Passage Bio has dosed the first patient with frontotemporal dementia with granulin mutations (FTD-GRN) with their

 in the phase 1/2 upliFT-D study (NCT04747431).

“Dosing the first patient in our upliFT-D trial is an important milestone for the Passage Bio team and for the PBFT02 program, our first program in the clinic for adults,” Edgar (Chip) Cale, interim chief executive officer, Passage Bio, said in a statement. “We look forward to continuing our important work to develop PBFT02 as a potential treatment option for the thousands of people living with FTD-GRN. We are grateful for the support from the families and clinical trial investigators who have chosen to participate in our studies.”

PBFT02 uses an adeno-associated virus vector (AAV1) to deliver a functional copy of the 

encodes progranulin, a deficiency of which is thought to contribute to lysosomal dysfunction. The therapy has shown preclinical efficacy in studies conducted by University of Pennsylvania’s Gene Therapy Program, Passage Bio’s collaborator on the program. Preclinical studies demonstrated broad transduction across the brain and increases in cerebrospinal fluid PGRN concentrations to more than 50-fold normal human concentrations.

Gene Therapy for Frontotemporal Dementia Granted Orphan Drug Status

“FTD-GRN is a devastating disease with no approved disease-modifying therapies, and we are hopeful this trial will provide evidence that PBFT02 could become a meaningful treatment option for adults living with FTD-GRN,” said Mark Forman, MD, PhD, chief medical officer of Passage Bio. “Our approach, which employs the AAV1 vector and intra cisterna magna (ICM) administration, provides a potential opportunity to achieve higher than normal levels of PGRN in the central nervous system, thereby overcoming the PGRN deficiency in GRN mutation carriers with a diagnosis of early symptomatic FTD-GRN. We look forward to building on our preclinical data with this Phase 1/2 trial.”

The upliFT-D study is a 2-year study with a 3-year safety extension that is evaluating PBFT02 delivered via ICM injection. The trial is currently enrolling patients with early symptomatic FTD-GRN between the ages of 35 to 75 years. The study will evaluate 2 dose levels of PBFT02 in 2 cohorts, with an optional third dose cohort.

The primary end point is safety and tolerability as measured by adverse events (AEs) and serious AEs. Other primary outcome measures include nerve conduction velocity, nerve conduction amplitude, and humoral response. Secondary outcome measures will assess clinical dementia rating, neurocognitive assessments, biomarkers of disease progression, brain anatomy, activities of daily living, and survival.

 with David Weinstein, MD, senior vice president, clinical development, Passage Bio, about ICM administration of gene therapies to the brain, a technique the company is employing in other programs such as their GM1 gangliosidosis gene therapy program, PBGM01.

“The brain has been a hard target because of the blood brain barrier. In order to get gene therapy into the brain, higher doses had to be used, and there was higher risk of toxicity using traditional approaches. I think the ICM approach shows us an alternative way. We’re able to use a dose of the vector much lower than has been used in prior trials and because we're injecting directly into the CSF, we're able to treat people who have preexisting antibodies,” Weinstein told 

Passage Bio doses first patient in global clinical trial of PBFT02 gene therapy for frontotemporal dementia with granulin mutations. News release. Passage Bio. August 11, 2022. https://www.globenewswire.com/en/news-release/2022/08/11/2496558/0/en/Passage-Bio-Doses-First-Patient-in-Global-Clinical-Trial-of-PBFT02-Gene-Therapy-for-Frontotemporal-Dementia-with-Granulin-Mutations.html

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PBFT02, developed by Passage Bio, is delivered via intra cisterna magna administration to the brain.

Frontotemporal Dementia Gene Therapy Trial Initiates Dosing

The FDA has given investigational new drug application (IND) clearance to Cure Rare Disease’s CRISPR therapeutic, CRD-TMH-001, for treating 

Following the approval, a single-patient trial will begin dosing at UMass Chan Medical School. Chan, in collaboration with the Lek Lab at Yale University, Charles River Laboratories, and other researchers, scientists, and clinicians, developed the therapy as part of a 3-year partnership.

“I’m pleased to share that the US FDA has approved our IND application to treat our first patient Terry. We received word just recently and will move into clinical trials in a couple of days, first with immune suppression and finally with administering of this first in human CRISPR therapeutic,” Richard Horgan, founder and chief executive officer, Cure Rare Disease, said in a video. “We’ve done more than develop a drug, we've developed a new framework by which we can treat and develop drugs for other rare and ultra-rare diseases that have no treatment.”

