Victoria Johnson

Although the road has not been smooth, 2023 was witness to unprecedented progress in the treatment landscape of Duchenne muscular dystrophy (DMD), with the approval of Sarepta Therapeutics’ delandistrogene moxeparvovec (SRP-9001; Elevidys) earlier this summer.

 Despite the milestone approval, only a small percentage of patients with DMD currently stand to benefit from the therapy. There is much work to be done in the field to improve care for all patients with DMD as well as to answer questions about the gene therapy’s long-term durability, efficacy, and safety.

Elevidys is an adeno-associated virus (AAVrh74) gene therapy delivering microdystrophin. It was approved for ambulatory pediatric patients aged 4 through 5 years with a confirmed mutation in the DMD gene, excluding patients with any deletion in exon 8 and/or exon 9. Its approval was based on data from Study 102 (NCT03769116), Study 103 (ENDEAVOR; NCT04626674), and Study 101 (NCT03375164). Study 102 failed its primary North Star Ambulatory Assessment (NSAA) end point although subgroup analyses revealed the strongest clinical benefit in boys aged 4-5 years, supporting the approval in only that narrow population.

“There's still significant unmet need. While the gene therapy approval is thrilling for all of us, there's still a narrow window of 4- to 5- year-olds. We have many people younger than 4 and many people over the age of 5, that are still in need of treatment. So, I think while the landscape is really amazing, and building every single day... time matters to these people. Time means progression of disease,” Pat Furlong, BSN, RN, founding president and chief executive officer, Parent Project Muscular Dystrophy (PPMD), told 

Sarepta recently announced topline data from its global, pivotal, phase 3 EMBARK study (Study SRP-9001-301; NCT05096221), which was also found to have failed its NSAA primary endpoint. The EMBARK study’s key primary end point was change in scores at week 52 compared to placebo, the difference in which was not statistically significant. Treated patients improved 2.6 points on NSAA total score compared to 1.9 points in placebo-treated patients for a 0.65-point difference (n = 125; 

 = .24). Key secondary end points of change in time to rise (TTR; 

= .0048) compared to placebo were statistically significant across all age groups. Although the complete data are not yet available, Sarepta also stated that other outcome measures such as stride velocity 95th centile (SV95C) and time to ascend 4 steps also demonstrated a consistent trend in treatment benefit in favor of ELEVIDYS.

“This drug is likely to be the most potent treatment method available today, although it is not as robust as many had hoped. Nonetheless, approval sets the stage for intensive analysis of the long-term effects of this gene therapy and will hopefully spur increased research and testing of improved next generation gene therapies," Jeffrey Chamberlain, PhD, professor and director, Sen. Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Washington School of Medicine told 

The data have somewhat dampened the enthusiasm of many patients and advocates that were hoping the gene therapy might be a permanent, revolutionary treatment for DMD. The data are current only available from 12 months of follow-up, and it remains to be seen how many years of durability current gene therapies will really yield—for both DMD and all fields with recent approvals of this relatively new mode of therapy.

“Some of the concerns that we have today are with these very high dose serious adverse events, that's one of the challenges with Duchenne. When you think that the body is comprised of 40 to 60% muscle – the amount of AAV that we need to put in the body in order to target all the different muscle groups is extremely high... Changing the actual route of administration may hold significant promise. And it's these data that are going to guide some of our thinking next year beyond where we are today,” Michael Kelly, PhD, chief scientific officer of CureDuchenne, told 

As dystrophin is the largest known human gene, the carrying capacity of AAV limits the feasibility of gene therapy to correct the mutated gene. Most companies including Sarepta have instead designed their gene therapies to express microdystrophin instead, but future research and new mechanisms of action and delivery may show greater efficacy and safety. Part of the difficulty in showing a definitive benefit with gene therapy is the heterogeneity of disease seen in patients with DMD and advocates are also pushing for the design of more accurate and precise outcome measures.

