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Feds aim to streamline gene therapy oversight
“As the NIH, the FDA, and research entities have moved to strengthen their individual oversight efforts, some overlaps have occurred,” Dr. Collins and Dr. Gottlieb wrote Aug. 15 in the New England Journal of Medicine. “Substantial duplication has arisen in the submission of initial protocols, annual reports, amendments, and reports of serious adverse events. Originally, these overlaps – which affect no other field in biomedical research – were viewed as harmonized reporting that enabled FDA to conduct regulatory oversight while maintaining confidentiality with sponsors and allowed NIH to provide transparency with regard to the research.”
With three approved treatments – two CAR T therapies and a treatment for a genetic retinal dystrophy – and more than 700 active investigational new drug applications in front of the FDA, “it seems reasonable to envision a day when gene therapy will be a mainstay of treatment for many diseases,” according to the editorial.
To remedy the situation, NIH officials Aug. 16 posted a proposed update to NIH guidance that seeks “to reduce the duplicative oversight burden by further limiting the role of NIH and RAC [Recombinant DNA Advisory Committee] in assessing gene therapy protocols and reviewing their safety information,” Dr. Collins and Dr. Gottlieb wrote. “Specifically, these proposals will eliminate RAC review and reporting requirements to the NIH for human gene therapy protocols. They will also revise the responsibility of institutional Biosafety Committees, which have local oversight for this research, making their review of human gene therapy protocols consistent with review of other research subject to the NIH Guidelines. Such streamlining will also appropriately place the focus of the NIH Guidelines squarely back on laboratory biosafety.”
RAC was originally established in 1974 to advise the NIH director on research involving manipulation of nucleic acids, but was later expanded to review and discuss protocols for gene therapy in humans.
The proposed structure provides an opportunity “to return the RAC to the spirit in which it was founded. ... The NIH envisions using the RAC as an advisory board on today’s emerging technologies, such as gene editing, synthetic biology, and neurotechnology, while harnessing the attributes that have long ensured its transparency,” they wrote.
This latest proposal follows a suite of FDA draft guidances on gene therapies issued in July that proposed new guidance on manufacturing issues, long-term follow-up, and pathways for clinical development in certain areas.
The guidance is scheduled for publication in the Federal Register on Aug. 17.
SOURCE: Collins FS and Gottlieb S. N Engl J Med. doi: 10.1056/NEJMp1810628.
“As the NIH, the FDA, and research entities have moved to strengthen their individual oversight efforts, some overlaps have occurred,” Dr. Collins and Dr. Gottlieb wrote Aug. 15 in the New England Journal of Medicine. “Substantial duplication has arisen in the submission of initial protocols, annual reports, amendments, and reports of serious adverse events. Originally, these overlaps – which affect no other field in biomedical research – were viewed as harmonized reporting that enabled FDA to conduct regulatory oversight while maintaining confidentiality with sponsors and allowed NIH to provide transparency with regard to the research.”
With three approved treatments – two CAR T therapies and a treatment for a genetic retinal dystrophy – and more than 700 active investigational new drug applications in front of the FDA, “it seems reasonable to envision a day when gene therapy will be a mainstay of treatment for many diseases,” according to the editorial.
To remedy the situation, NIH officials Aug. 16 posted a proposed update to NIH guidance that seeks “to reduce the duplicative oversight burden by further limiting the role of NIH and RAC [Recombinant DNA Advisory Committee] in assessing gene therapy protocols and reviewing their safety information,” Dr. Collins and Dr. Gottlieb wrote. “Specifically, these proposals will eliminate RAC review and reporting requirements to the NIH for human gene therapy protocols. They will also revise the responsibility of institutional Biosafety Committees, which have local oversight for this research, making their review of human gene therapy protocols consistent with review of other research subject to the NIH Guidelines. Such streamlining will also appropriately place the focus of the NIH Guidelines squarely back on laboratory biosafety.”
RAC was originally established in 1974 to advise the NIH director on research involving manipulation of nucleic acids, but was later expanded to review and discuss protocols for gene therapy in humans.
The proposed structure provides an opportunity “to return the RAC to the spirit in which it was founded. ... The NIH envisions using the RAC as an advisory board on today’s emerging technologies, such as gene editing, synthetic biology, and neurotechnology, while harnessing the attributes that have long ensured its transparency,” they wrote.
This latest proposal follows a suite of FDA draft guidances on gene therapies issued in July that proposed new guidance on manufacturing issues, long-term follow-up, and pathways for clinical development in certain areas.
The guidance is scheduled for publication in the Federal Register on Aug. 17.
SOURCE: Collins FS and Gottlieb S. N Engl J Med. doi: 10.1056/NEJMp1810628.
“As the NIH, the FDA, and research entities have moved to strengthen their individual oversight efforts, some overlaps have occurred,” Dr. Collins and Dr. Gottlieb wrote Aug. 15 in the New England Journal of Medicine. “Substantial duplication has arisen in the submission of initial protocols, annual reports, amendments, and reports of serious adverse events. Originally, these overlaps – which affect no other field in biomedical research – were viewed as harmonized reporting that enabled FDA to conduct regulatory oversight while maintaining confidentiality with sponsors and allowed NIH to provide transparency with regard to the research.”
With three approved treatments – two CAR T therapies and a treatment for a genetic retinal dystrophy – and more than 700 active investigational new drug applications in front of the FDA, “it seems reasonable to envision a day when gene therapy will be a mainstay of treatment for many diseases,” according to the editorial.
To remedy the situation, NIH officials Aug. 16 posted a proposed update to NIH guidance that seeks “to reduce the duplicative oversight burden by further limiting the role of NIH and RAC [Recombinant DNA Advisory Committee] in assessing gene therapy protocols and reviewing their safety information,” Dr. Collins and Dr. Gottlieb wrote. “Specifically, these proposals will eliminate RAC review and reporting requirements to the NIH for human gene therapy protocols. They will also revise the responsibility of institutional Biosafety Committees, which have local oversight for this research, making their review of human gene therapy protocols consistent with review of other research subject to the NIH Guidelines. Such streamlining will also appropriately place the focus of the NIH Guidelines squarely back on laboratory biosafety.”
RAC was originally established in 1974 to advise the NIH director on research involving manipulation of nucleic acids, but was later expanded to review and discuss protocols for gene therapy in humans.
The proposed structure provides an opportunity “to return the RAC to the spirit in which it was founded. ... The NIH envisions using the RAC as an advisory board on today’s emerging technologies, such as gene editing, synthetic biology, and neurotechnology, while harnessing the attributes that have long ensured its transparency,” they wrote.
This latest proposal follows a suite of FDA draft guidances on gene therapies issued in July that proposed new guidance on manufacturing issues, long-term follow-up, and pathways for clinical development in certain areas.
The guidance is scheduled for publication in the Federal Register on Aug. 17.
SOURCE: Collins FS and Gottlieb S. N Engl J Med. doi: 10.1056/NEJMp1810628.
Key clinical point: NIH and FDA are looking to streamline gene therapy development oversight.
Major finding: The proposal would return the function of the Recombinant DNA Advisory Committee (RAC) to a function more in line with its original mission.
Study details: Full proposal details are to be published in the Federal Register on Aug. 17.
Disclosures: The agency leaders reported no relevant disclosures in the production of the proposal.
Source: Collins FS and Gottlieb S. N Engl J Med. doi: 10.1056/NEJMp1810628.
Strategies for Treating Motor Fluctuations in Parkinson’s Disease
Improved delivery of levodopa and new therapies may help to reduce off time.
MIAMI—Motor fluctuations in Parkinson’s disease can arise from more than one cause, and a clinician needs to consider a range of possibilities. Most commonly, motor fluctuations arise as a consequence of chronic levodopa therapy, though the progression of parkinsonism is a contributing factor, according to an overview presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. The pharmacokinetics of levodopa provide the basis for studying most clinical patterns of motor fluctuations, and new pharmacologic strategies are under development to improve upon existing treatment options. 
“In recent years, there have been some exciting and novel directions of Parkinson’s disease therapeutics for motor fluctuations,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan.
A Need to Improve Levodopa Delivery
Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinson’s disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. “But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.”
During its 50 years of service to the Parkinson’s disease patient, levodopa has revolutionized the identity of this disorder. It has improved longevity, disability, and overall quality of life, and it inspired
Because the short-duration response pattern is associated with benefits as brief as two to three hours per oral immediate-release dose, the focus for improving levodopa has been the use of extension therapies. Blocking the breakdown of peripheral levodopa metabolism (the mechanism for catechol-O-methyltransferase inhibition) or slowing the central metabolism of dopamine (by inhibiting monoamine oxidase-type B) join extended-release carbidopa-levodopa preparations as ways to improve upon the immediate-release product. “While these strategies do provide some level of effectiveness, the problems of irregular responsiveness and up to several hours of daily ‘off’ time haven’t been solved. ‘Off’ time still imposes a major burden on many patients living with Parkinson’s disease,” said Dr. LeWitt. Like delayed onset of effect and rapid wearing-off, levodopa-induced dyskinesias present another challenge for understanding their origin and optimal control. While new mechanisms of blocking dyskinesia are being sought, a simpler solution can be more continuous levodopa delivery so that drug concentration peaks causing involuntary movements are averted.
Future Therapies Undergoing Trials Today
Several new therapeutic approaches have been developed for dealing with the shortcomings of current therapies, especially levodopa. “The first of these options was a tube inserted through the stomach into the upper small intestine for continuous pumping of a carbidopa-levodopa microsuspension gel –quite effective but not an easy choice for most patients,” said Dr. LeWitt. Less cumbersome ways to extend levodopa effects have been the several sustained-release formulations now under development. One is a gastric-retention product, termed the “Accordion Pill,” which slowly leaches carbidopa and levodopa to enhance their pharmacokinetic absorption profile. Another treatment strategy for motor fluctuations that, like the Accordion Pill, is also in worldwide clinical trials, involves continuous subcutaneous infusion of solubilized levodopa and carbidopa. With the latter approach, the drug is administered by a small pump adjusted to optimized rate of delivery. Dr. LeWitt also described another novel way for administering levodopa for rapid entry into the bloodstream for treating “off” states. This involves an inhalation device for pulmonary uptake of a micro-particulate levodopa formulation. In a recently completed study, “off” states were reversed rapidly with this approach.
Subcutaneous apomorphine infusion has already been used for more than 30 years in treating motor fluctuations. However, just recently, a more complete story of what this adjunctive therapy offers was reported from a large-scale randomized clinical trial in Europe. A similar study is underway in the United States and might lead to availability of apomorphine infusion in the near future, said Dr. LeWitt. Another approach to motor fluctuations can be found in a drug for motor fluctuations that does not act on dopaminergic pathways. This medication is istradefylline, a selective inhibitor of adenosine A2a receptors (which are located in the same pathway targeted by deep brain stimulation). In Japan, istradefylline is marketed for reducing “off” time, and studies with this drug are planned for review in the US, said Dr. LeWitt.
For a nonpharmacologic approach to managing motor fluctuations, neurosurgical targeting of brain circuitry with deep brain electrical stimulation has had several decades of experience. Another direction of neurosurgical intervention is under investigation; this involves gene therapy to improve the efficacy of oral levodopa therapy. “Inserting into the putamen a gene for producing an increase of L-aromatic amino acid decarboxylase appears to offer a way for enhancing dopamine formation. The clinical investigation currently underway is testing whether producing this localized alteration of brain neurochemistry might succeed at attenuating motor fluctuations,” said Dr. LeWitt
“In talking to patients about their experiences with motor fluctuations, my advice is to think both about levodopa pharmacokinetics and how the patient uses levodopa (since schedule compliance, the interaction of meals, and drinking sufficient water with medications commonly contribute to these problems). Fortunately, new treatment options are on their way to help in fighting back against the limitations of levodopa therapy,” Dr. LeWitt concluded.
