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Credit: University College
London Hospitals
A novel gene therapy can provide lasting clinical improvement for men with severe hemophilia B, according to research published in NEJM.
In a study of 10 men, the therapy increased factor IX levels, reduced bleeding episodes, and decreased the use of prophylactic factor IX concentrate. The therapy also allowed some patients to adopt a more active lifestyle.
Four patients experienced temporary increases in liver enzymes, but none reported late toxic effects at a median follow-up of 3 years.
“The data we are reporting mark a paradigm shift in treatment of hemophilia B and lay the groundwork for curing this major bleeding disorder,” said study author Amit Nathwani, MBChB, PhD, of the University College London Cancer Institute in the UK.
“The results also provide a solid platform for developing this gene transfer approach for treatment of other disorders, ranging from other congenital clotting deficiencies like hemophilia A to inborn errors of metabolism such as phenylketonuria.”
The therapy consists of a serotype 8 pseudotyped, self-complementary adeno-associated virus (AAV8) vector expressing a codon-optimized factor IX transgene (scAAV2/8-LP1-hFIXco).
Dr Nathwani and his colleagues tested scAAV2/8-LP1-hFIXco in 10 men with severe hemophilia B to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity.
Six of the patients had been enrolled in a phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose of the therapy. The other 4 patients received the high dose (2 × 1012 vector genomes per kg of body weight). Patients received scAAV2/8-LP1-hFIXco as a single infusion.
Factor IX levels rose in all 10 men following the infusion and have remained stable for a median of 3.2 years (range, 1.5 to 4.3 years).
Overall, episodes of spontaneous bleeding declined 90%. The use of factor IX replacement therapy dropped about 92% in the first 12 months after treatment with scAAV2/8-LP1-hFIXco.
In the 6 participants who received the highest dose of therapy, factor IX levels increased from less than 1% of normal levels to 5% or more.
The increase transformed their disease from severe to mild and enabled participation in sports such as soccer without the need for factor IX replacement therapy or an increase in the risk of bleeding.
Episodes of spontaneous bleeding and the use of factor IX replacement therapy declined for these patients more than 94% in the next 12 months.
Liver enzymes rose in 4 of the 6 patients who received the highest dose of scAAV2/8-LP1-hFIXco, possibly due to an immune response against the vector. The men had no symptoms and remained otherwise healthy. Their liver enzymes returned to the normal range following brief treatment with steroids.
“This study provides the first clear demonstration of the long-term safety and efficacy of gene therapy,” said study author Andrew Davidoff, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“The results so far have made a profound difference in the lives of study participants by dramatically reducing their risk of bleeding.”
Prior to receiving scAAV2/8-LP1-hFIXco, 7 of the men received factor IX replacement therapy at least once a week to prevent bleeding episodes. Others used replacement therapy as needed to halt bleeding or prior to surgeries.
Since joining the trial, 4 of these men ended the routine factor IX injections. And none have suffered spontaneous bleeding despite increased physical activity.
“Some patients have not required clotting factor injections for more than 4 years, which has been life-changing,” Dr Nathwani said.
The researchers estimated that overall spending on factor IX replacement therapy for study participants is down more than $2.5 million.
Twelve men have now joined this ongoing phase 1/2 trial. Half were treated at the University College London and half at St. Jude.
Discussions are underway about expanding the trial to include younger patients with hemophilia B. Meanwhile, work continues to improve and expand use of the vector for the treatment of hemophilia A. 
Credit: University College
London Hospitals
A novel gene therapy can provide lasting clinical improvement for men with severe hemophilia B, according to research published in NEJM.
In a study of 10 men, the therapy increased factor IX levels, reduced bleeding episodes, and decreased the use of prophylactic factor IX concentrate. The therapy also allowed some patients to adopt a more active lifestyle.
Four patients experienced temporary increases in liver enzymes, but none reported late toxic effects at a median follow-up of 3 years.
“The data we are reporting mark a paradigm shift in treatment of hemophilia B and lay the groundwork for curing this major bleeding disorder,” said study author Amit Nathwani, MBChB, PhD, of the University College London Cancer Institute in the UK.
“The results also provide a solid platform for developing this gene transfer approach for treatment of other disorders, ranging from other congenital clotting deficiencies like hemophilia A to inborn errors of metabolism such as phenylketonuria.”
The therapy consists of a serotype 8 pseudotyped, self-complementary adeno-associated virus (AAV8) vector expressing a codon-optimized factor IX transgene (scAAV2/8-LP1-hFIXco).
Dr Nathwani and his colleagues tested scAAV2/8-LP1-hFIXco in 10 men with severe hemophilia B to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity.
Six of the patients had been enrolled in a phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose of the therapy. The other 4 patients received the high dose (2 × 1012 vector genomes per kg of body weight). Patients received scAAV2/8-LP1-hFIXco as a single infusion.
Factor IX levels rose in all 10 men following the infusion and have remained stable for a median of 3.2 years (range, 1.5 to 4.3 years).
Overall, episodes of spontaneous bleeding declined 90%. The use of factor IX replacement therapy dropped about 92% in the first 12 months after treatment with scAAV2/8-LP1-hFIXco.
