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Chief medical officer, Ultragenyx Pharmaceuticals

Eric Crombez, PhD, senior vice president and chief medical officer of Ultragenyx Gene Therapy, discussed indications the company is targeting. 

Addressing Unmet Needs With Gene Therapy 

The chief scientific officer and chief medical officer of Ultragenyx Gene Therapy discussed the company’s future research in gene therapies. 

Selecting AAV Manufacturing Platforms 

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

Sarepta Therapeutics’ delandistrogene moxeparvovec-rokl (marketed as Elevidys), an adeno-associated virus (AAV) vector-based gene therapy for patients with Duchenne muscular dystrophy (DMD), was originally 

 under an accelerated approval pathway for a limited indication on June 22, 2023: ambulatory patients aged 4 to 5 years with DMD and a confirmed mutation in the DMD gene, excluding patients with any deletion in exon 8 and/or exon 9.

 Later, on June 20, 2024, the FDA approved the gene therapy for use in a broader indication: ambulatory patients (via traditional approval) and nonambulatory patients (via accelerated approval) with a confirmed mutation in the 

 gene who are 4 years of age or older and who do not have any deletion in exon 8 or exon 9 in the gene.

Elevidys is the most recent of several new options to come into the DMD paradigm within recent years, joining other treatments option such as exon-skipping therapy. Although these treatments are disease-modifying and have the potential for a transformative impact, none of them are curative, and they each carry their own risks. Furthermore, the uptake of Elevidys by the community is just beginning.

Nevertheless, in observance of World Duchenne Awareness Day, held annually on September 7, 

 has reached out to several experts to learn about the real-world experience of gene therapy’s use in DMD thus far. Insights from experts interviewed by 

 spoke to John Brandsema, MD, a pediatric neurologist in the Division of Neurology at Children’s Hospital of Philadelphia, about how the FDA’s approval of Elevidys changed the treatment landscape for DMD, how the experience of integrating the gene therapy into clinical practice has gone so far, and how doctors should help patients and families choose the right treatment option for DMD going forward. Brandsema explained how Elevidys fits into the rapidly expanding landscape of care for the disease, noting that the therapy offers patients the opportunity to get back a functional, although truncated, version of the gene that is mutated and nonfunctional in their own genome. He then went over the known safety risks of the therapy, as well as potential risks that are not yet confirmed. He emphasized the need for more long-term data, especially for older patients, as many patients treated thus far have been on the younger end of the spectrum.

Brandsema also discussed issues of access to Elevidys and other treatment options for DMD, noting that not all of the options are universally covered by patients' insurance and that some of the precautions and infrastructure that need to be in place to treat patients with gene therapy slow down the rate at which new patients can receive Elevidys. He also discussed the importance of age of treatment, noting that early treatment may help prevent further neurodegenerative effects of the disease, and as such comes with a sense of urgency, but that healthcare providers want to be able to provide the product to all patients and families who are interested, both those who are younger and older. As such, making decisions can be a balancing act. Brandsema also touched on the potential to combine multiple treatment options, such as gene therapy and exon-skipping therapy, for subsequent treatment of the same patients. He noted, however, that this may prove challenging from the perspective of insurance coverage and from the perspective of monitoring for adverse events (AEs), as the ability to attribute AEs to one treatment or the other may be confounded.

Brandsema discussed the gene therapy for DMD.

Elevidys: Balancing Risks and Rewards

Making Decisions in the Face of Rapidly Expanding Treatment Options

In addition to the new therapeutic options for DMD that have been approved over the past 5 or so years, a large number of clinical trials for novel DMD therapeutics, such as gene-editing therapies, are currently ongoing. As such, patients and their families may not only choose between FDA-approved options, but also between enrolling in one of several active clinical trials, as well.

 spoke to Barry J. Byrne, MD, PhD, the chief medical advisor of Muscular Dystrophy Association (MDA) and a physician-scientist at the University of Florida, to get his perspective on both the real-world experience with Elevidys’ integration into clinical practice and his view on treatment decision-making in the aforementioned world of new commercial and investigational treatment options. Byrne emphasized that this is a difficult time for decision-making with the number of options available and that doctors will need to play an active role in helping patients and their families to pick the treatment path that is right for them. He discussed several promising investigational treatments that are being evaluated by various companies and institutions right now and pointed out that the potential for combination treatments may expand the breadth of decision-making even further. Byrne also noted the importance of work being done by several muscular dystrophy advocacy groups, such as the 

, to distribute relevant educational information and materials to the patient community.