Craig M. McDonald, MD, on Safety and Efficacy of DMD Cell Therapy

CRD-TMH-001 is designed to upregulate an alternate isoform of the dystrophin protein with CRISPR technology, addressing muscle promoter and exon 1 mutations in the dystrophin gene. Cure Rare Disease believes the therapy has the potential to stabilize or even reverse DMD progression.

“The success of this collaborative project and the development framework that CRD has built demonstrates there is a more efficient way to develop therapeutics for rare disease patients who were previously told that there was no hope for them,” Horgan added to the statement. “This is just the beginning of CRD’s efforts to develop more therapeutics to treat rare and ultra-rare diseases, and we look forward to leveraging this approach to continue breaking down barriers in the drug development process for patients who need effective treatments now. As we celebrate this accomplishment, it is imperative that the US Centers for Medicare & Medicaid Services understand the financial hurdles that the rare disease community must overcome and consider the implementation of a reimbursement model to make this growing pathway accessible to more patients.”

In the trial, the participants will receive a single dose of CRD-THM-001 intravenously and will be monitored in the hospital for several days for serious adverse events (AEs). The patient will then be followed up for 15 years for safety and efficacy.

"It is inspiring to see Cure Rare Disease achieve FDA approval for the first-in-human IND using CRISPR-transactivator technology to treat a rare mutation causing Duchenne muscular dystrophy. Learnings from this significant accomplishment will undoubtedly benefit other rare disease patients and we look forward to continuing to collaborate with CRD in the future to help patients. We wish both the patient and family the best for the upcoming clinical trial, " Terence Flotte, MD, Dean, Provost & Executive Deputy Chancellor, UMass Chan, added to the statement.

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/

A single patient will be dosed with CRD-THM-001 in an upcoming trial.  

CRISPR Therapeutic Ready to Dose in Duchenne Muscular Dystrophy 

 has dosed the first patient in their company-sponsored phase 1/2 trial of the natural killer (NK) cell therapy GDA-201 for the potential treatment of follicular and diffuse large B cell lymphomas.

“We are excited to further advance the development of GDA-201, a NAM-enabled NK cell therapy candidate which we believe has the potential to be a new readily available, cryopreserved treatment option for cancer patients with relapsed/refractory lymphoma,” Ronit Simantov, MD, chief medical and scientific officer, Gamida Cell, said in a statement.

 “Our NK cells elicited an adaptive immune response in patients in the previous investigator-sponsored study with the fresh formulation of GDA-201, potentially leading to durable remissions. We are truly grateful for the contribution of all the participants and clinical collaborators who will allow us to continue studying GDA-201 in this multi-center open label trial.”

The study is beginning with a phase 1 dose escalation phase that will evaluate the safety of a cryopreserved, readily available formulation of GDA-201 in patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma, marginal zone lymphoma or mantle cell lymphoma. The phase 2 expansion phase will evaluate both safety and efficacy of the therapy in 63 participants with either FL or DLBCL. Participants have to have disease relapsed/refractory to at least 2 prior treatments, not excluding prior chimeric antigen receptor (CAR) T-cell therapy or stem cell transplant.

GDA-201 is developed using Gamida Cell’s proprietary nicotinamide (NAM) technology platform. The platform is designed to allow for expanded number and functionality of the NK cells to improve tumor cell killing and antibody-dependent cellular cytotoxicity. The therapy, in combination with standard-of-care antibody therapies, is being investigated in most hematologic malignancies and solid tumors.

1-Year Data on Omidubicel Shows Sustained Benefits, Reduced Infection Rates

The same formulation of GDA-201 is currently being investigated in an investigator-sponsored phase 1/2 study in relapsed/refractory multiple myeloma (MM) or relapsed/refractory CD20-positive non-Hodgkin lymphomas (NHL). The trial continues to enroll at Henry Ford Cancer Institute (Detroit, MI) and the Masonic Cancer Center at the University of Minnesota. This trial demonstrated GDA-201's potential in lymphoma in combination with rituximab.

Investigators found that out of 19 patients with NHL, 13 had complete responses and 1 had a partial response, for an overall response rate of 74% and a complete response rate of 68%. These participants had a median duration of response of 16 months (range, 5-36) and an overall survival rate of 78% (95% CI, 51-91) at 2 years. GDA-201 was well-tolerated and no dose-limiting toxicities were observed in the 19 patients with NHL as well as the 16 patients with MM. Common serious adverse events included thrombocytopenia, hypertension, neutropenia, febrile neutropenia, and anemia, but there were no cases of cytokine release syndrome, neurotoxic events, graft versus host disease or marrow aplasia.