“We don't see the full effect in that time period of clinical trials. We have to look for extended access programs, or certainly the cumulative data over time, to see both the durability and efficacy of these cell and gene therapies. I’m very thrilled about where we are, and hopeful for where we're going next,” Furlong said.

The criteria of Elevidys’ approval exclude most patients with DMD, including patients aged 6 - 7 years that were included in the pivotal trials of the therapy. Sarepta is continuing to work toward expanding the therapy’s approval to include older children and has cited the statistically significant changes in EMBARK’s secondary endpoints, seen across children aged both 4 - 5 years old and 6 - 7 years old, as support for an expanded approval. It remains to be seen whether further data from the study will support the move. Regardless of gene therapy’s potential future expansion to older patients, the treatment landscape for DMD in general must expand to provide care to patients that may not qualify for the newest, novel therapies.

Besides age, anti-AAV antibodies (nAB) remain a barrier gene therapy, whether patients are nAB+ from wild-type infections or prior AAV gene therapy. The latter becomes more of a concern as more AAV gene therapies are approved or enter the investigational pipeline with no current means of suppressing nABs, preventing patients from receiving other, possibly more efficacious, gene therapies in the future.

“Is there a window in which we need to treat early and is there some way we can manage people who have progressed past that window instead of just saying, well, they're not eligible for these drugs? What can we do for them? It may be a really different strategy. With gene therapy, where you're putting back the function of this gene that's missing, you can't put it into muscle that's not there. I think that's where we should be looking at combinations of things like stem cell therapy or other creative ways where we could potentially replace muscle. So, I think we're going to have to develop some new strategies for people who progress past that therapeutic window,” Sharon Hesterlee, PhD, chief research officer, Muscular Dystrophy Association (MDA), told 

Experts and advocates in the field continue to stress that this first-of-its-kind approval is a first step to potentially curing DMD and future research will continue to build off of lessons learned with Elevidys. Other programs far along the pipeline for treating DMD include Capricor Therapeutics’ CAP-1002, an investigational allogeneic cardiosphere-derived cell therapy being evaluated in the HOPE-3 clinical trial (NCT05126758); REGENXBIO’s AAV gene therapy RGX-202 being evaluated in the phase 1/2 AFFINITY trial (NCT05693142); and Pfizer’s fordadistrogene movaparvovec AAV gene therapy being evaluated in the phase 3 CIFFREO trial (NCT04281485).

“I think we're going to have enough variety of options that everyone is going to have the potential to benefit. I think it's very exciting. The big challenge for us as a community is figuring out how do we make that work... Every step forward brings new obstacles, but you're still making progress," Hesterlee said.

Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy. News release. Sarepta Therapeutics. June 22, 2023. News release. Sarepta Therapeutics. June 22, 2023. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene

Sarepta Therapeutics announces topline results from EMBARK, a global pivotal study of ELEVIDYS gene therapy for Duchenne muscular dystrophy. News release. Sarepta Therapeutics. October 30, 2023. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-topline-results-embark-global-0

Capricor Therapeutics announces positive Type-B meeting with the FDA to discuss pathway to BLA for CAP-1002 in Duchenne muscular dystrophy. News release. Capricor Therapeutics. September 29, 2023. Accessed October 3, 2023. https://www.capricor.com/investors/news-events/press-releases/detail/261/capricor-therapeutics-announces-positive-type-b-meeting

REGENXBIO presents interim clinical data from phase I/II AFFINITY DUCHENNE™ trial of RGX-202 at 28th Annual International Congress of the World Muscle Society. News release. REGENXBIO. October 3, 2023. https://www.prnewswire.com/news-releases/regenxbio-presents-interim-clinical-data-from-phase-iii-affinity-duchenne-trial-of-rgx-202-at-28th-annual-international-congress-of-the-world-muscle-society-301946289.html

Articles

For This Year in Medicine, CGTLive looks back at a landmark first approval, the new treatment opportunities it has provided, and the unmet needs in the field it has brought to light.