Byrne discussed the gene therapy for DMD.

Making Decisions for DMD Treatment

Limitations of Current Therapies and the Promise of Gene Therapy to Address Unmet Needs

Besides gene therapy, exon-skipping therapy is one of the primary approaches for treating DMD, with 4 FDA-approved drugs available; although, they only cover about 30% of patients because of specific genetic mutation requirements, according to a conversation 

 had with Emma Ciafaloni, MD, who serves as a professor of neurology and pediatrics at University of Rochester Medical Center.

In a news network interview, Ciafaloni told 

 that these treatments require weekly IV infusions, but advancements in next-generation exon-skipping drugs may lead to more effective therapies with less frequent dosing. In addition, Ciafaloni said that significant progress is being made in gene replacement therapies, where mini or microdystrophin genes are engineered to be small enough for delivery via AAV vectors, potentially offering a one-time IV infusion solution for broader patient populations.

Focusing on gene therapy and exon skipping medications, an expert on Duchenne muscular dystrophy discusses current and emerging treatment options.

Gene Therapy for Treatment of Duchenne Muscular Dystrophy

Efforts in the Duchenne Community to Educate Patients on Gene Therapy

, Michael Kelly, PhD, the chief scientific officer at CureDuchenne, and Deborah Miller, the CEO and founder of CureDuchenne, discussed a webinar focused on a new treatment for DMD, hosted by the organization in English and Spanish for the Duchenne community after the FDA approved the expansion label for Elevidys.

 The duo talked about how Diana Castro, MD, a neuromuscular specialist at the Neurology & Neuromuscular Care Center, shared her insights about its mechanism and the practical realities of treatment administration in the webinar. The webinar discussion emphasized the importance of educating both clinicians and families about the drug’s benefits and risks. In the discussion, Kelly highlighted the important role of physicians' experiences and the ongoing efforts of pharmaceutical companies to streamline drug access for patients.

During the conversation, Miller expressed her initial surprise and optimism about the expanded approval of Sarepta’s gene therapy, emphasizing the essential need for more treatment options in the DMD community. Both Kelly and Miller stressed the importance of patient choice in treatment, especially in a disease as progressive as DMD. Although they celebrated the progress made, they acknowledged the limitations of current gene therapy and shared their organizations' commitment to furthering research, including exploring new approaches like nonviral gene therapies and exon-skipping technologies.

The chief executive officer and the chief scientific officer at CureDuchenne talked about a recent webinar that discussed the broad FDA approval of a gene therapy for Duchenne muscular dystrophy, highlighting patient choice and the ongoing efforts to improve treatments.

Broad FDA Approval of Gene Therapy Expands Treatment Choices for Duchenne Muscular Dystrophy: Debra Miller & Michael Kelly, PhD

On the whole, it is an exciting time for the field of neuromuscular disease, as more and more disease-modifying treatments for devastating disorders like DMD become available to patients, and an even greater number are in or entering clinical trials. Although this is reason for optimism, the lack of an approved therapy that is curative and the different risks associated with the different treatment modalities, renders the decision-making process for treatment paths more complicated than ever for treating physicians, patients, and their families. 

As an addendum to the interviews with Brandsema and Byrne, 

 asked each whether they had any messages to share with the clinician and patient communities for World Duchenne Awareness Day this year.

“I would first like to wish everyone in the DMD community a very happy World Duchenne Awareness Day,” Brandsema said. “I think that we’ve come a long way as a community in terms of having new hope for a different experience of this disease based on both our strides with genetically-targeted as well as muscle-targeted therapies, but we still have a lot of work to do together as a community to have the best possible life lived with DMD.”

