Why is gene therapy for hemophilia taking so long?

 

SAN DIEGO – The goal of gene therapy for hemophilia and other genetic diseases is to achieve long-term expression and levels adequate to improve the phenotype of disease, according to Katherine A. High, MD.

“Sometimes people ask me, ‘Why is it taking so long to develop these therapeutics?’ ” Dr. High said at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “The answer is that gene therapy vectors are arguably one of the most complex therapeutics yet developed.”

Courtesy of Dr. Katherine High

Currently, gene therapy vectors consist of both a protein and a DNA/RNA component that must be precisely assembled. “Most vectors are engineered from viruses and it has taken time to understand and manage the human immune response, which was poorly predicted by animal models,” said Dr. High, a hematologist who is cofounder, president, and head of research and development at Philadelphia-based Spark Therapeutics. “It took 22 years from the first clinical trial of gene therapy vectors to the first licensed product.”

Spark Therapeutics is currently developing gene therapies for hemophilia A (SPK-8011) and hemophilia B (SPK-9001).

Hemostasis and thrombosis targets in gene therapy trials include hemophilia, as well as peripheral artery disease/claudication and congestive heart failure. In the latter, a prior phase 2b trial of adeno-associated virus (AAV) expressing SERCA2a did not support efficacy (Lancet 2016;387:1178-86), while a current trial of adenovirus 5–vector expressing adenylyl cyclase–type 6 is entering phase 3 study (NCT03360448).

To get a sense of how long it may take for a new class of therapeutics to become established, Dr. High noted that the first monoclonal antibody to be licensed was OKT3 (muromonab-CD3) in 1986, followed by abciximab in 1994, rituximab and daclizumab in 1997, and four additional products in 1998. By 2007, 8 of the top 20 biotech drugs were monoclonal antibodies.

Hemophilia has long been a favored gene therapy target because biology is in its favor. “It has a wide therapeutic window, it does not require tissue-specific expression of transgene, small and large animal models exist, and endpoints are well validated and easy to measure,” she said. “Thus, early gene-therapy clinical investigation since 1998 explored many strategies.”

 

There are several current investigational efforts in AAV-mediated gene transfer in hemophilia, including:

• A single-arm study to evaluate the efficacy and safety of valoctocogene roxaparvovec in hemophilia A patients at a dose of 4×10¹³ vector genome per kilogram (NCT03392974).
• A dose-ranging study of recombinant AAV2/6 human factor 8 gene therapy SB-525 in subjects with severe hemophilia A (NCT03061201).
• A safety and dose-escalation study of an adeno-associated viral vector for gene transfer in hemophilia A subjects (NCT03370172).

Other approaches in preclinical investigation include lentiviral transduction of hematopoietic stem cells with megakaryocyte-restricted expression, lentiviral transduction of liver cells and endothelial cells, and genome editing using zinc finger nucleases.

“AAV vectors are one of the smallest of all naturally occurring viruses,” said Dr. High, who is also emeritus professor of pediatrics at the University of Pennsylvania, Philadelphia. “The recombinant AAV consists of a highly ordered set of proteins [vector capsid] containing DNA [the active agent].”

 

Overall goals for a hemophilia gene therapy include long-term expression and levels adequate to prevent bleeds in someone with a normal active lifestyle. “We’d like to see consistency of results from one person to the next, and we’d like to use the lowest possible dose,” she said. “In the setting of gene transfer, the lower the dose, the lower the likelihood of immune responses that need to be managed. Theoretically, the lower the dose, the lower the risk of insertional mutagenesis, and the shorter-term duration of vector shedding in body fluids, including in semen.”

Going forward, a key question for researchers relates to the long-term effect of gene therapy. “How long is long enough?” Dr. High asked. “The longest reported durability is 8 years, with observation ongoing, from studies initially reported in men with severe hemophilia B. The durability in large animal models exceeds 10 years.”

Another unanswered question is what level of factor VIII to aim for in treatment. “Some data suggest that FVIII levels greater than 100 IU/dL are associated with a greater level of thrombosis,” Dr. High said. “So I think somewhere between 12% and 100% is probably the ideal level.”

dbrunk@mdedge.com

 

SAN DIEGO – The goal of gene therapy for hemophilia and other genetic diseases is to achieve long-term expression and levels adequate to improve the phenotype of disease, according to Katherine A. High, MD.

