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Caroline Diorio, MD, FRCPC, FAAP, an attending physician at the Cancer Center at Children's Hospital of Philadelphia, discussed a study she coauthored that was recently published in Blood.

Noninflammatory Neurotoxicity Events in Patients Receiving CAR-T

The attending physician at the Cancer Center at Children's Hospital of Philadelphia discussed a study she coauthored that was recently published in Blood.

Caroline Diorio, MD, FRCPC, FAAP, on Noninflammatory Neurotoxicity Events in Patients Receiving CAR-T

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

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.

Expanding Frontotemporal Dementia Gene Therapy to Both GRN and C9orf72 Mutations

This is the second part of an interview with Daniela van Eickels, MD, PhD, MPH. For the first part, 

Over the past 1 to 2 years, many small biotech companies joined the race to bring chimeric antigen receptor T-cell (CAR-T) therapy and other cell therapy modalities to autoimmune disease. Although, some large, established pharmaceutical companies, such as Bristol Myers Squibb (BMS), have also thrown their hats into the ring.

 interviewed Daniela van Eickels, MD, PhD, MPH, the vice president and head of medical affairs for BMS’s Cell Therapy Organization, about the company's plans for developing CAR-T products in autoimmune disease. She noted that BMS will be presenting data from 1 of its ongoing CAR-T trials in autoimmune disease at the 2024 American College of Rheumatology (ACR) Convergence, which will be held November 14 to 19, in Washington, DC. Van Eickels also discussed the importance of established players like BMS in pushing the field forward.

 Are there any specific cell therapy products in development for autoimmune disease now that you can speak about?

BMS has a robust development strategy in autoimmunity and we are currently exploring how we can bring designs to patients with severe respiratory lupus, to systemic sclerosis patients, to patients with inflammatory idiopathic myositis, but also to patients with neuroinflammatory diseases like multiple sclerosis. We have a lead candidate for this, this is CD19 NEX-T, which is a product that brings our experience from our best-in-class product, lisocabtagene maraleucel (liso-cel, marketed as Breyanzi), and the CD19 construct that we are using there, and a new manufacturing process that balances speed and reliability and aims to allow us to have even shorter turnaround time, increase capacity of the manufacturing, and also slightly adapt the cell composition of the final product in order to optimize patient outcomes. We currently have 2 multicohort studies underway with CD19 NEX-T, where we are investigating the safety and tolerability and effectiveness of CD19 NEX-T in patients with, on the one hand side, rheumatologic indications, like lupus,  sclerosis, and myositis, and on the other hand, the neurologic field, in our case, different forms of multiple sclerosis.

Is there anything you can share about the data BMS will be presenting at the ACR Convergence in November?

We will be presenting our first disclosure of preliminary results from 1 of the studies: the rheumatology program. The data will be presented by our primary investigator, Georg Schett, MD, the vice president of research and a professor of internal medicine at Friedrich-Alexander University Erlangen-Nürnberg, Germany. The session will be part of the cellular therapy section on November 17, at 4pm. We are very excited that we have the expertise of Professor Schett as a primary investigator to the program, as he has already a lot of experience investigating the mechanism of a deep immune reset in autoimmune diseases, and we're very much looking forward to this presentation.

Is there anything else you would like to share with our audience?

I think, generally speaking, we are very, very excited about the concept of deep immune reset. It's something that we are driving with utmost urgency, knowing that there are currently patients that are really suboptimally treated. We hope that by accelerating [this approach] we will really bring a real value to those patients. This is something that we really need to execute together with scientific experts, clinicians, and the patients that go on our studies. This is where we see the biggest value of an established player like BMS bringing that all together and also using our expertise in cellular therapies from other areas.

REFERENCE
1. Taking ACTioN. Bristol Myers Squibb. Website. Accessed October 6, 2024. https://www.bms.com/researchers-and-partners/areas-of-focus/our-research-in-immunology/taking-action.html

Daniela van Eickels, MD, PhD, MPH, the vice president and head of medical affairs for Bristol Myers Squibb’s Cell Therapy Organization, also discussed the company’s planned presentation at ACR Convergence 2024.

The Role of Established Pharmaceutical Companies in Bringing Cell Therapy to Autoimmune Disease

Manufacturing of adeno-associated virus (AAV) vector-based gene therapy products is a complex and expensive process with many steps. As such, companies working on development and manufacture of gene therapy products are often looking for new tools to streamline their workflows.

the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting

, held May 7 to 10, 2024, in Baltimore, MD, 

 Verdot shared information about their FlexiPro™ Chrom platform, which is intended to address a variety of bioprocessing needs. After the conference, 

® reached out to Sebastien Lefebvre, MSc, the vice president of R&D at Verdot, to learn more.

 My name is Sebastien Lefebvre, and I am vice president of R&D at Verdot. I have over 32 years of experience across several related fields including biopharmaceutical, electronics, and custom industrial engineering. For the last 20+ years, I have worked at Verdot leading their product and application development programs. I hold 2 MSc degrees in Mechanical Engineering and Biology.

Can you give us some background information about Verdot?

Verdot is a bioprocessing technology company, specializing in downstream purification including chromatography and filtration. It was founded in 1950 to provide custom design and manufacturing for industrial applications. In the 1980’s we started to see a need for customized equipment from the emerging biopharmaceutical industry. In 1988, we developed the first chromatography columns with motorized axial compression. This started our long history of collaboration with biopharma and contract development and manufacturing organizations (CDMOs) that has continued to this day. We have over 35 years of experience in the design and manufacturing of tailored single- and multi-use purification technologies through sustainable engineering. We have a strong commitment to quality, security of supply, and sustainability.

