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Lysosomal Disorders

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Authors

Chief scientific officer, CMT Research Foundation

The chief scientific officer of the CMT Research Foundation discussed investigative cell and gene therapy approaches for treating CMT. 

Keith Fargo, PhD, on Potential Treatment Avenues for Charcot-Marie-Tooth 

The chief scientific officer of the CMT Research Foundation discussed the foundation’s mission. 

Working to Find a Cure for Charcot-Marie-Tooth: Keith Fargo, PhD 

Patient use of the 2 FDA-approved gene therapy products for sickle cell disease (SCD), Vertex Pharmaceuticals' and CRISPR Therapeutics’ 

 (exa-cel; marketed as Casgevy) and bluebird bio’s 

 (lovo-cel; marketed as Lyfgenia), in the commercial setting has remained low.

Despite the approval of both gene therapy products by the FDA occurring simultaneously on December 8, 2023, only 4 patients have begun treatment with lovo-cel in the commercial setting, while 20 patients are reported to have begun treatment with exa-cel. Alongside the number for lovo-cel, bluebird also pointed out that this year 4 patients have started on elivaldogene autotemcel (Lenti-D, Skysona), its marketed gene therapy for cerebral adrenoleukodystrophy, and 19 patients have started on betibeglogene autotemcel (beti-cel, Zynteglo), its marketed gene therapy for transfusion dependent thalassemia (TDT). As such, bluebird bio has reported 23 total cell collections for SCD/TDT gene therapies lovo-cel and beti-cel. The company expects that patient uptake of the 3 aforementioned therapies will continue to increase, with 85 patient starts expected across the therapies by the end of the year.

“We are seeing clear evidence that our commercial launch is accelerating, with over 20 cell collections completed in SCD and TDT to date in 2024, and more than 40 additional patients already scheduled to initiate the treatment journey for a bluebird gene therapy by the end of this year,” Andrew Obenshain, MBA, the chief executive officer of bluebird bio, said in a statement.

 “We are further encouraged by the commitment to provide patient access across both commercial and government payers, most recently conveyed through multiple positive Medicaid decisions and the growing number of published coverage policies for Lyfgenia, and we expect approximately 85 patient starts across our portfolio this year.”

Notably, unlike lovo-cel, exa-cel is indicated for both SCD and TDT. Since Vertex has not clarified the breakdown of patients treated with exa-cel for each disease, direct comparison is difficult. The approval in TDT came slightly later, with 

“Vertex delivered another strong quarter of revenue growth coupled with outstanding execution across the business, and we are increasing our full year product revenue guidance,” Reshma Kewalramani, MD, the chief executive officer and president of Vertex, said in an August 1, 2024, statement.

 “Our focus for the second half of the year remains on commercial execution in cystic fibrosis and the global launch of Casgevy, readying for the upcoming potential launches of the vanzacaftor triple in cystic fibrosis and suzetrigine in acute pain, while rapidly advancing a robust pipeline that is poised to deliver value for patients and shareholders for the long term.”

Beyond gene therapy for SCD and TDT, uptake of 

hemophilia gene therapies has also been slow

. Although BioMarin’s valoctocogene roxaparvovec (val-rox, marketed as Roctavian) was approved in June 2023, the first patient outside of clinical trials 

 until December 2023, at the Center for Inherited Bleeding Disorders (CIBD) in California.

 Just this month, BioMarin announced that 

 with regard to val-rox, with the company now mainly focusing on distributing the gene therapy in the United States, Germany, and Italy, the 3 countries in which it has been approved for use by relevant regulatory authorities and is reimbursed.

 UniQure and CSL Behring’s hemophilia B gene therapy, etranacogene dezaparvovec (marketed as Hemgenix), which was 

, has also been slow to be embraced by patients.

