Gene Therapy

Click here to read supplement.

Gene therapy is a contemporary therapeutic intervention with recent positive results and regulatory approvals either completed or expected in the next several years for various con­ditions. In this supplement, learn more about:

• Basic principles of gene therapy
• In vivo vs ex vivo methods of gene transfer
• Vector types
• Clinical Considerations

About the Author

Click here to read supplement.

Click here to read supplement.

Gene therapy is a contemporary therapeutic intervention with recent positive results and regulatory approvals either completed or expected in the next several years for various con­ditions. In this supplement, learn more about:

• Basic principles of gene therapy
• In vivo vs ex vivo methods of gene transfer
• Vector types
• Clinical Considerations

About the Author

Click here to read supplement.

Click here to read supplement.

Gene therapy is a contemporary therapeutic intervention with recent positive results and regulatory approvals either completed or expected in the next several years for various con­ditions. In this supplement, learn more about:

• Basic principles of gene therapy
• In vivo vs ex vivo methods of gene transfer
• Vector types
• Clinical Considerations

About the Author

Click here to read supplement.

HOUSTON – Lentiviral gene therapy appears safe and was potentially effective in a rare primary immunodeficiency disease known as X-linked chronic granulomatous disease, said Donald B. Kohn, MD, of the University of California, Los Angeles.

Seven of nine patients treated were “alive and well” at 12 months’ follow-up after receiving lentiviral vector transduced CD34+ cells, Dr. Kohn reported in a late-breaking clinical trial session at the Transplantation & Cellular Therapy Meetings.

Most patients were able to discontinue antibiotic prophylaxis for this disease, which is associated with severe, recurrent, and prolonged life-threatening infections, he said.

Results of the small study provide “proof of concept” for use of the gene therapy in the disease, though additional studies are needed to formally assess the clinical safety and efficacy of the approach, he said.

The estimated incidence of chronic granulomatous disease is 1 in 200,000 births in the United States, and the X-linked form is most common, occurring in about 60% of patients, Dr. Kohn told attendees of the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Most of these patients are treated with antibacterial or antifungal prophylaxis. While allogeneic hematopoietic stem cell transplantation is also an option, according to Dr. Kohn, the approach is limited by a lack of matched donors and graft-versus-host disease.

Dr. Kohn reported results for nine patients in the United States and the United Kingdom who were treated with the same G1XCGD lentiviral vector. The patients, who ranged in age from 2 to 27 years, underwent CD34+ cell mobilization or bone marrow isolation, transduction with the lentiviral vector, busulfan conditioning, and autologous transplantation.

All patients had confirmed X-linked chronic granulomatous disease, and had had at least one severe infection or inflammatory complication requiring hospitalization.

There were no infusion-related adverse events, and one serious adverse event, which was an inflammatory syndrome that resolved with steroids. Two patients died from complications unrelated to gene therapy, Dr. Kohn reported.

“The other patients are basically doing quite well,” he said.

Of the seven patients alive at the 12-month follow up, six were reported as “clinically well” and off antibiotic prophylaxis, according to Dr. Kohn, while the seventh patient was clinically well and receiving antimicrobial support.

Dr. Kohn is a scientific advisory board member for Orchard Therapeutics, which licensed the lentiviral gene therapy for X-CGD discussed in his presentation. He is also an inventor of intellectual property related to the therapy that UCLA has licensed to Orchard.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

SOURCE: Kohn DB et al. TCT 2019, Abstract LBA1.

HOUSTON – Lentiviral gene therapy appears safe and was potentially effective in a rare primary immunodeficiency disease known as X-linked chronic granulomatous disease, said Donald B. Kohn, MD, of the University of California, Los Angeles.

Seven of nine patients treated were “alive and well” at 12 months’ follow-up after receiving lentiviral vector transduced CD34+ cells, Dr. Kohn reported in a late-breaking clinical trial session at the Transplantation & Cellular Therapy Meetings.

Most patients were able to discontinue antibiotic prophylaxis for this disease, which is associated with severe, recurrent, and prolonged life-threatening infections, he said.

Results of the small study provide “proof of concept” for use of the gene therapy in the disease, though additional studies are needed to formally assess the clinical safety and efficacy of the approach, he said.

The estimated incidence of chronic granulomatous disease is 1 in 200,000 births in the United States, and the X-linked form is most common, occurring in about 60% of patients, Dr. Kohn told attendees of the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Most of these patients are treated with antibacterial or antifungal prophylaxis. While allogeneic hematopoietic stem cell transplantation is also an option, according to Dr. Kohn, the approach is limited by a lack of matched donors and graft-versus-host disease.

Dr. Kohn reported results for nine patients in the United States and the United Kingdom who were treated with the same G1XCGD lentiviral vector. The patients, who ranged in age from 2 to 27 years, underwent CD34+ cell mobilization or bone marrow isolation, transduction with the lentiviral vector, busulfan conditioning, and autologous transplantation.

All patients had confirmed X-linked chronic granulomatous disease, and had had at least one severe infection or inflammatory complication requiring hospitalization.

There were no infusion-related adverse events, and one serious adverse event, which was an inflammatory syndrome that resolved with steroids. Two patients died from complications unrelated to gene therapy, Dr. Kohn reported.

“The other patients are basically doing quite well,” he said.

Of the seven patients alive at the 12-month follow up, six were reported as “clinically well” and off antibiotic prophylaxis, according to Dr. Kohn, while the seventh patient was clinically well and receiving antimicrobial support.

Dr. Kohn is a scientific advisory board member for Orchard Therapeutics, which licensed the lentiviral gene therapy for X-CGD discussed in his presentation. He is also an inventor of intellectual property related to the therapy that UCLA has licensed to Orchard.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

SOURCE: Kohn DB et al. TCT 2019, Abstract LBA1.

HOUSTON – Lentiviral gene therapy appears safe and was potentially effective in a rare primary immunodeficiency disease known as X-linked chronic granulomatous disease, said Donald B. Kohn, MD, of the University of California, Los Angeles.

Seven of nine patients treated were “alive and well” at 12 months’ follow-up after receiving lentiviral vector transduced CD34+ cells, Dr. Kohn reported in a late-breaking clinical trial session at the Transplantation & Cellular Therapy Meetings.

Most patients were able to discontinue antibiotic prophylaxis for this disease, which is associated with severe, recurrent, and prolonged life-threatening infections, he said.

Results of the small study provide “proof of concept” for use of the gene therapy in the disease, though additional studies are needed to formally assess the clinical safety and efficacy of the approach, he said.

The estimated incidence of chronic granulomatous disease is 1 in 200,000 births in the United States, and the X-linked form is most common, occurring in about 60% of patients, Dr. Kohn told attendees of the meeting held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research.