—Erica Tricarico
Suggested Reading
Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17:587-592.
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10);2731-2742.
LeWitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64-72.
Improved delivery of levodopa and new therapies may help to reduce off time.
Improved delivery of levodopa and new therapies may help to reduce off time.
MIAMI—Motor fluctuations in Parkinson’s disease can arise from more than one cause, and a clinician needs to consider a range of possibilities. Most commonly, motor fluctuations arise as a consequence of chronic levodopa therapy, though the progression of parkinsonism is a contributing factor, according to an overview presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. The pharmacokinetics of levodopa provide the basis for studying most clinical patterns of motor fluctuations, and new pharmacologic strategies are under development to improve upon existing treatment options.
“In recent years, there have been some exciting and novel directions of Parkinson’s disease therapeutics for motor fluctuations,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan.
A Need to Improve Levodopa Delivery
Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinson’s disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. “But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.”
During its 50 years of service to the Parkinson’s disease patient, levodopa has revolutionized the identity of this disorder. It has improved longevity, disability, and overall quality of life, and it inspired
Because the short-duration response pattern is associated with benefits as brief as two to three hours per oral immediate-release dose, the focus for improving levodopa has been the use of extension therapies. Blocking the breakdown of peripheral levodopa metabolism (the mechanism for catechol-O-methyltransferase inhibition) or slowing the central metabolism of dopamine (by inhibiting monoamine oxidase-type B) join extended-release carbidopa-levodopa preparations as ways to improve upon the immediate-release product. “While these strategies do provide some level of effectiveness, the problems of irregular responsiveness and up to several hours of daily ‘off’ time haven’t been solved. ‘Off’ time still imposes a major burden on many patients living with Parkinson’s disease,” said Dr. LeWitt. Like delayed onset of effect and rapid wearing-off, levodopa-induced dyskinesias present another challenge for understanding their origin and optimal control. While new mechanisms of blocking dyskinesia are being sought, a simpler solution can be more continuous levodopa delivery so that drug concentration peaks causing involuntary movements are averted.
Future Therapies Undergoing Trials Today
Several new therapeutic approaches have been developed for dealing with the shortcomings of current therapies, especially levodopa. “The first of these options was a tube inserted through the stomach into the upper small intestine for continuous pumping of a carbidopa-levodopa microsuspension gel –quite effective but not an easy choice for most patients,” said Dr. LeWitt. Less cumbersome ways to extend levodopa effects have been the several sustained-release formulations now under development. One is a gastric-retention product, termed the “Accordion Pill,” which slowly leaches carbidopa and levodopa to enhance their pharmacokinetic absorption profile. Another treatment strategy for motor fluctuations that, like the Accordion Pill, is also in worldwide clinical trials, involves continuous subcutaneous infusion of solubilized levodopa and carbidopa. With the latter approach, the drug is administered by a small pump adjusted to optimized rate of delivery. Dr. LeWitt also described another novel way for administering levodopa for rapid entry into the bloodstream for treating “off” states. This involves an inhalation device for pulmonary uptake of a micro-particulate levodopa formulation. In a recently completed study, “off” states were reversed rapidly with this approach.
Subcutaneous apomorphine infusion has already been used for more than 30 years in treating motor fluctuations. However, just recently, a more complete story of what this adjunctive therapy offers was reported from a large-scale randomized clinical trial in Europe. A similar study is underway in the United States and might lead to availability of apomorphine infusion in the near future, said Dr. LeWitt. Another approach to motor fluctuations can be found in a drug for motor fluctuations that does not act on dopaminergic pathways. This medication is istradefylline, a selective inhibitor of adenosine A2a receptors (which are located in the same pathway targeted by deep brain stimulation). In Japan, istradefylline is marketed for reducing “off” time, and studies with this drug are planned for review in the US, said Dr. LeWitt.
For a nonpharmacologic approach to managing motor fluctuations, neurosurgical targeting of brain circuitry with deep brain electrical stimulation has had several decades of experience. Another direction of neurosurgical intervention is under investigation; this involves gene therapy to improve the efficacy of oral levodopa therapy. “Inserting into the putamen a gene for producing an increase of L-aromatic amino acid decarboxylase appears to offer a way for enhancing dopamine formation. The clinical investigation currently underway is testing whether producing this localized alteration of brain neurochemistry might succeed at attenuating motor fluctuations,” said Dr. LeWitt
“In talking to patients about their experiences with motor fluctuations, my advice is to think both about levodopa pharmacokinetics and how the patient uses levodopa (since schedule compliance, the interaction of meals, and drinking sufficient water with medications commonly contribute to these problems). Fortunately, new treatment options are on their way to help in fighting back against the limitations of levodopa therapy,” Dr. LeWitt concluded.
—Erica Tricarico
Suggested Reading
Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17:587-592.
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10);2731-2742.
LeWitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64-72.
MIAMI—Motor fluctuations in Parkinson’s disease can arise from more than one cause, and a clinician needs to consider a range of possibilities. Most commonly, motor fluctuations arise as a consequence of chronic levodopa therapy, though the progression of parkinsonism is a contributing factor, according to an overview presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. The pharmacokinetics of levodopa provide the basis for studying most clinical patterns of motor fluctuations, and new pharmacologic strategies are under development to improve upon existing treatment options.
“In recent years, there have been some exciting and novel directions of Parkinson’s disease therapeutics for motor fluctuations,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan.
A Need to Improve Levodopa Delivery
Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinson’s disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. “But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.”
During its 50 years of service to the Parkinson’s disease patient, levodopa has revolutionized the identity of this disorder. It has improved longevity, disability, and overall quality of life, and it inspired
Because the short-duration response pattern is associated with benefits as brief as two to three hours per oral immediate-release dose, the focus for improving levodopa has been the use of extension therapies. Blocking the breakdown of peripheral levodopa metabolism (the mechanism for catechol-O-methyltransferase inhibition) or slowing the central metabolism of dopamine (by inhibiting monoamine oxidase-type B) join extended-release carbidopa-levodopa preparations as ways to improve upon the immediate-release product. “While these strategies do provide some level of effectiveness, the problems of irregular responsiveness and up to several hours of daily ‘off’ time haven’t been solved. ‘Off’ time still imposes a major burden on many patients living with Parkinson’s disease,” said Dr. LeWitt. Like delayed onset of effect and rapid wearing-off, levodopa-induced dyskinesias present another challenge for understanding their origin and optimal control. While new mechanisms of blocking dyskinesia are being sought, a simpler solution can be more continuous levodopa delivery so that drug concentration peaks causing involuntary movements are averted.
Future Therapies Undergoing Trials Today
Several new therapeutic approaches have been developed for dealing with the shortcomings of current therapies, especially levodopa. “The first of these options was a tube inserted through the stomach into the upper small intestine for continuous pumping of a carbidopa-levodopa microsuspension gel –quite effective but not an easy choice for most patients,” said Dr. LeWitt. Less cumbersome ways to extend levodopa effects have been the several sustained-release formulations now under development. One is a gastric-retention product, termed the “Accordion Pill,” which slowly leaches carbidopa and levodopa to enhance their pharmacokinetic absorption profile. Another treatment strategy for motor fluctuations that, like the Accordion Pill, is also in worldwide clinical trials, involves continuous subcutaneous infusion of solubilized levodopa and carbidopa. With the latter approach, the drug is administered by a small pump adjusted to optimized rate of delivery. Dr. LeWitt also described another novel way for administering levodopa for rapid entry into the bloodstream for treating “off” states. This involves an inhalation device for pulmonary uptake of a micro-particulate levodopa formulation. In a recently completed study, “off” states were reversed rapidly with this approach.
Subcutaneous apomorphine infusion has already been used for more than 30 years in treating motor fluctuations. However, just recently, a more complete story of what this adjunctive therapy offers was reported from a large-scale randomized clinical trial in Europe. A similar study is underway in the United States and might lead to availability of apomorphine infusion in the near future, said Dr. LeWitt. Another approach to motor fluctuations can be found in a drug for motor fluctuations that does not act on dopaminergic pathways. This medication is istradefylline, a selective inhibitor of adenosine A2a receptors (which are located in the same pathway targeted by deep brain stimulation). In Japan, istradefylline is marketed for reducing “off” time, and studies with this drug are planned for review in the US, said Dr. LeWitt.
For a nonpharmacologic approach to managing motor fluctuations, neurosurgical targeting of brain circuitry with deep brain electrical stimulation has had several decades of experience. Another direction of neurosurgical intervention is under investigation; this involves gene therapy to improve the efficacy of oral levodopa therapy. “Inserting into the putamen a gene for producing an increase of L-aromatic amino acid decarboxylase appears to offer a way for enhancing dopamine formation. The clinical investigation currently underway is testing whether producing this localized alteration of brain neurochemistry might succeed at attenuating motor fluctuations,” said Dr. LeWitt
“In talking to patients about their experiences with motor fluctuations, my advice is to think both about levodopa pharmacokinetics and how the patient uses levodopa (since schedule compliance, the interaction of meals, and drinking sufficient water with medications commonly contribute to these problems). Fortunately, new treatment options are on their way to help in fighting back against the limitations of levodopa therapy,” Dr. LeWitt concluded.
—Erica Tricarico
Suggested Reading
Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17:587-592.
Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10);2731-2742.
LeWitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64-72.
Spinal muscular atrophy added to newborn screening panel recommendations
Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which is used by state public health departments to screen newborns for genetic disorders.
Secretary of the Department of Health and Human Services Alex M. Azar II formally added SMA to the panel July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.
“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis – information that often is required to determine whether their child is eligible to participate in clinical trials.”
Adding SMA to the RUSP does not mean states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested wide variation in resources, infrastructure, funding, and time to implementation among states.
An estimated 1 in 11,000 newborns have SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brain stem and spinal cord leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the Food and Drug Administration approved nusinersen (Spinraza) for the disorder in December 2016, although the drug’s approval has raised some ethical questions.1-3
After reviewing the evidence at their February 8, 2018 meeting, the advisory committee recommended the addition of spinal muscular atrophy screening to the RUSP in a March 8, 2018, letter from committee chair Joseph A. Bocchini Jr., MD, who is a professor and the chairman of the department of pediatrics at Louisiana State University Health in Shreveport.
Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within 2 years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”
The advisory committee makes its recommendations to the HHS on which heritable disorders to include in the RUSP after they have assessed a systematic, evidence-based review assigned by the committee to an external independent group. Alex R. Kemper, MD, MPH, a professor of pediatrics at the Ohio State University and division chief of ambulatory pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of the journal Pediatrics and a member of the U.S. Preventive Services Task Force.
According to Secretary Azar’s summary in his July 2, 2018, letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”
Dr. Kemper elaborated in an interview that, “SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death but decrease the development of neurologic impairment. As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”
Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. (Other rarer cases are caused by mutations in different genes.) Without the SMN protein produced by SMN1, a person gradually loses muscle function.
A similar gene, SMN2, also can produce the SMN protein but in much lower amounts, typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein for a slower disease process.
The five types of spinal muscular atrophy are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Just over half (54%) of SMA cases are Type I, in which progressive weakness occurs over the first 6 months of life and results in early death. Only 18% of children with Type I live past age 4 years, and 68% die by age 2 years. Type 0 is rarer but more severe, usually causing fetal loss or early infant death.
Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but then experience respiratory failure and rarely reach their fourth decade. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after 1 year old or in adulthood.
Dr. Kemper’s group focused on the three types diagnosed in infancy: types I, II, and III.
Dr. Kemper emphasized in an interview that “it will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen. More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening so we not only know about outcomes in later childhood and adolescence but treatment approaches can be further refined and personalized.”