“We haven't seen a lot of patients dosed yet,” Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, told 

 regarding Hemegenix earlier in 2024. “And I don't think that’s related to either the enthusiasm of the clinicians or the patients, but really just the mechanics of how to deliver this in the clinical space, as opposed to the research trials... We've seen that a lot of the hemophilia treatment center sites have got their components together, their infrastructure and personnel so that they can actually start delivering this in the commercial setting. And so, I'm really looking forward to seeing this making a difference in patients' lives in a real world setting.”

REFERENCES
1. bluebird bio reports second quarter 2024 results and highlights operational progress and 2024 guidance. News release. bluebird bio, Inc. August 14, 2024. Accessed August 15, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-second-quarter-2024-results-and-highlights
2. Stock dive for bluebird as sickle cell gene therapy lags behind Vertex rival. News article. Anna Bratulic. FirstWord Pharma. August 14, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5885598
3. Vertex announces US FDA approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Incorporated. January 16, 2024. Accessed August 15, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene
4. Vertex reports second quarter 2024 financial results. News release. Vertex Pharmaceuticals Incorporated. August 1, 2024. Accessed August 15, 2024. https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-second-quarter-2024-financial-results
5. Center for Inherited Blood Disorders Administers Country's First Gene Therapy Infusion to Treat Hemophilia A. News release. Center for Inherited Blood Disorders. January 11, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5817834?from=article
6. BioMarin Announces Updated Strategy for ROCTAVIAN® to Focus on U.S., Germany and Ital. News release. BioMarin Pharmaceutical Inc. August 5, 2024. Accessed August 15, 2024. https://investors.biomarin.com/news/news-details/2024/BioMarin-Announces-Updated-Strategy-for-ROCTAVIAN-to-Focus-on-U.S.-Germany-and-Italy/default.aspx
7. FDA approves first gene therapy to treat adults with hemophilia B. News release. FDA. November 22, 2022. Accessed August 15, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b

bluebird bio has reported 23 total cell collections for SCD and TDT gene therapies lovo-cel and beti-cel and Vertex Pharmaceuticals has reported approximately 20 cell collections for SCD/TDT gene therapy exa-cel.

Topic

Uptake of Nononcology Gene Therapy Remains Slow in Hematology

(arsa-cel, OTL-200; Orchard Therapeutics) is a gene-edited cell therapy designed to restore arylsulfatase A (ARSA) enzyme activity in children with presymptomatic (PS) late infantile (LI), PS early juvenile (EJ), or early symptomatic (ES) early juvenile (EJ) metachromatic leukodystrophy (MLD).

 arsa-cel under the name Lenmeldy to become the first gene therapy for children with MLD to be approved in the United States, following its approval in the European Union, UK, Iceland, Switzerland, Liechtenstein and Norway under the name Libmeldy.1 Orchard Therapeutics previously announced that the FDA had accepted the biologics license application with 

The FDA’s decision was based on data from patients treated with arsa-cel across 2 clinical trials (NCT01560182; NCT03392987) and additional patients treated in expanded access frameworks. These patients had follow-up times ranging from 0.64 years to 12.19 years (median, 6.76).

“Metachromatic leukodystrophy, is a really important unmet need in the pediatric community. So, this is a disease that's rare, it affects about one in 40,000 children. And up until recently, we have had no curative treatment option for this,” Madeleine Powys, MBBS, Staff Specialist, Blood Transplant and Cell Therapies, The Children's Hospital at Westmead, told 

. "Autologous hematopoietic stem cell gene therapy has offered really promising new hope for these patients.”

Madeleine Powys, MBBS, on Lessons Learned With Libmeldy

Arsa-cel is currently being evaluated in 6 participants enrolled in a phase 3 clinical trial (NCT04283227). The trial enrolled participants with documented biochemical and molecular diagnosis of MLD, including low ARSA activity and identification of 2 disease-causing ARSA alleles, with novel mutations analyzed and excluded as common polymorphisms, alongside specific genotype criteria. Symptomatic individuals must have onset between 7 and 17 years of age, or pre-symptomatic participants must be less than 17 years at treatment initiation and have a sibling with late-juvenile MLD variant, along with normal cognitive and motor function, with seizures or disease signs revealed by instrumental evaluations not being exclusionary if present alone, and compliance with contraceptive use requirements if applicable, with signed informed consent or assent provided by the participant or guardian.