Most of these patients are treated with antibacterial or antifungal prophylaxis. While allogeneic hematopoietic stem cell transplantation is also an option, according to Dr. Kohn, the approach is limited by a lack of matched donors and graft-versus-host disease.

Dr. Kohn reported results for nine patients in the United States and the United Kingdom who were treated with the same G1XCGD lentiviral vector. The patients, who ranged in age from 2 to 27 years, underwent CD34+ cell mobilization or bone marrow isolation, transduction with the lentiviral vector, busulfan conditioning, and autologous transplantation.

All patients had confirmed X-linked chronic granulomatous disease, and had had at least one severe infection or inflammatory complication requiring hospitalization.

There were no infusion-related adverse events, and one serious adverse event, which was an inflammatory syndrome that resolved with steroids. Two patients died from complications unrelated to gene therapy, Dr. Kohn reported.

“The other patients are basically doing quite well,” he said.

Of the seven patients alive at the 12-month follow up, six were reported as “clinically well” and off antibiotic prophylaxis, according to Dr. Kohn, while the seventh patient was clinically well and receiving antimicrobial support.

Dr. Kohn is a scientific advisory board member for Orchard Therapeutics, which licensed the lentiviral gene therapy for X-CGD discussed in his presentation. He is also an inventor of intellectual property related to the therapy that UCLA has licensed to Orchard.

At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).

SOURCE: Kohn DB et al. TCT 2019, Abstract LBA1.

PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.

Will Pass/MDedge News

“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.

Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.

“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”

A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.


Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”

When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.

Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).

In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.

“This has stepped up the game hugely,” Dr. Pasi said.

The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.

Gene modification is also not coming anytime soon.

“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”

Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.

“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”

Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.

Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.

“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”

The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.

Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”

Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.

“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”

PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.

Will Pass/MDedge News

“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.

Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.

“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”

A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.


Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”

When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.

Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).

In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.

“This has stepped up the game hugely,” Dr. Pasi said.

The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.

Gene modification is also not coming anytime soon.

“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”

Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.

“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”

Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.

Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.

“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”

The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.

Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”

Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.

“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”

PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.

Will Pass/MDedge News

“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.

Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.

“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”

A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.


Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”

When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.

Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).

In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.

“This has stepped up the game hugely,” Dr. Pasi said.

The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.

Gene modification is also not coming anytime soon.

“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”

Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.

“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”

Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.

Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.

“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”

The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.

Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”

Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.

“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”

The high cost of chimeric antigen receptor (CAR) T-cell therapy largely limits its use to the sickest patients and prohibits experimentation in “less-diseased” populations, outcomes data suggest.

For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).

“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.

In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”

“Increasingly these are the big issues,” Mr. Schulthess said.

In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.

The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.

“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.

EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.

The latter is where Mr. Schulthess came in.

His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.

Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.

The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.

“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”

And that comes back to the fact that bone marrow units make money, he said.

CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.

In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.

“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”

Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).

“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.

Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.

Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.

“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”

Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”

Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.

Mr. Schulthess reported that his research was funded by the Dutch government.

sworcester@mdedge.com

The high cost of chimeric antigen receptor (CAR) T-cell therapy largely limits its use to the sickest patients and prohibits experimentation in “less-diseased” populations, outcomes data suggest.

For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).

“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.

In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”

“Increasingly these are the big issues,” Mr. Schulthess said.

In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.

The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.

“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.

EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.

The latter is where Mr. Schulthess came in.

His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.

Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.

The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.

“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”

And that comes back to the fact that bone marrow units make money, he said.

CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.

In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.

“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”

Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).

“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.

Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.

Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.

“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”

Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”

Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.

Mr. Schulthess reported that his research was funded by the Dutch government.

sworcester@mdedge.com

The high cost of chimeric antigen receptor (CAR) T-cell therapy largely limits its use to the sickest patients and prohibits experimentation in “less-diseased” populations, outcomes data suggest.

For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).

“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.

In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”

“Increasingly these are the big issues,” Mr. Schulthess said.

In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.

The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.

“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.

EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.

The latter is where Mr. Schulthess came in.

His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.

Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.

The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.

“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”

And that comes back to the fact that bone marrow units make money, he said.

CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.

In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.

“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”

Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).

“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.

Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.

Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.

“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”

Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”

Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.

Mr. Schulthess reported that his research was funded by the Dutch government.

sworcester@mdedge.com

Click here to read supplement. 

Gene therapy is a contemporary therapeutic intervention with recent positive results and regulatory approvals either completed or expected in the next several years for various con­ditions. In this supplement, learn more about:

• Basic principles of gene therapy
• In vivo vs ex vivo methods of gene transfer
• Vector types
• Clinical Considerations

About the Author

Click here to read supplement. 

Click here to read supplement. 

Gene therapy is a contemporary therapeutic intervention with recent positive results and regulatory approvals either completed or expected in the next several years for various con­ditions. In this supplement, learn more about:

• Basic principles of gene therapy
• In vivo vs ex vivo methods of gene transfer
• Vector types
• Clinical Considerations

About the Author

Click here to read supplement. 

Click here to read supplement. 

Gene therapy is a contemporary therapeutic intervention with recent positive results and regulatory approvals either completed or expected in the next several years for various con­ditions. In this supplement, learn more about:

• Basic principles of gene therapy
• In vivo vs ex vivo methods of gene transfer
• Vector types
• Clinical Considerations

About the Author

Click here to read supplement. 

PRAGUE – AMT-061, a gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector and a Padua variant human factor IX (hFIX) gene, provides clinically meaningful FIX activity, based on early results from an ongoing, phase 2b study.

Will Pass/ MDedge News

The findings provide traction for a phase 3 trial (HOPE-B; NCT03569891) which is currently enrolling, according to lead author Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California, San Diego.

Dr. Von Drygalski said that the results also demonstrate the positive impact of switching from a wild-type hFIX gene in AMT-060 to a Padua hFIX variant in AMT-061, achieved by replacing arginine with leucine at R338L.

Speaking at the annual congress of the European Association for Haemophilia and Allied Disorders, Dr. Von Drygalski referred to AMT-061 as the “enhanced version” of AMT-060. Prior to human trials, nonhuman primate studies comparing AMT-060 with AMT-061 demonstrated a 550% increase in factor IX activity, similar to previous reports of 600%-800% boosts from the Padua variant.

The current findings revealed early outcomes for three men with severe hemophilia B who were given AMT-061. The patients were between 43 years and 50 years of age and had been taking clotting factors prophylactically. Among them, annualized bleed rates ranged from one to five events per year. Two of the three men were HIV-positive, one had IgM antibodies against AAV5, and all three had neutralizing antibodies against AAV5.

“Of note,” Dr. Von Drygalski said, “two of the participants had previously been excluded from participation in gene therapy due to preexisting antibodies against AAV.”

