TBD Meeting (5315-16)

ORLANDO – Early experience with extended half-life clotting factor concentrates suggests these products are generally safe and effective, at least in the short term, according to hemophilia experts.

“In adolescent and adult patients, the extended half-life clotting factor concentrates demonstrate efficacy and safety in a variety of clinical settings, including prophylaxis, treatment of bleeds, and perisurgical hemostasis,” said Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre in Johannesburg, South Africa.

The X factor

Extended half-life products currently available or in development include those created through fusion technology, including factor VIII products for treatment of hemophilia A, factor IX for treating hemophilia B, and factor VII products for treating factor VII deficiency (Alexander’s Disease).

More recent products created through pegylation technology include recombinant FVIII products.

Factor IX EHL CFCs

The three recombinant factor IX (rFIX) products that have completed phase III clinical trials are: nonacog beta pegol (N9-GP), rFIXFc (Alprolix), and rFIX-FP (Idelvion). The latter two are approved by the U.S. Food and Drug Administration; the former is waiting European and U.S. approval.

In clinical trials in adolescents and adults, these agents were associated with low median annualized bleeding rates, as follows:

• rFIXFc: 3.0 for a 50 IU/kg dose given every 7 days, and 1.4 for a 100 IU/kg dose given every 10 days

• rFIX-FP: 0.0 for a 40 IU/kg dose given every 7 days, and 1.08 for a 75 IU/kg dose given every 14 days

• Nonacog beta pegol: 2.93 for a 10 IU/kg dose and 1.0 for a 40 IU/kg dose, each given every 7 days.

All of these agents effectively treated bleeding episodes after one or two doses, Dr. Mahlangu said. The respective overall hemostatic efficacy rates were 97.2%, 96.7%, and 97.1%.

Safety analyses from published studies showed that no patients exposed to any of these agents developed inhibiting antibodies, although three patients treated with rFIXFc and nonacog beta pegol each developed noninhibitory antibodies.

There were no deaths from thromboembolic episodes and no drug-related serious adverse events.

Data are more limited for children treated with rFIX products, Dr. Young noted. In studies thus far, no children developed inhibitors, although this population had been heavily pretreated, he noted. Median annualized bleeding rates ranged from 1 to 3 and did not differ significantly between the products.

Factor VIII EHL CFCs

Four factor VIII EHL products are available or in development: rFVIIIFc (Eloctate); antihemophilic factor, pegylated (Adynovate); turoctocog alfa pegol (N8-GP); and BAY 94-9027. The former two agents are approved in the United States.

In adults and adolescents, these products have half-lives comparatively shorter than those seen with Factor IX products, the researchers noted.

Annualized bleeding rates for patients on prophylaxis with these agents were less than 4 bleeds per year, ranging from 1.3 to 3.6. In all, 96% of bleeds that did occur could be resolved with one or two injections of the extended half-life rFVIII products.

All patients had at least 50 exposures to these products, and none have developed inhibitors to date.

Only one study has been published to date of factor VIII products in children, comparing a standard half-life product with rFVIIIFc, Dr. Young said.

In this study, the patients were treated with a twice weekly, split-dose regimen. No patients developed inhibitors, and the mean annualized bleeding rate was a low 1.96.

Dr. Mahlangu disclosed research grants from Bayer, Biogen, CSL Behring, Novo Nordisk, and Roche, and speakers bureau participation for Amgen, Biotest, Biogen, CSL Behring, Novo Nordisk, and Sobi. Dr. Young disclosed honoraria and consulting fees from Baxalta, Bayer, Biogen, CSL Behring, and Novo Nordisk. Ellis J. Neufeld, MD, PhD, the invited discussant of the presentation, disclosed institutional grants from Baxalta, Novo Nordisk, and Octapharma, consulting/advising for those companies and for CSL Behring, Genentech, Hema Biologics, and Pfizer.

ORLANDO – Early experience with extended half-life clotting factor concentrates suggests these products are generally safe and effective, at least in the short term, according to hemophilia experts.

“In adolescent and adult patients, the extended half-life clotting factor concentrates demonstrate efficacy and safety in a variety of clinical settings, including prophylaxis, treatment of bleeds, and perisurgical hemostasis,” said Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre in Johannesburg, South Africa.

The X factor

Extended half-life products currently available or in development include those created through fusion technology, including factor VIII products for treatment of hemophilia A, factor IX for treating hemophilia B, and factor VII products for treating factor VII deficiency (Alexander’s Disease).

More recent products created through pegylation technology include recombinant FVIII products.

Factor IX EHL CFCs

The three recombinant factor IX (rFIX) products that have completed phase III clinical trials are: nonacog beta pegol (N9-GP), rFIXFc (Alprolix), and rFIX-FP (Idelvion). The latter two are approved by the U.S. Food and Drug Administration; the former is waiting European and U.S. approval.

In clinical trials in adolescents and adults, these agents were associated with low median annualized bleeding rates, as follows:

• rFIXFc: 3.0 for a 50 IU/kg dose given every 7 days, and 1.4 for a 100 IU/kg dose given every 10 days

• rFIX-FP: 0.0 for a 40 IU/kg dose given every 7 days, and 1.08 for a 75 IU/kg dose given every 14 days

• Nonacog beta pegol: 2.93 for a 10 IU/kg dose and 1.0 for a 40 IU/kg dose, each given every 7 days.

All of these agents effectively treated bleeding episodes after one or two doses, Dr. Mahlangu said. The respective overall hemostatic efficacy rates were 97.2%, 96.7%, and 97.1%.

Safety analyses from published studies showed that no patients exposed to any of these agents developed inhibiting antibodies, although three patients treated with rFIXFc and nonacog beta pegol each developed noninhibitory antibodies.