“World Duchenne Awareness Day is really an opportunity for us as a provider community to reflect on all the new options there are for treatment,” Byrne said. “I think it will be fun to celebrate those developments—and the treatment landscape keeps improving. I think the provider community certainly welcomes that as do patients because it will ultimately really improve the lives of all those living with DMD and Becker muscular dystrophy, so we’re excited to contribute to that celebration.”

REFERENCES
1. Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy. News release. Sarepta Therapeutics. June 22, 2023. Accessed September 6, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene
2. Sarepta Therapeutics Announces Expanded US FDA Approval of ELEVIDYS to Duchenne Muscular Dystrophy Patients Ages 4 and Above. News release. Sarepta Therapeutics, Inc. June 20, 2024. Accessed September 6, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-us-fda-acceptance-efficacy?_ga=2.242068545.254033713.1708093077-1826905377.1708093076
3. Global Nonprofit CureDuchenne to Host Informational Webinars Following FDA Label Expansion of Sarepta Therapeutics’ Gene Therapy, ELEVIDYS. News Release. CureDuchenne. Published June 21, 2024. Accessed September 6, 2024. https://cureduchenne.org/general/global-nonprofit-cureduchenne-to-host-informational-webinars-following-fda-label-expansion-of-sarepta-therapeutics-gene-therapy-elevidys/

In honor of World Duchenne Awareness Day, held September 7, several experts have provided their insights on the real-world experience of gene therapy’s use in Duchenne muscular dystrophy.

Real-World Experience With Duchenne Muscular Dystrophy Gene Therapy

Biomarker data collected in the phase 1 GLEAN clinical trial (NCT04735471) evaluating Adicet Bio’s ADI-001, an investigational allogeneic chimeric antigen receptor (CAR)-engineered gamma delta T-cell therapy, for the treatment of B-cell malignancies, indicates the therapy’s potential to treat autoimmune disease, according to the company.

In lymph node biopsies from patients treated in the study, a mean exposure of 236,701 CAR T-cells per million across all dose levels was observed. Furthermore, CAR T-cells comprised 27% to 64% of total cellular material as measured by ddPCR in evaluable biopsies from patients treated at the 1x10

 dose level. In situ detection of granzyme B also indicated a “robust” activation profile. Analysis of secondary lymphoid tissue also revealed complete depletion of CD19+ B-cells alongside ADI-001 tissue trafficking and activation.

“These results clearly support the potential of ADI-001 and Adicet’s off-the-shelf gamma delta CAR T-cell platform, by demonstrating robust trafficking and complete B-cell depletion in tissue, while providing superior exposure of ADI-001 in secondary lymphoid tissue compared to published third-party data reported for alpha-beta CAR T therapies,” Blake Aftab, PhD, the chief scientific officer of Adicet Bio, said in a statement.

 “Together, the totality of our findings provide multiple levels of evidence highlighting the significant advantages of our approach and present a compelling opportunity for ADI-001 to extend B-cell targeting into tissues, as we look to address a range of autoimmune diseases in the clinic.”

Adicet currently has programs for ADI-001 in lupus nephritis (LN), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and antineutrophil cytoplasmic autoantibody associated vasculitis (AAV). Clearance of investigational new drug applications have been obtained from the FDA for each of these indications.

 The company expects to begin clinical trial enrollment activities for SLE, SSc, and AAV before the end of 2024. Based on expectations for site initiation and patient enrollment, initial clinical results may be announced in the first half of next year.

In a United States Securities and Exchange Commission (SEC) filing from September 10, 2024, Adicet stated its intention to strategically shift its focus for the development of ADI-001 to autoimmune diseases, including the aforementioned indications.

 The company also stated its intent to explore additional autoimmune disease indications for ADI-001 in the near-term future. As a result of the strategic reprioritization, the company noted that it would be discontinuing enrollment activities for patients with mantle cell lymphoma (MCL) in GLEAN. Although, the company has separately stated that it did not view the results in MCL as disappointing, according to FirstWord Pharma.

“Across all doses, 10 evaluable patients with MCL that were treated with ADI-001 demonstrated an overall response rate of 80%, a complete response rate of 60%, with a median duration of complete response of 17.5 months as of August 22, 2024,” the company pointed out in the SEC filing.