“Sometimes people ask me, ‘Why is it taking so long to develop these therapeutics?’ ” Dr. High said at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “The answer is that gene therapy vectors are arguably one of the most complex therapeutics yet developed.”

Courtesy of Dr. Katherine High

Currently, gene therapy vectors consist of both a protein and a DNA/RNA component that must be precisely assembled. “Most vectors are engineered from viruses and it has taken time to understand and manage the human immune response, which was poorly predicted by animal models,” said Dr. High, a hematologist who is cofounder, president, and head of research and development at Philadelphia-based Spark Therapeutics. “It took 22 years from the first clinical trial of gene therapy vectors to the first licensed product.”

Spark Therapeutics is currently developing gene therapies for hemophilia A (SPK-8011) and hemophilia B (SPK-9001).

Hemostasis and thrombosis targets in gene therapy trials include hemophilia, as well as peripheral artery disease/claudication and congestive heart failure. In the latter, a prior phase 2b trial of adeno-associated virus (AAV) expressing SERCA2a did not support efficacy (Lancet 2016;387:1178-86), while a current trial of adenovirus 5–vector expressing adenylyl cyclase–type 6 is entering phase 3 study (NCT03360448).

To get a sense of how long it may take for a new class of therapeutics to become established, Dr. High noted that the first monoclonal antibody to be licensed was OKT3 (muromonab-CD3) in 1986, followed by abciximab in 1994, rituximab and daclizumab in 1997, and four additional products in 1998. By 2007, 8 of the top 20 biotech drugs were monoclonal antibodies.

Hemophilia has long been a favored gene therapy target because biology is in its favor. “It has a wide therapeutic window, it does not require tissue-specific expression of transgene, small and large animal models exist, and endpoints are well validated and easy to measure,” she said. “Thus, early gene-therapy clinical investigation since 1998 explored many strategies.”

 

There are several current investigational efforts in AAV-mediated gene transfer in hemophilia, including:

• A single-arm study to evaluate the efficacy and safety of valoctocogene roxaparvovec in hemophilia A patients at a dose of 4×10¹³ vector genome per kilogram (NCT03392974).
• A dose-ranging study of recombinant AAV2/6 human factor 8 gene therapy SB-525 in subjects with severe hemophilia A (NCT03061201).
• A safety and dose-escalation study of an adeno-associated viral vector for gene transfer in hemophilia A subjects (NCT03370172).

Other approaches in preclinical investigation include lentiviral transduction of hematopoietic stem cells with megakaryocyte-restricted expression, lentiviral transduction of liver cells and endothelial cells, and genome editing using zinc finger nucleases.

“AAV vectors are one of the smallest of all naturally occurring viruses,” said Dr. High, who is also emeritus professor of pediatrics at the University of Pennsylvania, Philadelphia. “The recombinant AAV consists of a highly ordered set of proteins [vector capsid] containing DNA [the active agent].”

 

Overall goals for a hemophilia gene therapy include long-term expression and levels adequate to prevent bleeds in someone with a normal active lifestyle. “We’d like to see consistency of results from one person to the next, and we’d like to use the lowest possible dose,” she said. “In the setting of gene transfer, the lower the dose, the lower the likelihood of immune responses that need to be managed. Theoretically, the lower the dose, the lower the risk of insertional mutagenesis, and the shorter-term duration of vector shedding in body fluids, including in semen.”

Going forward, a key question for researchers relates to the long-term effect of gene therapy. “How long is long enough?” Dr. High asked. “The longest reported durability is 8 years, with observation ongoing, from studies initially reported in men with severe hemophilia B. The durability in large animal models exceeds 10 years.”

Another unanswered question is what level of factor VIII to aim for in treatment. “Some data suggest that FVIII levels greater than 100 IU/dL are associated with a greater level of thrombosis,” Dr. High said. “So I think somewhere between 12% and 100% is probably the ideal level.”

dbrunk@mdedge.com

 

SAN DIEGO – The goal of gene therapy for hemophilia and other genetic diseases is to achieve long-term expression and levels adequate to improve the phenotype of disease, according to Katherine A. High, MD.