There were no deaths from thromboembolic episodes and no drug-related serious adverse events.

Data are more limited for children treated with rFIX products, Dr. Young noted. In studies thus far, no children developed inhibitors, although this population had been heavily pretreated, he noted. Median annualized bleeding rates ranged from 1 to 3 and did not differ significantly between the products.

Factor VIII EHL CFCs

Four factor VIII EHL products are available or in development: rFVIIIFc (Eloctate); antihemophilic factor, pegylated (Adynovate); turoctocog alfa pegol (N8-GP); and BAY 94-9027. The former two agents are approved in the United States.

In adults and adolescents, these products have half-lives comparatively shorter than those seen with Factor IX products, the researchers noted.

Annualized bleeding rates for patients on prophylaxis with these agents were less than 4 bleeds per year, ranging from 1.3 to 3.6. In all, 96% of bleeds that did occur could be resolved with one or two injections of the extended half-life rFVIII products.

All patients had at least 50 exposures to these products, and none have developed inhibitors to date.

Only one study has been published to date of factor VIII products in children, comparing a standard half-life product with rFVIIIFc, Dr. Young said.

In this study, the patients were treated with a twice weekly, split-dose regimen. No patients developed inhibitors, and the mean annualized bleeding rate was a low 1.96.

Dr. Mahlangu disclosed research grants from Bayer, Biogen, CSL Behring, Novo Nordisk, and Roche, and speakers bureau participation for Amgen, Biotest, Biogen, CSL Behring, Novo Nordisk, and Sobi. Dr. Young disclosed honoraria and consulting fees from Baxalta, Bayer, Biogen, CSL Behring, and Novo Nordisk. Ellis J. Neufeld, MD, PhD, the invited discussant of the presentation, disclosed institutional grants from Baxalta, Novo Nordisk, and Octapharma, consulting/advising for those companies and for CSL Behring, Genentech, Hema Biologics, and Pfizer.

ORLANDO – Early experience with extended half-life clotting factor concentrates suggests these products are generally safe and effective, at least in the short term, according to hemophilia experts.

“In adolescent and adult patients, the extended half-life clotting factor concentrates demonstrate efficacy and safety in a variety of clinical settings, including prophylaxis, treatment of bleeds, and perisurgical hemostasis,” said Johnny Mahlangu, MD, director of the Haemophilia Comprehensive Care Centre in Johannesburg, South Africa.

The X factor

Extended half-life products currently available or in development include those created through fusion technology, including factor VIII products for treatment of hemophilia A, factor IX for treating hemophilia B, and factor VII products for treating factor VII deficiency (Alexander’s Disease).

More recent products created through pegylation technology include recombinant FVIII products.

Factor IX EHL CFCs

The three recombinant factor IX (rFIX) products that have completed phase III clinical trials are: nonacog beta pegol (N9-GP), rFIXFc (Alprolix), and rFIX-FP (Idelvion). The latter two are approved by the U.S. Food and Drug Administration; the former is waiting European and U.S. approval.

In clinical trials in adolescents and adults, these agents were associated with low median annualized bleeding rates, as follows:

• rFIXFc: 3.0 for a 50 IU/kg dose given every 7 days, and 1.4 for a 100 IU/kg dose given every 10 days

• rFIX-FP: 0.0 for a 40 IU/kg dose given every 7 days, and 1.08 for a 75 IU/kg dose given every 14 days

• Nonacog beta pegol: 2.93 for a 10 IU/kg dose and 1.0 for a 40 IU/kg dose, each given every 7 days.

All of these agents effectively treated bleeding episodes after one or two doses, Dr. Mahlangu said. The respective overall hemostatic efficacy rates were 97.2%, 96.7%, and 97.1%.

Safety analyses from published studies showed that no patients exposed to any of these agents developed inhibiting antibodies, although three patients treated with rFIXFc and nonacog beta pegol each developed noninhibitory antibodies.

There were no deaths from thromboembolic episodes and no drug-related serious adverse events.

Data are more limited for children treated with rFIX products, Dr. Young noted. In studies thus far, no children developed inhibitors, although this population had been heavily pretreated, he noted. Median annualized bleeding rates ranged from 1 to 3 and did not differ significantly between the products.

Factor VIII EHL CFCs

Four factor VIII EHL products are available or in development: rFVIIIFc (Eloctate); antihemophilic factor, pegylated (Adynovate); turoctocog alfa pegol (N8-GP); and BAY 94-9027. The former two agents are approved in the United States.

In adults and adolescents, these products have half-lives comparatively shorter than those seen with Factor IX products, the researchers noted.

Annualized bleeding rates for patients on prophylaxis with these agents were less than 4 bleeds per year, ranging from 1.3 to 3.6. In all, 96% of bleeds that did occur could be resolved with one or two injections of the extended half-life rFVIII products.

All patients had at least 50 exposures to these products, and none have developed inhibitors to date.

Only one study has been published to date of factor VIII products in children, comparing a standard half-life product with rFVIIIFc, Dr. Young said.

In this study, the patients were treated with a twice weekly, split-dose regimen. No patients developed inhibitors, and the mean annualized bleeding rate was a low 1.96.

Dr. Mahlangu disclosed research grants from Bayer, Biogen, CSL Behring, Novo Nordisk, and Roche, and speakers bureau participation for Amgen, Biotest, Biogen, CSL Behring, Novo Nordisk, and Sobi. Dr. Young disclosed honoraria and consulting fees from Baxalta, Bayer, Biogen, CSL Behring, and Novo Nordisk. Ellis J. Neufeld, MD, PhD, the invited discussant of the presentation, disclosed institutional grants from Baxalta, Novo Nordisk, and Octapharma, consulting/advising for those companies and for CSL Behring, Genentech, Hema Biologics, and Pfizer.

