
BALTIMORE – Drugmakers and researchers at the American Society of Gene & Cell Therapy's annual meeting from May 7 to 11 reported data on gene therapies they're developing for a variety of rare diseases. Below are brief reports on data readouts investigators presented on potential treatments for neuronopathic mucopolysaccharidosis type II, pyruvate kinase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis type VI, and glycogen storage disease type Ia.
Regenxbio's RGX-121
Laura Pisani, Regenxbio's clinical development lead, on Tuesday confirmed that the company plans to seek accelerated approval from the US Food and Drug Administration for its investigational gene therapy, RGX-121, for neuronopathic mucopolysaccharidosis type II (nMPS II).
Regenxbio plans to file a biologics license application in the second half of the year that includes data on how D2S6 biomarker levels change in cerebrospinal fluid (CSF) following RGX-121 administration. The company hopes to establish the D2S6 biomarker, a glycosaminoglycan and component of heparan sulfate, as a surrogate endpoint reasonably likely to predict clinical benefit with RGX-121 in nMPS II patients, she said.
"There's no security," Pisani said of the company's ability to establish D2S6 as a surrogate biomarker; however, she pointed to recent comments from Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, indicating the agency's openness to using the accelerated approval pathway to get rare disease gene therapies to market faster. "There seems to be a wave of change," Pisani added.
MPS II, also called Hunter syndrome, is caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), which results in an accumulation of glycosaminoglycans within lysosomes. That buildup leads to damage that affects physical and neurological development. Regenxbio aims to address this with RGX-121, which is designed to deliver a functional version of the IDS gene to the central nervous system.
Rockville, Maryland-based Regenxbio previously said it would consider taking RGX-121 through the accelerated approval pathway and submit data on its activity in nMPS II patients from a Phase I/II/III trial, dubbed CAMPSIITE. As of January 2023, Regenxbio had enrolled 15 patients between 4 months and 5 years of age with nMPS II, a severe form of the condition, into the Phase I/II portion of this open-label, single-arm, dose-escalation study.
Patients who have received the gene therapy in this study continue to show sustained clinical and biomarker improvements nearly a year after treatment, Pisani said presenting an interim data readout on Tuesday.
Researchers observed dose-dependent reductions in glycosaminoglycans found in CSF. They also found that levels of D2S6 decreased and approached normal levels in the highest-dose cohort, which was sustained 48 weeks post-treatment. The highest dose tested in the Phase I/II part of the study is the dose the firm is taking into the pivotal Phase III portion.
Most patients who received either of the two higher doses in the Phase I/II study have either discontinued intravenous enzyme replacement therapy (ERT), which is a standard treatment for the condition, or remained off of it. In the highest-dose cohort, three of five patients discontinued ERT, and one is ERT-naive.
Neurodevelopmental assessments have indicated continued skill acquisition or at least stability in most of the treated patients, with improvements potentially dependent on the extent of neurological deficits at baseline.
"It is very important to note that we cannot have the same expectations in patients who are dosed early with conserved cognitive function and patients who are dosed later and with more deteriorated cognitive function," Pisani said. She didn't disclose what clinical endpoint Regenxbio would use in a confirmatory trial if the firm is successful in its accelerated approval bid for RGX-121.
RGX-121 is given to patients through an image-guided intracisternal injection. "It allows widespread biodistribution to the CNS," Pisani said. "It's also possible to be done in an interventional radiology suite, at least here in the US."
In cases when a patient can't receive an intracisternal injection, an intracerebroventricular injection will be available as a backup method. One patient in the Phase I/II portion of the CAMPSIITE trial needed this latter mode of administration.
Telethon Institute of Genetics and Medicine's Mucopolysaccharidosis Type VI Gene Therapy
Nicola Brunetti-Pierri of the Telethon Institute of Genetics and Medicine in Pozzuoli, Italy, reported follow-up data from four patients with the autosomal recessive mucopolysaccharidosis type VI (MPS VI) who received an investigational gene therapy within an ongoing Phase I/II trial. The open label, dose-escalation, multicenter clinical study is assessing the safety and efficacy of a single intravenous infusion of AAV8.TBG.hARSB, a recombinant adeno-associated virus serotype 8 vector expressing the human arylsulfatase B (ARSB) gene under the control of a liver specific promoter.
MPS VI is a progressive disease due to ARSB gene mutations. It causes inflammation and scarring of tissues and organs, as well as skeletal abnormalities. Heart disease and airway blockage are common causes of death in MPS VI patients. Those with severe forms of the disease may only live until late childhood or adolescence.