 “Patients were heavily pretreated with a median of 3 prior lines of therapy and 30% of patients had progressed on prior CAR-T.”

A phase 1 clinical trial (NCT06375993) for ADI-001 in LN is currently active, but not yet recruiting, according to its clinicaltrials.gov page, which was most recently updated on June 5, 2024. Notably, in June 2024, the FDA granted fast track designation to ADI-001 for treating relapsed/refractory class III or class IV LN.

“We believe ADI-001 has best-in-class potential for autoimmune diseases and we are excited about the opportunity to expand ADI-001 clinical development beyond LN to include patients with SLE, SSc and AAV,” Chen Schor, the president and chief executive officer of Adicet Bio, said in an August 2024 statement.

 “We have initiated startup activities at multiple clinical sites and expect to begin enrolling patients with LN in our phase 1 study in the third quarter of 2024.”

REFERENCES
1. ADI-001 clinical biomarker data demonstrate robust tissue trafficking and complete B-cell depletion in secondary lymphoid tissue. News release. Adicet Bio, Inc. September 19, 2024. Accessed September 24, 2024. https://investor.adicetbio.com/news-releases/news-release-details/adi-001-clinical-biomarker-data-demonstrate-robust-tissue
2. Adicet reports second quarter 2024 financial results and provides business updates. News release. Adicet Bio, Inc. August 13, 2024. Accessed September 24, 2024. https://investor.adicetbio.com/news-releases/news-release-details/adicet-reports-second-quarter-2024-financial-results-and
3. United States Securities and Exchange Commission Form 8-K. Adicet Bio, Inc. September 10, 2024. Accessed September 24, 2024. https://investor.adicetbio.com/static-files/45f3f5de-47ac-41cb-b2c7-2a59784e9e4c
4. Adicet joins industry trend by redirecting cell therapy to autoimmune diseases. News article. Anna Bratulic, FirstWord Pharma. September 11, 2024. Accessed September 24, 2024. https://firstwordpharma.com/story/5894359
5. Adicet Bio Receives FDA Fast Track Designation for ADI-001 in Lupus Nephritis. News release. Adicet Bio, Inc. June 5, 2024. Accessed September 24, 2024. https://www.businesswire.com/news/home/20240605481965/en/Adicet-Bio-Receives-FDA-Fast-Track-Designation-for-ADI-001-in-Lupus-Nephritis

In lymph node biopsies from patients treated in the study, a mean exposure of 236,701 CAR T-cells per million across all dose levels was observed.

Biomarker Data from Oncology Trial for Adicet Bio’s Gamma Delta T-cell Therapy ADI-001 Indicates Potential for Use in Autoimmune Disease

Vironexis Biotherapeutics has received clearance of its investigational new drug (IND) application from the FDA for VNX-101, an adeno-associated virus (AAV) vector-based gene therapy, enabling a phase 1/2 clinical trial in CD19+ acute lymphoblastic leukemia.

VNX-101 is intended to transduce cells of the liver, causing them to express a transgene coding for a bispecific T-cell engager. This T-cell engager, which binds to CD19 on tumor cells and CD3 on T-cells, is intended to facilitate the targeted killing of the cancer cells by endogenous T-cells. It is based on the company’s TransJoin platform, which it is also working on applying to a variety other cancers through different investigational products; these other therapeutic candidates currently remain in preclinical development. The announcement of the IND clearance also coincides with the company’s exit from stealth, and follows a $26 million round of seed financing.

“We’re excited to launch Vironexis from stealth and reveal our noteworthy progress advancing AAV-delivered T-cell immunotherapy,” Samit Varma, the cofounder and chief executive officer of Vironexis, said in a statement.

 “Our novel technology builds on the power of T-cell immunotherapy while overcoming key shortcomings and challenges of existing approaches such as chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies. We believe we have the opportunity to dramatically improve upon the safety, efficacy and durability of these drug classes, while streamlining manufacturing and significantly lessening the burden of treatment for patients. Our focus on execution has yielded an expansive pipeline and a clinic-ready lead program in just 3 years. We’re working as quickly as possible to transform the future of cancer treatments for patients.”