Nusinersen works by altering the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which thereby increases how much SMN protein is produced. Concerns about the medication, however, have included its cost – $750,000 in the first year and $375,000 every following year for life – and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and then once annually, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.2
Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (for example, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.2
Yet evidence to date is favorable in children with early onset. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”
Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.”
“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past 1 year of age are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of 4 million births.
At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs at $1 or less per screen.
The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University, Durham, N.C. No disclosures were provided for evidence review group members.
References
1. Gene Ther. 2017 Sep;24(9):534-8.
2. JAMA Intern Med. 2018 Jun 1;178(6):743-44.
3. JAMA Pediatr. 2018 Feb 1;172(2):188-92.
Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which is used by state public health departments to screen newborns for genetic disorders.
Secretary of the Department of Health and Human Services Alex M. Azar II formally added SMA to the panel July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.
“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis – information that often is required to determine whether their child is eligible to participate in clinical trials.”
Adding SMA to the RUSP does not mean states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested wide variation in resources, infrastructure, funding, and time to implementation among states.
An estimated 1 in 11,000 newborns have SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brain stem and spinal cord leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the Food and Drug Administration approved nusinersen (Spinraza) for the disorder in December 2016, although the drug’s approval has raised some ethical questions.1-3
After reviewing the evidence at their February 8, 2018 meeting, the advisory committee recommended the addition of spinal muscular atrophy screening to the RUSP in a March 8, 2018, letter from committee chair Joseph A. Bocchini Jr., MD, who is a professor and the chairman of the department of pediatrics at Louisiana State University Health in Shreveport.
Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within 2 years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”
The advisory committee makes its recommendations to the HHS on which heritable disorders to include in the RUSP after they have assessed a systematic, evidence-based review assigned by the committee to an external independent group. Alex R. Kemper, MD, MPH, a professor of pediatrics at the Ohio State University and division chief of ambulatory pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of the journal Pediatrics and a member of the U.S. Preventive Services Task Force.
According to Secretary Azar’s summary in his July 2, 2018, letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”
Dr. Kemper elaborated in an interview that, “SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death but decrease the development of neurologic impairment. As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”
Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. (Other rarer cases are caused by mutations in different genes.) Without the SMN protein produced by SMN1, a person gradually loses muscle function.
A similar gene, SMN2, also can produce the SMN protein but in much lower amounts, typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein for a slower disease process.
The five types of spinal muscular atrophy are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Just over half (54%) of SMA cases are Type I, in which progressive weakness occurs over the first 6 months of life and results in early death. Only 18% of children with Type I live past age 4 years, and 68% die by age 2 years. Type 0 is rarer but more severe, usually causing fetal loss or early infant death.
Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but then experience respiratory failure and rarely reach their fourth decade. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after 1 year old or in adulthood.
Dr. Kemper’s group focused on the three types diagnosed in infancy: types I, II, and III.
Dr. Kemper emphasized in an interview that “it will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen. More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening so we not only know about outcomes in later childhood and adolescence but treatment approaches can be further refined and personalized.”
Nusinersen works by altering the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which thereby increases how much SMN protein is produced. Concerns about the medication, however, have included its cost – $750,000 in the first year and $375,000 every following year for life – and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and then once annually, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.2
Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (for example, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.2
Yet evidence to date is favorable in children with early onset. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”
Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.”
“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past 1 year of age are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of 4 million births.
At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs at $1 or less per screen.
The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University, Durham, N.C. No disclosures were provided for evidence review group members.
References
1. Gene Ther. 2017 Sep;24(9):534-8.
2. JAMA Intern Med. 2018 Jun 1;178(6):743-44.
3. JAMA Pediatr. 2018 Feb 1;172(2):188-92.
Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which is used by state public health departments to screen newborns for genetic disorders.
Secretary of the Department of Health and Human Services Alex M. Azar II formally added SMA to the panel July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.
“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis – information that often is required to determine whether their child is eligible to participate in clinical trials.”
Adding SMA to the RUSP does not mean states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested wide variation in resources, infrastructure, funding, and time to implementation among states.
An estimated 1 in 11,000 newborns have SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brain stem and spinal cord leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the Food and Drug Administration approved nusinersen (Spinraza) for the disorder in December 2016, although the drug’s approval has raised some ethical questions.1-3
After reviewing the evidence at their February 8, 2018 meeting, the advisory committee recommended the addition of spinal muscular atrophy screening to the RUSP in a March 8, 2018, letter from committee chair Joseph A. Bocchini Jr., MD, who is a professor and the chairman of the department of pediatrics at Louisiana State University Health in Shreveport.
Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within 2 years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”
The advisory committee makes its recommendations to the HHS on which heritable disorders to include in the RUSP after they have assessed a systematic, evidence-based review assigned by the committee to an external independent group. Alex R. Kemper, MD, MPH, a professor of pediatrics at the Ohio State University and division chief of ambulatory pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of the journal Pediatrics and a member of the U.S. Preventive Services Task Force.
According to Secretary Azar’s summary in his July 2, 2018, letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”
Dr. Kemper elaborated in an interview that, “SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death but decrease the development of neurologic impairment. As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”
Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. (Other rarer cases are caused by mutations in different genes.) Without the SMN protein produced by SMN1, a person gradually loses muscle function.
A similar gene, SMN2, also can produce the SMN protein but in much lower amounts, typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein for a slower disease process.
The five types of spinal muscular atrophy are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Just over half (54%) of SMA cases are Type I, in which progressive weakness occurs over the first 6 months of life and results in early death. Only 18% of children with Type I live past age 4 years, and 68% die by age 2 years. Type 0 is rarer but more severe, usually causing fetal loss or early infant death.
Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but then experience respiratory failure and rarely reach their fourth decade. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after 1 year old or in adulthood.
Dr. Kemper’s group focused on the three types diagnosed in infancy: types I, II, and III.
Dr. Kemper emphasized in an interview that “it will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen. More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening so we not only know about outcomes in later childhood and adolescence but treatment approaches can be further refined and personalized.”
Nusinersen works by altering the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which thereby increases how much SMN protein is produced. Concerns about the medication, however, have included its cost – $750,000 in the first year and $375,000 every following year for life – and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and then once annually, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.2
Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (for example, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.2
Yet evidence to date is favorable in children with early onset. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”
Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.”
“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past 1 year of age are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of 4 million births.
At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs at $1 or less per screen.
The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University, Durham, N.C. No disclosures were provided for evidence review group members.
References
1. Gene Ther. 2017 Sep;24(9):534-8.
2. JAMA Intern Med. 2018 Jun 1;178(6):743-44.
3. JAMA Pediatr. 2018 Feb 1;172(2):188-92.
FDA Efforts to Advance Development of Gene Therapies
FDA Commissioner Scott Gottlieb, MD, releases a statement on the agency’s efforts to advance development of gene therapies.
Once just a theory, gene therapies are now a therapeutic reality for some patients. These platforms may have the potential to treat and cure some of our most intractable and vexing diseases. The policy framework we construct for how these products should be developed, reviewed by regulators, and reimbursed, will help set the stage for the continued advancement of this new market. Last year, we announced our comprehensive policy framework for regenerative medicine, including a draft guidance that describes the expedited programs, such as the breakthrough therapy designation, and the regenerative medicine advanced therapy (RMAT) designation, that may be available to sponsors of these therapies. Today, we’re unveiling a complementary framework for the development, review and approval of gene therapies.
In the past 12 months, we’ve seen three separate gene therapy products approved by the FDA. This reflects the rapid advancements in this field. An inflection point was reached with the development of vectors that could reliably deliver gene cassettes in vivo, into cells and human tissue. In the future, we expect this field to continue to expand, with the potential approval of new treatments for many debilitating diseases. These therapies hold great promise. Our new steps are aimed at fostering developments in this innovative field.
Gene therapies are being studied in many areas, including genetic disorders, autoimmune diseases, heart disease, cancer and HIV/AIDS. We look forward to working with the academic and research communities to make safe and effective products a reality for more patients. But we know that we still have much to learn about how these products work, how to administer them safely, and whether they will continue to work properly in the body without causing adverse side effects over long periods of time. In contrast to traditional drug review, some of the more challenging questions when it comes to gene therapy relate to product manufacturing and quality, or questions about the durability of response, which often can’t be fully answered in any reasonably sized pre-market trial. For some of these products, we may need to accept some level of uncertainty around these questions at the time of approval. For example, in some cases the long-term durability of the effect won’t be fully understood at the time of approval. Effective tools for reliable post-market follow up, such as required post-market clinical trials, are going to be one key to advancing this field and helping to ensure that our approach fosters safe and innovative treatments.
Even when there may be uncertainty about some questions, we need to make certain we assure patient safety and adequately characterize the potential risks and demonstrated benefits of these products. In part because of the added questions that often surround a new technology like gene therapy, these products are initially being aimed at devastating diseases, many of which lack available therapies, including some diseases that are fatal. In such cases of devastating diseases without available therapies, we’ve traditionally been willing to accept more uncertainty to facilitate timely access to promising therapies. In such cases, drug sponsors are generally required to conduct post-marketing clinical trials, known as phase 4 confirmatory trials, to confirm clinical benefit of the drug. This is the direction Congress gave the FDA by creating vehicles like the accelerated approval pathway.
When it comes to novel technologies like gene therapy, the FDA is steadfastly committed to a regulatory path that maintains the agency’s gold standard for assuring safety and efficacy. As we develop this evidence-based framework, we’re going to have to modernize how we approach certain aspects of these products in order to make sure our approach is tailored to the unique challenges created by these new platforms.
Today, we’re taking a step toward shaping this modern structure for the regulation of gene therapy. The agency is issuing a suite of six scientific guidance documents intended to serve as the building blocks of a modern, comprehensive framework for how we’ll help advance the field of gene therapy while making sure new products meet the FDA’s gold standard for safety and effectiveness.
These policies are part of our efforts to communicate the steps we’re taking to provide clear recommendations to sponsors and researchers, so that we can better support innovation. The documents are being issued in draft form so that we can solicit public input on these new policies. As with all draft guidances, all of the comments we receive will be carefully considered prior to finalizing these documents. We’re committed to working with stakeholders to bring novel treatments to the market while ensuring the safety of patients.
Disease-Specific Gene Therapy Guidances
The FDA has issuing three new draft guidance documents on the development of gene therapy products for specific disease categories. These are the first three disease-specific guidances that the agency is issuing for gene therapy products. Our new commitment to develop disease-specific guidance documents reflects the increasing activity in this field, and its growing importance to advancing public health.
Human Gene Therapy for Hemophilia: Gene therapy products for hemophilia are now being developed as single-dose treatments that may enable long-term production of the missing or abnormal coagulation factor in patients. This may reduce or eliminate the need for coagulation factor replacement. To define the proper development pathway for such products, we’re issuing a new draft guidance on gene therapy products that are targeted to the treatment of hemophilia. Once finalized, this new guidance will provide recommendations on the FDA’s current thinking on clinical trial design and preclinical considerations to support the development of these gene therapy products. Among other elements, the draft guidance provides recommendations regarding surrogate endpoints that could be used by sponsors pursuing accelerated approval of gene therapy products that are intended for treatment of hemophilia.
Human Gene Therapy for Retinal Disorders: Another area of fast-paced activity is gene therapy products targeted to the treatment of retinal disorders. The Human Gene Therapy for Retinal Disorders guidance, once finalized, will assist those developing gene therapy products for a wide variety of retinal disorders affecting both adult and pediatric patients. Gene therapy products currently undergoing clinical trials in the United States for retinal disorders are commonly delivered by intravitreal injections (into the fluid portion of the eye), or by subretinal injections (beneath the retina). In some cases, the gene therapy products are encapsulated in a device to be implanted within the eye. This new guidance document will focus on issues that are specific to gene therapies for retinal disorders. The document provides recommendations related to product development, preclinical testing, and clinical trial design for such products.