After Elevidys: DMD Advocacy Past First Gene Therapy Approval

It’s no question that it has been a challenging year for biotech. Early-phase failures, unexpected adverse events, and an increasingly crowded landscape have sent some once-promising firms packing with their pipelines in hand.

Still, there’s no shortage of exciting things to come from the field of cell and gene therapy. With 26 current therapies FDA-approved,

 3 new gene therapies approved this year alone, and a 5-year pipeline filled with nearly 40 contenders,

 it’s clear that everyone should be paying very close attention to this burgeoning space.

With such an expansive pipeline comes a flood of clinical trials, and that’s where the FDA took particular action in 2022. Looking to homogenize expectations around clinical trial design and execution, the FDA released 3 separate guidance documents in 2022 focused on the following topics: gene editing, gene therapy for neurodegenerative diseases, and gene therapy umbrella trials.

Early in the year, the FDA’s Center for Biologics Evaluation and Research issued draft guidance for industry players developing gene therapy products that involve gene editing. The document reflects the concerns surrounding safety of gene-editing strategies—namely off-target effects—for the treatment of a range of disorders.

Touching on product design, manufacturing, testing, as well as preclinical safety and clinical trial design, the guidance outlines information that should be included in a sponsor’s investigational new drug application in order for the agency to effectively evaluate the investigational therapy.

The guidance primarily focused on reducing and assessing risk at every stage, including in preclinical studies, where the agency suggested that studies be designed to assess toxicity associated with delivery of the therapy, modification of the genomic structure, and expression of the gene product, as well as any off-target activity and chromosomal rearrangements, and the consequences of such.

At the clinical stage, the guidance emphasized the importance of selecting first-in-human study populations based on risk-benefit and with staggered patient enrollment to best evaluate administration of a gene editing product.

Lastly, the guidance addresses the unknown, with the FDA recommending that industry sponsors follow clinical trial participants who undergo gene editing for a minimum of 15 years to better capture both immediate and long-term safety developments that can be a direct result of gene editing, including “off-target editing, unintended consequences of on- and off-target editing, and the unknown long-term effects of on- and off-target editing,” the agency wrote.

Gene Therapy for Neurodegenerative Diseases

In October 2022, the FDA followed up by releasing a finalized guidance document for industry focused on gene therapies for neurodegenerative diseases,4 which touched on considerations for chemistry, manufacturing, and controls, as well as preclinical studies and clinical trials. Although most considerations for gene therapies in this space are similar to others, the administration of the gene therapy product requires special consideration in this population. 

The FDA acknowledged that the range of “neurodegenerative diseases” is variable and wide, advising that innovative trial designs may be more fitting in monogenic disorders with a well-characterized and consistent natural history instead of randomized, placebo-controlled trials to expedite clinical development when there is an expected, clinically meaningful treatment benefit. On the other hand, disorders with poorly understood etiology and variable natural history may benefit best from randomized, placebo-controlled trials. In all cases, the FDA encouraged sponsors to consider innovative clinical trial designs as gene therapies are fundamentally different from other drugs and should not limited for evaluation by traditional clinical trial designs.

Dealing with such a vulnerable population, the agency stressed that all participants in gene therapy trials for neurodegenerative diseases receive the best standard of care, and to this end some gene therapy products should be evaluated in conjunction with approved treatments. Participants should also be allowed to cross over to other treatment cohorts when appropriate and follow-up should continue after crossover. Concerning placebo/sham-controlled trials, the FDA said that sham procedures should be as minimally invasive as possible, and in fact, external controls may be appropriate when there is an unmet medical need, controls are not practical or ethical, populations are comparable, there is a large, expected treatment effect, and the disease course is well understood.

Eligibility should consider disease severity as part of the risk-benefit profile, and trials should first enroll adults and then pediatric patients when assessing diseases that affect both populations. Additional considerations and safeguards apply for children in these trials, including minimal risk or an acceptable risk-benefit profile.