“Interest in NK cell therapies has increased in recent years as a potential alternative to current cell therapies, as NK cells have the potential to be effective in hematological and solid tumors while avoiding common safety issues,” Veronika Bachanova, MD, PhD, University of Minnesota, added to the statement.

 “We are particularly excited about Gamida’s cryopreserved formulation of GDA-201, which has potential as a new treatment option for patients.”

Gamida Cell is also developing their allogeneic hematopoietic stem cell transplant candidate omidubicel with the NAM technology platform. The FDA accepted a biologics license application (BLA) for

The BLA was supported by data from the phase 3 clinical trial (NCT02730299), which demonstrated faster hematopoietic recovery and fewer early transplant-related complications with omidubicel treatment compared with standard umbilical cord blood transplantation (UCBT).

1. Gamida Cell announces dosing of first patient in company-sponsored phase 1/2 study of NK cell therapy candidate GDA-201. News release. Gamida Cell. August 10, 2022. 

https://www.businesswire.com/news/home/20220810005248/en/Gamida-Cell-Announces-Dosing-of-First-Patient-in-Company-Sponsored-Phase-12-Study-of-NK-Cell-Therapy-Candidate-GDA-201


2. Gamida Cell announces FDA acceptance of Biologics License Application for omidubicel with priority review. News release. Gamida Cell, Ltd. August 1, 2022. https://www.biospace.com/article/releases/gamida-cell-announces-fda-acceptance-of-biologics-license-application-for-omidubicel-with-priority-review/?keywords=Gamida+Cell
3. Horwitz ME, Stiff PJ, Cutler C, et al. Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study. 

. 2021;138(16):1429-1440. doi:10.1182/blood.2021011719

The FDA recently accepted the company’s BLA for omidubicel for priority review. 

NK Cell Therapy Trial Doses First Patient With Lymphoma 

The cell and gene therapy sectors are growing exponentially, with new players emerging daily and much progress being made both in and out of the lab. 

Around the Helix is your chance to catch up with the latest news in cell and gene therapies, including partnerships, pipeline updates, and more.

1. Allogeneic Cell Therapy Trial to Initiate in Ovarian Cancer

The FDA has cleared Avenge Bio’s investigational new drug application (IND) for AVB-001, an allogeneic cell therapy, for the potential treatment of metastatic peritoneal cancers.

2. Phase 2/3 Mesothelioma Cell Therapy Trial Completes Final Patient Active Follow-up

The last patient has completed the follow-up period for Amphera’s phase 2/3 clinical trial (DENIM; NCT03610360) of MesoPher, an autologous cell therapy being evaluated for the treatment of mesothelioma.

3. iPSC-Derived Allogeneic Cell Therapies to Be Focus of New Venture From ElevateBio, Boston Children’s

ElevateBio is partnering with George Daley, MD, PhD, and Boston Children’s Hospital with the intention of using a novel platform for developing cell therapies derived from induced pluripotent stem cells (iPSCs).

4. UniQure Pauses High Dose of AMT-130 Huntington Disease Gene Therapy for Severe Adverse Events

Following the report of promising 12-month data for the lower-dose cohort in the Phase 1/2 study of gene therapy AMT-130 for the treatment of Huntington disease, UniQure has announced that it has since paused enrollment in its higher-dose cohort due to the occurrence of suspected unexpected severe adverse reactions (SUSARs).

5. Sarepta, Broad Institute Strike Licensing Agreement for New Class of AAV Vectors for Gene Therapy

A licensing agreement has been executed between Sarepta Therapeutics and the Broad Institute of MIT and Harvard for Sarepta’s MyoAAV, a new group of adeno-associated viruses (AAV) for use in the treatment of Duchenne muscular dystrophy (DMD) and 4 other neuromuscular and cardiac indications.

6. IND Cleared for Non-Hodgkin Lymphoma T-Cell Therapy

The FDA has cleared Marker Therapeutics’ IND for MT-601, an investigative T-cell therapy for the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL).

7. Allogeneic Cell Therapy for Multiple Hematologic Malignancies Being Assessed in Phase 3 Clinical Trial

Orca Bio has initiated its phase 3 clinical trial for Orca-T, an allogeneic cell therapy being evaluated for the treatment of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and high-risk myelodysplastic syndromes (MDS).

8. RoslinCT and Lykan Bioscience to Form New CDMO Focused on Cell Therapy

The newly combined group will focus its efforts on providing cGMP manufacturing and process development expertise for both autologous and allogeneic cell therapies

9. Global Stem Cells Group Opens Facilities in Indonesia

The new facilities are being launched in a partnership with Dr. Yanti Aesthetic Clinics and will specialize in stem cell therapy and regenerative medicine.