Human Gene Therapy for Rare Diseases: Rare diseases are those that affect fewer than 200,000 people in the United States. The National Institutes of Health reports that nearly 7,000 rare diseases affect more than 25 million Americans. About 80 percent of rare diseases are caused by a single-gene defect, and about half of all rare diseases affect children. Since most rare diseases have no approved therapies, there is a significant unmet need. The Human Gene Therapy for Rare Diseases guidance, once finalized, will provide recommendations on preclinical, manufacturing and clinical trial design for all phases of the clinical development program for these types of gene therapies. The information is intended to assist sponsors in the design of clinical development programs, where there may be limited study population size, potential feasibility and safety issues, as well as issues relating to the interpretation of effectiveness.
Guidances on Manufacturing Gene Therapies
The FDA is also providing new and comprehensive updates to three existing guidances that address manufacturing issues related to gene therapy. These updates reflect input from many stakeholders. We encourage additional feedback on these documents during the comment period.
The first draft guidance, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), provides sponsors with recommendations on how to provide sufficient CMC information to assure safety, identity, quality, purity and strength/potency of investigational gene therapy products. The guidance applies to human gene therapies and to combination products that contain a human gene therapy in combination with a drug or device. In addition, this guidance is organized to follow the structure of the FDA guidance on the Common Technical Document.
The second draft guidance, Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up, provides additional recommendations regarding the proper testing for RCR during the manufacture of retroviral vector-based gene therapy products, as well as during the follow-up monitoring of patients who’ve received retroviral vector-based gene therapy products. Specifically, the draft guidance recommends the identification and amount of material to be tested. The guidance also provides advice on general testing methods.
The third draft guidance, Long Term Follow-Up After Administration of Human Gene Therapy Products, provides recommendations regarding the design of long-term follow-up (LTFU) observational studies for the collection of data on delayed adverse events following administration of a gene therapy product. Because of some of the additional uncertainty intrinsic to a novel platform like gene therapy -- including questions related to the durability of the treatment effects as well as the theoretical potential for off-target effects if the genes do not insert correctly -- there’s an increased need for robust long-term follow-up of patients in the post-market period. This guidance describes product characteristics, patient-related factors, and the preclinical and clinical data that should be considered when assessing the need for LTFU observations and describes the features related to effective post-market follow up.
Once finalized, these draft guidances will replace previous guidances issued by the FDA in April 2008 (CMC) and November 2006 (RCR and LTFU).
The field of gene therapy has progressed rapidly since these guidances were first issued. Therefore, the FDA is updating these guidances to provide sponsors with the agency’s most up-to-date thinking.
Our goal is to help promote safe and effective product development in this field. We’ll continue to work with the product sponsors to help make the development and approval of these innovative gene therapies more efficient, while putting in place the regulatory controls needed to ensure that the resulting therapies are both safe and effective. We’ll also make full use of our expedited programs such as breakthrough therapy designation and regenerative medicine advanced therapy designation whenever possible.
Gene therapy represents one of the most promising opportunities for developing highly effective and even curative treatments for many vexing disorders. Some of these products are almost certainly going to change the contours of medical practice, and the destiny of patients with some debilitating diseases.
The FDA’s goal is to help these innovations advance in a framework that assures the safety and effectiveness of these resulting treatments, and continues to build peoples’ confidence in this novel area of medicine.
–Scott Gottlieb, MD
FDA Commissioner Scott Gottlieb, MD, releases a statement on the agency’s efforts to advance development of gene therapies.
FDA Commissioner Scott Gottlieb, MD, releases a statement on the agency’s efforts to advance development of gene therapies.
Once just a theory, gene therapies are now a therapeutic reality for some patients. These platforms may have the potential to treat and cure some of our most intractable and vexing diseases. The policy framework we construct for how these products should be developed, reviewed by regulators, and reimbursed, will help set the stage for the continued advancement of this new market. Last year, we announced our comprehensive policy framework for regenerative medicine, including a draft guidance that describes the expedited programs, such as the breakthrough therapy designation, and the regenerative medicine advanced therapy (RMAT) designation, that may be available to sponsors of these therapies. Today, we’re unveiling a complementary framework for the development, review and approval of gene therapies.
In the past 12 months, we’ve seen three separate gene therapy products approved by the FDA. This reflects the rapid advancements in this field. An inflection point was reached with the development of vectors that could reliably deliver gene cassettes in vivo, into cells and human tissue. In the future, we expect this field to continue to expand, with the potential approval of new treatments for many debilitating diseases. These therapies hold great promise. Our new steps are aimed at fostering developments in this innovative field.
Gene therapies are being studied in many areas, including genetic disorders, autoimmune diseases, heart disease, cancer and HIV/AIDS. We look forward to working with the academic and research communities to make safe and effective products a reality for more patients. But we know that we still have much to learn about how these products work, how to administer them safely, and whether they will continue to work properly in the body without causing adverse side effects over long periods of time. In contrast to traditional drug review, some of the more challenging questions when it comes to gene therapy relate to product manufacturing and quality, or questions about the durability of response, which often can’t be fully answered in any reasonably sized pre-market trial. For some of these products, we may need to accept some level of uncertainty around these questions at the time of approval. For example, in some cases the long-term durability of the effect won’t be fully understood at the time of approval. Effective tools for reliable post-market follow up, such as required post-market clinical trials, are going to be one key to advancing this field and helping to ensure that our approach fosters safe and innovative treatments.
Even when there may be uncertainty about some questions, we need to make certain we assure patient safety and adequately characterize the potential risks and demonstrated benefits of these products. In part because of the added questions that often surround a new technology like gene therapy, these products are initially being aimed at devastating diseases, many of which lack available therapies, including some diseases that are fatal. In such cases of devastating diseases without available therapies, we’ve traditionally been willing to accept more uncertainty to facilitate timely access to promising therapies. In such cases, drug sponsors are generally required to conduct post-marketing clinical trials, known as phase 4 confirmatory trials, to confirm clinical benefit of the drug. This is the direction Congress gave the FDA by creating vehicles like the accelerated approval pathway.
When it comes to novel technologies like gene therapy, the FDA is steadfastly committed to a regulatory path that maintains the agency’s gold standard for assuring safety and efficacy. As we develop this evidence-based framework, we’re going to have to modernize how we approach certain aspects of these products in order to make sure our approach is tailored to the unique challenges created by these new platforms.
Today, we’re taking a step toward shaping this modern structure for the regulation of gene therapy. The agency is issuing a suite of six scientific guidance documents intended to serve as the building blocks of a modern, comprehensive framework for how we’ll help advance the field of gene therapy while making sure new products meet the FDA’s gold standard for safety and effectiveness.
These policies are part of our efforts to communicate the steps we’re taking to provide clear recommendations to sponsors and researchers, so that we can better support innovation. The documents are being issued in draft form so that we can solicit public input on these new policies. As with all draft guidances, all of the comments we receive will be carefully considered prior to finalizing these documents. We’re committed to working with stakeholders to bring novel treatments to the market while ensuring the safety of patients.
Disease-Specific Gene Therapy Guidances
The FDA has issuing three new draft guidance documents on the development of gene therapy products for specific disease categories. These are the first three disease-specific guidances that the agency is issuing for gene therapy products. Our new commitment to develop disease-specific guidance documents reflects the increasing activity in this field, and its growing importance to advancing public health.
Human Gene Therapy for Hemophilia: Gene therapy products for hemophilia are now being developed as single-dose treatments that may enable long-term production of the missing or abnormal coagulation factor in patients. This may reduce or eliminate the need for coagulation factor replacement. To define the proper development pathway for such products, we’re issuing a new draft guidance on gene therapy products that are targeted to the treatment of hemophilia. Once finalized, this new guidance will provide recommendations on the FDA’s current thinking on clinical trial design and preclinical considerations to support the development of these gene therapy products. Among other elements, the draft guidance provides recommendations regarding surrogate endpoints that could be used by sponsors pursuing accelerated approval of gene therapy products that are intended for treatment of hemophilia.
Human Gene Therapy for Retinal Disorders: Another area of fast-paced activity is gene therapy products targeted to the treatment of retinal disorders. The Human Gene Therapy for Retinal Disorders guidance, once finalized, will assist those developing gene therapy products for a wide variety of retinal disorders affecting both adult and pediatric patients. Gene therapy products currently undergoing clinical trials in the United States for retinal disorders are commonly delivered by intravitreal injections (into the fluid portion of the eye), or by subretinal injections (beneath the retina). In some cases, the gene therapy products are encapsulated in a device to be implanted within the eye. This new guidance document will focus on issues that are specific to gene therapies for retinal disorders. The document provides recommendations related to product development, preclinical testing, and clinical trial design for such products.
Human Gene Therapy for Rare Diseases: Rare diseases are those that affect fewer than 200,000 people in the United States. The National Institutes of Health reports that nearly 7,000 rare diseases affect more than 25 million Americans. About 80 percent of rare diseases are caused by a single-gene defect, and about half of all rare diseases affect children. Since most rare diseases have no approved therapies, there is a significant unmet need. The Human Gene Therapy for Rare Diseases guidance, once finalized, will provide recommendations on preclinical, manufacturing and clinical trial design for all phases of the clinical development program for these types of gene therapies. The information is intended to assist sponsors in the design of clinical development programs, where there may be limited study population size, potential feasibility and safety issues, as well as issues relating to the interpretation of effectiveness.
Guidances on Manufacturing Gene Therapies
The FDA is also providing new and comprehensive updates to three existing guidances that address manufacturing issues related to gene therapy. These updates reflect input from many stakeholders. We encourage additional feedback on these documents during the comment period.
The first draft guidance, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), provides sponsors with recommendations on how to provide sufficient CMC information to assure safety, identity, quality, purity and strength/potency of investigational gene therapy products. The guidance applies to human gene therapies and to combination products that contain a human gene therapy in combination with a drug or device. In addition, this guidance is organized to follow the structure of the FDA guidance on the Common Technical Document.
The second draft guidance, Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up, provides additional recommendations regarding the proper testing for RCR during the manufacture of retroviral vector-based gene therapy products, as well as during the follow-up monitoring of patients who’ve received retroviral vector-based gene therapy products. Specifically, the draft guidance recommends the identification and amount of material to be tested. The guidance also provides advice on general testing methods.
The third draft guidance, Long Term Follow-Up After Administration of Human Gene Therapy Products, provides recommendations regarding the design of long-term follow-up (LTFU) observational studies for the collection of data on delayed adverse events following administration of a gene therapy product. Because of some of the additional uncertainty intrinsic to a novel platform like gene therapy -- including questions related to the durability of the treatment effects as well as the theoretical potential for off-target effects if the genes do not insert correctly -- there’s an increased need for robust long-term follow-up of patients in the post-market period. This guidance describes product characteristics, patient-related factors, and the preclinical and clinical data that should be considered when assessing the need for LTFU observations and describes the features related to effective post-market follow up.
Once finalized, these draft guidances will replace previous guidances issued by the FDA in April 2008 (CMC) and November 2006 (RCR and LTFU).
The field of gene therapy has progressed rapidly since these guidances were first issued. Therefore, the FDA is updating these guidances to provide sponsors with the agency’s most up-to-date thinking.
Our goal is to help promote safe and effective product development in this field. We’ll continue to work with the product sponsors to help make the development and approval of these innovative gene therapies more efficient, while putting in place the regulatory controls needed to ensure that the resulting therapies are both safe and effective. We’ll also make full use of our expedited programs such as breakthrough therapy designation and regenerative medicine advanced therapy designation whenever possible.
Gene therapy represents one of the most promising opportunities for developing highly effective and even curative treatments for many vexing disorders. Some of these products are almost certainly going to change the contours of medical practice, and the destiny of patients with some debilitating diseases.
The FDA’s goal is to help these innovations advance in a framework that assures the safety and effectiveness of these resulting treatments, and continues to build peoples’ confidence in this novel area of medicine.