Each man was given a single dose of 2 x 10¹³ gene copies/kg of AMT-061 intravenously. The primary endpoint was efficacy at 6 weeks after administration. Ongoing secondary endpoints include patient-reported bleeding and FIX concentrate use, joint health, patient-reported quality of life, and laboratory parameters. Patients will be followed for 1 year.

Within 2 weeks, all three men achieved meaningful levels of FIX. Two of three patients demonstrated an upward trend of FIX activity that peaked at about 50% of normal. The third patient’s levels plateaued sooner, with the most recent reading at week 14 showing 25%. Mean factor IX activity level was 38% of normal 12 weeks after gene therapy.

“These clotting factor activity levels translated into complete control [of bleeding] with no requirement for factor IX replacement after infusion,” Dr. Von Drygalski said. For comparison, AMT-060, the wild-type version, only achieved levels of 3%-13%, which are less clinically meaningful.

Along with demonstrating efficacy, AMT-061 was well tolerated. One patient had two adverse events that resolved without treatment: very mild C-reactive protein elevation and transient headache. One patient had a very mild and transient AST elevation (week 2, 43 U/L; week 4, 48 U/L) that resolved without treatment. No patients had ALT elevations and immunosuppression was not needed.

These findings provide a strong foundation for the phase 3 HOPE-B trial, which will include about 50 patients with FIX activity no greater than 2%. Dr. Von Drygalski noted that patients with AAV5-neutralizing antibodies will not be excluded.

The investigators reported financial relationships with Bayer, UniQure, Pfizer, Novo Nordisk, Shire, and others.

SOURCE: Von Drygalski A et al. EAHAD 2019, Abstract OR10.

PRAGUE – AMT-061, a gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector and a Padua variant human factor IX (hFIX) gene, provides clinically meaningful FIX activity, based on early results from an ongoing, phase 2b study.

Will Pass/ MDedge News

The findings provide traction for a phase 3 trial (HOPE-B; NCT03569891) which is currently enrolling, according to lead author Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California, San Diego.

Dr. Von Drygalski said that the results also demonstrate the positive impact of switching from a wild-type hFIX gene in AMT-060 to a Padua hFIX variant in AMT-061, achieved by replacing arginine with leucine at R338L.

Speaking at the annual congress of the European Association for Haemophilia and Allied Disorders, Dr. Von Drygalski referred to AMT-061 as the “enhanced version” of AMT-060. Prior to human trials, nonhuman primate studies comparing AMT-060 with AMT-061 demonstrated a 550% increase in factor IX activity, similar to previous reports of 600%-800% boosts from the Padua variant.

The current findings revealed early outcomes for three men with severe hemophilia B who were given AMT-061. The patients were between 43 years and 50 years of age and had been taking clotting factors prophylactically. Among them, annualized bleed rates ranged from one to five events per year. Two of the three men were HIV-positive, one had IgM antibodies against AAV5, and all three had neutralizing antibodies against AAV5.

“Of note,” Dr. Von Drygalski said, “two of the participants had previously been excluded from participation in gene therapy due to preexisting antibodies against AAV.”

Each man was given a single dose of 2 x 10¹³ gene copies/kg of AMT-061 intravenously. The primary endpoint was efficacy at 6 weeks after administration. Ongoing secondary endpoints include patient-reported bleeding and FIX concentrate use, joint health, patient-reported quality of life, and laboratory parameters. Patients will be followed for 1 year.

Within 2 weeks, all three men achieved meaningful levels of FIX. Two of three patients demonstrated an upward trend of FIX activity that peaked at about 50% of normal. The third patient’s levels plateaued sooner, with the most recent reading at week 14 showing 25%. Mean factor IX activity level was 38% of normal 12 weeks after gene therapy.

“These clotting factor activity levels translated into complete control [of bleeding] with no requirement for factor IX replacement after infusion,” Dr. Von Drygalski said. For comparison, AMT-060, the wild-type version, only achieved levels of 3%-13%, which are less clinically meaningful.

Along with demonstrating efficacy, AMT-061 was well tolerated. One patient had two adverse events that resolved without treatment: very mild C-reactive protein elevation and transient headache. One patient had a very mild and transient AST elevation (week 2, 43 U/L; week 4, 48 U/L) that resolved without treatment. No patients had ALT elevations and immunosuppression was not needed.

These findings provide a strong foundation for the phase 3 HOPE-B trial, which will include about 50 patients with FIX activity no greater than 2%. Dr. Von Drygalski noted that patients with AAV5-neutralizing antibodies will not be excluded.

The investigators reported financial relationships with Bayer, UniQure, Pfizer, Novo Nordisk, Shire, and others.

SOURCE: Von Drygalski A et al. EAHAD 2019, Abstract OR10.

PRAGUE – AMT-061, a gene therapy consisting of an adeno-associated virus serotype 5 (AAV5) vector and a Padua variant human factor IX (hFIX) gene, provides clinically meaningful FIX activity, based on early results from an ongoing, phase 2b study.

Will Pass/ MDedge News

The findings provide traction for a phase 3 trial (HOPE-B; NCT03569891) which is currently enrolling, according to lead author Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California, San Diego.

Dr. Von Drygalski said that the results also demonstrate the positive impact of switching from a wild-type hFIX gene in AMT-060 to a Padua hFIX variant in AMT-061, achieved by replacing arginine with leucine at R338L.

Speaking at the annual congress of the European Association for Haemophilia and Allied Disorders, Dr. Von Drygalski referred to AMT-061 as the “enhanced version” of AMT-060. Prior to human trials, nonhuman primate studies comparing AMT-060 with AMT-061 demonstrated a 550% increase in factor IX activity, similar to previous reports of 600%-800% boosts from the Padua variant.

The current findings revealed early outcomes for three men with severe hemophilia B who were given AMT-061. The patients were between 43 years and 50 years of age and had been taking clotting factors prophylactically. Among them, annualized bleed rates ranged from one to five events per year. Two of the three men were HIV-positive, one had IgM antibodies against AAV5, and all three had neutralizing antibodies against AAV5.

“Of note,” Dr. Von Drygalski said, “two of the participants had previously been excluded from participation in gene therapy due to preexisting antibodies against AAV.”

Each man was given a single dose of 2 x 10¹³ gene copies/kg of AMT-061 intravenously. The primary endpoint was efficacy at 6 weeks after administration. Ongoing secondary endpoints include patient-reported bleeding and FIX concentrate use, joint health, patient-reported quality of life, and laboratory parameters. Patients will be followed for 1 year.

Within 2 weeks, all three men achieved meaningful levels of FIX. Two of three patients demonstrated an upward trend of FIX activity that peaked at about 50% of normal. The third patient’s levels plateaued sooner, with the most recent reading at week 14 showing 25%. Mean factor IX activity level was 38% of normal 12 weeks after gene therapy.

