The FDA has approved UniQure and CSL Behring’s etranacogene dezaparvovec (EtranaDez), now marketed as Hemgenix, for treating adults with 

who currently use Factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” Peter Marks, MD, PhD, director, Center for Biologics Evaluation and Research, FDA, said in the release.

“Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

The FDA accepted the biologics license application (BLA) for Hemgenix for priority review in May 2022.

 The BLA was supported by positive data from 54 participants with hemophilia B in the pivotal phase 3 HOPE-B trial (NCT03569891).

The HOPE-B trial met its primary endpoint of reduction in annualized bleeding rate (ABR) post-treatment compared with baseline FIX prophylactic therapy, with mean FIX activity of 39.0 IU/dL (standard deviation [SD], 18.7; range, 8.2-97.1) at 6 months post-treatment and 36.9 IU/dL (SD, 21.4; range, 4.5-122.9) at 18 months.

The 52-week adjusted ABR for all bleeds was reduced by 64% (

= .0002) from 4.19 during the ≥ 6-month lead-in period to 1.51 during months 7-18 and there was an overall 97% reduction in mean unadjusted annualized FIX consumption.

BioMarin Prepares for PDUFA Delay for Val-Rox Hemophilia Gene Therapy

Hemgenix was well-tolerated, with no serious treatment-related adverse events (AEs), although common AEs include liver enzyme elevations, headache, mild infusion-related reactions and flu-like symptoms. No inhibitors to FIX were reported.

“The HOPE-B trial was the first phase 3 study in hemophilia B and has the largest cohort of gene therapy for hemophilia B to report to date. It is also the only trial to include participants with neutralizing antibodies to AAV and this is really unique," investigator 

, professor and head of coagulation disorders and Comprehensive Care Centre, University Hospital of Frankfurt, Germany, previously told 

Hemgenix is an adeno-associated virus gene therapy that delivers the Padua variant of the FIX gene to liver cells via an intravenous infusion. It was previously granted breakthrough therapy designation by the FDA and Priority Medicine (PRIME) regulatory initiative by the EMA. The EMA is currently reviewing a Marketing Authorization Application for EtranaDez in hemophilia B.

Earlier this year, the Institute for Clinical and Economic Review (ICER) concluded that the price of EtranaDez should be

.4 They also suggested a cap of $1.9 million for valoctocogene roxaparvovec (val-rox; Roctavian; BioMarin) for hemophilia A. CSL Behring announced that Hemgenix would cost $3.5 million, less than the $5 million "shared savings" that ICER estimated the therapy could save for the overall healthcare system.

ICER EtranaDez a B+ score for “moderate certainty” of a small or substantial health benefit and “high certainty” of at least a small net health benefit compared with factor IX prophylaxis.

 Primary concerns were limited long-term follow-up safety and durability data.

“HEMGENIX is unique in its approach to increasing mean factor IX activity and hemostatic protection in those with hemophilia B, and today’s approval could fundamentally transform the treatment paradigm for this life-long condition,” investigator Steven Pipe, MD, professor and the Laurence A. Boxer Research Professor of Pediatrics and Professor of Pathology, University of Michigan, said in a statement.

 “As a clinician, I look forward to being able to provide a new treatment option that may help patients treated with HEMGENIX become free from the regular infusion schedule that many people living with hemophilia B rely on to protect them from the debilitating effects of the condition.”

1. FDA approves first gene therapy to treat adults with hemophilia B. News release. FDA. November 22, 2022. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b


2. uniQure Announces FDA Acceptance of Biologics License Application for EtranacogeneDezaparvovec under Priority Review. News release. uniQure. May 24, 2022. 

https://tools.eurolandir.com/tools/Pressreleases/GetPressRelease/?ID=4109235&lang=en-GB&companycode=nl-qure&v=


3. uniQure and CSL Behring announce primary endpoint achieved in HOPE-B pivotal trial of EtranacogeneDezaparvovec gene therapy in patients with Hemophilia B. News release. UniQure. December 9, 2021. https://www.cslbehring.com/newsroom/2021/hope-b-gene-therapy-for-hemophilia-b-topline-results
4. Institute for Clinical and Economic Review. Gene therapy for hemophilia B and an update on gene therapy for hemophilia A: Effectiveness and value. November 3, 2022. https://icer.org/wp-content/uploads/2022/05/Hemophilia_Revised-Report_Updated_For-Publication_110322.pdf
5. U.S. Food and Drug Administration approves CSL’s HEMGENIX® (etranacogene dezaparvovec-drlb), the first gene therapy for hemophilia B. News release. CSL Behring. November 22, 2022. https://www.cslbehring.com/newsroom/2022/fda-hemgenix


Articles

A marketing authorization application for etranacogene dezaparvovec is currently under review by the EMA. 