–Scott Gottlieb, MD
Once just a theory, gene therapies are now a therapeutic reality for some patients. These platforms may have the potential to treat and cure some of our most intractable and vexing diseases. The policy framework we construct for how these products should be developed, reviewed by regulators, and reimbursed, will help set the stage for the continued advancement of this new market. Last year, we announced our comprehensive policy framework for regenerative medicine, including a draft guidance that describes the expedited programs, such as the breakthrough therapy designation, and the regenerative medicine advanced therapy (RMAT) designation, that may be available to sponsors of these therapies. Today, we’re unveiling a complementary framework for the development, review and approval of gene therapies.
In the past 12 months, we’ve seen three separate gene therapy products approved by the FDA. This reflects the rapid advancements in this field. An inflection point was reached with the development of vectors that could reliably deliver gene cassettes in vivo, into cells and human tissue. In the future, we expect this field to continue to expand, with the potential approval of new treatments for many debilitating diseases. These therapies hold great promise. Our new steps are aimed at fostering developments in this innovative field.
Gene therapies are being studied in many areas, including genetic disorders, autoimmune diseases, heart disease, cancer and HIV/AIDS. We look forward to working with the academic and research communities to make safe and effective products a reality for more patients. But we know that we still have much to learn about how these products work, how to administer them safely, and whether they will continue to work properly in the body without causing adverse side effects over long periods of time. In contrast to traditional drug review, some of the more challenging questions when it comes to gene therapy relate to product manufacturing and quality, or questions about the durability of response, which often can’t be fully answered in any reasonably sized pre-market trial. For some of these products, we may need to accept some level of uncertainty around these questions at the time of approval. For example, in some cases the long-term durability of the effect won’t be fully understood at the time of approval. Effective tools for reliable post-market follow up, such as required post-market clinical trials, are going to be one key to advancing this field and helping to ensure that our approach fosters safe and innovative treatments.
Even when there may be uncertainty about some questions, we need to make certain we assure patient safety and adequately characterize the potential risks and demonstrated benefits of these products. In part because of the added questions that often surround a new technology like gene therapy, these products are initially being aimed at devastating diseases, many of which lack available therapies, including some diseases that are fatal. In such cases of devastating diseases without available therapies, we’ve traditionally been willing to accept more uncertainty to facilitate timely access to promising therapies. In such cases, drug sponsors are generally required to conduct post-marketing clinical trials, known as phase 4 confirmatory trials, to confirm clinical benefit of the drug. This is the direction Congress gave the FDA by creating vehicles like the accelerated approval pathway.
When it comes to novel technologies like gene therapy, the FDA is steadfastly committed to a regulatory path that maintains the agency’s gold standard for assuring safety and efficacy. As we develop this evidence-based framework, we’re going to have to modernize how we approach certain aspects of these products in order to make sure our approach is tailored to the unique challenges created by these new platforms.
Today, we’re taking a step toward shaping this modern structure for the regulation of gene therapy. The agency is issuing a suite of six scientific guidance documents intended to serve as the building blocks of a modern, comprehensive framework for how we’ll help advance the field of gene therapy while making sure new products meet the FDA’s gold standard for safety and effectiveness.
These policies are part of our efforts to communicate the steps we’re taking to provide clear recommendations to sponsors and researchers, so that we can better support innovation. The documents are being issued in draft form so that we can solicit public input on these new policies. As with all draft guidances, all of the comments we receive will be carefully considered prior to finalizing these documents. We’re committed to working with stakeholders to bring novel treatments to the market while ensuring the safety of patients.
Disease-Specific Gene Therapy Guidances
The FDA has issuing three new draft guidance documents on the development of gene therapy products for specific disease categories. These are the first three disease-specific guidances that the agency is issuing for gene therapy products. Our new commitment to develop disease-specific guidance documents reflects the increasing activity in this field, and its growing importance to advancing public health.
Human Gene Therapy for Hemophilia: Gene therapy products for hemophilia are now being developed as single-dose treatments that may enable long-term production of the missing or abnormal coagulation factor in patients. This may reduce or eliminate the need for coagulation factor replacement. To define the proper development pathway for such products, we’re issuing a new draft guidance on gene therapy products that are targeted to the treatment of hemophilia. Once finalized, this new guidance will provide recommendations on the FDA’s current thinking on clinical trial design and preclinical considerations to support the development of these gene therapy products. Among other elements, the draft guidance provides recommendations regarding surrogate endpoints that could be used by sponsors pursuing accelerated approval of gene therapy products that are intended for treatment of hemophilia.
Human Gene Therapy for Retinal Disorders: Another area of fast-paced activity is gene therapy products targeted to the treatment of retinal disorders. The Human Gene Therapy for Retinal Disorders guidance, once finalized, will assist those developing gene therapy products for a wide variety of retinal disorders affecting both adult and pediatric patients. Gene therapy products currently undergoing clinical trials in the United States for retinal disorders are commonly delivered by intravitreal injections (into the fluid portion of the eye), or by subretinal injections (beneath the retina). In some cases, the gene therapy products are encapsulated in a device to be implanted within the eye. This new guidance document will focus on issues that are specific to gene therapies for retinal disorders. The document provides recommendations related to product development, preclinical testing, and clinical trial design for such products.
Human Gene Therapy for Rare Diseases: Rare diseases are those that affect fewer than 200,000 people in the United States. The National Institutes of Health reports that nearly 7,000 rare diseases affect more than 25 million Americans. About 80 percent of rare diseases are caused by a single-gene defect, and about half of all rare diseases affect children. Since most rare diseases have no approved therapies, there is a significant unmet need. The Human Gene Therapy for Rare Diseases guidance, once finalized, will provide recommendations on preclinical, manufacturing and clinical trial design for all phases of the clinical development program for these types of gene therapies. The information is intended to assist sponsors in the design of clinical development programs, where there may be limited study population size, potential feasibility and safety issues, as well as issues relating to the interpretation of effectiveness.
Guidances on Manufacturing Gene Therapies
The FDA is also providing new and comprehensive updates to three existing guidances that address manufacturing issues related to gene therapy. These updates reflect input from many stakeholders. We encourage additional feedback on these documents during the comment period.
The first draft guidance, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), provides sponsors with recommendations on how to provide sufficient CMC information to assure safety, identity, quality, purity and strength/potency of investigational gene therapy products. The guidance applies to human gene therapies and to combination products that contain a human gene therapy in combination with a drug or device. In addition, this guidance is organized to follow the structure of the FDA guidance on the Common Technical Document.
The second draft guidance, Testing of Retroviral Vector-Based Gene Therapy Products for Replication Competent Retrovirus (RCR) during Product Manufacture and Patient Follow-up, provides additional recommendations regarding the proper testing for RCR during the manufacture of retroviral vector-based gene therapy products, as well as during the follow-up monitoring of patients who’ve received retroviral vector-based gene therapy products. Specifically, the draft guidance recommends the identification and amount of material to be tested. The guidance also provides advice on general testing methods.
The third draft guidance, Long Term Follow-Up After Administration of Human Gene Therapy Products, provides recommendations regarding the design of long-term follow-up (LTFU) observational studies for the collection of data on delayed adverse events following administration of a gene therapy product. Because of some of the additional uncertainty intrinsic to a novel platform like gene therapy -- including questions related to the durability of the treatment effects as well as the theoretical potential for off-target effects if the genes do not insert correctly -- there’s an increased need for robust long-term follow-up of patients in the post-market period. This guidance describes product characteristics, patient-related factors, and the preclinical and clinical data that should be considered when assessing the need for LTFU observations and describes the features related to effective post-market follow up.
Once finalized, these draft guidances will replace previous guidances issued by the FDA in April 2008 (CMC) and November 2006 (RCR and LTFU).
The field of gene therapy has progressed rapidly since these guidances were first issued. Therefore, the FDA is updating these guidances to provide sponsors with the agency’s most up-to-date thinking.
Our goal is to help promote safe and effective product development in this field. We’ll continue to work with the product sponsors to help make the development and approval of these innovative gene therapies more efficient, while putting in place the regulatory controls needed to ensure that the resulting therapies are both safe and effective. We’ll also make full use of our expedited programs such as breakthrough therapy designation and regenerative medicine advanced therapy designation whenever possible.
Gene therapy represents one of the most promising opportunities for developing highly effective and even curative treatments for many vexing disorders. Some of these products are almost certainly going to change the contours of medical practice, and the destiny of patients with some debilitating diseases.
The FDA’s goal is to help these innovations advance in a framework that assures the safety and effectiveness of these resulting treatments, and continues to build peoples’ confidence in this novel area of medicine.
–Scott Gottlieb, MD
TissueGene-C effects on knee OA seen at 3 years
LIVERPOOL, ENGLAND – TissueGene-C continues to show promise as a potential disease-modifying osteoarthritis drug, according to the long-term follow-up data of a phase 3 trial.
Within 2-3 years of receiving a single injection of the novel cell-gene therapy, patients with moderate knee OA were still experiencing significant improvement in the coprimary endpoints of knee symptoms, function, sports activity, and knee pain versus baseline values.
Differences in International Knee Documentation Committee (IKDC) scores from baseline to 2 and 3 years were a respective 15.3 and 14.8 points (both P less than .05 vs. baseline). Pain, assessed on a visual analog scale, was also significantly improved from baseline to 2 and 3 years (score changes –23.5 and –23.3; P less than .05 vs. baseline).
There were also significant improvements in the secondary endpoint of pain, stiffness, and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), with changes in scores of –19.8 and –17.4 versus baseline at 2 and 3 years, respectively (both P less than .05 vs. baseline).
“INVOISSA-K [TissueGene-C] is the first-in-class cell and gene therapy for the treatment of knee OA,” Dr. Lee reminded delegates at the congress, which is sponsored by the Osteoarthritis Research Society International. The novel treatment was made by collecting chondrocytes from a subject with polydactyl hands and then culturing these to create two subpopulations of cells, one with allogenic chondrocytes and the other with genetically modified chondrocytes that overexpress transforming growth factor-beta1. These subpopulations are then mixed in the ratio of 3:1 and delivered in a single intra-articular injection.
Dr. Lee, who is the president and chief executive officer of Kolon TissueGene, Rockville, Md., reported new findings of a phase 3 trial conducted exclusively in Korea at 12 study centers, the results of which were first presented at OARSI 2016.
At that time only the 12-month primary endpoint data were available, which showed that TissueGene-C improved IKDC scores from baseline by a significantly greater amount than a saline placebo, with changes in scores of 15.1 and 5 points, respectively, versus baseline values. Improvements in IKDC scores were seen as early as 3 months but only became significantly better than placebo at 6 months.
Similarly, visual analog scale pain scores had improved from baseline as early as 3 months but were only significantly different from placebo at 6 months (–23.4 change from baseline for TissueGene-C vs. –14.6 for placebo) and out to 12 months (–24.5 vs. –10.3). WOMAC scores with TissueGene-C were only significantly different from placebo at 12 months (–13.5 vs. –6.2 from baseline, respectively).
The 12-month OMERACT-OARSI responder rate was 84% for TissueGene-C and 45% for placebo. The most common adverse events seen with TissueGene-C were related to the injection site, with peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection-site pain (5%) reported.
A total of 163 patients were recruited into the study, all had Kellgren-Lawrence grade 3 knee OA, which was also graded as 3 or 4 on the International Cartilage Regeneration & Joint Preservation Society scale. Major lesions had be 6 cm2 or smaller. Active treatment was given to 78 patients, and 81 received placebo. The primary assessment period was at 12 months, but patients continued to be followed out to 5 years.
At OARSI 2018, Dr. Lee presented the findings of 12-month structural modification analyses for the first time. These showed that while the osteophyte score on MRI was not significantly different from baseline in the active-treatment arm, there was a significantly increased osteophyte score and total cartilage defect in the placebo-treated patients versus baseline values.