In light of the IND clearance, Vironexis anticipates initiation of the planned phase 1/2 trial within the final quarter of this year. According to Vironexis, VNX-101 will be the first AAV vector-based immunotherapy for the treatment of cancer to enter clinical trials. Preclinical research regarding technology key to the TransJoin platform, carried out by Timothy Cripe, MD, PhD, the chief of the division of pediatric hematology/oncology/bone and marrow transplant at Nationwide Children’s Hospital, and cofounder and board member of Vironexis, and colleagues, was previously published in Science Advances in 2022.

“In summary, we propose that long-term stable expression of biotherapeutics achievable by gene transfer can be leveraged to solve both the problem of fluctuating drug levels inherent to traditional administration routes and the cumbersome mechanics that accompany continuous intravenous infusions,” Cripe and colleagues wrote in the journal publication.

 “For cancer, the advantage of our strategy is not only the single therapeutic administration rather than frequent clinic and hospital visits but also the prospect of long-term, consistent pressure on tumor cells that could address persistent micrometastatic disease that mediates relapse. We also developed a companion TransSkip on-switch that enables on-demand expression for scenarios in which only short-term or intermittent expression is preferable. These technologies conceptually open a broad new area of gene therapy to solve therapeutic challenges extending well beyond the correction of single-gene disorders.”

Notably, VNX-101 is not the only viral vector-based gene therapy in general to be applied to cancer.

 (Adstiladrin), a nonreplicating adenovirus vector-based gene therapy that contains a transgene for interferon alfa-2b protein, was approved by the FDA in 2022 for the treatment of adult patients with high-risk, Bacillus Calmette-Guerin-unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. In 2024, Ferring 

launched 3 new postmarketing clinical trials

REFERENCES
1. Vironexis Biotherapeutics launches with FDA clearance of IND application for first-ever clinical trial of an AAV-delivered cancer immunotherapy. News release. Vironexis Biotherapeutics. September 12, 2024. Accessed September 17, 2024. https://vironexis.com/vironexis-biotherapeutics-launches-with-fda-clearance-of-ind-application-for-first-ever-clinical-trial-of-an-aav-delivered-cancer-immunotherapy/
2. Cripe TP, Hutzen B, Currier MA, et al. Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics. Sci Adv. 2022;8(28):eabm1890. doi: 10.1126/sciadv.abm1890
3. Phase 4 study evaluating use of Adstiladrin® (nadofaragene firadenovec-vncg) in real-world setting. News release. Ferring Pharmaceuticals. January 24, 2024. Accessed September 17, 2024. https://ferringusa.com/?press=phase-4-study-evaluating-use-of-adstiladrin-nadofaragene-firadenovec-vncg-in-real-world-setting
4. Ferring adds three new studies to non-muscle invasive bladder cancer clinical trial program with Adstiladrin® (nadofaragene firadenovec-vncg). News release. Ferring Pharmaceuticals. April 16, 2024. Accessed September 17, 2024. https://www.businesswire.com/news/home/20240415649389/en/Ferring-Adds-Three-New-Studies-to-Non-Muscle-Invasive-Bladder-Cancer-Clinical-Trial-Program-With-ADSTILADRIN%C2%AE-nadofaragene-firadenovec-vncg

VNX-101 is intended to transduce cells of the liver, causing them to express a transgene coding for a bispecific T-cell engager.

Vironexis Biotherapeutics’ AAV Vector-Based Immunotherapy VNX-101 Cleared for US Trial in Acute Lymphoblastic Leukemia

This is the second part of an interview with Jeffrey Chamberlain, PhD. For the first part, 

Although the FDA's approval of Sarepta Therapeutics’ delandistrogene moxeparvovec-rokl (marketed as Elevidys) for Duchenne muscular dystrophy (DMD) revolutionized the field of neuromuscular disease, much work remains to be done. At the 

2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference

, held March 3-6, in Orlando, Florida, numerous presentations were given on new approaches to treating DMD and real world use of Elevidys itself.

 spoke with Jeffrey Chamberlain, PhD, Professor, Neurology and Medical Genetics, and Adjunct Professor, Biochemistry, and McCaw Endowed Chair of Muscular Dystrophy at University of Washington, about which presentations stood out to him at the conference. Chamberlain noted studies covering safety risks of Elevidys and research that may be useful in addressing these risks.

