote in the poster.

REFERENCES
1. Long-term data from omidubicel phase 3 trial demonstrates overall survival and sustainable durable outcomes for patients with blood cancers at the Society of Hematologic Oncology Meeting. News release. Gamida Cell. September 29, 2022. 

https://www.businesswire.com/news/home/20220929005316/en/Long-Term-Data-from-Omidubicel-Phase-3-Trial-Demonstrates-Overall-Survival-and-Sustainable-Durable-Outcomes-for-Patients-with-Blood-Cancers-at-the-Society-of-Hematologic-Oncology-Meeting


2. Lin C, Schwarzbach A, Montesinos P, et al. Multicenter long-term follow-up of allogeneic hematopoietic cell transplantation with omidubicel: A pooled analysis of five prospective clinical trials. Presented at: 10th Annual Meeting of the SOHO, September 28- October 1, Houston, Texas.

Disease-free survival was 56% in 105 participants over 3 years. 

Omidubicel Improves Survival in Hematologic Malignancies With HSCT 

BioMarin has resubmitted the biologics license application (BLA) to the FDA for valoctocogene roxaparvovec (val-rox; BMN-270), an adeno-associated virus (AAV)-based gene therapy intended to treat hemophilia A.

submitted a BLA for val-rox in August 2020

, which was rejected with a request for 2-year follow-up data.

 with requests for additional durability and safety data.

 in August 2022 with conditional marketing authorization.

BioMarin’s new FDA BLA resubmission includes data from the 2-year results of the GENEr8-1 phase 3 study (NCT03370913) and additional 5-year follow-up data from an on-going phase 1/2 dose-escalation study.

 Patients treated with val-rox in the global GENEr8-1 clinical trial showed stable and durable control of bleeding and reductions in both mean annualized bleeding rate and mean annualized Factor VIII infusion rate.

draft report released by the Institute for Clinical and Economic Review (ICER)

 in mid-September 2022 evaluated data from the GENEr8-1 study and compared val-rox favorably with standards of care for hemophilia A in terms of patient benefit and cost, though the support came with several caveats and substantial uncertainty.

 Around the same time, BioMarin also revealed in an SEC filing that it is 

investigating a case of B-cell acute lymphoblastic leukemia

"We are pleased to reach this point in the development program for val-rox and look forward to working with the FDA with the goal of bringing a potentially transformative therapy to people with severe hemophilia A in the United States," Hank Fuchs, MD, president of worldwide research and development, BioMarin, said in a statement.

 "This large and robust data set provided in this BLA resubmission shows an encouraging efficacy profile. We remain committed to sharing these data with the public, along with even longer-term data generated through our ongoing clinical trials and any post-approval studies, to further our understanding of AAV gene therapy in severe hemophilia A and of gene therapies more broadly."

 vg/kg doses of val-rox have been generally well-tolerated without delayed-onset treatment related adverse events (AEs). Common AEs associated with val-rox include transient infusion associated reactions, mild to moderate rises in liver enzymes without long-lasting clinical sequelae, and alanine aminotransferase elevation, with the latter being noted as most common. Aspartate aminotransferase elevation has been observed in 63% of clinical trial participants, while nausea and headache have been observed in 34% of participants, and fatigue has been observed in 28% of participants. To date, no participants have developed inhibitors to Factor VIII, and thromboembolic events or malignancy associated with val-rox have not been reported.

In addition to the previously mentioned studies, val-rox is also being investigated in a phase 3 clinical trial (Study 270-303) at a dose of 6x10

 vg/kg in combination with prophylactic corticosteroids for patients with severe hemophilia A. Another phase 1/2 study of the gene therapy at 6x10

 vg/kg for patients with severe hemophilia A with pre-existing AAV5 antibodies (Study 270-203) is also underway, as is a phase 1/2 study at the same dose for patients with severe hemophilia A with active or prior Factor VIII inhibitors (Study 270-205). 

BioMarin is not the only company currently investigating gene therapy for the treatment of hemophilia. The ICER report also covered CSL’s 

, an investigational gene therapy intended for the treatment of hemophilia B.

Pfizer and Sangamo also announced reopening of enrollment

 in the phase 3 AFFINE study (NCT04370054) of giroctocogene fitelparvovec, an investigational gene therapy intended to treat moderately severe to severe hemophilia A.

 reported promising data from a clinical trial of 

 (verbrinacogene setparvovec; Freeline Therapeutics) in July 2022.

1. Biomarin resubmits biologics license application (BLA) for valoctocogeneroxaparvovec AAV gene therapy for severe hemophilia A to the FDA. News release. BioMarin Pharmaceutical Inc. September 29, 2022. 

https://investors.biomarin.com/2022-09-29-BioMarin-Resubmits-Biologics-License-Application-BLA-for-Valoctocogene-Roxaparvovec-AAV-Gene-Therapy-for-Severe-Hemophilia-A-to-the-FDA

2. BioMarin delays hemophilia a therapy valoctocogene roxaparvovec filing as FDA calls for more data. News release. BioMarin. May 31, 2022. 

https://www.biospace.com/article/fda-needs-more-data-for-biomarin-s-hemophilia-a-therapy/

3. BioMarin delays hemophilia a therapy valoctocogeneroxaparvovec filing as FDA calls for more data. News release. BioMarin. May 31, 2022. 

4. First gene therapy for adults with severe hemophilia A, BioMarin's ROCTAVIAN™ (valoctocogene roxaparvovec), approved by European Commission (EC). News release. BioMarin. August 24, 2022. 

https://investors.biomarin.com/2022-08-24-First-Gene-Therapy-for-Adults-with-Severe-Hemophilia-A,-BioMarins-ROCTAVIAN-TM-valoctocogene-roxaparvovec-,-Approved-by-European-Commission-EC

5. Gene therapy for hemophilia B and an update on gene therapy for hemophilia A: effectiveness and value. Draft Evidence Report. The Institute for Clinical and Economic Review. September 13, 2022. 

https://icer.org/wp-content/uploads/2022/05/ICER_Hemophilia-Draft-Evidence-Report_09132022_Updated.pdf

6. Securities and Exchange Commission, Form 8-K. BioMarin Pharmaceuticals. September 12, 2022. Accessed September 14, 2022. https://app.quotemedia.com/data/downloadFiling?webmasterId=101533&ref=116942054&type=HTML&symbol=BMRN&companyName=BioMarin+Pharmaceutical+Inc.&formType=8-K&dateFiled=2022-09-12&CK=1048477 

7. Pfizer and Sangamo Therapeutics announce phase 3 trial of investigational gene therapy for hemophilia A has re-opened recruitment. News release. Pfizer. September 23, 2022. 

https://www.pfizer.com/news/announcements/pfizer-and-sangamo-therapeutics-announce-phase-3-trial-investigational-gene

8. Chowdary P, Shapiro S, Makris M, et al. Phase 1–2 trial of AAVS3 gene therapy in patients with hemophilia B. 

. 2022; 387:237-247 doi: 10.1056/NEJMoa2119913

A prior resubmission in June 2022 was delayed with requests for additional durability and safety data. 