The FDA advised that most early-phase gene therapy trials should incorporate a dose-ranging study design with dose exploration and expansion. One-time products should start with a likely therapeutic dose, so participants have a chance to benefit. These doses should be informed by preclinical studies. Some invasive gene therapy procedures should be done unilaterally before being cleared for bilateral administration.

As in other gene therapy trials, safety and immunogenicity are top concerns. To mitigate immune responses, participants should be closely monitored and cellular and humoral immune responses to the vector and transgene measured by immunoassays. Immunosuppressants may be used to minimize immune response before and after treatment, with adequate justification. Participants should continue to be closely monitored while on immunosuppressants.

While early-phase trials primarily assess safety and tolerability of gene therapy products, the FDA encouraged that trials also assess activity, efficacy, potential clinical benefit, biomarkers, and potential surrogate end points of these products to guide further clinical development. For pivotal trials, end points should be clinically meaningful and measure or predict a clinical benefit. Surrogate endpoints may be appropriate under the accelerated approval pathway when targeted well-understood underlying monogenic changes; these must be communicated with the FDA before clinical trials.

The FDA continued to recommend long-term follow-up to assess safety and durability and to collect patient experience data. It also touched on available expedited program designations, including regenerative medicine advanced therapy, breakthrough therapy, and fast track designations; accelerated approval; and priority review. Again, the FDA encouraged communication throughout the development process and highlighted meetings available, such as pre-investigational new drug (IND) meetings and INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) meetings.

Most recently, in November 2022, the FDA released final guidance for umbrella trials studying multiple versions of a cell or gene therapy product in early-phase clinical trials.

 The agency noted that these kinds of umbrella trials provide beneficial flexibility and efficiency in developing novel therapies but reinforced the need for multiple INDs, primary and secondaries, for each version of the therapy being studied. It provided recommendations for organization and structure of INDs, submission of data, and decisions regarding versions to advance to later-stage trials. Safety reporting, and therefore potential clinical holds, may affect single INDs/arms or the whole trial. Primary/secondary INDs must be updated as priorities in development shift and some product versions are dropped and others advanced. Alternative approaches are available and, if desired, the FDA urged sponsors to contact the agency.

Peter Bross, MD, chief, oncology branch, Center for Biologics Evaluation and Research,spoke about how academia and industry can work best with the FDA to ensure clear communication and efficient pathways to approval.

“When working with the FDA, it’s a matter of clear communication and transparency. We are very limited in time. We encourage sponsors, both academic and commercial industry, to request meetings. Unfortunately, sometimes we can't accommodate everyone's requests,” Bross said. “I just hope that people recognize that we have a lot of competing priorities, but we want to help and will help as best we can. In terms of how we can optimize that communication, transparency is very important.”

Approved Cellular and Gene Therapy Products. US Food and Drug Administration website. Updated November 22, 2022. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products

Gene Therapy Pipeline 3Q 2022-1Q 2027. CVS Health. Updated July 12, 2022. https://payorsolutions.cvshealth.com/sites/default/files/q3-2022-gene-therapy-treatments-approval-timelines.pdf

US Food and Drug Administration. Human Gene Therapy Products Incorporating Human Genome Editing: Draft Guidance for Industry. https://www.fda.gov/media/156894/download. Updated March 21, 2022. Accessed November 30, 2022.

US Food and Drug Administration. Human gene therapy for neurodegenerative diseases: Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-gene-therapy-neurodegenerative-diseases. Updated October 25, 2022. Accessed December 2, 2022.

US Food and Drug Administration. Studying multiple versions of a cellular or gene therapy product in an early-phase clinical trial: Guidance for industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/studying-multiple-versions-cellular-or-gene-therapy-product-early-phase-clinical-trial. Updated November 18, 2022. Accessed December 2, 2022.