“These clotting factor activity levels translated into complete control [of bleeding] with no requirement for factor IX replacement after infusion,” Dr. Von Drygalski said. For comparison, AMT-060, the wild-type version, only achieved levels of 3%-13%, which are less clinically meaningful.

Along with demonstrating efficacy, AMT-061 was well tolerated. One patient had two adverse events that resolved without treatment: very mild C-reactive protein elevation and transient headache. One patient had a very mild and transient AST elevation (week 2, 43 U/L; week 4, 48 U/L) that resolved without treatment. No patients had ALT elevations and immunosuppression was not needed.

These findings provide a strong foundation for the phase 3 HOPE-B trial, which will include about 50 patients with FIX activity no greater than 2%. Dr. Von Drygalski noted that patients with AAV5-neutralizing antibodies will not be excluded.

The investigators reported financial relationships with Bayer, UniQure, Pfizer, Novo Nordisk, Shire, and others.

SOURCE: Von Drygalski A et al. EAHAD 2019, Abstract OR10.

The Centers for Medicare & Medicaid Services has proposed to cover chimeric antigen receptor (CAR) T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness, according to a Feb. 15 announcement.

Penn Medicine

The proposed national coverage determination would require CMS to cover CAR T-cell therapies nationwide when the treatment is offered in CMS-approved registries or clinical studies in which patients are monitored for 2 or more years following treatment.

Results from the studies would help CMS identify which patients benefit most from CAR T-cell therapies and inform future coverage decisions, CMS Administrator Seema Verma said.

“CAR T-cell therapy was the first FDA-approved gene therapy, marking the beginning of an entirely new approach to treating serious and even life-threatening diseases,” Ms. Verma said in a statement. “Today’s proposed coverage decision would improve access to this therapy while deepening CMS’s understanding of how patients in Medicare respond to it, so the agency can ensure that it is paying for CAR T-cell therapy for cases in which the benefits outweigh the risks.”

As part of the proposal, CMS would cover autologous treatment with T cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development when prescribed by a treating oncologist and performed in a hospital, according to a summary of the proposal.

The patient and hospital must meet specific criteria to be eligible for coverage, including that patients have relapsed or refractory cancer and do not have a comorbidity that would otherwise preclude patient benefit.

Hospitals, meanwhile, must have a cellular therapy program consisting of an integrated medical team that includes a clinical program director, a quality manager, and at least one physician experienced in cellular therapy, among other requirements.

CMS also would require that treatment is an FDA-approved biologic, providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication. Repeat treatment would be covered only when a new primary cancer diagnosis is made by the treating oncologist and certain patient conditions are met.

Both inpatient and outpatient settings for the CAR T-cell therapy treatment are acceptable under the proposal. In either case, the patient and the hospital must be participating in a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least 2 years, and addresses a set of approved evidence-development questions. Additionally, all registries must be reviewed and approved by CMS.

The proposed national coverage determination was the result of an Aug. 22, 2018 meeting of the Medicare Evidence Development & Coverage Advisory Committee. The committee provides CMS with an external assessment of the appropriateness of therapies under review.

Public comments about the CAR T-cell therapy proposal will be accepted online here until March 15. A final decision on the proposal is expected by May 2019.

The agency’s proposal follows an Aug. 17 final rule by CMS that sets a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorizes CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigns ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018. CMS also approved a temporary New Technology Add-On Payment for use of the therapies with a maximum threshold of $186,500.

In April 2018, CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

agallegos@mdedge.com

The Centers for Medicare & Medicaid Services has proposed to cover chimeric antigen receptor (CAR) T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness, according to a Feb. 15 announcement.

Penn Medicine

The proposed national coverage determination would require CMS to cover CAR T-cell therapies nationwide when the treatment is offered in CMS-approved registries or clinical studies in which patients are monitored for 2 or more years following treatment.

Results from the studies would help CMS identify which patients benefit most from CAR T-cell therapies and inform future coverage decisions, CMS Administrator Seema Verma said.

“CAR T-cell therapy was the first FDA-approved gene therapy, marking the beginning of an entirely new approach to treating serious and even life-threatening diseases,” Ms. Verma said in a statement. “Today’s proposed coverage decision would improve access to this therapy while deepening CMS’s understanding of how patients in Medicare respond to it, so the agency can ensure that it is paying for CAR T-cell therapy for cases in which the benefits outweigh the risks.”

As part of the proposal, CMS would cover autologous treatment with T cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development when prescribed by a treating oncologist and performed in a hospital, according to a summary of the proposal.

The patient and hospital must meet specific criteria to be eligible for coverage, including that patients have relapsed or refractory cancer and do not have a comorbidity that would otherwise preclude patient benefit.

Hospitals, meanwhile, must have a cellular therapy program consisting of an integrated medical team that includes a clinical program director, a quality manager, and at least one physician experienced in cellular therapy, among other requirements.

CMS also would require that treatment is an FDA-approved biologic, providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication. Repeat treatment would be covered only when a new primary cancer diagnosis is made by the treating oncologist and certain patient conditions are met.

Both inpatient and outpatient settings for the CAR T-cell therapy treatment are acceptable under the proposal. In either case, the patient and the hospital must be participating in a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least 2 years, and addresses a set of approved evidence-development questions. Additionally, all registries must be reviewed and approved by CMS.

The proposed national coverage determination was the result of an Aug. 22, 2018 meeting of the Medicare Evidence Development & Coverage Advisory Committee. The committee provides CMS with an external assessment of the appropriateness of therapies under review.

Public comments about the CAR T-cell therapy proposal will be accepted online here until March 15. A final decision on the proposal is expected by May 2019.

The agency’s proposal follows an Aug. 17 final rule by CMS that sets a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorizes CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigns ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018. CMS also approved a temporary New Technology Add-On Payment for use of the therapies with a maximum threshold of $186,500.

In April 2018, CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

agallegos@mdedge.com

The Centers for Medicare & Medicaid Services has proposed to cover chimeric antigen receptor (CAR) T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness, according to a Feb. 15 announcement.

Penn Medicine

The proposed national coverage determination would require CMS to cover CAR T-cell therapies nationwide when the treatment is offered in CMS-approved registries or clinical studies in which patients are monitored for 2 or more years following treatment.

Results from the studies would help CMS identify which patients benefit most from CAR T-cell therapies and inform future coverage decisions, CMS Administrator Seema Verma said.

“CAR T-cell therapy was the first FDA-approved gene therapy, marking the beginning of an entirely new approach to treating serious and even life-threatening diseases,” Ms. Verma said in a statement. “Today’s proposed coverage decision would improve access to this therapy while deepening CMS’s understanding of how patients in Medicare respond to it, so the agency can ensure that it is paying for CAR T-cell therapy for cases in which the benefits outweigh the risks.”