Hemgenix First Gene Therapy Approved for Hemophilia B 

The FDA has cleared Legend Biotech’s investigational new drug application (IND) for LB2102, a chimeric antigen receptor (CAR) T-cell therapy for the treatment of adult patients with extensive stage 

“Lung cancer is a debilitating disease that often spreads quickly. On average, only seven percent of patients with SCLC are alive five years after receiving their diagnosis,” Lida Pacaud, MD, vice president, clinical development, Legend Biotech, said in a statement.

“We are eagerly awaiting the start of this Phase 1 trial, and we hope that the study will provide much needed insight into the potential of this investigational CAR-T therapy.”

Legend Biotech will soon initiate a phase 1, first-in-human, clinical trial to evaluate preliminary efficacy and safety of LB2102. The study will enroll patients with extensive stage SCLC as well as large cell neuroendocrine carcinoma and will seek to determine the recommended phase 2 dose of the therapy.

 CAR Monocyte Therapy Fast Tracked for Peripheral T-Cell Lymphoma

LB2102 is an autologous CAR T-cell therapy selectively targeted toward delta-like ligand 3 (DLL-3). DLL-3 is highly restricted to expression in malignancies including SCLC and LCNEC as well as some prostate cancers and neuroendocrine tumors. As shown in previous studies, the target is also linked to tumor growth, invasion, and migration.

Most recently, in July 2022, Legend Biotech revealed in an SEC filing that it had 

 for LB1901, an investigational autologous anti-CD4+ CAR T-cell therapy for the treatment of adults with relapsed/refractory T-cell lymphoma (R/R TCL).

The company stated that it had decided to prioritize other candidates in its pipeline with the termination, which was partially based on the lack of clinical benefit seen in an investigator-initiated study conducted in China on a similar Legend Biotech CAR T-cell therapy candidate which expresses the same CAR protein as LB1901.

The trial (NCT04712864) was an open-label, multicenter, first-in-human study with a target enrollment of 50 adult participants with histologically confirmed CD4+ R/R peripheral T-cell lymphoma (PTCL) or R/R cutaneous (TCL)who had previously been treated with at least 2 prior lines of systemic antineoplastic therapy. On May 25, 2022, just 6 weeks prior to the termination, the FDA lifted a 

 placed on February 11, 2022. The hold was placed after Legend voluntarily paused the trial due to a case of low CD4+ T-cell counts in the peripheral blood of the only patient who had been dosed at that time. As of February 2022, the patient had not experienced drug-related serious adverse events and was being monitored in accordance with protocol.

1. Legend Biotech announces FDA clearance of IND application for LB2102 in extensive stage small cell lung cancer. News release. Legend Biotech. November 21, 2022. 

https://legendbiotech.com/legend-news/legend-biotech-announces-fda-clearance-of-ind-application-for-lb2102-in-extensive-stage-small-cell-lung-cancer/


2. SEC. Form 6K: Legend Biotech Corporation. July 7, 2022. https://www.sec.gov/Archives/edgar/data/0001801198/000115752322000824/a52773325.htm

The IND clearance comes after Legend terminated another clinical trial in T-cell lymphoma in July 2022. 

Legend Biotech Brings SCLC CAR T to Trials 

The Prescription Drug User Fee Act (PDUFA) date for Gamida Cell’s omidubicel, an investigational allogeneic hematopoietic stem cell transplant (HSCT) candidate intended for the treatment of patients with hematological cancers, has been extended from its original January 30, 2023, date to May 1, 2023.

The extension comes more than 3 months after the company 

 for filing with priority review of omidubicel’s biologics license application (BLA) by the FDA in August 2022.

 The extension is related to laboratory data for intermediate time points from patients participating in the phase 3 clinical trial (NCT0273029) that Gamida Cell gave in response to a request for information issued by the FDA, which the agency considered a major amendment.

 The company noted that these laboratory results are consistent with data included in previous submissions. Gamida Cell’s late-cycle meeting with the FDA has additionally been rescheduled to the first quarter of next year.

“We appreciate the FDA’s collaboration as they conduct their review of omidubicel,” Abigail “Abbey” Jenkins, president and chief executive officer, Gamida Cell, said in a statement regarding the news.

 “If approved, omidubicel will be the first and only advanced cell therapy for patients with blood cancer in need of an allogeneic stem cell transplant. We are committed to bringing this potentially transformative therapy forward as quickly as possible.”