ORLANDO – Transitioning patients with hemophilia from standard clotting factor concentrates to newer extended half-life products takes planning, education, and a little patience, but the payoff can be better hemostasis, a hemophilia treatment specialist said.

“Real-world experience shows us that you can maintain effective protection with less infusion with these new products, but we also know that each person should be evaluated individually when determining what their specific optimal treatment is,” said Jennifer Maahs, a hemophilia nurse practitioner at the Indiana Hemophilia and Thrombosis Center in Indianapolis.

Staff and patient education about the proper use of newer extended half-life (EHL) products is the key to success, she added in an oral session at the World Federation of Hemophilia World Congress.

The new EHL products allow for longer intervals between doses, especially with EHL recombinant factor IX used to treat hemophilia B. Prophylaxis with standard factor IX concentrates requires doses of 25-40 IU/kg twice weekly; in contrasts, EHL products can be given in various doses based on patient responses of either 50 IU/kg every 7 days, 100 IU/kg every 10 days, 25-40 IU/kg every 7 days, or 50-75 IU/kg every 14 days.

In general, the longer intervals between dosing occur in adults; young children tend to require more frequent dosing and have lower levels of factor recovery, she noted.

Extended Experience

Her center currently has more than 100 patients maintained on prolonged half-life factor VIII and factor IX products.

“We have really learned a lot of lessons along the way, and we have had to modify our approach based on these lessons,” she said. “Each patient situation is unique, and everything needs to be individualized.”

Staff review the published literature to educate themselves on the EHL products and prepare answers to expected questions from patients. Ms. Maahs suggested identifying key staff who are best equipped to answer specific questions.

“From a patient standpoint, we’ve developed a patient notification letter, so for any new product that comes out – for example a new factor VIII product – the notification gets sent out factor VIII patients, and we do that for every new product that comes out,” she said.

PK OK

Pharmacokinetic (PK) analyses may also be helpful in transitioning patients to EHL products.

To test patient responses to new products, her center tests patients for recovery from 15 minutes to 1 hour post-infusion, which will provide information about how the patient may respond to the product during a bleeding episode.

If the patient is on prophylaxis they will evaluate trough effectiveness to determine that patient’s responsiveness at the lowest level prior to the next infusion. Testing at other time points may be required based on the patient’s individual clinical history.

Center staff talk with each patient to discuss his needs and capabilities. If the patient is currently being managed with on-demand therapy, the talk may center on obstacles to utilization of prophylaxis and the patient’s desired infusion interval.

For patients currently on prophylaxis, they discuss the current regimen frequency and dose and assess how well it’s working. Staff members also provide information about alternative approaches to therapy, and ask patients specifically about their activity levels and dates of activity, compared with currently scheduled infusion days.

Patients are also educated about the reconstitution requirements for the new product, and are told to use up any remaining concentrates before switching over to the new product.

“As we move forward, within 2 to 4 weeks of starting a new therapy, we like to obtain a trough to see how their prophylaxis is working. At that time we ask how have you been doing on the new product, are you having any breakthrough bleeding, and how are you feeling about it,” Ms. Maahs said.

Weekly phone calls to the patient during the first month are also very helpful for reinforcing information about dosing regimens for bleeding episodes, reminding patients to call in if they experience a lead, and encouraging them to keep a treatment log. The phone call can also be helpful in identifying potential product-related reactions or other issues, she said.

‘Big impact’

“What’s the impact that we’ve seen? With factor IX, it has been really big. Previous on-demand patients have agreed that, ‘gosh, I’m infusing a couple of times a month anyway,’ so starting an every 14-day prophylactic regimen seems pretty reasonable,” she said.

“We’ve had infusion schedules in children change from twice weekly to once weekly and that has really decreased the burden of disease,” she added.

A few adults, however, have gone back to standard half-life products because of concerns that they would not be able to infuse when they thought they needed treatment, she noted.

The impact of the EHL factor VIII products has been smaller, although it has allowed slight increases in the dosing intervals (from every other day to every third day in children, for example), and has overall decreased the average number of monthly infusions from about 15 to about 10.

Some adolescents and young adults, who often have been on prophylaxis for all of their lives, have experienced absent or only minimal joint disease, and some have been able to extend their dosing intervals from every 4 to every 5 to 7 days, she said.

Ms. Maahs disclosed serving on advisory committees to Baxalta, Novo Nordisk, Biogen, Genentech, and CSL, and receiving honoraria related to those activities.

ORLANDO – Transitioning patients with hemophilia from standard clotting factor concentrates to newer extended half-life products takes planning, education, and a little patience, but the payoff can be better hemostasis, a hemophilia treatment specialist said.

“Real-world experience shows us that you can maintain effective protection with less infusion with these new products, but we also know that each person should be evaluated individually when determining what their specific optimal treatment is,” said Jennifer Maahs, a hemophilia nurse practitioner at the Indiana Hemophilia and Thrombosis Center in Indianapolis.

Staff and patient education about the proper use of newer extended half-life (EHL) products is the key to success, she added in an oral session at the World Federation of Hemophilia World Congress.

The new EHL products allow for longer intervals between doses, especially with EHL recombinant factor IX used to treat hemophilia B. Prophylaxis with standard factor IX concentrates requires doses of 25-40 IU/kg twice weekly; in contrasts, EHL products can be given in various doses based on patient responses of either 50 IU/kg every 7 days, 100 IU/kg every 10 days, 25-40 IU/kg every 7 days, or 50-75 IU/kg every 14 days.

In general, the longer intervals between dosing occur in adults; young children tend to require more frequent dosing and have lower levels of factor recovery, she noted.

Extended Experience

Her center currently has more than 100 patients maintained on prolonged half-life factor VIII and factor IX products.