The four patients were in the high-dose cohort and received 6 x 1012 gene copies per kilogram body weight of the therapy, which is meant to counter the accumulation of glycosaminoglycans (GAG) that occurs in multiple organs in patients with the disorder. Over a median follow-up of 48 months, the patients, ages 5 to 10, showed sustained serum ARSB activity with no loss of transgene, a modest increase in urinary GAG, and no significant changes in pulmonary function and endurance, as measured by the six-minute walk test and the three-minute stair climb.
The investigators chose to restart standard-of-care enzyme replacement therapy (ERT) in one patient, due to a rise in GAG levels without an accompanying drop in serum ARSB roughly two and a half years after initially receiving the gene therapy. When asked what could have made this patient different than the others, Brunetti-Pierri said this remains unknown and cautioned against drawing firm conclusions from such a small patient cohort.
Despite restarting ERT in one patient, none of the participants experienced any adverse events over the study period, nor did they encounter any issues related to cardiac function, as measured by echocardiogram. Liver and spleen sizes also remained within the reference ranges. While the liver of one patient did slightly increase in size during the study period, it remained within the normal range.
Overall, according to the investigators, the data showed that a single intravenous administration of AAV8.TBG.hARSB was generally safe and effective, supporting liver-directed gene therapy for MPS VI.
Rocket Pharmaceuticals' RP-L301
A Rocket Pharmaceuticals-sponsored Phase I clinical trial of RP-L301, a lentiviral-mediated gene therapy for the rare hemolytic anemia pyruvate kinase deficiency (PKD), showed a favorable safety profile and increased hemoglobin production, with no need for post-engraftment transfusions up to 36 months following treatment.
PKD is caused by mutations in the PKLR gene and can lead to anemia, an enlarged spleen, and iron buildup, which can be life-threatening in severe cases. RP-L301 targets hematopoietic stem and progenitor cells in patients who have undergone spleen surgery. Two adult and two pediatric patients with severe PKD have so far been treated and have two years of follow-up data.
Data presented at the meeting showed that RP-L301 has conferred sustained meaningful clinical improvement across both cohorts. None of the patients have required blood cell transfusion following neutrophil engraftment and all patients showed improved anemia and bilirubin biomarkers as well as improved hemoglobin levels, with three of the four patients having normalized hemoglobin levels up to three years post-infusion. Both adult patients also reported improved quality of life, as measured by increases in their FACT-An and SF-36 scores.
Preparations for a Phase II trial, which will seek to recruit approximately 10 patients, are now underway. That trial is expected to launch later this year or sometime next year.
Orchard Therapeutics' Lenmeldy
Orchard Therapeutics' Lenmeldy (atidarsagene autotemcel) preserves cognitive and motor development in pediatric patients with metachromatic leukodystrophy (MLD), particularly among those treated pre-symptomatically, according to the latest trials results of the gene therapy presented during the Presidential Symposium on Wednesday.
The US Food and Drug Administration earlier this year approved Lenmeldy for certain children with MLD, making it the first gene therapy treatment for the rare neurometabolic disorder. MLD is caused by a deficiency of the enzyme arylsulfatase A (ARSA), leading to an accumulation of sulfatides in cells that damage the brain and nervous system. The gene therapy has also been approved by the European Commission, UK Medicines and Healthcare Products Regulatory Agency, and Swiss Agency for Therapeutic Products, where it is branded as Libmeldy.
Lenmeldy comprises patients' autologous hematopoietic stem cells, which are genetically modified ex vivo with lentiviral vectors to encode a functional version of the ARSA gene. The one-time gene therapy has a $4.25 million wholesale acquisition price, making it the most expensive commercially available drug.
The FDA approval was based on a review of an earlier analysis of this data, including 37 children with MLD who had been monitored for up to 12 years. Now, the latest long-term results presented at the conference were based on an analysis of 39 patients with early-onset MLD who were treated with Lenmeldy across two clinical trials and an expanded access framework. Researchers compared these patients' outcomes against natural history data from 49 untreated patients.
The earliest treated patient had 12 years of follow-up data, but the median length of follow-up was 6.76 years.
According to the study results, the risk of severe motor impairment or death was significantly reduced in pre-symptomatic late-infantile and pre-symptomatic early-juvenile patients, and there was a slower progression of decline in early-symptomatic, early-juvenile patients, said Alessandro Aiuti, deputy director of clinical research at the San Raffaele Telethon Institute for Gene Therapy, also known as SR-Tiget, in Milan, Italy.