Omidubicel has previously been granted breakthrough therapy designation by the FDA and orphan drug designation by both the FDA and the European Medicines Agency.

 The investigational product consists of umbilical cord blood–derived cells modified with the company’s nicotinamide (NAM) technology which is intended to increase the amount and potency of the cells.

Data from omidubicel’s phase 3 trial showing an improvement in survival for patients with hematological malignancies receiving allogeneic HSCT were recently

 at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO), which took place September 28-October 1 in Houston, Texas.

 Participants included in the analysis achieved an overall survival rate of 63% (95% CI, 53%-73%) and a disease-free survival rate of 56% (95% CI, 47%-67%) at a median follow-up of 22 months (range, 0.3-122.5) overall and 35.7 months (range, 11.7-122.5) for survivors.

1. Gamida Cell provides regulatory update on omidubicel. News release. Gamida Cell Ltd. November 21, 2022. 

https://investors.gamida-cell.com/news-events/press-releases/news-release-details/gamida-cell-provides-regulatory-update-omidubicel

2. Gamida Cell announces FDA acceptance of biologics license application for omidubicel with priority review. News release. Gamida Cell Ltd. August 1, 2022.

https://investors.gamida-cell.com/news-events/press-releases/news-release-details/gamida-cell-announces-fda-acceptance-biologics

3. Gamida Cell. Our R&D. Website. Accessed November 22, 2022. 

4. 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.

Omidubicel’s BLA was originally accepted for priority review in August of this year.

Omidubicel PDUFA Date Extended to May 2023

“We want to explore opportunities in the allogeneic field. And of course, that's what I think a lot of companies are currently trying and there's a lot of excitement about it. So how do we move from this autologous treatment to an off the shelf treatment, which obviously would be better in terms of treatment cost and also in terms of time to treatment... we have a very promising early phase development in solid tumors.”

Tessa Therapeutics is targeting both hematological malignancies and solid tumors, with its autologous chimeric antigen receptor (CAR) T-cell therapy programs as well as allogeneic virus-specific T-cell therapies. The company recently 

 with relapsed/refractory classical Hodgkin lymphoma (cHL) in the phase 1b ACTION clinical trial (NCT05352828) of TT11, an autologous CD30-targeted chimeric antigen receptor T-cell (CAR-T) therapy being developed as a second-line treatment in combination with nivolumab in August 2022. TT11 is also being evaluated as a monotherapy in later lines of treatment for cHL in the phase 2 CHARIOT trial (NCT04268706).

 spoke with Thomas Willemsen, president and chief executive officer, Tessa Therapeutics, to learn more about the company and its technologies. He discussed Tessa’s current cell therapy programs as well as allogeneic programs for solid tumors in early development. He also touched on upcoming milestones for the company in 2023.

Tessa Therapeutics doses first patient in phase 1b clinical trial investigating TT11 in combination with nivolumab for t he treatment of relapsed/refractory classical Hodgkin lymphoma (cHL). News release. Tessa Therapeutics. August 17, 2022. 

https://www.tessacell.com/2022/08/17/tessa-therapeutics-doses-first-patient-in-phase-1b-clinical-trial-investigating-tt11-in-combination-with-nivolumab-for-the-treatment-of-relapsed-refractory-classical-hodgkin-lymphoma-chl/

Videos

Thomas Willemsen, president and chief executive officer, Tessa Therapeutics, discussed the company’s technologies and 2023 milestones. 

Targeting Hematological Malignancies With Autologous and Allogeneic Cell Therapies  

Data from the phase 2/3 AAVance clinical trial (NCT03612869) of Lysogene’s LYS-SAF302, an investigational gene therapy intended for the treatment of 

 type IIIA (MPS IIIA; Sanfilippo syndrome type A), demonstrated promising efficacy for patients enrolled under the age of 30 months, but failed to meet its primary and key secondary efficacy end points for older patients.

LYS-SAF302 consists of a functional copy of 

, the disease-targeted gene, delivered via AAVrh.10, an adeno-associated virus carrier directed at central nervous system cells. It is intended as a 1-time treatment and is administered at 6 intracerebral sites. LYS-SAF302 was previously granted fast track, rare pediatric disease, and orphan drug designations by the FDA and orphan medicinal product designation by the European Medicines Agency. Lysogene had previously granted 

 development and commercialization rights for LYS-SAF302 in the United States and other non-European Union territories and responsibility for global commercial supply of the gene therapy product, but this agreement was terminated effective July 11, 2022.