As part of the proposal, CMS would cover autologous treatment with T cells expressing at least one chimeric antigen receptor (CAR) through coverage with evidence development when prescribed by a treating oncologist and performed in a hospital, according to a summary of the proposal.

The patient and hospital must meet specific criteria to be eligible for coverage, including that patients have relapsed or refractory cancer and do not have a comorbidity that would otherwise preclude patient benefit.

Hospitals, meanwhile, must have a cellular therapy program consisting of an integrated medical team that includes a clinical program director, a quality manager, and at least one physician experienced in cellular therapy, among other requirements.

CMS also would require that treatment is an FDA-approved biologic, providing targeted therapy for a known antigen expressed in the patient’s cancer according to an FDA indication. Repeat treatment would be covered only when a new primary cancer diagnosis is made by the treating oncologist and certain patient conditions are met.

Both inpatient and outpatient settings for the CAR T-cell therapy treatment are acceptable under the proposal. In either case, the patient and the hospital must be participating in a prospective, national, audited registry that consecutively enrolls patients, accepts all manufactured products, follows the patient for at least 2 years, and addresses a set of approved evidence-development questions. Additionally, all registries must be reviewed and approved by CMS.

The proposed national coverage determination was the result of an Aug. 22, 2018 meeting of the Medicare Evidence Development & Coverage Advisory Committee. The committee provides CMS with an external assessment of the appropriateness of therapies under review.

Public comments about the CAR T-cell therapy proposal will be accepted online here until March 15. A final decision on the proposal is expected by May 2019.

The agency’s proposal follows an Aug. 17 final rule by CMS that sets a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorizes CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigns ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018. CMS also approved a temporary New Technology Add-On Payment for use of the therapies with a maximum threshold of $186,500.

In April 2018, CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.

agallegos@mdedge.com

SAN DIEGO – Investigational SPK-8011 gene transfer results in safe, durable, dose-dependent Factor VIII (FVIII) expression in patients with severe or moderately severe hemophilia A, according to preliminary findings from an ongoing phase 1/2 study.

An overall reduction of 97% was seen in both the annualized bleeding rate (ABR) and annualized infusion rate (AIR) in the first 12 patients treated with SPK-8011, which is a Spark Therapeutics product that consists of a bioengineered AAV capsid expressing B domain-deleted FVIII under the control of a liver-specific promoter, principal investigator Lindsey A. George, MD, reported at the annual meeting of the American Society of Hematology.

Study subjects were men aged 18-52 years, including 11 with severe disease and 1 with moderately severe disease, who received a single infusion of either 5E11 vg/kg (2 patients), 1E12 vg/kg (3 patients), or 2E12 vg/kg (7 patients).

“All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis,” said Dr. George, associate professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician in the division of hematology at Children’s Hospital of Philadelphia.

In the two men in the 5E11 dose cohort, mean FVIII levels beginning 12 weeks after infusion were 13%, and neither experienced bleeding events, had elevated transaminase levels, or required steroids, she said, noting that FVIII expression remained stable for at least 66 weeks (and up to 78 weeks in one patient).

The three men in the 1E12 dose cohort had mean FVIII levels of 15% beginning at 12 weeks post infusion, and the levels were stable for at least 46 weeks.

The first patient was infused with a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second patient received multiple infusions for a traumatic bleed beginning at day 195. Both received a successful course of tapering steroids, at 12 and 7 weeks after infusion, respectively, for declining FVIII levels, Dr. George said.

The third subject had no bleeding and did not receive factor infusions or steroids, she added.

In the highest dose cohort (2E12), five of seven subjects had FVIII levels between 16% and 49%.

Steroids were required and given between 6 and 11 weeks after infusion in five of the seven patients in that cohort for either declining FVIII levels, a rise in alanine aminotransferase (ALT) above baseline, or elevated IFN-g ELISPOTs to AAV capsid. The steroids normalized ALT levels and extinguished the ELISPOT signal in all cases.

In two patients, FVIII levels showed limited stabilization, and fell to less than 6%. This was most likely due to the immune response, Dr. George explained, noting that in one of the two patients no bleeds were reported through 12 weeks of follow-up, while the other experienced four bleeds through 37 weeks of observation.

SPK-8011 was well tolerated in this study, which had cumulative follow-up of 506 weeks at the time of Dr. George’s presentation. No inhibitor formation was noted in the safety analysis and the only serious adverse event – the immune response to AAV capsid – has resolved, she said.

Data from the lowest dose cohort (5E11) are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events, she said. However, she noted that the loss of some FVIII expression in two patients in the 2E12 dose cohort (which eventually stabilized on steroids), and the fact that five of seven subjects in this cohort required steroids, suggests a possible role for prophylactic steroid administration in patients treated with SPK-8011.

“Gene transfer for hemophilia A offers the potential for a one-time disease-altering treatment that eliminates bleed risk and could free patients from the burden of lifelong chronic therapy,” Dr. George said.

A phase 3 run-in study is planned, she added.

Spark Therapeutics sponsored the study. Dr. George reported equity ownership related to the University of Pennsylvania and consultancy for Pfizer.

sworcester@mdedge.com

SOURCE: High K et al., ASH 2018, Abstract 487.

SAN DIEGO – Investigational SPK-8011 gene transfer results in safe, durable, dose-dependent Factor VIII (FVIII) expression in patients with severe or moderately severe hemophilia A, according to preliminary findings from an ongoing phase 1/2 study.

An overall reduction of 97% was seen in both the annualized bleeding rate (ABR) and annualized infusion rate (AIR) in the first 12 patients treated with SPK-8011, which is a Spark Therapeutics product that consists of a bioengineered AAV capsid expressing B domain-deleted FVIII under the control of a liver-specific promoter, principal investigator Lindsey A. George, MD, reported at the annual meeting of the American Society of Hematology.

Study subjects were men aged 18-52 years, including 11 with severe disease and 1 with moderately severe disease, who received a single infusion of either 5E11 vg/kg (2 patients), 1E12 vg/kg (3 patients), or 2E12 vg/kg (7 patients).

“All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis,” said Dr. George, associate professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician in the division of hematology at Children’s Hospital of Philadelphia.

In the two men in the 5E11 dose cohort, mean FVIII levels beginning 12 weeks after infusion were 13%, and neither experienced bleeding events, had elevated transaminase levels, or required steroids, she said, noting that FVIII expression remained stable for at least 66 weeks (and up to 78 weeks in one patient).

The three men in the 1E12 dose cohort had mean FVIII levels of 15% beginning at 12 weeks post infusion, and the levels were stable for at least 46 weeks.