Subchondral bone changes at 12 months showed a trend for less bone area change with TissueGene-C than placebo and a trend for increased cartilage thickness. Greater reductions in serum CTX-1 and urine CTX-II were seen with active treatment than placebo, relative to screening values.
X-ray evaluation of joint-space narrowing showed that nonprogression was more likely in patients treated with TissueGene-C than with placebo (77% vs. 57%), although this was not significant. In addition, fewer patients treated with TissueGene-C than placebo who needed a total knee replacement at 2 years (0% and 7.5%) and at 3 years (2% and 14%).
TissueGene-C “has great potential” for being the first disease-modifying osteoarthritis drug to get to market, Dr. Lee suggested.
The clinical development program for TissueGene-C is further advanced in Korea than in the United States, where a phase 3 trial is about to start recruitment soon.
“We started our clinical trials in 2005 in Korea and in the U.S. simultaneously,” Dr. Lee said, noting that a biologics license application submitted in Korea in 2016 had been accepted by the Ministry of Food and Drug Safety on July 12, 2017, while only phase 1 and 2 trials have been completed in the United States
The study was funded by Kolon Life Science and TissueGene. Dr. Lee is an employee of TissueGene.
SOURCE: Lee B et al. Osteoarthritis Cartilage. 2018 Apr;26(1):S43-4.
LIVERPOOL, ENGLAND – TissueGene-C continues to show promise as a potential disease-modifying osteoarthritis drug, according to the long-term follow-up data of a phase 3 trial.
Within 2-3 years of receiving a single injection of the novel cell-gene therapy, patients with moderate knee OA were still experiencing significant improvement in the coprimary endpoints of knee symptoms, function, sports activity, and knee pain versus baseline values.
Differences in International Knee Documentation Committee (IKDC) scores from baseline to 2 and 3 years were a respective 15.3 and 14.8 points (both P less than .05 vs. baseline). Pain, assessed on a visual analog scale, was also significantly improved from baseline to 2 and 3 years (score changes –23.5 and –23.3; P less than .05 vs. baseline).
There were also significant improvements in the secondary endpoint of pain, stiffness, and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), with changes in scores of –19.8 and –17.4 versus baseline at 2 and 3 years, respectively (both P less than .05 vs. baseline).
“INVOISSA-K [TissueGene-C] is the first-in-class cell and gene therapy for the treatment of knee OA,” Dr. Lee reminded delegates at the congress, which is sponsored by the Osteoarthritis Research Society International. The novel treatment was made by collecting chondrocytes from a subject with polydactyl hands and then culturing these to create two subpopulations of cells, one with allogenic chondrocytes and the other with genetically modified chondrocytes that overexpress transforming growth factor-beta1. These subpopulations are then mixed in the ratio of 3:1 and delivered in a single intra-articular injection.
Dr. Lee, who is the president and chief executive officer of Kolon TissueGene, Rockville, Md., reported new findings of a phase 3 trial conducted exclusively in Korea at 12 study centers, the results of which were first presented at OARSI 2016.
At that time only the 12-month primary endpoint data were available, which showed that TissueGene-C improved IKDC scores from baseline by a significantly greater amount than a saline placebo, with changes in scores of 15.1 and 5 points, respectively, versus baseline values. Improvements in IKDC scores were seen as early as 3 months but only became significantly better than placebo at 6 months.
Similarly, visual analog scale pain scores had improved from baseline as early as 3 months but were only significantly different from placebo at 6 months (–23.4 change from baseline for TissueGene-C vs. –14.6 for placebo) and out to 12 months (–24.5 vs. –10.3). WOMAC scores with TissueGene-C were only significantly different from placebo at 12 months (–13.5 vs. –6.2 from baseline, respectively).
The 12-month OMERACT-OARSI responder rate was 84% for TissueGene-C and 45% for placebo. The most common adverse events seen with TissueGene-C were related to the injection site, with peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection-site pain (5%) reported.
A total of 163 patients were recruited into the study, all had Kellgren-Lawrence grade 3 knee OA, which was also graded as 3 or 4 on the International Cartilage Regeneration & Joint Preservation Society scale. Major lesions had be 6 cm2 or smaller. Active treatment was given to 78 patients, and 81 received placebo. The primary assessment period was at 12 months, but patients continued to be followed out to 5 years.
At OARSI 2018, Dr. Lee presented the findings of 12-month structural modification analyses for the first time. These showed that while the osteophyte score on MRI was not significantly different from baseline in the active-treatment arm, there was a significantly increased osteophyte score and total cartilage defect in the placebo-treated patients versus baseline values.
Subchondral bone changes at 12 months showed a trend for less bone area change with TissueGene-C than placebo and a trend for increased cartilage thickness. Greater reductions in serum CTX-1 and urine CTX-II were seen with active treatment than placebo, relative to screening values.
X-ray evaluation of joint-space narrowing showed that nonprogression was more likely in patients treated with TissueGene-C than with placebo (77% vs. 57%), although this was not significant. In addition, fewer patients treated with TissueGene-C than placebo who needed a total knee replacement at 2 years (0% and 7.5%) and at 3 years (2% and 14%).
TissueGene-C “has great potential” for being the first disease-modifying osteoarthritis drug to get to market, Dr. Lee suggested.
The clinical development program for TissueGene-C is further advanced in Korea than in the United States, where a phase 3 trial is about to start recruitment soon.
“We started our clinical trials in 2005 in Korea and in the U.S. simultaneously,” Dr. Lee said, noting that a biologics license application submitted in Korea in 2016 had been accepted by the Ministry of Food and Drug Safety on July 12, 2017, while only phase 1 and 2 trials have been completed in the United States
The study was funded by Kolon Life Science and TissueGene. Dr. Lee is an employee of TissueGene.
SOURCE: Lee B et al. Osteoarthritis Cartilage. 2018 Apr;26(1):S43-4.
LIVERPOOL, ENGLAND – TissueGene-C continues to show promise as a potential disease-modifying osteoarthritis drug, according to the long-term follow-up data of a phase 3 trial.
Within 2-3 years of receiving a single injection of the novel cell-gene therapy, patients with moderate knee OA were still experiencing significant improvement in the coprimary endpoints of knee symptoms, function, sports activity, and knee pain versus baseline values.
Differences in International Knee Documentation Committee (IKDC) scores from baseline to 2 and 3 years were a respective 15.3 and 14.8 points (both P less than .05 vs. baseline). Pain, assessed on a visual analog scale, was also significantly improved from baseline to 2 and 3 years (score changes –23.5 and –23.3; P less than .05 vs. baseline).
There were also significant improvements in the secondary endpoint of pain, stiffness, and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), with changes in scores of –19.8 and –17.4 versus baseline at 2 and 3 years, respectively (both P less than .05 vs. baseline).
“INVOISSA-K [TissueGene-C] is the first-in-class cell and gene therapy for the treatment of knee OA,” Dr. Lee reminded delegates at the congress, which is sponsored by the Osteoarthritis Research Society International. The novel treatment was made by collecting chondrocytes from a subject with polydactyl hands and then culturing these to create two subpopulations of cells, one with allogenic chondrocytes and the other with genetically modified chondrocytes that overexpress transforming growth factor-beta1. These subpopulations are then mixed in the ratio of 3:1 and delivered in a single intra-articular injection.
Dr. Lee, who is the president and chief executive officer of Kolon TissueGene, Rockville, Md., reported new findings of a phase 3 trial conducted exclusively in Korea at 12 study centers, the results of which were first presented at OARSI 2016.
At that time only the 12-month primary endpoint data were available, which showed that TissueGene-C improved IKDC scores from baseline by a significantly greater amount than a saline placebo, with changes in scores of 15.1 and 5 points, respectively, versus baseline values. Improvements in IKDC scores were seen as early as 3 months but only became significantly better than placebo at 6 months.
Similarly, visual analog scale pain scores had improved from baseline as early as 3 months but were only significantly different from placebo at 6 months (–23.4 change from baseline for TissueGene-C vs. –14.6 for placebo) and out to 12 months (–24.5 vs. –10.3). WOMAC scores with TissueGene-C were only significantly different from placebo at 12 months (–13.5 vs. –6.2 from baseline, respectively).
The 12-month OMERACT-OARSI responder rate was 84% for TissueGene-C and 45% for placebo. The most common adverse events seen with TissueGene-C were related to the injection site, with peripheral edema (9%), arthralgia (8%), joint swelling (6%), and injection-site pain (5%) reported.
A total of 163 patients were recruited into the study, all had Kellgren-Lawrence grade 3 knee OA, which was also graded as 3 or 4 on the International Cartilage Regeneration & Joint Preservation Society scale. Major lesions had be 6 cm2 or smaller. Active treatment was given to 78 patients, and 81 received placebo. The primary assessment period was at 12 months, but patients continued to be followed out to 5 years.
At OARSI 2018, Dr. Lee presented the findings of 12-month structural modification analyses for the first time. These showed that while the osteophyte score on MRI was not significantly different from baseline in the active-treatment arm, there was a significantly increased osteophyte score and total cartilage defect in the placebo-treated patients versus baseline values.
Subchondral bone changes at 12 months showed a trend for less bone area change with TissueGene-C than placebo and a trend for increased cartilage thickness. Greater reductions in serum CTX-1 and urine CTX-II were seen with active treatment than placebo, relative to screening values.
X-ray evaluation of joint-space narrowing showed that nonprogression was more likely in patients treated with TissueGene-C than with placebo (77% vs. 57%), although this was not significant. In addition, fewer patients treated with TissueGene-C than placebo who needed a total knee replacement at 2 years (0% and 7.5%) and at 3 years (2% and 14%).
TissueGene-C “has great potential” for being the first disease-modifying osteoarthritis drug to get to market, Dr. Lee suggested.
The clinical development program for TissueGene-C is further advanced in Korea than in the United States, where a phase 3 trial is about to start recruitment soon.
“We started our clinical trials in 2005 in Korea and in the U.S. simultaneously,” Dr. Lee said, noting that a biologics license application submitted in Korea in 2016 had been accepted by the Ministry of Food and Drug Safety on July 12, 2017, while only phase 1 and 2 trials have been completed in the United States
The study was funded by Kolon Life Science and TissueGene. Dr. Lee is an employee of TissueGene.
SOURCE: Lee B et al. Osteoarthritis Cartilage. 2018 Apr;26(1):S43-4.
REPORTING FROM OARSI 2018
Key clinical point: A single intra-articular injection of TissueGene C produced significant and long-term relief of knee osteoarthritis.
Major finding: Changes in baseline International Knee Documentation Committee and visual analog scale pain scores from baseline to 2 and 3 years were 15.3 and 14.8 points (P less than .05), and –23.5 and –23.3 (P less than .05), respectively.
Study details: A multicenter, phase 3, randomized, double-blind, placebo-controlled trial of 163 patients with knee osteoarthritis.
Disclosures: The study was funded by Kolon Life Science and TissueGene. Dr. Lee is an employee of TissueGene.
Source: Lee B et al. Osteoarthritis Cartilage. 2018 Apr;26(1):S43-4.
Payers part of the drug-pricing problem, says FDA commissioner
WASHINGTON –
“Payers are going to have to decide what they want,” Dr. Gottlieb said at the conference sponsored by America’s Health Insurance Plans. “Do they want the short-term profit boost that comes with these rebates or in the long-run assist in their function” to make things better for patients, for providers, and those who pay for care.
It is possible to spur competition while working within the confines of the rebate-based system, he said. “I don’t see these as binary choices. You can have your cake and eat it too. Or in this case your rebates.”
His comments received a quick rebuttal from AHIP.
“There is a lot of blame being pushed around,” Daniel Nam, AHIP executive director of federal programs, said in an interview. “Along with the blame are a lot of distractions, misdirections, and these easy one-off fixes or problems that pop their head up and come and go. ... We try to stay focused on what is the real problem and that is essentially the starting price.”