Twenty-five of 26 pre-symptomatic late-infantile and pre-symptomatic early-juvenile patients maintained their ability to walk as of their most recent follow-up visit, and most patients demonstrated preservation of cognitive abilities and speech. By contrast, most natural history patients experienced rapid motor and cognitive decline and loss of speech, according to researchers.
The gene therapy was most effective in patients who received it early in their disease course, before symptom onset, Aiuti noted. "It will be very important to achieve early diagnosis and early treatment," he said.
In terms of gene expression, researchers observed restoration of ARSA activity in peripheral blood mononuclear cells in all patients by three months after treatment and restoration in cerebrospinal fluid by three to six months, which was sustained through follow-up. All patients had stable multilineage engraftment of the gene-corrected cells.
Ultragenyx's DTX401
Patients with glycogen storage disease type Ia (GSDIa) have been able to decrease their standard therapy after receiving an experimental gene therapy, with improved clinical outcomes sustained for up to five years, according to clinical trial data presented Thursday.
GSDIa is a metabolic disorder in which, due to deficiency in the enzyme glucose 6-phosphatase (G6Pase), patients are unable to produce normal glucose levels, which can result in hypoglycemia. The standard treatment is an oral glucose replacement therapy, such as consuming uncooked cornstarch daily.
Ultragenyx is developing DTX401 as an intravenously infused gene therapy that delivers a functional copy of the G6PC gene, which encodes G6Pase.
Researchers during a session on in vivo gene therapies presented long-term efficacy data on 12 patients with GSDIa who participated in an open-label, dose-escalation Phase I/II trial and follow-up study, in which patients were monitored for up to 5.5 years. At baseline, patients were prescribed anywhere between 170 grams to 405 grams of cornstarch per day, John Mitchell, associate professor in the endocrinology and metabolism division's pediatrics department at McGill University Health Center in Canada.
By one-year post-treatment, which was the study period for the Phase I/II trial, patients' total daily cornstarch consumption on average decreased 68 percent from baseline. In the follow-up study, patients sustained a reduction in daily cornstarch intake, on average, by 71 percent from baseline.
As of their recorded last visit, daily cornstarch doses were reduced or stable in 10 of the 12 subjects, and half of all participants had reduced their daily cornstarch dose frequency by half or more. There were two participants that reported an increase in the frequency of daily cornstarch doses they were prescribed, but by five years post-treatment, one ultimately had a 58 percent decrease in daily cornstarch intake overall and the other had a 49 percent decrease.
Mitchell stressed a need for physicians to closely monitor patients who receive this gene therapy, adjusting their cornstarch intake and their diet accordingly.
"We have to make sure that the patients are taking a balanced diet and still maintaining their glucose control," he said.
Shanghai Vitalgen BioPharma's VGN-R08b & VGR-R01
Researchers presented early data on two therapeutic programs in development at the Chinese biopharmaceutical company Shanghai Vitalgen BioPharma during a session on in vivo gene therapies Thursday.
Shanghai Vitalgen's VGN-R08b seeks to treat acute neuronopathic Gaucher disease, a severe form of the rare genetic disorder caused by mutations in the GBA1 gene. Those mutations result in a deficiency in the lysosomal enzyme GCase, which is necessary to metabolize glycolipids. VGN-R08b, which is administered through an intracerebroventricular injection, aims to deliver a functional copy of the GBA1 gene.
Six infants have been treated so far in an ongoing dose-escalation trial. GCase activity in cerebrospinal fluid increased significantly in all patients, and Lyso-GL1 — a metabolite of GCase that's known to accumulate in those with Gaucher disease — decreased significantly.
"As early as one week after dosing, you see significant elevation of GCase activity," said Shin-Shay Tian, senior VP of discovery research at Shanghai Vitalgen. However, she noted that when it comes to changes in levels of Lyso-GL1, two patients' levels have fluctuated, initially decreasing as expected but then increasing. She said investigators will continue to monitor whether the Lyso-GL1 levels stabilize.
Neurological symptoms like neck hyperextension, peripheral hypertonia, and myoclonic seizures also have improved in severity or disappeared within six months of follow-up. Of four patients who had the most severe symptoms, and who had previously been taking another therapy called ambroxol to control their neurological symptoms, all discontinued it within six months of receiving the gene therapy.