The first patient was infused with a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second patient received multiple infusions for a traumatic bleed beginning at day 195. Both received a successful course of tapering steroids, at 12 and 7 weeks after infusion, respectively, for declining FVIII levels, Dr. George said.

The third subject had no bleeding and did not receive factor infusions or steroids, she added.

In the highest dose cohort (2E12), five of seven subjects had FVIII levels between 16% and 49%.

Steroids were required and given between 6 and 11 weeks after infusion in five of the seven patients in that cohort for either declining FVIII levels, a rise in alanine aminotransferase (ALT) above baseline, or elevated IFN-g ELISPOTs to AAV capsid. The steroids normalized ALT levels and extinguished the ELISPOT signal in all cases.

In two patients, FVIII levels showed limited stabilization, and fell to less than 6%. This was most likely due to the immune response, Dr. George explained, noting that in one of the two patients no bleeds were reported through 12 weeks of follow-up, while the other experienced four bleeds through 37 weeks of observation.

SPK-8011 was well tolerated in this study, which had cumulative follow-up of 506 weeks at the time of Dr. George’s presentation. No inhibitor formation was noted in the safety analysis and the only serious adverse event – the immune response to AAV capsid – has resolved, she said.

Data from the lowest dose cohort (5E11) are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events, she said. However, she noted that the loss of some FVIII expression in two patients in the 2E12 dose cohort (which eventually stabilized on steroids), and the fact that five of seven subjects in this cohort required steroids, suggests a possible role for prophylactic steroid administration in patients treated with SPK-8011.

“Gene transfer for hemophilia A offers the potential for a one-time disease-altering treatment that eliminates bleed risk and could free patients from the burden of lifelong chronic therapy,” Dr. George said.

A phase 3 run-in study is planned, she added.

Spark Therapeutics sponsored the study. Dr. George reported equity ownership related to the University of Pennsylvania and consultancy for Pfizer.

sworcester@mdedge.com

SOURCE: High K et al., ASH 2018, Abstract 487.

SAN DIEGO – Investigational SPK-8011 gene transfer results in safe, durable, dose-dependent Factor VIII (FVIII) expression in patients with severe or moderately severe hemophilia A, according to preliminary findings from an ongoing phase 1/2 study.

An overall reduction of 97% was seen in both the annualized bleeding rate (ABR) and annualized infusion rate (AIR) in the first 12 patients treated with SPK-8011, which is a Spark Therapeutics product that consists of a bioengineered AAV capsid expressing B domain-deleted FVIII under the control of a liver-specific promoter, principal investigator Lindsey A. George, MD, reported at the annual meeting of the American Society of Hematology.

Study subjects were men aged 18-52 years, including 11 with severe disease and 1 with moderately severe disease, who received a single infusion of either 5E11 vg/kg (2 patients), 1E12 vg/kg (3 patients), or 2E12 vg/kg (7 patients).

“All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis,” said Dr. George, associate professor of pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, and an attending physician in the division of hematology at Children’s Hospital of Philadelphia.

In the two men in the 5E11 dose cohort, mean FVIII levels beginning 12 weeks after infusion were 13%, and neither experienced bleeding events, had elevated transaminase levels, or required steroids, she said, noting that FVIII expression remained stable for at least 66 weeks (and up to 78 weeks in one patient).

The three men in the 1E12 dose cohort had mean FVIII levels of 15% beginning at 12 weeks post infusion, and the levels were stable for at least 46 weeks.

The first patient was infused with a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second patient received multiple infusions for a traumatic bleed beginning at day 195. Both received a successful course of tapering steroids, at 12 and 7 weeks after infusion, respectively, for declining FVIII levels, Dr. George said.

The third subject had no bleeding and did not receive factor infusions or steroids, she added.

In the highest dose cohort (2E12), five of seven subjects had FVIII levels between 16% and 49%.

Steroids were required and given between 6 and 11 weeks after infusion in five of the seven patients in that cohort for either declining FVIII levels, a rise in alanine aminotransferase (ALT) above baseline, or elevated IFN-g ELISPOTs to AAV capsid. The steroids normalized ALT levels and extinguished the ELISPOT signal in all cases.

In two patients, FVIII levels showed limited stabilization, and fell to less than 6%. This was most likely due to the immune response, Dr. George explained, noting that in one of the two patients no bleeds were reported through 12 weeks of follow-up, while the other experienced four bleeds through 37 weeks of observation.

SPK-8011 was well tolerated in this study, which had cumulative follow-up of 506 weeks at the time of Dr. George’s presentation. No inhibitor formation was noted in the safety analysis and the only serious adverse event – the immune response to AAV capsid – has resolved, she said.

Data from the lowest dose cohort (5E11) are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events, she said. However, she noted that the loss of some FVIII expression in two patients in the 2E12 dose cohort (which eventually stabilized on steroids), and the fact that five of seven subjects in this cohort required steroids, suggests a possible role for prophylactic steroid administration in patients treated with SPK-8011.

“Gene transfer for hemophilia A offers the potential for a one-time disease-altering treatment that eliminates bleed risk and could free patients from the burden of lifelong chronic therapy,” Dr. George said.

A phase 3 run-in study is planned, she added.

Spark Therapeutics sponsored the study. Dr. George reported equity ownership related to the University of Pennsylvania and consultancy for Pfizer.

sworcester@mdedge.com

SOURCE: High K et al., ASH 2018, Abstract 487.

SAN DIEGO – A novel human factor VIII variant shows promise for the treatment of severe hemophilia A, according to preliminary findings from the ongoing Gene Therapy for Hemophilia A (GO-8) phase 1/2 dose-escalation study.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

A single peripheral vein infusion of the factor VIII (FVIII) variant resulted in FVIII activity levels of about 6% versus levels of no more than 1% of normal at study entry in the first four patients, Pratima Chowdary, MD, reported at the annual meeting of the American Society of Hematology.

The variant, known as scAAV2/8-LP1-hFIXco, is being investigated for safety and efficacy in the GO-8 investigator-led, open-label, nonrandomized trial at a low, mid, and high dose (2 x 10¹¹ vector genomes/kg, 6 x 10¹¹ vector genomes/kg, and 2 x 10¹² vector genomes/kg), said Dr. Chowdary, a consultant hematologist at Royal Free Hospital London.

The main study period is 6 months and 15 years of follow-up are offered.

The first patient received the low dose and achieved FVIII of about 6% within 1 week. That level persisted for about 6 weeks when the patient developed a transaminitis, which promptly responded to steroids.

His steady-state FVIII within a few weeks was 7% by one-stage assay and about 3% by chromogenic assay, Dr. Chowdary said.