“We have really learned a lot of lessons along the way, and we have had to modify our approach based on these lessons,” she said. “Each patient situation is unique, and everything needs to be individualized.”

Staff review the published literature to educate themselves on the EHL products and prepare answers to expected questions from patients. Ms. Maahs suggested identifying key staff who are best equipped to answer specific questions.

“From a patient standpoint, we’ve developed a patient notification letter, so for any new product that comes out – for example a new factor VIII product – the notification gets sent out factor VIII patients, and we do that for every new product that comes out,” she said.

PK OK

Pharmacokinetic (PK) analyses may also be helpful in transitioning patients to EHL products.

To test patient responses to new products, her center tests patients for recovery from 15 minutes to 1 hour post-infusion, which will provide information about how the patient may respond to the product during a bleeding episode.

If the patient is on prophylaxis they will evaluate trough effectiveness to determine that patient’s responsiveness at the lowest level prior to the next infusion. Testing at other time points may be required based on the patient’s individual clinical history.

Center staff talk with each patient to discuss his needs and capabilities. If the patient is currently being managed with on-demand therapy, the talk may center on obstacles to utilization of prophylaxis and the patient’s desired infusion interval.

For patients currently on prophylaxis, they discuss the current regimen frequency and dose and assess how well it’s working. Staff members also provide information about alternative approaches to therapy, and ask patients specifically about their activity levels and dates of activity, compared with currently scheduled infusion days.

Patients are also educated about the reconstitution requirements for the new product, and are told to use up any remaining concentrates before switching over to the new product.

“As we move forward, within 2 to 4 weeks of starting a new therapy, we like to obtain a trough to see how their prophylaxis is working. At that time we ask how have you been doing on the new product, are you having any breakthrough bleeding, and how are you feeling about it,” Ms. Maahs said.

Weekly phone calls to the patient during the first month are also very helpful for reinforcing information about dosing regimens for bleeding episodes, reminding patients to call in if they experience a lead, and encouraging them to keep a treatment log. The phone call can also be helpful in identifying potential product-related reactions or other issues, she said.

‘Big impact’

“What’s the impact that we’ve seen? With factor IX, it has been really big. Previous on-demand patients have agreed that, ‘gosh, I’m infusing a couple of times a month anyway,’ so starting an every 14-day prophylactic regimen seems pretty reasonable,” she said.

“We’ve had infusion schedules in children change from twice weekly to once weekly and that has really decreased the burden of disease,” she added.

A few adults, however, have gone back to standard half-life products because of concerns that they would not be able to infuse when they thought they needed treatment, she noted.

The impact of the EHL factor VIII products has been smaller, although it has allowed slight increases in the dosing intervals (from every other day to every third day in children, for example), and has overall decreased the average number of monthly infusions from about 15 to about 10.

Some adolescents and young adults, who often have been on prophylaxis for all of their lives, have experienced absent or only minimal joint disease, and some have been able to extend their dosing intervals from every 4 to every 5 to 7 days, she said.

Ms. Maahs disclosed serving on advisory committees to Baxalta, Novo Nordisk, Biogen, Genentech, and CSL, and receiving honoraria related to those activities.

ORLANDO – Transitioning patients with hemophilia from standard clotting factor concentrates to newer extended half-life products takes planning, education, and a little patience, but the payoff can be better hemostasis, a hemophilia treatment specialist said.

“Real-world experience shows us that you can maintain effective protection with less infusion with these new products, but we also know that each person should be evaluated individually when determining what their specific optimal treatment is,” said Jennifer Maahs, a hemophilia nurse practitioner at the Indiana Hemophilia and Thrombosis Center in Indianapolis.

Staff and patient education about the proper use of newer extended half-life (EHL) products is the key to success, she added in an oral session at the World Federation of Hemophilia World Congress.

The new EHL products allow for longer intervals between doses, especially with EHL recombinant factor IX used to treat hemophilia B. Prophylaxis with standard factor IX concentrates requires doses of 25-40 IU/kg twice weekly; in contrasts, EHL products can be given in various doses based on patient responses of either 50 IU/kg every 7 days, 100 IU/kg every 10 days, 25-40 IU/kg every 7 days, or 50-75 IU/kg every 14 days.

In general, the longer intervals between dosing occur in adults; young children tend to require more frequent dosing and have lower levels of factor recovery, she noted.

Extended Experience

Her center currently has more than 100 patients maintained on prolonged half-life factor VIII and factor IX products.

“We have really learned a lot of lessons along the way, and we have had to modify our approach based on these lessons,” she said. “Each patient situation is unique, and everything needs to be individualized.”

Staff review the published literature to educate themselves on the EHL products and prepare answers to expected questions from patients. Ms. Maahs suggested identifying key staff who are best equipped to answer specific questions.

“From a patient standpoint, we’ve developed a patient notification letter, so for any new product that comes out – for example a new factor VIII product – the notification gets sent out factor VIII patients, and we do that for every new product that comes out,” she said.

PK OK

Pharmacokinetic (PK) analyses may also be helpful in transitioning patients to EHL products.

To test patient responses to new products, her center tests patients for recovery from 15 minutes to 1 hour post-infusion, which will provide information about how the patient may respond to the product during a bleeding episode.

If the patient is on prophylaxis they will evaluate trough effectiveness to determine that patient’s responsiveness at the lowest level prior to the next infusion. Testing at other time points may be required based on the patient’s individual clinical history.

Center staff talk with each patient to discuss his needs and capabilities. If the patient is currently being managed with on-demand therapy, the talk may center on obstacles to utilization of prophylaxis and the patient’s desired infusion interval.

For patients currently on prophylaxis, they discuss the current regimen frequency and dose and assess how well it’s working. Staff members also provide information about alternative approaches to therapy, and ask patients specifically about their activity levels and dates of activity, compared with currently scheduled infusion days.