In the 6 participants who received the highest dose of therapy, factor IX levels increased from less than 1% of normal levels to 5% or more.
The increase transformed their disease from severe to mild and enabled participation in sports such as soccer without the need for factor IX replacement therapy or an increase in the risk of bleeding.
Episodes of spontaneous bleeding and the use of factor IX replacement therapy declined for these patients more than 94% in the next 12 months.
Liver enzymes rose in 4 of the 6 patients who received the highest dose of scAAV2/8-LP1-hFIXco, possibly due to an immune response against the vector. The men had no symptoms and remained otherwise healthy. Their liver enzymes returned to the normal range following brief treatment with steroids.
“This study provides the first clear demonstration of the long-term safety and efficacy of gene therapy,” said study author Andrew Davidoff, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“The results so far have made a profound difference in the lives of study participants by dramatically reducing their risk of bleeding.”
Prior to receiving scAAV2/8-LP1-hFIXco, 7 of the men received factor IX replacement therapy at least once a week to prevent bleeding episodes. Others used replacement therapy as needed to halt bleeding or prior to surgeries.
Since joining the trial, 4 of these men ended the routine factor IX injections. And none have suffered spontaneous bleeding despite increased physical activity.
“Some patients have not required clotting factor injections for more than 4 years, which has been life-changing,” Dr Nathwani said.
The researchers estimated that overall spending on factor IX replacement therapy for study participants is down more than $2.5 million.
Twelve men have now joined this ongoing phase 1/2 trial. Half were treated at the University College London and half at St. Jude.
Discussions are underway about expanding the trial to include younger patients with hemophilia B. Meanwhile, work continues to improve and expand use of the vector for the treatment of hemophilia A.
Credit: University College
London Hospitals
A novel gene therapy can provide lasting clinical improvement for men with severe hemophilia B, according to research published in NEJM.
In a study of 10 men, the therapy increased factor IX levels, reduced bleeding episodes, and decreased the use of prophylactic factor IX concentrate. The therapy also allowed some patients to adopt a more active lifestyle.
Four patients experienced temporary increases in liver enzymes, but none reported late toxic effects at a median follow-up of 3 years.
“The data we are reporting mark a paradigm shift in treatment of hemophilia B and lay the groundwork for curing this major bleeding disorder,” said study author Amit Nathwani, MBChB, PhD, of the University College London Cancer Institute in the UK.
“The results also provide a solid platform for developing this gene transfer approach for treatment of other disorders, ranging from other congenital clotting deficiencies like hemophilia A to inborn errors of metabolism such as phenylketonuria.”
The therapy consists of a serotype 8 pseudotyped, self-complementary adeno-associated virus (AAV8) vector expressing a codon-optimized factor IX transgene (scAAV2/8-LP1-hFIXco).
Dr Nathwani and his colleagues tested scAAV2/8-LP1-hFIXco in 10 men with severe hemophilia B to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity.
Six of the patients had been enrolled in a phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose of the therapy. The other 4 patients received the high dose (2 × 1012 vector genomes per kg of body weight). Patients received scAAV2/8-LP1-hFIXco as a single infusion.
Factor IX levels rose in all 10 men following the infusion and have remained stable for a median of 3.2 years (range, 1.5 to 4.3 years).
Overall, episodes of spontaneous bleeding declined 90%. The use of factor IX replacement therapy dropped about 92% in the first 12 months after treatment with scAAV2/8-LP1-hFIXco.
In the 6 participants who received the highest dose of therapy, factor IX levels increased from less than 1% of normal levels to 5% or more.
The increase transformed their disease from severe to mild and enabled participation in sports such as soccer without the need for factor IX replacement therapy or an increase in the risk of bleeding.
Episodes of spontaneous bleeding and the use of factor IX replacement therapy declined for these patients more than 94% in the next 12 months.
Liver enzymes rose in 4 of the 6 patients who received the highest dose of scAAV2/8-LP1-hFIXco, possibly due to an immune response against the vector. The men had no symptoms and remained otherwise healthy. Their liver enzymes returned to the normal range following brief treatment with steroids.
“This study provides the first clear demonstration of the long-term safety and efficacy of gene therapy,” said study author Andrew Davidoff, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“The results so far have made a profound difference in the lives of study participants by dramatically reducing their risk of bleeding.”
Prior to receiving scAAV2/8-LP1-hFIXco, 7 of the men received factor IX replacement therapy at least once a week to prevent bleeding episodes. Others used replacement therapy as needed to halt bleeding or prior to surgeries.
Since joining the trial, 4 of these men ended the routine factor IX injections. And none have suffered spontaneous bleeding despite increased physical activity.
“Some patients have not required clotting factor injections for more than 4 years, which has been life-changing,” Dr Nathwani said.
The researchers estimated that overall spending on factor IX replacement therapy for study participants is down more than $2.5 million.
Twelve men have now joined this ongoing phase 1/2 trial. Half were treated at the University College London and half at St. Jude.
Discussions are underway about expanding the trial to include younger patients with hemophilia B. Meanwhile, work continues to improve and expand use of the vector for the treatment of hemophilia A.