The remaining patients received the mid dose and also achieved FVIII levels of about 6% within a week. Patient 2 started on prophylactic steroids at week 6, per protocol, and did not experience transaminitis, but also had no increase in FVIII level, compared with the low-dose patient, which may be explained by the potential drug half-life, she noted.

Patient 3 reached a FVIII level of about 30% by week 4. He developed transaminitis at that time, which was about 2 weeks before planned prophylactic drug administration, but the transaminitis was controlled by steroids over a period of about 8-10 weeks.

“His steady-state FVIII level by one stage was 34% and by chromogenic assay was 17%. He has not had any bleeds since his gene transfer and has not required any FVIII concentrate either,” she said.

Patient 4 reached a FVIII level of about 40% by week 4. He was given prophylactic steroids at that time because of the occurrence of transaminitis at week 4 in Patient 3.

The patient developed transaminitis during steroid taper about 4 weeks later, perhaps because of the rapid taper, Dr. Chowdary said, adding that the transaminitis was well controlled with steroids, but follow-up in this patient has only been about 12 weeks.

“The characteristics of FVIII expression in this patient are very similar to the previous patient. ... We suspect he will have a steady-state level of about 30%,” she said. “Again, he’s had no bleeds since his gene transfer and has not required any FVIII concentrate.”

The single infusion of this novel vector was well tolerated in each patient, with no evidence of infusion-related reactions, neutralizing anti-FVIII antibodies, or vector-related adverse events.

“The transgene expression was achieved in all patients and at both vector dosages,” Dr. Chowdary said. “What is very important is that the levels of less than 10% had only a modest impact on the bleed rates and FVIII usage, whereas an expression of more than 10% resulted in zero bleeds and the patient did not require any additional FVIII treatment.”

The data are “encouraging,” she said. “We look forward to escalating the dose in the next patient.”

Dr. Chowdary reported financial relationships with Bayer, CSL Behring, Baxalta, Baxter, Biogen, Freeline, Novo Nordisk, Pfizer, Roche, Shire, and SOBI.

sworcester@mdedge.com

SOURCE: Chowdary P et al. ASH 2018, Abstract 489.

SAN DIEGO – A novel human factor VIII variant shows promise for the treatment of severe hemophilia A, according to preliminary findings from the ongoing Gene Therapy for Hemophilia A (GO-8) phase 1/2 dose-escalation study.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

A single peripheral vein infusion of the factor VIII (FVIII) variant resulted in FVIII activity levels of about 6% versus levels of no more than 1% of normal at study entry in the first four patients, Pratima Chowdary, MD, reported at the annual meeting of the American Society of Hematology.

The variant, known as scAAV2/8-LP1-hFIXco, is being investigated for safety and efficacy in the GO-8 investigator-led, open-label, nonrandomized trial at a low, mid, and high dose (2 x 10¹¹ vector genomes/kg, 6 x 10¹¹ vector genomes/kg, and 2 x 10¹² vector genomes/kg), said Dr. Chowdary, a consultant hematologist at Royal Free Hospital London.

The main study period is 6 months and 15 years of follow-up are offered.

The first patient received the low dose and achieved FVIII of about 6% within 1 week. That level persisted for about 6 weeks when the patient developed a transaminitis, which promptly responded to steroids.

His steady-state FVIII within a few weeks was 7% by one-stage assay and about 3% by chromogenic assay, Dr. Chowdary said.

The remaining patients received the mid dose and also achieved FVIII levels of about 6% within a week. Patient 2 started on prophylactic steroids at week 6, per protocol, and did not experience transaminitis, but also had no increase in FVIII level, compared with the low-dose patient, which may be explained by the potential drug half-life, she noted.

Patient 3 reached a FVIII level of about 30% by week 4. He developed transaminitis at that time, which was about 2 weeks before planned prophylactic drug administration, but the transaminitis was controlled by steroids over a period of about 8-10 weeks.

“His steady-state FVIII level by one stage was 34% and by chromogenic assay was 17%. He has not had any bleeds since his gene transfer and has not required any FVIII concentrate either,” she said.

Patient 4 reached a FVIII level of about 40% by week 4. He was given prophylactic steroids at that time because of the occurrence of transaminitis at week 4 in Patient 3.

The patient developed transaminitis during steroid taper about 4 weeks later, perhaps because of the rapid taper, Dr. Chowdary said, adding that the transaminitis was well controlled with steroids, but follow-up in this patient has only been about 12 weeks.

“The characteristics of FVIII expression in this patient are very similar to the previous patient. ... We suspect he will have a steady-state level of about 30%,” she said. “Again, he’s had no bleeds since his gene transfer and has not required any FVIII concentrate.”

The single infusion of this novel vector was well tolerated in each patient, with no evidence of infusion-related reactions, neutralizing anti-FVIII antibodies, or vector-related adverse events.

“The transgene expression was achieved in all patients and at both vector dosages,” Dr. Chowdary said. “What is very important is that the levels of less than 10% had only a modest impact on the bleed rates and FVIII usage, whereas an expression of more than 10% resulted in zero bleeds and the patient did not require any additional FVIII treatment.”

The data are “encouraging,” she said. “We look forward to escalating the dose in the next patient.”

Dr. Chowdary reported financial relationships with Bayer, CSL Behring, Baxalta, Baxter, Biogen, Freeline, Novo Nordisk, Pfizer, Roche, Shire, and SOBI.

sworcester@mdedge.com

SOURCE: Chowdary P et al. ASH 2018, Abstract 489.

SAN DIEGO – A novel human factor VIII variant shows promise for the treatment of severe hemophilia A, according to preliminary findings from the ongoing Gene Therapy for Hemophilia A (GO-8) phase 1/2 dose-escalation study.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

A single peripheral vein infusion of the factor VIII (FVIII) variant resulted in FVIII activity levels of about 6% versus levels of no more than 1% of normal at study entry in the first four patients, Pratima Chowdary, MD, reported at the annual meeting of the American Society of Hematology.

The variant, known as scAAV2/8-LP1-hFIXco, is being investigated for safety and efficacy in the GO-8 investigator-led, open-label, nonrandomized trial at a low, mid, and high dose (2 x 10¹¹ vector genomes/kg, 6 x 10¹¹ vector genomes/kg, and 2 x 10¹² vector genomes/kg), said Dr. Chowdary, a consultant hematologist at Royal Free Hospital London.

The main study period is 6 months and 15 years of follow-up are offered.

The first patient received the low dose and achieved FVIII of about 6% within 1 week. That level persisted for about 6 weeks when the patient developed a transaminitis, which promptly responded to steroids.

His steady-state FVIII within a few weeks was 7% by one-stage assay and about 3% by chromogenic assay, Dr. Chowdary said.