Patients are also educated about the reconstitution requirements for the new product, and are told to use up any remaining concentrates before switching over to the new product.

“As we move forward, within 2 to 4 weeks of starting a new therapy, we like to obtain a trough to see how their prophylaxis is working. At that time we ask how have you been doing on the new product, are you having any breakthrough bleeding, and how are you feeling about it,” Ms. Maahs said.

Weekly phone calls to the patient during the first month are also very helpful for reinforcing information about dosing regimens for bleeding episodes, reminding patients to call in if they experience a lead, and encouraging them to keep a treatment log. The phone call can also be helpful in identifying potential product-related reactions or other issues, she said.

‘Big impact’

“What’s the impact that we’ve seen? With factor IX, it has been really big. Previous on-demand patients have agreed that, ‘gosh, I’m infusing a couple of times a month anyway,’ so starting an every 14-day prophylactic regimen seems pretty reasonable,” she said.

“We’ve had infusion schedules in children change from twice weekly to once weekly and that has really decreased the burden of disease,” she added.

A few adults, however, have gone back to standard half-life products because of concerns that they would not be able to infuse when they thought they needed treatment, she noted.

The impact of the EHL factor VIII products has been smaller, although it has allowed slight increases in the dosing intervals (from every other day to every third day in children, for example), and has overall decreased the average number of monthly infusions from about 15 to about 10.

Some adolescents and young adults, who often have been on prophylaxis for all of their lives, have experienced absent or only minimal joint disease, and some have been able to extend their dosing intervals from every 4 to every 5 to 7 days, she said.

Ms. Maahs disclosed serving on advisory committees to Baxalta, Novo Nordisk, Biogen, Genentech, and CSL, and receiving honoraria related to those activities.

ORLANDO – Boys with hemophilia have a better quality of life when they are managed with intensive bleeding prophylaxis with clotting factor concentrates rather than on-demand therapy, results of an international study suggest.

An analysis of pooled data from six studies conducted in eight countries showed that boys with severe hemophilia who received limited on-demand factor replacement had significantly lower health-related quality of life (HRQoL) scores than did boys treated prophylactically, reported Victoria Price, MB, of Dalhousie University, Halifax, N.S., and colleagues.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

“Early initiation of intensive prophylaxis has the greatest impact on HRQoL in boys with severe hemophilia. HRQoL in boys with severe hemophilia exposed to early initiation of intensive prophylaxis is comparable to boys with mild hemophilia receiving on-demand therapy,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

In countries where patients have access to safe clotting factor concentrates, prophylaxis has become the standard of care for management of hemophilia A and B, because it has been shown to reduce the frequency of bleeds. But because of the small sample sizes in most studies of hemophilia, it has been difficult to determine whether prophylaxis actually has a significant effect on HRQoL, the investigators noted.

To get an answer to that question, they looked at data from six studies in boys younger than 18 that measured HRQoL using the same standard instrument, the Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT). The studies were conducted in Brazil, Canada, China, France, Germany, the Netherlands, Spain, and the United Kingdom.

Patients in the studies were grouped into one of five categories:

• Early initiation with intensive prophylaxis (Germany, the Netherlands, Spain, UK)

• Gradual initiation with intensive prophylaxis (Canada, France)

• Late initiation with limited prophylaxis (Brazil, China)

• On-demand with good access to factor (Canada and European nations)

• On-demand with variable or limited access to factor (Brazil and China).

Data on a total of 254 boys with severe hemophilia were analyzed and compared with estimated scores from boys with mild hemophilia in the pooled dataset.

Of the boys with severe hemophilia, 220 (86.6% had hemophilia A, and 34 (13.4%) had hemophilia B. They ranged in age from 4.4 to 17.9 years; 21 of the boys were younger than 7 years.

The investigators found that in a linear regression model, patients with early initiation and intensive prophylaxis had the highest CHO-KLAT scores, followed by those who had gradual initiation with intensive prophylaxis (P = .003), late initiation/limited prophylaxis (P = .005), on-demand with good access (P = .008) and, lastly, on-demand with limited access to factor (P less than .001)

The authors noted that the differences by treatment group in the analysis were defined by expert consensus, and may not reflect changes in treatment protocols over the last 10 years. The studies were published between 2006 and 2016.

“Despite this limitation, important differences were observed between groups,” they wrote.

The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.

ORLANDO – Boys with hemophilia have a better quality of life when they are managed with intensive bleeding prophylaxis with clotting factor concentrates rather than on-demand therapy, results of an international study suggest.

An analysis of pooled data from six studies conducted in eight countries showed that boys with severe hemophilia who received limited on-demand factor replacement had significantly lower health-related quality of life (HRQoL) scores than did boys treated prophylactically, reported Victoria Price, MB, of Dalhousie University, Halifax, N.S., and colleagues.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

“Early initiation of intensive prophylaxis has the greatest impact on HRQoL in boys with severe hemophilia. HRQoL in boys with severe hemophilia exposed to early initiation of intensive prophylaxis is comparable to boys with mild hemophilia receiving on-demand therapy,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

In countries where patients have access to safe clotting factor concentrates, prophylaxis has become the standard of care for management of hemophilia A and B, because it has been shown to reduce the frequency of bleeds. But because of the small sample sizes in most studies of hemophilia, it has been difficult to determine whether prophylaxis actually has a significant effect on HRQoL, the investigators noted.

To get an answer to that question, they looked at data from six studies in boys younger than 18 that measured HRQoL using the same standard instrument, the Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT). The studies were conducted in Brazil, Canada, China, France, Germany, the Netherlands, Spain, and the United Kingdom.