He noted that if a treatment has a high starting price, such at coming gene therapies that could cost $1 million per patient, “it creates a pressure on the industry and it threatens our health care system to be unsustainable in the long term. What we are worried about is that there is no check on [the pharmaceutical industry’s] ability to set high list prices and even subsequently increase them.”
Mr. Nam noted that there is a fine balance that needs to be achieved to allow manufacturers to profit while at the same time ensuring access to therapies at reasonable prices.
“We believe in the free market and competition, but we feel like there are levers that could bring down the list price very effectively,” such as meaningful competition. “The situation that we have now is really more about the list price being way too high and unchallenged at this moment.”
Mr. Nam also took issue with the characterization that insurers are gaming the rebate system for profit.
“With the rebates, plans and PBMs [pharmacy benefit managers] want the lowest net cost,” he said. “That is our end goal. When you have this accusation that plans manipulate the rebate structure in order to skim off a couple of dollars here and there ... they are giving plans a lot more credit than what they can actually do at the negotiation table.”
He said the rebate system “is not perfect by any means, but I think drawing a conclusion of an imperfect system that [creates] a perverse incentive for insurers is completely distracting from the real problem” of high list prices.
WASHINGTON –
“Payers are going to have to decide what they want,” Dr. Gottlieb said at the conference sponsored by America’s Health Insurance Plans. “Do they want the short-term profit boost that comes with these rebates or in the long-run assist in their function” to make things better for patients, for providers, and those who pay for care.
It is possible to spur competition while working within the confines of the rebate-based system, he said. “I don’t see these as binary choices. You can have your cake and eat it too. Or in this case your rebates.”
His comments received a quick rebuttal from AHIP.
“There is a lot of blame being pushed around,” Daniel Nam, AHIP executive director of federal programs, said in an interview. “Along with the blame are a lot of distractions, misdirections, and these easy one-off fixes or problems that pop their head up and come and go. ... We try to stay focused on what is the real problem and that is essentially the starting price.”
He noted that if a treatment has a high starting price, such at coming gene therapies that could cost $1 million per patient, “it creates a pressure on the industry and it threatens our health care system to be unsustainable in the long term. What we are worried about is that there is no check on [the pharmaceutical industry’s] ability to set high list prices and even subsequently increase them.”
Mr. Nam noted that there is a fine balance that needs to be achieved to allow manufacturers to profit while at the same time ensuring access to therapies at reasonable prices.
“We believe in the free market and competition, but we feel like there are levers that could bring down the list price very effectively,” such as meaningful competition. “The situation that we have now is really more about the list price being way too high and unchallenged at this moment.”
Mr. Nam also took issue with the characterization that insurers are gaming the rebate system for profit.
“With the rebates, plans and PBMs [pharmacy benefit managers] want the lowest net cost,” he said. “That is our end goal. When you have this accusation that plans manipulate the rebate structure in order to skim off a couple of dollars here and there ... they are giving plans a lot more credit than what they can actually do at the negotiation table.”
He said the rebate system “is not perfect by any means, but I think drawing a conclusion of an imperfect system that [creates] a perverse incentive for insurers is completely distracting from the real problem” of high list prices.
WASHINGTON –
“Payers are going to have to decide what they want,” Dr. Gottlieb said at the conference sponsored by America’s Health Insurance Plans. “Do they want the short-term profit boost that comes with these rebates or in the long-run assist in their function” to make things better for patients, for providers, and those who pay for care.
It is possible to spur competition while working within the confines of the rebate-based system, he said. “I don’t see these as binary choices. You can have your cake and eat it too. Or in this case your rebates.”
His comments received a quick rebuttal from AHIP.
“There is a lot of blame being pushed around,” Daniel Nam, AHIP executive director of federal programs, said in an interview. “Along with the blame are a lot of distractions, misdirections, and these easy one-off fixes or problems that pop their head up and come and go. ... We try to stay focused on what is the real problem and that is essentially the starting price.”
He noted that if a treatment has a high starting price, such at coming gene therapies that could cost $1 million per patient, “it creates a pressure on the industry and it threatens our health care system to be unsustainable in the long term. What we are worried about is that there is no check on [the pharmaceutical industry’s] ability to set high list prices and even subsequently increase them.”
Mr. Nam noted that there is a fine balance that needs to be achieved to allow manufacturers to profit while at the same time ensuring access to therapies at reasonable prices.
“We believe in the free market and competition, but we feel like there are levers that could bring down the list price very effectively,” such as meaningful competition. “The situation that we have now is really more about the list price being way too high and unchallenged at this moment.”
Mr. Nam also took issue with the characterization that insurers are gaming the rebate system for profit.
“With the rebates, plans and PBMs [pharmacy benefit managers] want the lowest net cost,” he said. “That is our end goal. When you have this accusation that plans manipulate the rebate structure in order to skim off a couple of dollars here and there ... they are giving plans a lot more credit than what they can actually do at the negotiation table.”
He said the rebate system “is not perfect by any means, but I think drawing a conclusion of an imperfect system that [creates] a perverse incentive for insurers is completely distracting from the real problem” of high list prices.
REPORTING FROM AHIP 2018
Genetic therapy lowers joint bleeding in hemophilia B
COPENHAGEN – It’s early days yet, but results look highly promising for the ability of an experimental gene-transfer therapy to improve coagulation parameters in patients with severe hemophilia B.
In a phase I/II dose-escalation study, a single 1-hour infusion of the gene-transfer product, labeled SPK-9001, resulted in factor IX activity levels ranging from 25% to 39% of normal in four men with severe or moderately severe hemophilia B, reported Dr. Katherine A High, president and chief scientific officer of Spark Therapeutics, maker of the product.
“One of the most remarkable features of the data in my mind has been a very consistent performance,” she said at a briefing at the annual congress of the European Hematology Association.
The product consists of a vector containing a novel bio-engineered adeno-associated virus (AAV) capsid with tropism for liver, and a factor IX cassette that carries a strong liver-specific promoter to drive the expression of the factor IX variant, dubbed factor IX Padua.
“The hypothesis of the work was that if we could engineer a vector efficient enough, we would be able to infuse it at a dose low enough that it would drive loads of expression greater than 12% of normal, which in previous work has been shown to be associated with an absence of joint bleeds in natural history studies of people with mild disease, and that infusion at a low dose would eliminate the need for any type of immune suppression with steroids,” Dr. High said.
Other attempts at genetic engineering in patients with hemophilia B have been hampered by the need to use high doses of vector that can induce an immune response, thereby negating the benefit of therapy.
In this ongoing study, conducted in Mississippi, Pennsylvania, and California, males 18 and older with a confirmed diagnosis of hemophilia B (defined as equal to or less than 2 IU/dL or 2% endogenous factor IX) who have received 50 or more days of exposure to factor IX products are enrolled. The patients must have a minimum average of four bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions, no measurable factor IX inhibitor as assessed by the central laboratory, and no prior history of inhibitors to factor IX protein.
In an oral session at the congress, Dr. Spencer Sullivan, assistant professor of pediatrics and medicine at the University of Mississippi Medical Center in Jackson, presented data on four men whose age ranges from 18 to 47 years.
In the dose-escalation phase of the study, the patients received single infusions of SPK-9001 at an initial starting dose of 5 x 1011 vector genomes of body weight. They were followed for 7-26 weeks after gene transfer for factor IX activity levels, liver enzymes, bleeding episode, and factor usage. As of May 22, 2016, the first four patients showed factor IX activity levels of 32%, 39%, 25%, and 27% of normal, respectively.
All subjects are currently off prophylactic factor IX infusions. During the course of follow-up, one patient infused himself with factor IX once, treating himself 2 days after vector infusion for a suspected ankle bleed.
Asked by a reporter how durable the effect was, Dr. High replied that in dog models of hemophilia B the effect of the gene transfer has been durable.
The best evidence to date of durability in humans, she said, comes from investigators at University College in London (England), who found that if patients can make it past the first 8-10 weeks without developing an immune response to the transfer product, they are likely to do well, and to have a durable effect, she said.
Dr. Anton Hagenbeek, from the Academic Medical Center, University of Amsterdam, who moderated the briefing but was not involved in the study, said that Dr. High was “to be congratulated for these best data ever seen.”
He asked, facetiously, whether she thought that “thousands of patients would buy a ticket to Philadelphia.” The “City of Brotherly Love” is home to one of the trial sites and to Spark headquarters.
The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.
COPENHAGEN – It’s early days yet, but results look highly promising for the ability of an experimental gene-transfer therapy to improve coagulation parameters in patients with severe hemophilia B.
In a phase I/II dose-escalation study, a single 1-hour infusion of the gene-transfer product, labeled SPK-9001, resulted in factor IX activity levels ranging from 25% to 39% of normal in four men with severe or moderately severe hemophilia B, reported Dr. Katherine A High, president and chief scientific officer of Spark Therapeutics, maker of the product.
“One of the most remarkable features of the data in my mind has been a very consistent performance,” she said at a briefing at the annual congress of the European Hematology Association.
The product consists of a vector containing a novel bio-engineered adeno-associated virus (AAV) capsid with tropism for liver, and a factor IX cassette that carries a strong liver-specific promoter to drive the expression of the factor IX variant, dubbed factor IX Padua.
“The hypothesis of the work was that if we could engineer a vector efficient enough, we would be able to infuse it at a dose low enough that it would drive loads of expression greater than 12% of normal, which in previous work has been shown to be associated with an absence of joint bleeds in natural history studies of people with mild disease, and that infusion at a low dose would eliminate the need for any type of immune suppression with steroids,” Dr. High said.
Other attempts at genetic engineering in patients with hemophilia B have been hampered by the need to use high doses of vector that can induce an immune response, thereby negating the benefit of therapy.
In this ongoing study, conducted in Mississippi, Pennsylvania, and California, males 18 and older with a confirmed diagnosis of hemophilia B (defined as equal to or less than 2 IU/dL or 2% endogenous factor IX) who have received 50 or more days of exposure to factor IX products are enrolled. The patients must have a minimum average of four bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions, no measurable factor IX inhibitor as assessed by the central laboratory, and no prior history of inhibitors to factor IX protein.
In an oral session at the congress, Dr. Spencer Sullivan, assistant professor of pediatrics and medicine at the University of Mississippi Medical Center in Jackson, presented data on four men whose age ranges from 18 to 47 years.
In the dose-escalation phase of the study, the patients received single infusions of SPK-9001 at an initial starting dose of 5 x 1011 vector genomes of body weight. They were followed for 7-26 weeks after gene transfer for factor IX activity levels, liver enzymes, bleeding episode, and factor usage. As of May 22, 2016, the first four patients showed factor IX activity levels of 32%, 39%, 25%, and 27% of normal, respectively.
All subjects are currently off prophylactic factor IX infusions. During the course of follow-up, one patient infused himself with factor IX once, treating himself 2 days after vector infusion for a suspected ankle bleed.
Asked by a reporter how durable the effect was, Dr. High replied that in dog models of hemophilia B the effect of the gene transfer has been durable.
The best evidence to date of durability in humans, she said, comes from investigators at University College in London (England), who found that if patients can make it past the first 8-10 weeks without developing an immune response to the transfer product, they are likely to do well, and to have a durable effect, she said.
Dr. Anton Hagenbeek, from the Academic Medical Center, University of Amsterdam, who moderated the briefing but was not involved in the study, said that Dr. High was “to be congratulated for these best data ever seen.”
He asked, facetiously, whether she thought that “thousands of patients would buy a ticket to Philadelphia.” The “City of Brotherly Love” is home to one of the trial sites and to Spark headquarters.
The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.
COPENHAGEN – It’s early days yet, but results look highly promising for the ability of an experimental gene-transfer therapy to improve coagulation parameters in patients with severe hemophilia B.