With several newly approved therapies hitting the market and an overflowing pipeline, the FDA has stepped in to help keep the burgeoning world of biotech on track.

Running With Scissors: The FDA Moves to Tame Gene Therapy Drug Development

This article was originally published on 

The gene therapy etranacogene dezaparvovec (EtranaDez), now marketed as Hemgenix, has been approved by the FDA for treating adults with 

 who currently use Factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes. 

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” Peter Marks, MD, PhD, director, Center for Biologics Evaluation and Research, FDA, said in the 

. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

The FDA accepted the biologics license application (BLA) for UniQure and CSL Behring’s Hemgenix for priority review in May 2022. The BLA was supported by positive data from 54 patients with hemophilia B in the pivotal phase 3 HOPE-B trial (NCT03569891).

The HOPE-B trial met its primary endpoint of reduction in annualized bleeding rate (ABR) post-treatment compared with baseline FIX prophylactic therapy, with mean FIX activity of 39.0 IU/dL (standard deviation [SD], 18.7; range, 8.2-97.1) at 6 months post-treatment and 36.9 IU/dL (SD, 21.4; range, 4.5-122.9) at 18 months.3 The 52-week adjusted ABR for all bleeds was reduced by 64% (

= .0002) from 4.19 during the ≥ 6-month lead-in period to 1.51 during months 7-18 and there was an overall 97% reduction in mean unadjusted annualized FIX consumption.

BioMarin Prepares for PDUFA Delay for Val-Rox Hemophilia Gene Therapy

Hemgenix was well-tolerated, with no serious treatment-related adverse events (AEs), although common AEs include liver enzyme elevations, headache, mild infusion-related reactions and flu-like symptoms. No inhibitors to FIX were reported.

“The HOPE-B trial was the first phase 3 study in hemophilia B and has the largest cohort of gene therapy for hemophilia B to report to date. It is also the only trial to include participants with neutralizing antibodies to AAV and this is really unique," investigator 

, professor and head of coagulation disorders and Comprehensive Care Centre, University Hospital of Frankfurt, Germany, previously told 

Hemgenix is an adeno-associated virus gene therapy that delivers the Padua variant of the FIX gene to liver cells via an intravenous infusion. It was previously granted breakthrough therapy designation by the FDA and Priority Medicine (PRIME) regulatory initiative by the EMA. The EMA is currently reviewing a Marketing Authorization Application for EtranaDez in hemophilia B.

Earlier this year, the Institute for Clinical and Economic Review (ICER) concluded that the price of EtranaDez should be 

.4 They also suggested a cap of $1.9 million for valoctocogene roxaparvovec (val-rox; Roctavian; BioMarin) for hemophilia A.

ICER EtranaDez a B+ score for “moderate certainty” of a small or substantial health benefit and “high certainty” of at least a small net health benefit compared with factor IX prophylaxis. Primary concerns were limited long-term follow-up safety and durability data.

The BLA was supported by positive data from 54 patients with hemophilia B in the pivotal phase 3 HOPE-B trial.

FDA Approves First Gene Therapy for Hemophilia B

This article was orginially published on 

The US Food and Drug Administration (FDA) has 

 bluebird bio’s gene therapy betibeglogene autotemcel (beti-cel), now marketed as ZYNTEGLO, for adult and pediatric patients with β-thalassemia who require regular red blood cell (RBC) transfusions (transfusion dependent thalassemia; TDT).

“The FDA approval of ZYNTEGLO offers people with beta-thalassemia the possibility of freedom from burdensome regular red blood cell transfusions and iron chelation, and unlocks new possibilities in their daily lives,” Andrew Obenshain, chief executive officer, bluebird bio, said in a 

 experience multiple health issues including dizziness, weakness, fatigue, and bone abnormalities among other serious complications. Because the inherited blood disorder reduces the amount of normal hemoglobin and red blood cells, those affected aren't able to sufficiently transmit oxygen through the body.