The remaining patients received the mid dose and also achieved FVIII levels of about 6% within a week. Patient 2 started on prophylactic steroids at week 6, per protocol, and did not experience transaminitis, but also had no increase in FVIII level, compared with the low-dose patient, which may be explained by the potential drug half-life, she noted.

Patient 3 reached a FVIII level of about 30% by week 4. He developed transaminitis at that time, which was about 2 weeks before planned prophylactic drug administration, but the transaminitis was controlled by steroids over a period of about 8-10 weeks.

“His steady-state FVIII level by one stage was 34% and by chromogenic assay was 17%. He has not had any bleeds since his gene transfer and has not required any FVIII concentrate either,” she said.

Patient 4 reached a FVIII level of about 40% by week 4. He was given prophylactic steroids at that time because of the occurrence of transaminitis at week 4 in Patient 3.

The patient developed transaminitis during steroid taper about 4 weeks later, perhaps because of the rapid taper, Dr. Chowdary said, adding that the transaminitis was well controlled with steroids, but follow-up in this patient has only been about 12 weeks.

“The characteristics of FVIII expression in this patient are very similar to the previous patient. ... We suspect he will have a steady-state level of about 30%,” she said. “Again, he’s had no bleeds since his gene transfer and has not required any FVIII concentrate.”

The single infusion of this novel vector was well tolerated in each patient, with no evidence of infusion-related reactions, neutralizing anti-FVIII antibodies, or vector-related adverse events.

“The transgene expression was achieved in all patients and at both vector dosages,” Dr. Chowdary said. “What is very important is that the levels of less than 10% had only a modest impact on the bleed rates and FVIII usage, whereas an expression of more than 10% resulted in zero bleeds and the patient did not require any additional FVIII treatment.”

The data are “encouraging,” she said. “We look forward to escalating the dose in the next patient.”

Dr. Chowdary reported financial relationships with Bayer, CSL Behring, Baxalta, Baxter, Biogen, Freeline, Novo Nordisk, Pfizer, Roche, Shire, and SOBI.

sworcester@mdedge.com

SOURCE: Chowdary P et al. ASH 2018, Abstract 489.

SAN DIEGO – Therapeutic expression of factor IX remains stable with no late toxicities occurring at up to 8.6 years after a single infusion of a novel gene therapy in patients with severe hemophilia B, according to interim follow-up data from a phase 1/2 dose-escalation study.

The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.

However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.

At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 10¹¹, 6 x 10¹¹, or 2 x 10¹² vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.

“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.

The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.

“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”

Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”

Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.

“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.

Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.

“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.

Dr. Reiss reported having no relevant disclosures

sworcester@mdedge.com

SOURCE: Reiss UM et al. ASH 2018, Abstract 491.

SAN DIEGO – Therapeutic expression of factor IX remains stable with no late toxicities occurring at up to 8.6 years after a single infusion of a novel gene therapy in patients with severe hemophilia B, according to interim follow-up data from a phase 1/2 dose-escalation study.

The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.

However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.

At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 10¹¹, 6 x 10¹¹, or 2 x 10¹² vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.

“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.

The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.

“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”

Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”

Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.

“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.

Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.

“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.

Dr. Reiss reported having no relevant disclosures

sworcester@mdedge.com

SOURCE: Reiss UM et al. ASH 2018, Abstract 491.

SAN DIEGO – Therapeutic expression of factor IX remains stable with no late toxicities occurring at up to 8.6 years after a single infusion of a novel gene therapy in patients with severe hemophilia B, according to interim follow-up data from a phase 1/2 dose-escalation study.

The therapy – a self-complementary adeno-associated virus vector containing a codon-optimized factor IX gene, under control of a synthetic liver specific promoter and pseudotyped with serotype 8 capsid (scAAV2/8-LP1-hFIXco) – was previously shown to result in a dose-dependent increase in plasma factor IX levels in all 10 patients enrolled in the study, and an earlier update showed stable factor IX activity for at least 3 years, Ulrike M. Reiss, MD, reported at the annual meeting of the American Society of Hematology.

However, declining factor IX expression over time remains a concern, because AAV-mediated transgene expression is mediated mainly by episomally retained viral genomes, which may be lost with natural turnover of hepatocytes, noted Dr. Reiss, director of the clinical hematology division and the Hemophilia Treatment Center at St. Jude Children’s Research Hospital in Memphis.

At the “halfway mark,” with a median follow-up of 6.7 years in 10 patients aged 18-64 years who were treated with doses of either 2 x 10¹¹, 6 x 10¹¹, or 2 x 10¹² vector genomes per kg (in 2, 2, and 6 patients, respectively), “factor IX expression has been persistent and stable in all participants after vector infusion,” she said.

“Factor IX expression was vector-dose dependent, achieving average levels of 1.9%-2.3% at the lower doses, and 5.1% at the high vector dose. All patients converted from having severe hemophilia to mild-moderate hemophilia,” she added.

The single significant adverse event observed during annual follow-up evaluations in the patients was a vector-related, immune-mediated liver inflammation occurring within 2-3 months of infusion in four of the six high-dose participants.

“There was complete resolution in all cases after a short course of corticosteroids over 8-12 weeks, including the taper. There were no late sequelae or any recurrence of transaminitis over time,” Dr. Reiss said. “We did not observe any new factor IX inhibitor or any late toxicity in any of these participants.”

Additionally, a comparison of average data across 3 years prior to gene therapy with the average data at 6.7 years after gene therapy showed that the annualized bleed rate decreased by 82% in the 10 participants and factor IX use decreased by 66%. In the high-dose group, the bleed rate decreased from 21 bleeds to 2 bleeds per year, and vector consumption was markedly reduced to a mean of 500 IU/kg per year from a mean of more than 2800 IU/kg per year. “Only one of the six patients in the high-dose group currently continues on prophylaxis treatment, whereas three in the low- and mid-dose groups are currently on prophylaxis,” she said. “In all [patients], the interval between prophylactic infusions has lengthened.”

Of note, Dr. Reiss and her colleagues explored the ability of using a modified, empty capsid-reduced vector preparation of the gene therapy to prevent the transaminitis seen in the 2-3 months after infusion. A new clinical preparation of scAAV2/8-LP1-hFIXco was manufactured with most of the empty particles removed by cesium chloride density centrifugation, but this approach provided no benefit in that regard.

“This further supports the observation that the anticapsid immune response is vector-dose dependent,” she said.

Additionally, the pattern of humoral response to AAV8 capsid was consistent with the primary immune response in participants.

“High IgG antibody titers have persisted for over 6 years; this finding is important because it will preclude these patients from any retreatment with the same vector or even potentially alternative AAV vectors of other serotypes with cross-reactive antigenicity,” she said.

Dr. Reiss reported having no relevant disclosures

sworcester@mdedge.com

SOURCE: Reiss UM et al. ASH 2018, Abstract 491.