Patients in the studies were grouped into one of five categories:

• Early initiation with intensive prophylaxis (Germany, the Netherlands, Spain, UK)

• Gradual initiation with intensive prophylaxis (Canada, France)

• Late initiation with limited prophylaxis (Brazil, China)

• On-demand with good access to factor (Canada and European nations)

• On-demand with variable or limited access to factor (Brazil and China).

Data on a total of 254 boys with severe hemophilia were analyzed and compared with estimated scores from boys with mild hemophilia in the pooled dataset.

Of the boys with severe hemophilia, 220 (86.6% had hemophilia A, and 34 (13.4%) had hemophilia B. They ranged in age from 4.4 to 17.9 years; 21 of the boys were younger than 7 years.

The investigators found that in a linear regression model, patients with early initiation and intensive prophylaxis had the highest CHO-KLAT scores, followed by those who had gradual initiation with intensive prophylaxis (P = .003), late initiation/limited prophylaxis (P = .005), on-demand with good access (P = .008) and, lastly, on-demand with limited access to factor (P less than .001)

The authors noted that the differences by treatment group in the analysis were defined by expert consensus, and may not reflect changes in treatment protocols over the last 10 years. The studies were published between 2006 and 2016.

“Despite this limitation, important differences were observed between groups,” they wrote.

The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.

ORLANDO – Boys with hemophilia have a better quality of life when they are managed with intensive bleeding prophylaxis with clotting factor concentrates rather than on-demand therapy, results of an international study suggest.

An analysis of pooled data from six studies conducted in eight countries showed that boys with severe hemophilia who received limited on-demand factor replacement had significantly lower health-related quality of life (HRQoL) scores than did boys treated prophylactically, reported Victoria Price, MB, of Dalhousie University, Halifax, N.S., and colleagues.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

“Early initiation of intensive prophylaxis has the greatest impact on HRQoL in boys with severe hemophilia. HRQoL in boys with severe hemophilia exposed to early initiation of intensive prophylaxis is comparable to boys with mild hemophilia receiving on-demand therapy,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

In countries where patients have access to safe clotting factor concentrates, prophylaxis has become the standard of care for management of hemophilia A and B, because it has been shown to reduce the frequency of bleeds. But because of the small sample sizes in most studies of hemophilia, it has been difficult to determine whether prophylaxis actually has a significant effect on HRQoL, the investigators noted.

To get an answer to that question, they looked at data from six studies in boys younger than 18 that measured HRQoL using the same standard instrument, the Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT). The studies were conducted in Brazil, Canada, China, France, Germany, the Netherlands, Spain, and the United Kingdom.

Patients in the studies were grouped into one of five categories:

• Early initiation with intensive prophylaxis (Germany, the Netherlands, Spain, UK)

• Gradual initiation with intensive prophylaxis (Canada, France)

• Late initiation with limited prophylaxis (Brazil, China)

• On-demand with good access to factor (Canada and European nations)

• On-demand with variable or limited access to factor (Brazil and China).

Data on a total of 254 boys with severe hemophilia were analyzed and compared with estimated scores from boys with mild hemophilia in the pooled dataset.

Of the boys with severe hemophilia, 220 (86.6% had hemophilia A, and 34 (13.4%) had hemophilia B. They ranged in age from 4.4 to 17.9 years; 21 of the boys were younger than 7 years.

The investigators found that in a linear regression model, patients with early initiation and intensive prophylaxis had the highest CHO-KLAT scores, followed by those who had gradual initiation with intensive prophylaxis (P = .003), late initiation/limited prophylaxis (P = .005), on-demand with good access (P = .008) and, lastly, on-demand with limited access to factor (P less than .001)

The authors noted that the differences by treatment group in the analysis were defined by expert consensus, and may not reflect changes in treatment protocols over the last 10 years. The studies were published between 2006 and 2016.

“Despite this limitation, important differences were observed between groups,” they wrote.

The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.

ORLANDO – The traditional view that women who are hemophilia carriers are unaffected by the disease may not be accurate, because many hemophilia carriers experience abnormal bleeding, a hemophilia specialist contends.

“We do know that hemophilia carriers have increased bleeding scores compared to controls,” said Michelle Sholzberg, MD, a hematologist and medical director of the coagulation laboratory at St. Michael’s Hospital in Toronto.

Bleeding in carriers is predominantly mucocutaneous bleeding, and may include epistaxis, heavy menstrual bleeding, bleeding with interventional procedures, and postpartum hemorrhage, she said at the World Federation of Hemophilia World Congress.

The majority of women who carry a factor VIII or factor IX mutation on one X chromosome have factor levels ranging from 0.40 to 0.60 IU/mL, which are generally considered to be adequate for hemostasis.

Yet, “we know that many carriers bleed, and in fact there are carriers who bleed with higher factor levels that are truly in the normal range,” Dr. Sholzberg said.

Normal coagulation factor levels in the general population range from about 0.50 to 1.50 IU/mL. By this standard, approximately 30% of hemophilia carriers have low factor levels, she said.

Joint damage

In addition, 14%-19% of hemophilia A carriers report hemarthrosis, and there is an association in factor VIII or IX deficiencies among hemophilia carriers and reduced joint range of motion. In one study, this decreased range of motion was evident as early as the preteen years, and was suggestive of subclinical musculoskeletal bleeding among carriers. In a separate study, investigators found evidence that hemophilia A carriers have pathologic and radiologic evidence of structural joint damage.

Variability in factor levels among carriers may be caused by lyonization (the inactivation of one of the X-chromosomes), ABO blood type, the presence of mutations in genes encoding for von Willebrand factor, compound heterozygosity or homozygosity, or Turner’s mosaicism.