“After more than a decade of research and clinical development, and through the perseverance of clinicians, patients, and their families, the approval of ZYNTEGLO marks a watershed moment for the field of gene therapy. As the first ex-vivo lentiviral vector gene therapy approved in the US for the treatment of people with betathalassemia, we are ushering in a new era in which gene therapy has the potential to transform existing treatment paradigms for diseases that currently carry a lifelong burden of care," Obenshain continued.

Beti-cel is an autologous, lentiviral gene therapy that delivers a modified form of the β-globin gene into patients’ hematopoietic stem cells ex vivo which are then infused back into the patient to enable corrected levels of hemoglobin production without regular RBC transfusions. The therapy will only be available at qualified treatment centers with expertise in stem cells, cell and gene therapy, and β-thalassemia.

“Today’s approval is an important advance in the treatment of beta-thalassemia, particularly in individuals who require ongoing red blood cell transfusions,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research said. “Given the potential health complications associated with this serious disease, this action highlights the FDA’s continued commitment to supporting development of innovative therapies for patients who have limited treatment options.”

ZYNTEGLO was reviewed under Priority Review and was granted Orphan Drug designation and Breakthrough Therapy designation by the FDA. The therapy is currently being evaluated in the phase 3 HGB-207 study (NCT02906202), from which recent data demonstrated transfusion independence in 20 of 22 evaluable patients (91%), including 6 of 7 patients (86%) younger than 12 years of age.

“Transfusion-dependent beta-thalassemia is associated with an intense treatment burden and significant health risks related to regular red blood transfusions and iron management,” Alexis A. Thompson, MD, MPH, Chief, Division of Hematology, Children's Hospital of Philadelphia, added. “As a clinician and an investigator in the ZYNTEGLO clinical development program, I celebrate the therapeutic potential of this treatment for patients and its implications for the field of gene therapy, all made possible through the incredible courage of patients and families who participated in the clinical trials.”

Trials investigating beti-cel, the phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies were previously under a clinical hold, lifted in June 2021, along with other programs from bluebird using the lentiviral vector BB205 including the phase 1/2 HGB-206 and phase 3 HGB210 trials of LentiGlobin for sickle cell disease.

The lentiviral vector was being investigated following the diagnosis of acute myeloid leukemia (AML) in a patient treated with bb1111 around 6 years ago in a phase 1/2 study and another suspected unexpected serious adverse reaction (SUSAR) of myelodysplastic syndrome, although these patients were not treated with ZYNTEGLO. Further investigation concluded that the MDS was a misdiagnosis and the AML was not due to the lentiviral vector.

Most recently, the FDA Cellular, Tissue, and Gene Therapies Advisory Committee cast a 

 of beti-cel in patients with TDT with a non–β0/β0 genotype, calling the efficacy of the drug "remarkable" and "life-changing". The Institute for Clinical and Economic Review (ICER) also gave beti-cel a rating of B+, concluding that therapy is superior to standard of care for patients with β-thalassemia, but the magnitude of this superiority is still uncertain due to known risks with myeloablative conditioning and unknown durability.

 in support of the company's candidate for the treatment of early active cerebral adrenoleukodystrophy (CALD), elivaldogene autotemcel (eli-cel; Lenti-D), the PDUFA date for which is September 16, 2022.

“The Cooley’s Anemia Foundation applauds the FDA’s approval of ZYNTEGLO for people with beta-thalassemia who require regular red blood cell transfusions. The availability of a one-time gene therapy which offers the possibility of transfusion independence opens up new and exciting opportunities for those who are medically eligible to receive this treatment option,” Craig Butler, National Executive Director, Cooley’s Anemia Foundation, said. “While advances in treatment have been of enormous benefit to those with beta-thalassemia, a potentially curative therapy may offer a true lifechanging experience.”

“The approval of ZYNTEGLO marks a watershed moment for the field of gene therapy," Andrew Obenshain, CEO of Bluebird Bio says. 