The exclusion criteria for the study include documented HIV infection, malignant neoplasia except localized skin cancer or hereditary cancer syndrome unless successfully treated with no recurrence, myelodysplasia, acute myeloid leukemia, or serious hematological disorders, current enrollment in other interventional trials, prior allogeneic HSPC gene therapy or gene therapy, symptomatic herpes zoster unresponsive to treatment, active tuberculosis unless on antibiotic prophylaxis, acute or chronic stable Hepatitis B or positive Hepatitis C RNA test result unless specific conditions are met, end-organ dysfunction, severe infection not responsive to treatment, or other severe diseases deemed inappropriate for the study by the investigator. Additionally, testing for other transmissible infectious agents may be considered, and participants with elevated liver enzymes or bilirubin may be included after discussion and agreement with the medical monitor.

The study’s primary measures involve assessing the OTpbmsL-200 Arylsulfatase A (ARSA) activity levels in cerebrospinal fluid (CSF) and the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter brain regions, both evaluated at 24 months post-treatment, with changes from baseline being monitored.

Secondary measures involve evaluating changes in ARSA activity levels in CSF and neuronal metabolite ratio in white matter brain regions, assessing ARSA levels in peripheral blood mononuclear cells (PBMCs) and specific subtypes, comparing neuronal metabolite ratios to baseline, siblings, or untreated controls, determining engraftment through lentiviral positivity in bone marrow progenitors and vector copy number in BM cells and PBMCs, assessing severity scale for brain MRI, neurocognitive function, full neurological clinical examination, gross motor function classification, nerve conduction velocity, Vineland Adaptive Behavior Scale, and monitoring conditioning regimen and non-conditioning-related adverse events up to 8 years post gene therapy, along with hematological reconstitution, infusion-related reactions, immune response, abnormal clonal proliferation, replication-competent lentivirus, and integration site analysis findings over time.

, held February 4-9, in San Diego, California, by Vera Gallo, MD, staff pediatrician, San Raffaele Telethon Institute for Gene Therapy. The data were from 5 patients with LJ MLD that had follow-up ranging from 3.2 to 21.3 months (median, 17.3). At the time of treatment, 3 patients had PS MLD and 2 had ES MLD. The group included a 2.7-year-old girl (PS), a 9.9-year-old boy (ES), a 15.2-year-old boy (PS), a 6.6-year-old girl (PS), and 10.9-year-old boy (ES) as of the December 2023 cutoff date.

"This represents of course, the proof of principle that gene therapy with ex- vivo lentiviral gene therapy into stem cells can correct a lysosomal storage disorder (LSD)... and could be applicable to other LSDS. So we're working on new diseases to bring this approach of enzyme correction also to other LSDs," investigator Alessandro Aiuti, MD, PhD, deputy director, clinical research, and head, Clinical Research Unit, San Raffaele Telethon Institute for gene therapy, and Group leader, Pathogenesis and therapy, primary immunodeficiencies unit, and full professor, Università Vita Salute San Raffaele, and chief of clinic, Pediatric Immunohematology Unit, San Raffaele, told 

Data from these participants showed that they all had normal hematological reconstitution and engraftment that was consistent with arsa-cel outcomes seen in patients with early-onset MLD who have been treated in other settings. Time to neutrophil engraftment ranged from 26 to 42 days (median, 33) posttreatment and time to platelet engraftment ranged from 25 to 46 days (median, 26) posttreatment. ARSA activity reached supranormal levels in the PBMCs and in CD15+ cells and increased to normal levels in the CSF in 3 patients for whom central nervous system pharmacodynamic efficacy measures were available.At 90 days after administration of arsa-cel transduced bone marrow progenitors made up between 23.81% to 81.25% of bone marrow progenitors. At this time point, the PBMCs showed a median vector copy number (VCN) of 0.49 copies/cell and the CD15+ cells showed a median VCN of 0.82 copies/cell.