 Were you excited to see any specific talks or trends in research at MDA this year?

There were a number of really exciting presentations made at the meeting. The advances that are coming along are not only in the study of different types of muscular dystrophy and the mechanisms that are leading to these diseases, but also different approaches for therapies. With my own interest being in gene therapy, I tend to gravitate towards the talks on gene therapy. There's a lot of exciting developments there. There's many different approaches now for gene therapy, even for DMD, but also increasingly for other types of muscular dystrophy. There were several very exciting talks about new mouse models and new, larger animal models for different types of muscular dystrophy. There's also a nice combination of basic mechanistic studies and how some of the newer therapeutics relate to that. [There are] some studies on new biomarkers for different types of muscular dystrophy that are really important for doing clinical studies because often the changes in actual strength of muscular dystrophy patients will change fairly slowly so having a biomarker, particularly a serum biomarker, can be a really fantastic way to get a preview of whether your interventions are having an impact. 

But one of the exciting things is there have been developments in small molecule drugs that are having an impact on different types of muscular dystrophy; oligonucleotide therapeutics, particularly antisense therapeutics, that are having impacts; as well as new viral vectors and things of that nature. One of the things I thought was particularly exciting was some developments in lentiviral technology. Lentiviral vectors have traditionally just been used in stem cell therapies, particularly hematopoietic stem cell therapies. But there was a development by the lab of Doug Millay, PhD, [associate professor, UC Department of Pediatrics] where he's been able to make a myotropic version of a lentiviral vector that's looking remarkably effective at delivering large genes to muscle stem cells. I think that's going to be an important complement to many of these other therapies that are coming along.

What about the research on the real-world use of Elevidys?

Even though we now have an approved gene therapy for DMD, it's not a perfect drug. It seems to be the best thing so far and we're very excited about that. But there were a number of talks about some adverse events (AEs) that have been seen in some of these trials. One of the challenges for the muscular dystrophies is that even though we can now use these AAV vectors to deliver genes to muscle, it requires extraordinarily high doses, on the level of about 100 times higher doses than you need for liver gene therapy or other things like that. That's been associated in some patients (certainly not in all the patients) with some serious AEs, mostly related to activation of the innate immune response. 

So there were discussions about which patients has that been seen in? What are the early signs of these adverse events? What are the best ways to get in there and try to reduce problems that may be associated with that? Then there were also several presentations on ways to maybe overcome that. One of the more exciting areas, I think, is that there are new generations of delivery vehicles; not only new types of AAV vectors, but also new lentiviral vectors that may be effective. We're hoping that these more potent delivery vehicles will allow us to lower the dose. I think that's going to be important for reducing some of the serious AEs that have been seen in the muscle gene therapy trials.

This transcript has been edited for clarity.

Click here to view more coverage of the 2024 MDA Conference.

REFERENCE
Muscular Dystrophy Association Announces Recipient of 2024 MDA Legacy Award for Achievement in Research, is Jeffrey Chamberlain, Ph.D., Leading Professor in Gene Therapy. News release. January 30, 2024. https://finance.yahoo.com/news/muscular-dystrophy-association-announces-recipient-145900986.html

Jeffrey Chamberlain, PhD, McCaw Endowed Chair of Muscular Dystrophy at University of Washington, highlighted studies presented at MDA's 2024 conference.


Ongoing Research Seeks to Address Challenges With Muscular Dystrophy Gene Therapy

Ractigen Therapeutics has received orphan drug designation (ODD) from the FDA for RAG-18, its investigational small activating RNA (saRNA) that is currently in preclinical development for the treatment of cases of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) caused by any mutation in the 

Notably, the therapy previously received a rare pediatric disease designation from the FDA in July 2024. According to Ractigen, it is the first saRNA therapy to receive both designations from the agency.

