 Weekly Rewind! We’ve compiled 5 highlights from this week’s coverage of advances in gene and cell therapies, including FDA actions, notable research, and interviews with experts across the field.

FDA Accepts Beti-Cel BLA for β-thalassemia

The FDA has accepted bluebird bio’s Biologics License Application for betibeglogene autotemcel (beti-cel) for the potential treatment of β-thalassemia. The gene therapy, which will receive priority review, has a PDUFA date of May 20, 2022.

Overcoming Challenges With CAR T Therapies in Solid Tumors: Julian Molina, MD, PhD

The hematologist/oncologist from Mayo Clinic discussed the role of HLA loss in a variety of cancers. He also outlined the challenges of CAR T-cell therapies in treating solid tumors and how Tmod technology may overcome these.

Gene-Edited, Autologous HSP Cells Correct Metabolic Activity in Hurler Syndrome

Autologous hematopoietic stem and progenitor cells transduced ex vivo with an IDUA–encoding lentiviral vector yielded extensive metabolic correction in peripheral tissues and the central nervous system in patients with Hurler syndrome (mucopolysaccharidosis type 1, Hurler variant) according to data from a recent phase 1/2 study (NCT03488394).

Targeting the Putamen in AADC Deficiency: Paul Wuh-Liang Hwu, MD, PhD

The professor from National Taiwan University Hospital discussed the benefits of delivering gene therapy directly to the putamen in AADC deficiency. Hwu is an investigator on the trials of PTC-AADC, an investigational gene therapy in this indication.

Hemophilia A Gene Therapy Shows Sustained Factor VIII Expression

SPK-8011, an investigational gene therapy for hemophilia A, was well-tolerated and yielded sustained Factor VIII expression in treated men, according to data from a phase 1/2 study (NCT03003533) and its long-term follow-up study (NCT03432520).

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Review top news and interview highlights from the week ending November 26, 2021. 

GeneTherapyLive’s Weekly Rewind – November 26, 2021

“We started our pipeline with a Sanfilippo-focused program, because I had a child affected with this syndrome. Back then, there were no programs around for this disease. That was the genesis of Lysogene. Later on, based on what we had learned on the Sanfilippo or MPS type 3 program, we decided to apply our knowledge and expertise to other indications.”

Lysogene is focused on developing gene therapies for neurodegenerative lysosomal storage disorders. This mission is personal for founder Karen Pignet-Aiach, whose own child was born with mucopolysaccharidosis type 3 (MPS type 3), also known as Sanfilippo syndrome.

Lysogene’s lead program, LYS-SAF302, is being evaluated in the phase 2/3 AAVance trial (NCT03612869), which has enrolled 20 participants with MPS type 3A. The trial has previously reported reductions in cerebrospinal fluid sulfate heparin levels as well as GM2 and GM3 ganglioside compared to baseline. Another program, LYS-GM101, is being evaluated in a phase 1/2 clinical trial (NCT04273269) that dosed its first participant with GM1 gangliosidosis in August 2021.

 spoke with Aiach, who also serves as chair and chief executive officer, to learn more about Lysogene and its patient-focused therapy development. Ralph Laufer, PhD, chief scientific officer, also discussed the advantages of Lysogene’s AAV delivery methods.

Lysogene announces first patient in the United States dosed with LYS-GM101 investigational gene therapy for the treatment of GM1 gangliosidosis. News release. Lysogene. August 30, 2021. https://www.biospace.com/article/releases/-lysogene-announces-first-patient-in-the-united-states-dosed-with-lys-gm101-investigational-gene-therapy-for-the-treatment-of-gm1-gangliosidosis-/

Videos

The chief executive and scientific officers of Lysogene discussed Lysogene’s patient-focused therapy development. 

Developing Gene Therapies for Indications With Unmet Needs 

This content originally appeared on our sister site, 

 (RMAT) designation to  CTX110 (CRISPR Therapeutics), an allogeneic chimeric antigen receptor T-cell therapy that targets CD19-positive B-cell malignancies.

“This RMAT designation is based on the encouraging clinical data we have presented thus far, and it is an important milestone that recognizes the transformative potential of CTX110 for the treatment of hematological malignancies,” said Samarth Kulkarni, PhD, chief executive officer of CRISPR Therapeutics, in a press release. “We look forward to working closely with the FDA as we continue our efforts to bring this important new therapeutic modality to patients.”

The designation follows positive results reported with CTX110 from the large B-cell lymphoma (LBCL) cohort in the 

 (NCT04035434). In 26 patients with LBCL followed for at least 28 days, the objective response rate (ORR) was 58% with complete responses (CRs) in 38% of patients.

The 6-month CR rate in the LBCL cohort was 21% with the longest response having exceeded 18 months. Investigators noted, in a press release, that these responses were similar to what has been achieved in this population with CAR T-cell therapy.