In terms of safety, there were no serious adverse events (SAEs) deemed potentially related to arsa-cel. One nonserious AE deemed potentially related to the therapy, a case of erythematous rash, occurred in 1 patient. No SAEs deemed potentially related to the Busulfan conditioning regimen occurred; although cases of febrile neutropenia, cytopenia, and stomatitis were deemed to have potential relation to the regimen. An SAE of upper respiratory tract infection occurred in 1 patient. One patient with prolonged thrombocytopenia who had previously experienced treatment-failure with allogeneic transplant in the form of autologous reconstitution was administered thrombopoietin receptor agonist therapy for 5 months. No multilineage engraftment of transduced cells or malignancy occurred and there was no indication of clonal expansion or replication competent lentivirus.

1. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed March 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystroph
2. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. News release. Orchard Therapeutics. September 18, 2023. Accessed September 18, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-acceptance-biologics-license
3. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsageneautotemcel (autologous hematopoietic stem cell gene therapy) preserves cognitive and motor development in early-onset metachromatic leukodystrophy with up to 12 years follow-up. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #92
4. Gallo V, Calbi V, De Mattia F, et al. Lentiviral hematopoietic stem cell gene therapy (atidarsageneautotemcel) for late juvenile metachromatic leukodystrophy (MLD). Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #96

The gene-edited cell therapy has been approved as Lenmeldy by the FDA. 

Phase 3 Trial Seeks to Continue Supporting Arsa-Cel Gene Therapy for MLD 

As cell therapy programs begin to dip into the field of solid tumors, one of the leading solid tumor indications being investigated is gastrointestinal (GI) cancers. One company developing a cell therapy program for GI cancers is CARsgen, whose chimeric antigen receptor (CAR) T-cell therapy 

 (satri-cel; CT041; CARsgen) is being assessed in patients with in patients with heavily pretreated Claudin18.2 (CLDN18.2)-positive advanced gastric/gastroesophageal (GC/GEJ) or pancreatic cancer (PC).

"We have a trial going on in gastric cancer with another very interesting target, which is CLDN18.2 which is widely expressed on GC/GEJ and PC as well. Right now the focus has been on the gastric cancer, which has been reported on from the phase 2 trial that is showing some very interesting promising results. So definitely stay tuned there," Maria Pia Morelli, MD, PhD, assistant professor, department of GI medical oncology, division of cancer medicine, MD Anderson Cancer Center, The University of Texas, told 

Satri-cel is an autologous, CLDN18.2-targeted CART-cell therapy that has received regenerative medicine advanced therapeutic and orphan drug designation (ODD) from the FDA for GC/GEJ cancers and PRIorityMEdicines and ODD designations from the European Medicines Agency.

“This is worldwide the first CLDN18.2 program that has received multiple countries’ investigational new drug (IND) clearance... the program is also the first solid tumor CAR-T program that has received multiple designations [from regulatory agencies,” Hong Ma, MD, Sr. Vice President of Clinical Development for Cancer Immunotherapy, CARsgen,

The ELIMYN18.2 trial is evaluating the safety and efficacy of satri-cel in patients with advanced GC/GEJ or PC whose disease had progressed or was unresponsive to at least 2 prior lines (GC/GEJ) or 1 prior line (PC) of systemic therapy. The study followed a modified 3+3 dose escalation/de-escalation scheme with 5 dose levels (DL). Participants received a preconditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel before receiving 1-3 cycles of satri-cel.

Maria Pia Morelli, MD, PhD, on Considerations for Cell Therapy in GI Cancers

The trial’s primary endpoints are the incidence of adverse events (AEs) and identification of maximum tolerated dose and dose-limiting toxicities in the phase 1b portion and objective response rate (ORR) in the phase 2 part. Secondary outcome measures are ORR in the phase 1b portion; duration of response, disease control rate, progression free survival, overall survival, utilization of hospital resources, health related quality of life, pharmacokinetics and biodistribution, CLDN18.2 ICH assay, anti-CT041 antibodies, cytokine expression level in blood in both portions; and incidence of AEs in the phase 2 portion.