At Verdot, we are a dedicated, close-knit team of bioprocessing engineers and scientists. Our headquarters and manufacturing facilities are in Riom, located right in the heart of France.

What is the FlexiPro platform and how is it unique?

The FlexiPro™ platform consists of our single-use good manufacturing practice (GMP) purification systems, including the FlexiPro™ Chrom and the FlexiPro™ TFF. One of the unique features of the platform is the interchangeable pump-head design, which enables a single system to cover multiple process scales.

I would say that the inspiration for the FlexiPro™ platform came from listening to our customers’ needs and translating those needs into an agile design. In 2015, we developed a precursor to the FlexiPro™ Chrom system that only offered 2 flow ranges, which were designed to meet the requirements for monoclonal antibody and vaccine workflows. During the following year, several customers with gene therapy applications commented that the system hardware met their requirements with precise flow control, the shallow linear gradient capabilities, and dual wavelength fraction collection; however, their applications required much smaller volumes and flow ranges. Leaning into our collaborative style, we added the Very Low Flow Kit with 1/8" ID tubing and the Ultra Low Flow Kit, with its 1/16” ID tubing capable of working with an 8mL column. The resulting design was the basis for the current FlexiPro™ Chrom system.

This multirange capability, enabling customers to scale up or down, or cover multiple steps, with 1 system, is what makes the FlexiPro™ platform unique. Let me quickly walk through a scenario using the FlexiPro™ TFF system: After harvest and clarification of AAV, the product will need to be concentrated, for example, from 1000 L down to 20 L. To accomplish this in an acceptable time (~5-6 hours), it will require a large filter and a high flowrate, let’s say 60 LPM. The FlexiPro™ TFF system with the Very High Flow Kit covers this need. Further downstream, after chromatography unit operations, the product may require buffer exchange before moving to fill-finish. The same FlexiPro™ system can be equipped with the Very Low Flow pump head in just a few minutes, enabling diafiltration with the Very Low Flow Kit which has a very small void volume.

The FlexiPro™ platform provides uncompromising performance since the same high level of precision flow rate control is maintained regardless of the flow kit used, and maintain accurate dilution and gradient control, and pressure control, for Chrom and TFF systems, respectively.

Offering a high-performance system is not sufficient if the flow kits can't be delivered on time. During the COVID-19 pandemic, we were able to deliver flow kits in a timely manner due to the strength of our supply chain, while our competitors’ delivery dates stretched out into many months. Today, we have set our supply chain targets to be able to deliver flow kits with a very short lead time.

True to our collaborative spirit and approach, our customers have direct access to our R&D and process automation experts, as well as their designated project manager. We often assist our customers during process development and the first GMP run to ensure their success.

Click here to view more coverage of the 2024 ASGCT Annual Meeting.

Sebastien Lefebvre, MSc, the vice president of R&D at Verdot, discussed the company's unique platform.

Verdot's FlexiPro Chrom Platform Helps Address Bioprocessing Needs for Gene Therapy Manufacturing

This interview originally appeared on our sister site, 

The chief research officer of the Muscular Dystrophy Association discussed the upcoming MDA Clinical and Scientific Conference, which will be held March 16-19, in Dallas, Texas.

Sharon Hesterlee, PhD, on MDA 2025 as a Mixer for Strategies and Collaboration

"Our goal is really about community—bringing together all these different facets, from clinical care to research, to create incredible momentum."

The Muscular Dystrophy Association (MDA) will hold the annual MDA Clinical and Scientific Conference for 2025 from March 16 to 19 in Dallas, Texas. The 4-day event will gather scientific and medical professionals, patients, and advocacy groups to discuss and share the latest advances in the field of neuromuscular disorders. Research pertaining to the range of neuromuscular disorders, from amyotrophic lateral sclerosis (ALS), to Duchenne muscular dystrophy, to spinal muscular atrophy, to limb-girdle muscular dystrophy, to myasthenia gravis, to Charcot-Marie-Tooth disease, and more will be represented at the meeting.

Furthermore, there will be session tracks featured on topics including strategies for regenerating muscle and nerve tissue, new insights into disease mechanisms, clinical experience in gene therapy, access and reimbursement, and clinical trial readouts. Notably, MDA's 2024 Clinical and Scientific Conference was the largest global gathering of the neuromuscular disease community, with 1492 in-person and 567 virtual attendees from over 30 countries. Those who are registered with MDA may partake in the virtual meeting in 2025 at no-cost or may register in-person at the patient/caregiver rate until allotted spots are filled.

In anticipation of the upcoming meeting, 

, reached out to Sharon Hesterlee, PhD, the chief research officer of the Muscular Dystrophy Association, to discuss the primary focus areas of the 2025 conference, particularly in muscle regeneration and ALS research. Hesterlee also spoke about how the conference addresses the challenges of workforce diversity and training in neuromuscular specialties. She also talked about the roles of advocacy groups and allied health professionals in shaping the discussions at the upcoming meeting.

Click here to register for the upcoming 2025 MDA Conference

REFERENCE
1. Registration Now Open for the 2025 MDA Clinical & Scientific Conference Featuring the Latest Innovations in Neuromuscular Disease Research and Care with Global Leaders, March 16-19 in Dallas, TX. News Release. MDA. July 30, 2024. Accessed October 24, 2024. https://www.mda.org/press-releases/2024/registration-now-open-for-the-2025-mda-clinical-and-scientific-conference-featuring-the-latest-innovations-in-neuromuscular-disease-research-and-care-with-global-leaders-march-16-19-in-dallas-tx

Caroline Diorio, MD, FRCPC, FAAP

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