Gene Therapies for ALS, Friedreich’s Ataxia the Focus of New CRISPR, Capsida Partnership

In terms of safety, there were no cases of grade 3 or higher cytokine release syndrome and rate of infection and immune effector cell-associated neurotoxicity syndrome were low.

The study is ongoing and aiming to enroll 143 patients with relapsed or refractory nonHodgkin lymphoma. The coprimary end points of the study include the incidence of adverse events and dose-limiting toxicities and ORR. Secondary end points explored in the study include duration of response, duration of clinical benefit, progression-free survival, overall survival, and ORR in the B-cell acute lymphoblastic leukemia population.

To be eligible for inclusion in the study, patients are required to be 18 years of age with NHL, or between the ages of 18 and 70 years with B-cell ALL. All patients must have an ECOG performance status of 0 or 1, adequate renal, liver, cardiac, and pulmonary organ function, and be using acceptable method of contraception throughout the study.

Patients who have been previously treated with gene therapy or genetically modified cell therapy are excluded from the study. The study also excludes individuals who recently underwent allogeneic hematopoetic stem cell transplant, have history of central nervous system involvement, or seizure disorder, have bacterial or viral infection, a previous or concurrent malignancy, received anti-cancer therapy within 15 days, have an immunodeficiency disorder, or are pregnant or breastfeeding.

Patients who meet the study criteria are being actively recruited at treatment centers in 15 states.

With a RMAT designation, clinical trial development and application reviews for CTX110 will be expedited by the FDA based on the drug’s potential to treat, modify, reverse, or cure a serious or life-threating disease or condition. 

1. CRISPR Therapeutics announces fda regenerative medicine advanced therapy (RMAT) designation granted to CTX110™ for the treatment of relapsed or refractory cd19+ b-cell malignancies. News release. CRISPR Therapeutics. November 22, 2021. Accessed November 23, 2021.


2. CRISPR Therapeutics reports positive results from its phase 1 CARBON trial of CTX110™ in relapsed or refractory cd19+ b-cell malignancies. News release. CRISPR Therapeutics. October 12, 2021. Accessed November 23, 2021.

In 26 patients with LBCL followed for at least 28 days, the objective response rate (ORR) was 58% with complete responses (CRs) in 38% of patients.

CD19+ B-Cell Malignancy Cell Therapy Receives RMAT Designation

“We are platform agnostic in the sense that we develop our therapies based on high unmet need in the clinic, so we start with the end in mind. First, there are patients with rare monogenic diseases, many of whom have no treatment alternatives... There are thousands of these patients out there. Because of this philosophy, Rocket has... both an ex-vivo lentiviral platform and an in-vivo AAV platform... We want clear, clean mechanisms of action that will predict good responses with gene therapy and we want sizable enough indications to really benefit a large number of patients.”

Rocket Pharma uses both an ex-vivo lentiviral platform and in-vivo adenoviral platform to develop gene therapies for rare, monogenic diseases.

The company’s lead programs include RP-L102 (NCT04248439) for the treatment of Fanconi anemia and RP-L201 (NCT03812263) for the treatment of leukocyte adhesion deficiency-I (LAD-1), both lentiviral therapies being evaluated in phase 2 studies. 

Rocket also recently announced positive data from the phase 1 study (NCT03882437) of the adenoviral therapy RP-A501 for the treatment of Danon disease, which showed that the therapy is well-tolerated with sustained clinical benefit. The trial will continue evaluating the low-dose but not the high-dose therapy after a dose-limiting toxicity of thrombotic microangiopathy was observed.

 spoke with Gaurav Shah, MD, cofounder and chief executive officer, Rocket Pharmaceuticals, to learn more about the company’s platform-agnostic approach to creating gene therapies tailor-fit to different monogenic diseases. He discussed manufacturing and advantages of both ex-vivo and in-vivo approaches.

Rocket Pharmaceuticals announces positive updates from phase 1 clinical trial of RP-A501 in Danon disease. News release. Rocket Pharmaceuticals. November 15, 2021. https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-announces-positive-updates-phase-1

The chief executive officer of Rocket Pharmaceuticals, Gaurav Shah, MD, discussed the company’s ex-vivo and in-vivo gene therapy platforms. 

Advantages of Developing Platform-Agnostic Gene Therapies 

The FDA has placed Pfizer and Sangamo Therapeutics’ phase 3 AFFINE study (NCT04370054) of giroctocogene fitelparvovec (SB-525; PF-07055480) for the 

The hold follows the companies’ voluntary pause of screening and dosing in the trial after some treated participants experienced Factor VIII (FVIII) activity greater than 150%. No patients have experienced thrombotic events and some have been treated with anticoagulants to reduce this risk. The trial will be paused until protocols are amended.

“Ensuring the safety of study participants is our first priority. All participants in the Phase 3 study are under close observation and are being carefully monitored for thrombotic events and FVIII activity levels, as per study protocol. Those participants with FVIII activity greater than 150% are being closely monitored and managed by the study investigators," Pfizer wrote in a study update.