10. NETs-targeted Adoptive Cell Therapies to be Focus of New Collaboration Between Xenetic Biosciences and VolitionRx

The collaboration will attempt to develop cell therapies for the treatment of solid cancers by combining Volition's Nu.Q NETs Test and Xenetic's DNase-Armored CAR-T platform.

11. Charles River Laboratories Receives EMA Approval to Manufacture Allogeneic Cell Therapy at Memphis Facility

The approval marks the first time a North American CDMO has been approved by the European Medicines Agency (EMA) to commercially produce an allogeneic cell therapy.

12. Merck's MilliporeSigma Launches Full Viral Vector Offering

The VirusExpress 293 AAV Production Platform will provide AAV, Lentiviral, CDMO, CTO, and process development to pharmaceutical companies.

13. Bristol Myers Squibb and GentiBio to Collaborate on Treg Therapies to Treat IBD

The companies will aim to use disease-specific engineered regulatory T cells (Tregs) for restoration of immune tolerance and tissue repair in patients with Inflammatory Bowl Diseases (IBD).

Catch up on the latest news, breakthroughs, and announcements from biotechnology companies making advancements in cell and gene therapies. 

Around the Helix: Cell and Gene Therapy Company Updates – August 10, 2022 

 (ide-cel; Abecma; Bristol Myers Squibb; 2seventy bio) significantly improved progression-free survival (PFS) in people with relapsed/refractory multiple myeloma (R/R MM) compared with standard regimens, according to updated data from the phase 3 KarMMa-3 trial (NCT03651128).

“Results from the KarMMa-3 study clearly demonstrate the clinical benefit of using a CAR T cell therapy earlier in the multiple myeloma treatment paradigm,” Anne Kerber, senior vice president and head, Cell Therapy Development, Bristol Myers Squibb, said in a statement.

 “These data reinforce our commitment to unlocking the full potential of cell therapy as we strive to build on the company’s heritage of innovation in blood cancers and transform patients’ lives through science.”

The pivotal, randomized, multicenter, phase 3 KarMMA-3 trial is evaluating ide-cel in adults with MM that have relapsed after 2 to 4 prior lines of therapy and refractory to the last regimen. It is the first randomized clinical trial evaluating a chimeric antigen receptor (CAR) T-cell therapy in MM. Participants in the trial were randomized to treatment with ide-cel or combinations of daratumumab, pomalidomide, dexamethasone, bortezomib, ixazomib, lenalidomide, carfilzomib, or elotuzumab.

These new data, from a prespecified interim analysis, indicate that KarMMA-3 met its primary end point of statistically significantly improving PFS in treated study participants. The data also demonstrate an improvement in the trial's key secondary end point of overall response rate compared with standard regimens. Investigators continue follow-up to assess overall survival, another key secondary end point.

Frederick Locke, MD, on the Impact Potential of CAR T-Cell Therapies in Hematologic Malignancies

“We are extremely pleased to have met the KarMMa-3 primary endpoint at an interim analysis. These results help to advance our efforts to make Abecma available for earlier lines of treatment for patients and we look forward to discussing these results with regulatory authorities,” Steve Bernstein, MD, chief medical officer, 2seventy bio, added to the statement.

 “Today’s results are another important proof point for the transformative potential of autologous cell therapy and underscore the importance of continuing to study Abecma in earlier treatment settings for multiple myeloma.”

Ide-cel is the first BCMA-directed CAR T-cell therapy approved in the US for treating R/R MM after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. The therapy is developed by Bristol Myers Squibb and 2seventy bio and 

for this indication in March 2021. It is also approved in the European Union, Switzerland, 

, Canada, and the United Kingdom in patients who have received at least 3 prior lines of therapy. 

Safety data from KarMMA-3 were consistent with the safety profile seen in the pivotal KarMMA trial (NCT03361748), with no new safety signals. Further analyses of the data will be presented at an upcoming scientific meeting.

Further supporting ide-cel's efficacy, a recent comparison of health-related quality-of-life (HRQoL) scores presented at the European Hematology Association (EHA) 2022 Congress in June demonstrated that participants in KarMMA had

 than those treated with belantamab mafodotin in the DREAMM-2 study (NCT03525678).

 These data were presented by Nina Shah, MD, professor, Department of Medicine, University of California San Francisco.