In a phase I/II dose-escalation study, a single 1-hour infusion of the gene-transfer product, labeled SPK-9001, resulted in factor IX activity levels ranging from 25% to 39% of normal in four men with severe or moderately severe hemophilia B, reported Dr. Katherine A High, president and chief scientific officer of Spark Therapeutics, maker of the product.
“One of the most remarkable features of the data in my mind has been a very consistent performance,” she said at a briefing at the annual congress of the European Hematology Association.
The product consists of a vector containing a novel bio-engineered adeno-associated virus (AAV) capsid with tropism for liver, and a factor IX cassette that carries a strong liver-specific promoter to drive the expression of the factor IX variant, dubbed factor IX Padua.
“The hypothesis of the work was that if we could engineer a vector efficient enough, we would be able to infuse it at a dose low enough that it would drive loads of expression greater than 12% of normal, which in previous work has been shown to be associated with an absence of joint bleeds in natural history studies of people with mild disease, and that infusion at a low dose would eliminate the need for any type of immune suppression with steroids,” Dr. High said.
Other attempts at genetic engineering in patients with hemophilia B have been hampered by the need to use high doses of vector that can induce an immune response, thereby negating the benefit of therapy.
In this ongoing study, conducted in Mississippi, Pennsylvania, and California, males 18 and older with a confirmed diagnosis of hemophilia B (defined as equal to or less than 2 IU/dL or 2% endogenous factor IX) who have received 50 or more days of exposure to factor IX products are enrolled. The patients must have a minimum average of four bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions, no measurable factor IX inhibitor as assessed by the central laboratory, and no prior history of inhibitors to factor IX protein.
In an oral session at the congress, Dr. Spencer Sullivan, assistant professor of pediatrics and medicine at the University of Mississippi Medical Center in Jackson, presented data on four men whose age ranges from 18 to 47 years.
In the dose-escalation phase of the study, the patients received single infusions of SPK-9001 at an initial starting dose of 5 x 1011 vector genomes of body weight. They were followed for 7-26 weeks after gene transfer for factor IX activity levels, liver enzymes, bleeding episode, and factor usage. As of May 22, 2016, the first four patients showed factor IX activity levels of 32%, 39%, 25%, and 27% of normal, respectively.
All subjects are currently off prophylactic factor IX infusions. During the course of follow-up, one patient infused himself with factor IX once, treating himself 2 days after vector infusion for a suspected ankle bleed.
Asked by a reporter how durable the effect was, Dr. High replied that in dog models of hemophilia B the effect of the gene transfer has been durable.
The best evidence to date of durability in humans, she said, comes from investigators at University College in London (England), who found that if patients can make it past the first 8-10 weeks without developing an immune response to the transfer product, they are likely to do well, and to have a durable effect, she said.
Dr. Anton Hagenbeek, from the Academic Medical Center, University of Amsterdam, who moderated the briefing but was not involved in the study, said that Dr. High was “to be congratulated for these best data ever seen.”
He asked, facetiously, whether she thought that “thousands of patients would buy a ticket to Philadelphia.” The “City of Brotherly Love” is home to one of the trial sites and to Spark headquarters.
The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.
At THE EHA CONGRESS
Key clinical point:. The experimental SPK-9001 is a gene transfer product carrying a strong factor IX promoter.
Major finding: A single one-hour infusion of SPK-9001 was associated with factor IX activity levels ranging from 25% to 39% of normal.
Data source: Dose-escalation cohort of four adult males in a phase I/II study.
Disclosures: The study is sponsored by Spark Therapeutics and Pfizer. Dr. High is president and chief scientific officer of Spark. Dr. Sullivan and Dr. Hagenbeek reported no relevant disclosures.
Experts call for international cooperation on human gene editing
Human gene editing is no longer the stuff of science fiction, and the powerful new technologies that make it possible raise important scientific, ethical, and societal questions.
The organizing committee for a 3-day International Summit On Gene Editing that convened experts from around the world to discuss the issues associated with human gene-editing research, has called upon the international community to work together to establish norms for acceptable uses of human gene editing.
In a statement issued Dec. 3 at the close of the summit, the committee asked the summit cohosts – the U.S. National Academy of Sciences and U.S. National Academy of Medicine, the Royal Society (United Kingdom), and the Chinese Academy of Sciences – to take the lead in creating an ongoing international forum on gene editing and to work on formulating recommendations and guidelines.
“While each nation ultimately has the authority to regulate activities under its jurisdiction, the human genome is shared among all nations,” the committee wrote. “The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.”
The committee also concluded that:
• Intensive basic and preclinical research is needed, with a specific research focus on technologies for editing genetic sequences in human cells, potential benefits and risks of proposed clinical uses for gene editing, and understanding of the biology of human embryos and germline cells. Any early human embryo or germline cells that undergo gene editing should not be used to establish a pregnancy, the committee wrote.
• Improved understanding of the risks of somatic cell editing – such as inaccurate editing – is needed, as is understanding of the potential benefits of each proposed genetic modification. Such uses of gene editing, which are intended to affect only the individual who receives them, can be “appropriately and rigorously evaluated within existing and evolving regulatory frameworks for gene therapy,” they noted.
• Germline editing poses particularly important issues, such as the challenges with predicting harmful effects of genetic changes, including interactions with other genetic variants and with the environment. Moral and ethical considerations, such as the possibility of permanent genetic enhancements that could exacerbate social inequalities or be used coercively, must also be considered. The committee said that “it would be irresponsible to proceed with any clinical use of germline editing” unless and until the safety and efficacy issues have been resolved, and there is broad consensus about the appropriateness of a proposed application.
“At present these criteria have not been met for any proposed clinical use,” the committee wrote, adding that safety issues have not been adequately explored, and the cases of most compelling benefit are limited.
As the science advances and social views evolve, the clinical use of germline editing should be regularly revisited, they wrote.
The presidents of each of the organizations that hosted the summit welcomed the call for ongoing global discussion on issues related to human gene editing.
In a written response they said that they “stand ready to establish a continuing forum for assessment of the many scientific, medical, and ethical questions surrounding the pursuit of human gene-editing applications,” and will coordinate with other academies around the world and other international scientific and medical institutions in that endeavor.
“This is an important moment in human history and we have a responsibility to provide all sections of society with an informed basis for making decisions about this technology, especially for uses that would affect generations to come,” they wrote.
Human gene editing is no longer the stuff of science fiction, and the powerful new technologies that make it possible raise important scientific, ethical, and societal questions.
The organizing committee for a 3-day International Summit On Gene Editing that convened experts from around the world to discuss the issues associated with human gene-editing research, has called upon the international community to work together to establish norms for acceptable uses of human gene editing.
In a statement issued Dec. 3 at the close of the summit, the committee asked the summit cohosts – the U.S. National Academy of Sciences and U.S. National Academy of Medicine, the Royal Society (United Kingdom), and the Chinese Academy of Sciences – to take the lead in creating an ongoing international forum on gene editing and to work on formulating recommendations and guidelines.
“While each nation ultimately has the authority to regulate activities under its jurisdiction, the human genome is shared among all nations,” the committee wrote. “The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.”
The committee also concluded that:
• Intensive basic and preclinical research is needed, with a specific research focus on technologies for editing genetic sequences in human cells, potential benefits and risks of proposed clinical uses for gene editing, and understanding of the biology of human embryos and germline cells. Any early human embryo or germline cells that undergo gene editing should not be used to establish a pregnancy, the committee wrote.
• Improved understanding of the risks of somatic cell editing – such as inaccurate editing – is needed, as is understanding of the potential benefits of each proposed genetic modification. Such uses of gene editing, which are intended to affect only the individual who receives them, can be “appropriately and rigorously evaluated within existing and evolving regulatory frameworks for gene therapy,” they noted.
• Germline editing poses particularly important issues, such as the challenges with predicting harmful effects of genetic changes, including interactions with other genetic variants and with the environment. Moral and ethical considerations, such as the possibility of permanent genetic enhancements that could exacerbate social inequalities or be used coercively, must also be considered. The committee said that “it would be irresponsible to proceed with any clinical use of germline editing” unless and until the safety and efficacy issues have been resolved, and there is broad consensus about the appropriateness of a proposed application.
“At present these criteria have not been met for any proposed clinical use,” the committee wrote, adding that safety issues have not been adequately explored, and the cases of most compelling benefit are limited.
As the science advances and social views evolve, the clinical use of germline editing should be regularly revisited, they wrote.
The presidents of each of the organizations that hosted the summit welcomed the call for ongoing global discussion on issues related to human gene editing.
In a written response they said that they “stand ready to establish a continuing forum for assessment of the many scientific, medical, and ethical questions surrounding the pursuit of human gene-editing applications,” and will coordinate with other academies around the world and other international scientific and medical institutions in that endeavor.
“This is an important moment in human history and we have a responsibility to provide all sections of society with an informed basis for making decisions about this technology, especially for uses that would affect generations to come,” they wrote.
Human gene editing is no longer the stuff of science fiction, and the powerful new technologies that make it possible raise important scientific, ethical, and societal questions.
The organizing committee for a 3-day International Summit On Gene Editing that convened experts from around the world to discuss the issues associated with human gene-editing research, has called upon the international community to work together to establish norms for acceptable uses of human gene editing.
In a statement issued Dec. 3 at the close of the summit, the committee asked the summit cohosts – the U.S. National Academy of Sciences and U.S. National Academy of Medicine, the Royal Society (United Kingdom), and the Chinese Academy of Sciences – to take the lead in creating an ongoing international forum on gene editing and to work on formulating recommendations and guidelines.
“While each nation ultimately has the authority to regulate activities under its jurisdiction, the human genome is shared among all nations,” the committee wrote. “The international community should strive to establish norms concerning acceptable uses of human germline editing and to harmonize regulations, in order to discourage unacceptable activities while advancing human health and welfare.”
The committee also concluded that:
• Intensive basic and preclinical research is needed, with a specific research focus on technologies for editing genetic sequences in human cells, potential benefits and risks of proposed clinical uses for gene editing, and understanding of the biology of human embryos and germline cells. Any early human embryo or germline cells that undergo gene editing should not be used to establish a pregnancy, the committee wrote.
• Improved understanding of the risks of somatic cell editing – such as inaccurate editing – is needed, as is understanding of the potential benefits of each proposed genetic modification. Such uses of gene editing, which are intended to affect only the individual who receives them, can be “appropriately and rigorously evaluated within existing and evolving regulatory frameworks for gene therapy,” they noted.
• Germline editing poses particularly important issues, such as the challenges with predicting harmful effects of genetic changes, including interactions with other genetic variants and with the environment. Moral and ethical considerations, such as the possibility of permanent genetic enhancements that could exacerbate social inequalities or be used coercively, must also be considered. The committee said that “it would be irresponsible to proceed with any clinical use of germline editing” unless and until the safety and efficacy issues have been resolved, and there is broad consensus about the appropriateness of a proposed application.
“At present these criteria have not been met for any proposed clinical use,” the committee wrote, adding that safety issues have not been adequately explored, and the cases of most compelling benefit are limited.
As the science advances and social views evolve, the clinical use of germline editing should be regularly revisited, they wrote.
The presidents of each of the organizations that hosted the summit welcomed the call for ongoing global discussion on issues related to human gene editing.
In a written response they said that they “stand ready to establish a continuing forum for assessment of the many scientific, medical, and ethical questions surrounding the pursuit of human gene-editing applications,” and will coordinate with other academies around the world and other international scientific and medical institutions in that endeavor.
“This is an important moment in human history and we have a responsibility to provide all sections of society with an informed basis for making decisions about this technology, especially for uses that would affect generations to come,” they wrote.
FROM THE INTERNATIONAL SUMMIT ON HUMAN GENE EDITING