Clotting factor levels can also change with pregnancy, with hemophilia A carriers experiencing an increase in mean factor VIII levels from 0.46 IU/mL prepregnancy to 1.21 IU/mL in the third trimester, and hemophilia B carriers having a corresponding rise in factor IX levels from 0.31 IU/mL to 0.48 IU/mL, and many carriers still have suboptimal factor levels at pregnancy, Dr. Sholzberg said.

Postpartum hemorrhagic complications among carriers can lead to iron-deficiency anemia. The Centers for Disease Control and Prevention recommends testing all nonpregnant women for anemia every 5-10 years throughout their childbearing years, and annual objective testing for women with risk factors, she noted.

“I think we can all appreciate now that the multidisciplinary approach is important for women with bleeding disorders, and carriers of hemophilia can be safely cared for at HTCs [hemophilia treatment centers],” she said.

Carriers should be treated with a multimodal approach that enhances patient education and awareness, with an emphasis on self-report of symptoms and communication with health care providers.

“It’s also critical never to start a conversation with a woman who has a bleeding disorder with ‘Do you have heavy menstrual bleeding?’ I think we all know that the answer is almost always ‘No, I don’t,’ and that’s because if she has bled heavily for her entire life, she doesn’t know what normal is,” Dr. Sholzberg said.

She described a typical comprehensive care plan for a pregnant hemophilia A carrier. The plan will include information about the diagnosis, recommendations to the obstetricians to avoid the use of invasive instrumentation, anesthesia recommendations, recommendations for care of the mother regarding hemostatic agents, postpartum tranexamic acid, and factor levels, and hematology recommendations for the newborn.

Dr. Sholzberg disclosed research support and/or honoraria from Shire (previously Baxter, Baxalta), Octapharma, CSL Behring, Pfizer, and Novo Nordisk, and advisory committee activity for Shire.

ORLANDO – The traditional view that women who are hemophilia carriers are unaffected by the disease may not be accurate, because many hemophilia carriers experience abnormal bleeding, a hemophilia specialist contends.

“We do know that hemophilia carriers have increased bleeding scores compared to controls,” said Michelle Sholzberg, MD, a hematologist and medical director of the coagulation laboratory at St. Michael’s Hospital in Toronto.

Bleeding in carriers is predominantly mucocutaneous bleeding, and may include epistaxis, heavy menstrual bleeding, bleeding with interventional procedures, and postpartum hemorrhage, she said at the World Federation of Hemophilia World Congress.

The majority of women who carry a factor VIII or factor IX mutation on one X chromosome have factor levels ranging from 0.40 to 0.60 IU/mL, which are generally considered to be adequate for hemostasis.

Yet, “we know that many carriers bleed, and in fact there are carriers who bleed with higher factor levels that are truly in the normal range,” Dr. Sholzberg said.

Normal coagulation factor levels in the general population range from about 0.50 to 1.50 IU/mL. By this standard, approximately 30% of hemophilia carriers have low factor levels, she said.

Joint damage

In addition, 14%-19% of hemophilia A carriers report hemarthrosis, and there is an association in factor VIII or IX deficiencies among hemophilia carriers and reduced joint range of motion. In one study, this decreased range of motion was evident as early as the preteen years, and was suggestive of subclinical musculoskeletal bleeding among carriers. In a separate study, investigators found evidence that hemophilia A carriers have pathologic and radiologic evidence of structural joint damage.

Variability in factor levels among carriers may be caused by lyonization (the inactivation of one of the X-chromosomes), ABO blood type, the presence of mutations in genes encoding for von Willebrand factor, compound heterozygosity or homozygosity, or Turner’s mosaicism.

Clotting factor levels can also change with pregnancy, with hemophilia A carriers experiencing an increase in mean factor VIII levels from 0.46 IU/mL prepregnancy to 1.21 IU/mL in the third trimester, and hemophilia B carriers having a corresponding rise in factor IX levels from 0.31 IU/mL to 0.48 IU/mL, and many carriers still have suboptimal factor levels at pregnancy, Dr. Sholzberg said.

Postpartum hemorrhagic complications among carriers can lead to iron-deficiency anemia. The Centers for Disease Control and Prevention recommends testing all nonpregnant women for anemia every 5-10 years throughout their childbearing years, and annual objective testing for women with risk factors, she noted.

“I think we can all appreciate now that the multidisciplinary approach is important for women with bleeding disorders, and carriers of hemophilia can be safely cared for at HTCs [hemophilia treatment centers],” she said.

Carriers should be treated with a multimodal approach that enhances patient education and awareness, with an emphasis on self-report of symptoms and communication with health care providers.

“It’s also critical never to start a conversation with a woman who has a bleeding disorder with ‘Do you have heavy menstrual bleeding?’ I think we all know that the answer is almost always ‘No, I don’t,’ and that’s because if she has bled heavily for her entire life, she doesn’t know what normal is,” Dr. Sholzberg said.

She described a typical comprehensive care plan for a pregnant hemophilia A carrier. The plan will include information about the diagnosis, recommendations to the obstetricians to avoid the use of invasive instrumentation, anesthesia recommendations, recommendations for care of the mother regarding hemostatic agents, postpartum tranexamic acid, and factor levels, and hematology recommendations for the newborn.

Dr. Sholzberg disclosed research support and/or honoraria from Shire (previously Baxter, Baxalta), Octapharma, CSL Behring, Pfizer, and Novo Nordisk, and advisory committee activity for Shire.

ORLANDO – The traditional view that women who are hemophilia carriers are unaffected by the disease may not be accurate, because many hemophilia carriers experience abnormal bleeding, a hemophilia specialist contends.

“We do know that hemophilia carriers have increased bleeding scores compared to controls,” said Michelle Sholzberg, MD, a hematologist and medical director of the coagulation laboratory at St. Michael’s Hospital in Toronto.