1. Bristol Myers Squibb and 2seventy bio announce topline results from KarMMa-3 Trial showing abecma (idecabtagenevicleucel) significantly improves progression-free survival versus standard regimens in relapsed and refractory multiple myeloma. News release. Bristol Myers Squibb. August 10, 2022. 

https://news.bms.com/news/corporate-financial/2022/Bristol-Myers-Squibb-and-2seventy-bio-Announce-Topline-Results-from-KarMMa-3-Trial-Showing-Abecma-idecabtagene-vicleucel-Significantly-Improves-Progression-Free-Survival-Versus-Standard-Regimens-in-Relapsed-and-Refractory-Multiple-Myeloma/default.aspx


2. U.S. Food and Drug Administration approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagenevicleucel), the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb and bluebird bio. March 26, 2021. Accessed March 26, 2021. 


3. Shah N, Ayers D, Cope S, et al. Health-related quality of life in patients with relapsed/refractory multiple myeloma (RRMM) treated with idecabtagenevicleucel vs belantamabmafodotin: A matching-adjusted indirect comparison study. Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Poster #P170

A recent comparison of health-related quality of life scores also favored ide-cel over belantamab mafodotin treatment. 

Ide-Cel Shows Benefit in Earlier Use in R/R Multiple Myeloma 

The FDA has cleared Marker Therapeutics’ investigational new drug application (IND) for MT-601, an investigative T-cell therapy for the treatment of relapsed/refractory 

“This new clinical trial will build upon results that were observed in the phase 1/2 TACTAL study conducted by Baylor College of Medicine, which assessed the safety and efficacy of 5-antigen-directed multiTAA-specific T cell product,” Mythili Koneru, MD, PhD, chief medical officer, Marker Therapeutics, said in a statement. “In the TACTAL study, BCM observed long-term CR rates that were comparable to recently approved CD19 CAR-T therapies, even at very low cell doses. Unlike CD19 CAR-T cell therapies, patients receiving multiTAA-specific T cell product had superior durability of response, without the severe toxicities that commonly occur with other adoptive cell therapies, such as cytokine release syndrome or neurotoxicity. Based on these results, we believe that multiTAA-specific T cell products can be easily administered in an outpatient setting without hospitalization.”

Marker will be initiating a phase 1 trial evaluating MT-601 in patients for whom CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has failed or who are ineligible for CAR T-cell therapy. MT-601 is a multi-tumor-associated antigen (multiTAA)-specific T cell therapy that is targeting the antigens NY-ESO-1, MAGEA4, PRAME, Survivin, SSX, and WT-1.

“FDA clearance of our IND for MT-601 is a significant milestone as we advance our pipeline in a number of Company-sponsored trials,” Peter L. Hoang, president and chief executive officer, Marker, added to the statement. “We believe that MT-601, which targets six tumor-associated antigens highly expressed in lymphoma, has the potential to build upon results of the TACTAL study. We look forward to initiating our Company-sponsored Phase 1 study next year.”

IND Cleared for γδ T-Cell Therapy in Non-Hodgkin Lymphoma

MT-106 was evaluated in the previous TACTAL study (NCT01333046) conducted at Baylor College of Medicine. The therapy was evaluated against the same TAAS with the exception of WT-1. The therapy showed a tolerable safety profile in patients with NHL and the IND clearance included the addition of the WT-1 antigen for evaluation. The study will evaluate a dose level of 200 million cells per infusion of MT-601, an increase from the 10-40 million cell dose range used in the TACTAL study. Marker Therapeutics has developed and adapted a 9-day manufacturing process to support the dose increase.

“We believe that the most important finding of the TACTAL study was that the administration of multiTAA therapy consistently drove an enhanced immunological response from the patient’s own immune system, which we believe was due to the lack of lymphodepletion which allowed the patient’s own immune system to play a part,” Koneru added to the statement. “We believe that this phenomenon, known as epitope spreading, was critical in driving more durable responses than have been observed with other cell therapies like TCRs and CAR-Ts. It is notable that none of the patients who developed a CR in the TACTAL study relapsed during the follow up period, and several patients have been in CR for over five years at their last follow-up. This contrasts strongly with the experience of CD-19 CAR-Ts, where up to 40% of patients are expected to relapse within 12 months of developing a complete response.”

Marker Therapeutics announces FDA clearance of IND for MT-601, the six-antigen targeted t cell therapy for the treatment of relapsed/refractory non-Hodgkin lymphoma. News release. Marker Therapeutics. August 4, 2022. https://finance.yahoo.com/news/marker-therapeutics-announces-fda-clearance-203700185.html

Marker will initiate a company-sponsored study after an initial trial at Baylor College of Medicine showed positive safety data. 