American Society of Clinical Oncology (ASCO)

 Genitourinary Cancers (GI) Symposium, held January 18-20, in San Francisco, California, by Gregory P. Botta, MD, PhD, associate professor of medicine, University of California San Diego.

Data were presented from 19 patients, 7 with GC/GEJ and 12 with PC, with a median of 4 (range, 2-10; GC/GEJ) and 7 (range, 1-5; PC) lines of treatment, and a median of 29.3 (range, 13.7-74.7; GC/GEJ) and 20.6 (range, 7.7-97.7; PC) months since diagnosis. Participants received a median of 2 infusions of satri-cel (range, 1-3).

Investigators found that the safety profile of satri-cel was manageable, although all patients had at least grade 3 treatment-emergent adverse events (AEs) and there were 4 serious treatment-emergent AEs related to satri-cel. The related TEAEs of at least grade 3 were cytokine release syndrome, hypotension, increased liver enzymes, hypoxia, and increased lipase. There was 1 case of grade 1 immune effector cell-associated neurotoxicity syndrome.

Participants had a median follow-up of 8.9 months (range, 1.5-18.7) and were treated at DL1 (250-300x10

, n = 7). Objective response rate was 42.9% (n = 3) in GC/GEJ, 16.7% (n = 2) in PC, and 42.9% overall in DL3, which was selected as the recommended phase 2 dose (RP2D). There was 1 complete response (CR) in GC/GEJ in DL3, 2 partial responses (PRs) in GC/GEJ, and 2 PRs in PC in DL3. Clinical benefit rate (CBR) was 57.1% (n = 4) in GC/GEJ, 33.3% in PC (n = 4), and 71.4% in DL3. Median duration of response (DOR) was 6.9 months in GC/GEJ (range, 2.6-not estimable [ES]), 3.4 months (range, 3.0-NE) in PC, and 3.7 months (range, 3.0-NE) in DL3.

“The next step, for gastric cancer, we shouldn't consider whether it can be moved to the early line, because solid tumors is very difficult to treat and gastric cancer is probably one of the most difficult to treat cancers. The results are promising but it is last line, and we hope the early line we want to test and see if there's a potential to cure the cancer,” Ma said.

 along with 2 other of CARsgen’s clinical stage CAR T-cell therapies, CT053, also known as zevorcabtagene autoleucel (zevor-cel), and CT071, over chemistry, manufacturing, and controls-related concerns that arose after an FDA inspection of the company’s manufacturing facility in Durham, North Carolina.

CARsgen is planning to conduct a comprehensive review and improve its Current Good Manufacturing Practices (cGMP) at the facility and is “committed to working closely with the FDA to address the findings to ensure the smooth progress and production quality for clinical trials and launching applications.

(CT041-ST-01; NCT04581473) in China in advanced gastric cancer.3 The therapy is also set to be evaluated in conjunction with Moderna’s mRNA cancer vaccine as announced in August 2023.

1. Botta GP, Kelly RJ, Jin Z, et al. CLDN18.2 chimeric antigen receptor T cell therapy for patients with advanced gastric and pancreatic adenocarcinoma: Results of ELIMYN18.2 phase 1b clinical trial. Presented at: 2024 ASCO GI; January 18-20; San Francisco, California. Abstract #356
2. Inside information announcement clinical hold in the U.S. due to CMC related questions. CARsgen. Letter.
3. CARsgen 2022 interim results: Innovative CAR t-cell technologies and robust pipeline. News release. CARsgen. August 24, 2022. https://www.prnewswire.com/news-releases/carsgen-2022-interim-results-innovative-car-t-cell-technologies-and-robust-pipeline-301611224.html
4. CARsgen collaborates with Moderna to evaluate CT041 in combination with an mRNA cancer vaccine. News release. CARsgen. August 21, 2023. https://www.carsgen.com/en/news/2023-08-21/

The trial is assessing satri-cel CAR T-cell therapy, which is currently on clinical hold due to CMC concerns. 