At the same session on Thursday, Shiyi Yin, a postgraduate at Beijing Tongren Hospital-Capital Medical University, presented preliminary Phase I/II trial data on VGR-R01, an investigational gene therapy that Shanghai Vitalgen is developing for bietti crystalline dystrophy (BCD). The rare and severe ocular disease is caused by mutations in the CYP4V2 gene. Shanghai Vitalgen is preparing for a Phase III trial of the gene therapy and is discussing the study protocol with the Center for Drug Evaluation at the National Medical Products Administration in China.
In the open-label, single-arm, dose-escalation Phase I/II trial, patients received a subretinal injection of the gene therapy, which is designed to deliver a functional copy of the CYP4V2 gene to one eye. As of late 2023, 12 patients with BCD had received the gene therapy and have been monitored for a median of 128 days, or about 18 weeks.
Eight of the 12 patients experienced a significant improvement in visual acuity in the treated eye compared to baseline, and all patients experienced an average increase in a mobility test designed to assess functional vision. Four patients who had started the trial with very low vision at baseline were among the responders, Yin said.
All patients experienced at least one treatment-emergent adverse event. The two types of events determined to be related to the gene therapy, keratic precipitates and eye inflammation, were considered mild to moderate in severity, according to Yin. The most common of the adverse events were related to the administration procedure and were also mild or moderate.
Forge Biologics' FBX-101
Five patients who received Forge Biologics' experimental gene therapy for infantile Krabbe disease (IKD), which is typically characterized by muscle weakness, among other symptoms, are now able to walk independently, according to data from a late-breaking abstract presented Friday.
IKD, also known as globoid cell leukodystrophy, is a fatal neurodegenerative disorder caused by mutations in the GALC gene that encodes the enzyme galactosylceramidase, without which patients cannot form myelin, which is needed to protect nerve cells. FBX-101 aims to treat the disease by delivering a functional version of the GALC gene to cells within the central and peripheral nervous system and is administered to patients intravenously.
In Forge Biologics' Phase I/II trial, REKLAIM, investigators tested two immune modulation strategies for administering the gene therapy, and treated patients while they were either myeloablated or immune suppressed. All patients received the gene therapy at least 21 days after undergoing infusion umbilical cord blood transplantation, which is currently considered standard care as a way to stop IKD progression, but that doesn't improve the decline in motor function that is also associated with the disease.
On Friday, Maria Escolar, Forge's chief medical officer, reported results from the first five IKD patients who were treated with a low dose of FBX-101 as part of this dose-escalating trial. Two patients were treated during myeloablation, while three were treated during immune suppression. Neither group of patients had any serious treatment-related adverse events in the follow-up period, which ranged from six to 24 months. Both groups of patients achieved normal or improved gross motor skills.
The firm plans to begin treating patients with a higher dose of the gene therapy as part of the clinical trial this year, Escolar said.
BRL Medicine's BRL-101
An investigational treatment that uses CRISPR to edit a gene related to hemoglobin could improve outcomes for patients with transfusion-dependent beta-thalassemia (TDT), researchers said in a presentation Friday.
BRL Medicine's BRL-101 uses CRISPR to edit the BCL11A gene in patients' autologous CD34-positive cells, which typically represses fetal hemoglobin. By reducing the gene's expression, the treatment aims to reactivate fetal hemoglobin, which functions similarly to the adult version, BRL Medicine CEO Biao Zheng said during a session on cell and cell-based gene therapies.
TDT is a genetic blood disorder caused by mutations in the HBB gene that encodes for hemoglobin, which, when functional, is the protein that carries oxygen throughout the body. In the US and UK, Vertex Pharmaceuticals and CRISPR Therapeutics' gene-editing therapy Casgevy (exagamglogene autotemcel) has been approved as a treatment for TDT and sickle cell disease utilizing a similar approach, editing the BCL11A gene to increase production of fetal hemoglobin.
So far, BRL Medicine has dosed nine TDT patients with an intravenous infusion of BRL-101 in an open-label, single-arm Phase I/II trial. Separately, six TDT patients have received the gene therapy in investigator-initiated clinical trials. Across these 15 patients — all of whom had genetically confirmed TDT but different HBB genotypes — their average levels of fetal hemoglobin and total hemoglobin increased significantly after treatment. In fact, five months after treatment, the proportion of red blood cells that expressed fetal hemoglobin in peripheral blood reached 96 percent and continued to increase to 98 percent to 99 percent afterward.
Since receiving BRL-101, all patients have achieved independence from blood transfusions, a standard treatment for TDT. The earliest-treated patient has been free of transfusions for nearly four years, Zheng said.