Among the 12 patients in the trial’s main cohort, who were enrolled at 30 months of age or older, no statistically significant improvement in cognitive developmental quotient (DQ) at 24 months after treatment compared to patients in a natural history (NH) cohort was observed. In addition, there was no improvement observed in the main cohort compared to patients in the NH cohort with regard to percent of patients with stabilized or improved cognitive developmental age (DA), language DA, and motor DA at 24 months relative to baseline, nor was change observed in VABS-II standard scores.

However, for the study’s ancillary cohort, which included 6 patients enrolled at younger than 30 months of age, the mean rate of decline in DQ over 24 months (-1.0 ± 0.5 percentage points/month, mean ± SD, range -1.4 to -0.3) was 27% lower than for age-matched patients in the NH cohort (-1.5 ± 0.3 percentage points/month, mean ± SD, n=6; range -1.8 to -1.0), (

 = 0.037). Furthermore, among the 5 patients in the ancillary cohort who are now aged at least 40 ± 3 months, the average cognitive DA at this age (30.2 ± 8.4, mean ± SD, n=5; range 19 to 41) was 48% higher than in age-matched patients from the NH cohort (20.4 ± 6.7, mean ± SD, n=13; range 5 to 27) (

 = 0.019). Patients in the ancillary cohort additionally demonstrated at least 80% stabilization or improvement in cognitive DA, language DA, and motor DA, which were key secondary end points for the trial, and from baseline to 24 months after treatment showed no statistically significant reduction in mean VABS-II standard scores for total adaptive behavior, communication, daily living skills, socialization, and motor skills. From baseline to 24 months after administration, there was also no statistically significant reduction observed in mean cortical gray matter volume, a factor associated with cognitive decline that is typically known to decrease in patients with MPS IIIA. Lysogene expects that data analysis for this cohort will be completed in the first half of next year when all 6 of the children have reached the age of at least 48 months.

“While we are disappointed with the results in the main cohort of the patients enrolled at 30 months or older, these can likely be explained by the rapid progression of the disease and the recent learning from other clinical studies that gene therapy treatment of neurodegenerative diseases should be initiated at the earliest possible age in order to provide a therapeutic benefit before the onset of irreversible neuronal damage,” Karen Aiach, founder, chairman, and chief executive officer, Lysogene, said in a statement.

 “The positive signs of efficacy observed in very young children enrolled before the age of 30 months indicate that early dosing of LYS-SAF302 gene therapy in children with MPS IIIA might have a real beneficial effect on these patients and transform their lives. The trial results clearly delineate the patient population that would benefit from treatment with LYS-SAF302. We are very much encouraged by these results and are eager to continue our discussions with the regulatory agencies to take LYS-SAF302 to the next level in younger patients.”

In terms of safety, adverse events observed in the study were noted to be consistent with the natural history of MPS IIIA. However, for all participants treated in the study, MRI data also showed white matter abnormalities near injection sites. In most of the patients, these lesions have either stabilized or decreased in size. There were no clinically significant symptoms observed that were directly attributable to the abnormalities. 

The single-arm, multi-center, open-label AAVance trial enrolled 19 children 6 months and older with a documented MPS IIIA diagnosis, based on confirmed mutations in the 

 gene, and a cognitive DQ score on the BSID-III of 50% or above. Patients who had participated in another gene therapy or cell therapy clinical trial; patients who had previously used SGSH enzyme replacement therapy for more than 3 months; patients with a history of bleeding disorders and patients with a risk of bleeding following surgery; patients with any condition that would contraindicate treatment with relevant immunosuppressants; and patients who are homozygous for the S298P mutation or non-classical severe form of MPS IIIA, based on investigator's judgement, were excluded from the study. Running alongside AAVance is the app-based PROVide study, which is collecting video of patients in their home environments to further provide information on the treatment’s effect on children’s development.

“Even though AAVance did not meet its primary endpoint, the results in the subset of patients with MPS IIIA enrolled before the age of 30 months are extremely encouraging, as they show beneficial effects of treatment on cognitive development and key secondary outcome measures in this devastating childhood disease with no approved disease-modifying therapies”, Chester B. Whitley, professor at the Department of Pediatrics and Experimental and Clinical Pharmacology, University of Minnesota, and principal investigator, Lysosomal Disease Network, Minneapolis, MN, USA, added to the statement.

 “I look forward to continuing to work with Lysogene to analyze the phase 2/3 data and determine the most appropriate path to bringing gene therapy with LYS-SAF302 to those patients who have the highest potential to benefit from it.”