RAG-18 is intended to function through targeted activation of the 

 gene in muscle cells, leading to increased production of utrophin, the protein encoded by UTRN. Because utrophin is structurally and functionally similar to dystrophin, the protein that is deficient in patients with DMD, it is expected that its upregulation will provide clinical benefit. The activation takes place through RNA activation (RNAa), Ractigen’s platform technology designed to enable increased expression of endogenous genes through the targeting of gene regulatory domains with saRNAs. RAG-18 was administered via subcutaneous injection in preclinical research with the use of the company’s lipid-conjugated oligonucleotide (LiCO) technology.

“Receiving FDA ODD marks a pivotal achievement for RAG-18,” Long-Cheng Li, MD, the founder and chief executive officer of Ractigen Therapeutics, said in a statement.

 “Combined with the recent rare pediatric disease designation, it reflects the groundbreaking work we’re doing with RNAa and reinforces our commitment to making a real difference in the lives of those affected by rare diseases. This recognition fuels our determination to push forward with RAG-18’s development, aiming to bring innovative and life-changing treatments to DMD and BMD patients around the world.”

Ractigen presented cell line and mouse model data related to RAG-18 at the 2023 meeting of the Oligonucleotide Therapeutics Society (OTS), held October 22 to 25, in Barcelona, Spain.

 In skeletal muscle-derived cell lines, it was found that promoter-targeted saRNAs induced the expression of human utrophin mRNA and protein. Furthermore, lead saRNA candidates were evaluated for efficacy in a mouse model of DMD with knock-in of the human UTRN promoter (hUTRNp KI/KI x MDX mice), and the induction ability was validated in this model.

“In summary, our work provides initial evidence that saRNAs could be delivered to skeletal muscles and heart to activate endogenous utrophin gene,” first author Wei-Hsiang Lin and colleagues wrote in the poster presented at the conference.

 “Treatment of MDX mice bearing human UTRN promoter with a lead saRNA ameliorated muscle damage. Our approach could represent a novel and translatable therapeutic strategy for DMD and BMD caused by any mutation of the DMD gene.”

Ractigen’s pipeline includes a number of other saRNA therapies for various indications.

 The furthest along in development is RAG-01, which has entered a phase 1 clinical trial for the treatment of non-muscle invasive bladder cancer (NMIBC). It is intended to activate the expression of a relevant tumor suppressor gene that is usually silenced in bladder cancer cells.

“FDA investigational new drug (IND) application approval for RAG-01 is a major achievement for Ractigen and a significant advancement for saRNA technology worldwide,” Li said in April 2024, when the therapy received IND clearance in the United States.

 “This first-in-class saRNA therapy harnesses the power of RNAa to target the 

 gene, offering a promising new option for patients with limited treatment choices. This approval validates the potential of RAG-01 as a leading saRNA therapy and strengthens our position as innovators in RNA-based treatments.”

REFERENCES
1. Ractigen Therapeutics announces U.S. FDA orphan drug designation (ODD) granted to RAG-18 for the treatment of Duchenne muscular dystrophy and Becker muscular dystrophy. News release. August 22, 2024. Accessed September 5, 2024. https://www.ractigen.com/ractigen-therapeutics-announces-u-s-fda-orphan-drug-designation-odd-granted-to-rag-18-for-the-treatment-of-duchenne-muscular-dystrophy-and-becker-muscular-dystrophy/
2. Lin WH, Pan XJ, Duan CL, Liu KS, Kang M, Li LC. Therapeutic development of saRNA for Duchenne muscular dystrophy by targeted activation of utrophin. Presented at: 2023 meeting of the Oligonucleotide Therapeutics Society (OTS), held October 22 to 25, in Barcelona, Spain. Poster #P134
3. Ractigen Therapeutics. Our Pipeline. Website. Accessed September 5, 2024. https://www.ractigen.com/pipeline/
4. Ractigen Therapeutics announces FDA approval for RAG-01, a first-in-class saRNA therapy for BCG-unresponsive NMIBC. News release. April 26, 2024. Accessed September 5, 2024. https://www.ractigen.com/ractigen-therapeutics-announces-fda-approval-for-rag-01-a-first-in-class-sarna-therapy-for-bcg-unresponsive-nmibc/

Notably, the therapy previously received rare pediatric disease designation from the FDA in July 2024.

Eric Crombez, MD

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