“Sometimes people ask me, ‘Why is it taking so long to develop these therapeutics?’ ” Dr. High said at the biennial summit of the Thrombosis & Hemostasis Societies of North America. “The answer is that gene therapy vectors are arguably one of the most complex therapeutics yet developed.”

Courtesy of Dr. Katherine High

Currently, gene therapy vectors consist of both a protein and a DNA/RNA component that must be precisely assembled. “Most vectors are engineered from viruses and it has taken time to understand and manage the human immune response, which was poorly predicted by animal models,” said Dr. High, a hematologist who is cofounder, president, and head of research and development at Philadelphia-based Spark Therapeutics. “It took 22 years from the first clinical trial of gene therapy vectors to the first licensed product.”

Spark Therapeutics is currently developing gene therapies for hemophilia A (SPK-8011) and hemophilia B (SPK-9001).

Hemostasis and thrombosis targets in gene therapy trials include hemophilia, as well as peripheral artery disease/claudication and congestive heart failure. In the latter, a prior phase 2b trial of adeno-associated virus (AAV) expressing SERCA2a did not support efficacy (Lancet 2016;387:1178-86), while a current trial of adenovirus 5–vector expressing adenylyl cyclase–type 6 is entering phase 3 study (NCT03360448).

To get a sense of how long it may take for a new class of therapeutics to become established, Dr. High noted that the first monoclonal antibody to be licensed was OKT3 (muromonab-CD3) in 1986, followed by abciximab in 1994, rituximab and daclizumab in 1997, and four additional products in 1998. By 2007, 8 of the top 20 biotech drugs were monoclonal antibodies.

Hemophilia has long been a favored gene therapy target because biology is in its favor. “It has a wide therapeutic window, it does not require tissue-specific expression of transgene, small and large animal models exist, and endpoints are well validated and easy to measure,” she said. “Thus, early gene-therapy clinical investigation since 1998 explored many strategies.”

 

There are several current investigational efforts in AAV-mediated gene transfer in hemophilia, including:

• A single-arm study to evaluate the efficacy and safety of valoctocogene roxaparvovec in hemophilia A patients at a dose of 4×10¹³ vector genome per kilogram (NCT03392974).
• A dose-ranging study of recombinant AAV2/6 human factor 8 gene therapy SB-525 in subjects with severe hemophilia A (NCT03061201).
• A safety and dose-escalation study of an adeno-associated viral vector for gene transfer in hemophilia A subjects (NCT03370172).

Other approaches in preclinical investigation include lentiviral transduction of hematopoietic stem cells with megakaryocyte-restricted expression, lentiviral transduction of liver cells and endothelial cells, and genome editing using zinc finger nucleases.

“AAV vectors are one of the smallest of all naturally occurring viruses,” said Dr. High, who is also emeritus professor of pediatrics at the University of Pennsylvania, Philadelphia. “The recombinant AAV consists of a highly ordered set of proteins [vector capsid] containing DNA [the active agent].”

 

Overall goals for a hemophilia gene therapy include long-term expression and levels adequate to prevent bleeds in someone with a normal active lifestyle. “We’d like to see consistency of results from one person to the next, and we’d like to use the lowest possible dose,” she said. “In the setting of gene transfer, the lower the dose, the lower the likelihood of immune responses that need to be managed. Theoretically, the lower the dose, the lower the risk of insertional mutagenesis, and the shorter-term duration of vector shedding in body fluids, including in semen.”

Going forward, a key question for researchers relates to the long-term effect of gene therapy. “How long is long enough?” Dr. High asked. “The longest reported durability is 8 years, with observation ongoing, from studies initially reported in men with severe hemophilia B. The durability in large animal models exceeds 10 years.”

Another unanswered question is what level of factor VIII to aim for in treatment. “Some data suggest that FVIII levels greater than 100 IU/dL are associated with a greater level of thrombosis,” Dr. High said. “So I think somewhere between 12% and 100% is probably the ideal level.”

dbrunk@mdedge.com