1. Lysogene provides updates and topline results from phase 2/3 AAVance gene therapy clinical study. News release. Lysogene. November 18, 2022. 

https://www.lysogene.com/lysogene-provides-updates-and-topline-results-from-phase-2-3-aavance-gene-therapy-clinical-study/

2. Lysogene announces termination of license agreement with Sarepta for LYS-SAF302 program, regaining global commercial rights. News release. Lysogene. January 13, 2022. https://www.lysogene.com/lysogene-announces-termination-of-license-agreement-with-sarepta-for-lys-saf302-program-regaining-global-commercial-rights/

3. LYS-SAF302 clinical trial. Website. Lysogene. July 7, 2022. 

https://www.lysogene.com/lys-saf302-clinical-trials/

Statistically significant improvements in cognitive development were only seen in the cohort of patients younger than 30 months. 

MPS Type IIIA Gene Therapy Trial Fails Primary Endpoint 

PTC Therapeutics’ Upstaza (eladocagene exuparvovec), a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy intended to treat aromatic L–amino acid decarboxylase (AADC) deficiency with a severe phenotype, has received marketing authorization from the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of children aged 18 months or older.

Upstaza is delivered to the putamen via a 1-time treatment with a stereotactic surgical procedure and provides a functional copy of DDC, the disease-targeted gene. In clinical trials, treated participants who had not previously reached any developmental motor milestones mastered clinically meaningful motor skills including independent ambulation. Additionally, cognitive and language acquisition was achieved as early as 3 months after administration. Clinical benefits were shown to persist up to 10 years after administration. Additionally, reductions in symptoms that could lead to potentially fatal complications were observed.

"We are thrilled with the MHRA's rapid authorization of Upstaza," Stuart W. Peltz, PhD, chief executive officer, PTC Therapeutics, said in a statement regarding the news.

 "Patients in the UK with AADC deficiency are 1 step closer to having access to a much-needed disease modifying therapy. This is another milestone towards our commitment to advance innovative treatments and improve outcomes for people living with rare diseases."

The most common adverse events reported during Upstaza’s clinical trials included initial insomnia, irritability, and dyskinesia. Upstaza 

 in July of this year in all 27 European Union member states, Iceland, Norway, and Liechtenstein, approximately 12 years after the first patient was treated in a clinical trial in 2010.

 The approval came 2 months after the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) 

 based on results of 2 clinical trials for Upstaza (NCT01395641; NCT02926066) that were conducted in Taiwan.

 Upstaza is also approved in Northern Ireland.

"The approval of an AADC deficiency gene therapy in the UK will provide the opportunity to transform the prognosis for those born and living with this disease, and we are hopeful for access in the coming months,” Kirsty Hoyle, chief executive officer, Metabolic Support UK, added to the statement.

 “Without treatment, most children born with AADC deficiency will have difficulty with their development and many of the symptoms can be distressing and life-threatening. The impact on those living with AADC and their communities is significant, with children facing frequent hospitalizations, emergency visits, and requiring a multi-disciplinary team of highly trained specialists.”

Last month, PTC Therapeutics announced in a clinical and regulatory update that the company held a type C meeting with the FDA regarding a potential biologics license application (BLA) submission for Upstaza.

 It was noted that the FDA requested additional bioanalytical data to support comparability of the drug product evaluated in the clinical trials with commercial Upstaza. PTC Therapeutics mentioned in the press releasethat it is working to address the FDA’s request and that the company expects to make the BLA submission in the first half of next year.

, professor of pediatrics, an investigator on the Taiwanese trials, about questions that remain regarding AADC deficiency. "In AADC deficiency, we’re working with patients, we’re working on mice, and trying to really dig into the pathogenesis, especially in younger patients, what exactly happens to the brain without dopamine...” Hwu told 

 during the interview. "We need to learn more about what separates responders from non-responders."

1. Upstaza gene therapy granted marketing authorization for AADC deficiency by UK's MHRA. News release. PTC Therapeutics, Inc. November 17, 2022. 

https://ir.ptcbio.com/news-releases/news-release-details/upstazatm-gene-therapy-granted-marketing-authorization-aadc

2. Upstaza granted marketing authorization by European Commission as first disease-modifying treatment for AADC deficiency. News release. PTC Therapeutics. July 20, 2022. Accessed July 20, 2022. 

https://ir.ptcbio.com/news-releases/news-release-details/upstazatm-granted-marketing-authorization-european-commission

3. PTC Therapeutics receives positive CHMP opinion for Upstaza for the treatment of AADC deficiency. News release. PTC Therapeutics. May 20, 2022. 

https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-receives-positive-chmp-opinion-upstazatm

4. PTC Therapeutics provides a corporate update and reports third quarter financial results. News release. PTC Therapeutics, Inc. October 27, 2022. 

https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-provides-corporate-update-and-reports-third-0

The gene therapy was approved in the European Union earlier this year.