CARsgen Hopes to Show Continued GI Cancer Control in ELIMYN18.2 Trial 

This is the second part of an interview with William Chou, MD. For the first part, 

Passage Bio is currently evaluating its investigational gene therapy PBFT02 in patients with frontotemporal dementia with GRN mutations (FTD-GRN). Notably, the company also recently received positive feedback from the FDA in a Type C meeting regarding plans to expand eligibility for the study to patients with FTD with mutations in the 

 reached out to William Chou, MD, president and chief executive officer of Passage Bio, to get some more background information about PBFT02 and the promising early data it has generated so far in FTD-GRN. Chou also discussed remaining questions about the therapy's efficacy  and safety that will require more long-term data collection.

Can you give some background info about PBFT02?

Our lead program is PBFT02. It is in AAV that is administered directly to the central nervous system (CNS). The first indication that we are attacking with PBFT02 FTD patients who have a mutation in the granulin gene. FTD is the most common early onset dementia. This one particular genetic form of FTD strikes about 10% overall of FTD patients. In the US, about 6000 patients in have FTD with the granulin mutation. When patients have this mutation, they're haploinsufficient in creating a protein called progranulin. Their levels of progranulin are too low, and that leads to neurodegeneration. In FTD-GRN, lack of progranulin is the definitive proximal cause of this disease. Our AAV replaces that progranulin. It gives them a functioning granulin gene, and then they make progranulin in the CNS.

Can you speak about the progress of assessing this gene therapy so far?

We're very excited. We are in the midst of a phase 1/2 study of PBFT02 in patients who have FTD with the granulin mutation. We have treated 5 patients. At this point, we have shared data from the first 3 patients, and what we've seen so far we have been very excited about. So far, the levels of progranulin that this product has been able to achieve in these patients is quite high. It's markedly higher than any of the other developmental programs that are also looking to replace progranulin in these patients. The reason getting to these high levels is important is no one knows how high we need to get progranulin to really save neurodegeneration from happening in these patients. The the field believes there is some threshold that you have to get across, but no one knows what that threshold is. Now, for every patient who gets any modality, there is going to be variability in how high their target engagement is and how high their progranulin gets. It's like if you're on a statin, it may work better for some people, not as well for other people. If, on average, we can get to much higher levels, the variability patient to patient is going to be around a much higher level. Therefore our odds of being over that threshold of clinical effectiveness go way up, and there is no known toxicity from having high levels of progranulin. Therefore we have a very good window. We're really pleased with the levels that we've gotten to. They're about 2 to 3 times higher than the normal level, and certainly higher than what we've seen from other programs in the clinic.

Is there anything else you want to share about the program?

I mentioned before we've shared data from 3 patients. There's a couple of remaining questions in the near-term about our data. The first is that our first patient who we treated had 2 serious adverse events (SAEs), and we had given that patient a very low dose of immunosuppression. We subsequently increased the immunosuppression, and patients 2 and 3 hadn't no SAEs at all. [So] we had 1 patient with 2 SAEs and 2 patients who did much better with the new immunosuppression, but people are waiting to see more safety data to really feel good that we can safely administer this product with the immunosuppression regimen. So that's 1 piece of data that will be coming. We'll be releasing that at the 4th International Conference on Frontotemporal Dementias, held September 19 to 22, 2024, in Amsterdam, the Netherlands. 

The other big data that people are interested in is—we have seen other AAV programs in CNS that are looking to raise progranulin—we've seen progranulin levels in those other programs decline over time and not show durability out to 12 months. That's significant. If you're going to do a procedure, if you're going to get a gene therapy, you do want it to be a one-time therapy; that is the goal. We have to this date only shared data out to 6 months. In September, we'll be sharing our first 12 month data. I know many people are looking to see is this going to be durable, or is this going to show decline, like other programs have shown? Those are 2 big pieces of data that we will be sharing come September.