The study expects to enroll 63 participants with hemophilia A who have been followed on routine prophylaxis with FVIII products in the lead-in study (NCT03587116). The study is primarily assessing efficacy via annualized bleeding rate (ABR) over 12 months compared to ABR on FVIII replacement therapy as seen in the lead-in study period. Secondary outcome measures include FVIII activity levels, annualized infusion rate of exogenous FVIII activity, annualized FVIII consumption, joint health, patient-reported outcomes, quality-of-life measures, and adverse events (AEs) for up to 5 years after treatment.

Gene Therapies for Hemophilia Have Positive Real-World Impact, Studies Show

“We are committed to resuming patient dosing in this phase 3 program and believe this gene therapy, if approved, could represent an important treatment option for patients with hemophilia A. We will submit the protocol amendment and associated documents to Health Authorities in the countries where the trial is being conducted and respond to the FDA clinical hold to obtain agreements to proceed. In addition, Ethics Review Boards approvals for the clinical management guidelines and other proposed changes will be obtained before the amendment will be implemented. We expect dosing will resume once these are completed. This will happen at different times for each site depending on local review timelines,” Pfizer wrote.

The phase 1/2 Alta study (NCT03061201) previously demonstrated that giroctocogene fitelparvovec was generally well tolerated.

 The 5 patients in the high dose cohort sustained FVIII activity levels without bleeds or the need for prophylactic factor through up to 85 weeks. FVIII activity levels were clinically meaningful, with a geometric mean of around 71% between weeks 9 and 52. Pfizer and Sangamo dosed the first participant in the AFFINE study in October 2020. 

Giroctocogene fitelparvovec encodes complementary deoxyribonucleic acid for B domain deleted human FVIII, which is delivered via the AAV6 vector. The therapy is optimized for liver-specific expression by incorporating multi-factorial modifications to the liver-specific promoter module, FVIII transgene, synthetic polyadenylation signal, and vector backbone sequence. The FDA previously granted orphan drug, fast track, and regenerative medicine advanced therapy designations to the gene therapy. The EMA has also granted it orphan medicinal product designation.

1. Pfizer giroctocogene fitelparvovec (hemophilia A gene therapy) AFFINE phase 3 study update. News release. Pfizer. November 5, 2021. 

https://www.ehc.eu/pfizer-hemophilia-a-clinical-program-update_november-5th-2021/


2. Sangamo Therapeutics reports recent business and clinical highlights and third quarter 2021 financial results. News release. November 4, 2021. 

https://investor.sangamo.com/news-releases/news-release-details/sangamo-therapeutics-reports-recent-business-and-clinical


3. Pfizer and Sangamo dose first participant in phase 3 study evaluating hemophilia A gene therapy treatment. News release. Pfizer. October 7, 2020. Accessed November 23, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-sangamo-dose-first-participant-phase-3-study

Pfizer and Sangamo voluntarily paused the trial after participants experienced FVIII activity levels of over 150%. 

Hemophilia A Gene Therapy Placed on Clinical Hold 

"More aggressive, systemic treatments... can cause liver damage and damage other cells. In comparison, we deliver not very vigorously spreading virus by local injection [to the putamen]. The treatment is just involved in that region and does not spread out too much. That is safer and more effective.”

PTC Therapeutics recently announced updated data from a 5-year analysis of 3 clinical trials assessing PTC-AADC, a novel gene therapy delivered to the putamen for the potential treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. The analysis showed improvements in development, motor skills, and cognition in treated children with AADC deficiency.

Results from the analysis were presented at the 50th Child Neurology Society (CNS) Annual Meeting, September 29 to October 2, 2021. Investigators found that across trials, treated participants reached milestones not usually seen in the natural history of AADC deficiency, including being able to hold up their heads and sit or stand with support as early as 3 months after treatment. Communication skills also improved, as measured via Bayley-3 scores. 

 spoke with investigator Paul Wuh-Liang Hwu, MD, PhD, professor, pediatrics, National Taiwan University Hospital, to learn more about the putamen as a target for gene therapy in AADC deficiency. 

1. Results show long-lasting and holistic improvements in children with AADC deficiency treated with PTC-AADC gene therapy. News release. PTC Therapeutics. September 29, 2021. https://www.prnewswire.com/news-releases/results-show-long-lasting-and-holistic-improvements-in-children-with-aadc-deficiency-treated-with-ptc-aadc-gene-therapy-301387687.html
2. Hwu PWL, Kiening K, Anselm I, et al. Gene therapy in the putamen for curing AADC deficiency and Parkinson's disease. 

 2021;13:e14712. doi: 10.15252/emmm.202114712

The professor from National Taiwan University Hospital discussed the benefits of delivering gene therapy directly to the putamen in AADC deficiency. 