Four patients experienced serious adverse events, however. Decreased platelet count was the only event observed so far that researchers believe could be related to BRL-101. Most other events were caused by the myeloablative busulfan conditioning, such as shock, febrile infection, and veno-occlusive liver disease. All of the events resolved.
Rocket Pharmaceuticals' RP-L201
Researchers on Friday presented updated follow-up data on Rocket Pharmaceuticals' gene therapy for severe leukocyte adhesion deficiency-I (LAD-I), which is currently under priority review at the US Food and Drug Administration.
Rocket's RP-L201, which the FDA has said it expects to issue a decision on by June 30, engineers patients' autologous CD34-positive hematopoietic stem cells ex vivo with a lentiviral vector carrying a functional version of the ITGB2 gene. The firm has said it will brand the gene therapy as Kresladi (marnetegragene autotemcel).
The FDA initially said it would make its decision by March 31 but announced a three-month extension to review additional chemistry, manufacturing, and controls information.
The gene therapy is designed as a treatment for severe LAD-I, an immunodeficiency caused by mutations in the ITGB2 gene and is characterized by frequent bacterial and fungal infections. A curative treatment already available is allogeneic hematopoietic stem cell transplants, but these are not widely accessible due to the limited availability of eligible donors, said Donald Kohn, professor of pediatrics and microbiology, immunology, and molecular genetics at the University of California, Los Angeles, during a session on cell and cell-based gene therapies.
In the open-label, single-arm Phase I/II trial, data from which Rocket submitted to the FDA as part of its biological license application, researchers enrolled nine patients of at least 3 months of age with the disease. Eight of the patients have been monitored for at least two years post-treatment, and the remaining patient has nearly 22 months of follow-up data.
All nine of the patients have lived, and all sustained restoration of polymorphonucleocyte expression of CD18, a protein that includes a component encoded by ITGB2, suggesting durable correction of the gene. Compared to the pre-treatment period, researchers observed a marked reduction in patients' infection-related hospitalizations, prolonged hospitalizations of a week or longer, and significant infections that required hospitalization or intravenous antimicrobials. There was also improvement in disease-related skin and periodontal lesions and wound healing.
"Marne-cel clearly changed the course of severe LAD-I, with all patients surviving in the absence of allo stem cell transplant," Kohn said.
Regenxbio's RGX-202
A gene therapy under development at Regenxbio for Duchenne muscular dystrophy (DMD), RGX-202, was safe, well tolerated, and significantly improved patients' outcomes, according to an interim data readout Saturday from the ongoing Phase I/II Affinity Duchenne clinical trial.
DMD, a rare, inherited progressive muscle weakness disorder, is caused by mutations in the DMD gene, which in turn results in a deficiency of dystrophin protein. RGX-202 comprises a transgene that encodes key elements of naturally occurring dystrophin and expresses a microdystrophin protein, similar to the naturally occurring shortened dystrophin that protects muscles from degenerating.
In the Affinity Duchenne study, boys aged 4 through 11 with genetically confirmed DMD received either a low or high dose of the one-time adeno-associated virus gene therapy and were followed for 52 weeks. As of the May 3 data cutoff, three participants at the low dose and two at the high dose had robust transgene expression for at least three months after treatment. Participants given the low dose had microdystrophin levels between approximately 11 percent and 83 percent, while those given the high dose showed microdystrophin levels of approximately 21 percent and 76 percent.
All patients tolerated the therapy well. According to Jahannaz Dastgir, senior director of clinical development at Regenxbio, who presented the results, there were no serious adverse events, and patients did not have reductions in serum creatine kinase, a biomarker of muscle disease.
While this Phase I/II study's primary endpoints are safety and tolerability, researchers also tracked the gene therapy's preliminary efficacy. In that regard, patients showed significant improvements in functional assessments.
In videos shown during Dastgir's presentation, one patient who received the high dose of RGX-202 went from struggling to balance on one foot at baseline to comfortably hopping around on one foot at nine months post-therapy. Another video showed a 10-year-old patient at six months post-treatment with increased confidence and speed in climbing steps compared to baseline, as well as improvement in standing from the supine position, which is indicative of better stability.
The firm is now enrolling patients into the study's expansion phase, at the high dose, which will be the dose used in the pivotal study of RGX-202. "The initiation of a pivotal trial is expected in late third quarter of this year or early fourth quarter of this year," Dastgir said, "and Regenxbio plans to use RGX-202 microdystrophin as a surrogate endpoint likely to predict clinical benefit."