This transcript has been edited for clarity.

REFERENCES
1. Passage Bio announces positive feedback from FDA on expansion of upliFT-D trial of PBFT02 to include FTD-C9orf72 patients. News release. Passage Bio, Inc. July 16, 2024. Accessed July 19, 2024. https://www.passagebio.com/investors-and-news/press-releases-and-statements/news-details/2024/Passage-Bio-Announces-Positive-Feedback-from-FDA-on-Expansion-of-upliFT-D-Trial-of-PBFT02-to-Include-FTD-C9orf72-Patients/default.aspx
2. Passage Bio announces promising initial data from phase 1/2 clinical trial of PBFT02 in FTD-GRN and updated strategic priorities. News release. Passage Bio, Inc. December 20, 2023. Accessed July 19, 2024. https://www.passagebio.com/investors-and-news/press-releases-and-statements/news-details/2023/Passage-Bio-Announces-Promising-Initial-Data-From-Phase-12-Clinical-Trial-of-PBFT02-in-FTD-GRN-and-Updated-Strategic-Priorities/default.aspx

William Chou, MD, president and chief executive officer of Passage Bio, discussed feedback from a recent Type C meeting with the FDA.

Targeting Progranulin With Gene Therapy for Frontotemporal Dementia

Passage Bio, which is currently evaluating its investigational gene therapy PBFT02 in patients with frontotemporal dementia with GRN mutations (FTD-GRN), recently received positive feedback from the FDA in a Type C meeting regarding the company’s plans to expand eligibility for the study to patients with FTD with mutations in the 

 gene (FTD-C9orf72). Following the meeting, 

 reached out to William Chou, MD, president and chief executive officer of Passage Bio, to learn more.

Chou discussed the background and rationale behind the company's decision to seek alignment with the FDA on this move. He also highlighted some of the data supporting the discussion.

Can you discuss the Type C Meeting with the FDA and how Passage will use that feedback going forward?

This was a fantastic meeting from a lot of different perspectives. The goal of the meeting was to expand our current trial from just FTD-GRN patients to also include FTD patients who have a different mutation, a mutation called the 

 mutation, and this would be the first time that we've seen that a development program has used a gene therapy beyond just the population that is deficient in that 1 gene. The reason that we feel very excited about this approach is there is good preclinical evidence that raising progranulin can ameliorate a pathology called TDP-43 pathology. It's a cellular pathology. It happens in certain neurodegenerative diseases such as FTD with the 

 mutation, such as sporadic amyotrophic lateral sclerosis. If you can get to very high levels of progranulin in preclinical models, you can ameliorate TDP-43 pathology, and thereby ameliorate the neurodegeneration. We haven't seen before gene therapies raising a protein or an enzyme level and using that approach beyond just the genetically affected patient. In that sense, this type of approach is more like an oncology product, where you have a target, you start out within a certain cancer, and then you approach other tumor types where that mechanism might be beneficial. 

We shared with the FDA the preclinical evidence that raising progranulin could help in 

, and then we also shared with them our ongoing safety data, as well as our target engagement or efficacy data. We were very pleased that the FDA was completely aligned with our approach. I will be honest, the data that we shared with them was progranulin levels at 6 months that are up to a level of 27. The normal range in patients is about 3 to 8. We shared with them levels that were very high. FTD patients with the 

 mutation actually start out at a slightly higher level of progranulin because they're not deficient in it like the GRN patients are. So we expect that we'll get to even higher levels in FTD-

 patients. There's no literature on any toxicity from getting to high levels of progranulin and we came to agreement with the FDA that we are going to start FTD-

 patients at the exact same dose that we're using for FTD-GRN patients. What that tells us is that, like us, the FDA was not concerned about even getting to slightly higher levels than 27 of progranulin. For us, this was a very important signal not just for the potential efficacy of the program, but it also validated our study of the effects of progranulin and whether there could be any toxicity from higher levels. It really validated that as well.

Keith Fargo, PhD

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