Bleeding in carriers is predominantly mucocutaneous bleeding, and may include epistaxis, heavy menstrual bleeding, bleeding with interventional procedures, and postpartum hemorrhage, she said at the World Federation of Hemophilia World Congress.

The majority of women who carry a factor VIII or factor IX mutation on one X chromosome have factor levels ranging from 0.40 to 0.60 IU/mL, which are generally considered to be adequate for hemostasis.

Yet, “we know that many carriers bleed, and in fact there are carriers who bleed with higher factor levels that are truly in the normal range,” Dr. Sholzberg said.

Normal coagulation factor levels in the general population range from about 0.50 to 1.50 IU/mL. By this standard, approximately 30% of hemophilia carriers have low factor levels, she said.

Joint damage

In addition, 14%-19% of hemophilia A carriers report hemarthrosis, and there is an association in factor VIII or IX deficiencies among hemophilia carriers and reduced joint range of motion. In one study, this decreased range of motion was evident as early as the preteen years, and was suggestive of subclinical musculoskeletal bleeding among carriers. In a separate study, investigators found evidence that hemophilia A carriers have pathologic and radiologic evidence of structural joint damage.

Variability in factor levels among carriers may be caused by lyonization (the inactivation of one of the X-chromosomes), ABO blood type, the presence of mutations in genes encoding for von Willebrand factor, compound heterozygosity or homozygosity, or Turner’s mosaicism.

Clotting factor levels can also change with pregnancy, with hemophilia A carriers experiencing an increase in mean factor VIII levels from 0.46 IU/mL prepregnancy to 1.21 IU/mL in the third trimester, and hemophilia B carriers having a corresponding rise in factor IX levels from 0.31 IU/mL to 0.48 IU/mL, and many carriers still have suboptimal factor levels at pregnancy, Dr. Sholzberg said.

Postpartum hemorrhagic complications among carriers can lead to iron-deficiency anemia. The Centers for Disease Control and Prevention recommends testing all nonpregnant women for anemia every 5-10 years throughout their childbearing years, and annual objective testing for women with risk factors, she noted.

“I think we can all appreciate now that the multidisciplinary approach is important for women with bleeding disorders, and carriers of hemophilia can be safely cared for at HTCs [hemophilia treatment centers],” she said.

Carriers should be treated with a multimodal approach that enhances patient education and awareness, with an emphasis on self-report of symptoms and communication with health care providers.

“It’s also critical never to start a conversation with a woman who has a bleeding disorder with ‘Do you have heavy menstrual bleeding?’ I think we all know that the answer is almost always ‘No, I don’t,’ and that’s because if she has bled heavily for her entire life, she doesn’t know what normal is,” Dr. Sholzberg said.

She described a typical comprehensive care plan for a pregnant hemophilia A carrier. The plan will include information about the diagnosis, recommendations to the obstetricians to avoid the use of invasive instrumentation, anesthesia recommendations, recommendations for care of the mother regarding hemostatic agents, postpartum tranexamic acid, and factor levels, and hematology recommendations for the newborn.

Dr. Sholzberg disclosed research support and/or honoraria from Shire (previously Baxter, Baxalta), Octapharma, CSL Behring, Pfizer, and Novo Nordisk, and advisory committee activity for Shire.

ORLANDO – In patients with hemophilia who have therapeutic factor levels at the time of joint replacement surgery, prophylaxis against venous thromboembolism (VTE) may be unnecessary.

In a cohort study of patients with hemophilia A or B who underwent total joint replacement surgery while being in proper hemostasis with therapeutic factor levels, there were no clinically evident episodes of venous thromboembolism, even though none of the patients had received perioperative anticoagulant prophylaxis, reported investigators from the National Hemophilia Center and Institute of Thrombosis and Hemostasis at the Sheba Medical Center in Tel Hashomer, Israel.

© pavlen/iStockphoto

The data should be reassuring to clinicians whose patients with hemophilia require major orthopedic procedures, said lead author Dr. Anna Seltser, an orthopedic resident at Sheba Medical Center, in an interview.

“We have a lot of hemophilia patients who are not well treated because they live in the desert or distant communities, and we also sometimes treat patients from the Palestinian side of the Gaza Strip who don’t have access to care and need this type of surgery,” she said.

“We collected what I think is the biggest series of patients until now, we didn’t give any of them VTE prophylaxis, and none of them had any DVT [deep vein thrombosis], PE [pulmonary embolism], or similar complication,” she said.

Skip the heparin?

VTE prophylaxis with low-molecular-weight heparin, warfarin, or other anticoagulant agents is a common practice following orthopedic surgery in patients without bleeding disorders. But for patients with severe hemophilia, who often require major joint replacement surgery following years of bleeding-induced arthropathy, it’s unclear whether perioperative anticoagulation is beneficial, the investigators noted in a scientific poster at the World Federation of Hemophilia World Congress.

Dr. Seltser and colleagues therefore conducted a prospective cohort study of 50 patients with hemophilia A or B treated with major joint surgery and subsequent revisions from 1988 through 2015 at their center. In all, 47 patients had severe hemophilia A, 2 had mild hemophilia A, and 1 had hemophilia B.

The authors analyzed data on demographics, comorbidities, type of surgery, use of factor concentrates therapy around the time of surgery, and complications during follow-up, including massive hemorrhage, infections, implant loosening, DVT, and PE.

The patients underwent a total of 74 primary joint replacements (16 hips, 52 knees, and 6 ankles) and 23 revision surgeries.

As noted, there were no episodes of either DVT or PE among any of the patients. All but one complication occurred among patients undergoing total knee replacement. These included three cases of hemarthrosis, three limited-range-of-motion cases requiring closed manipulations, four soft-tissue hematomas, and one case each of superficial wound infection, urinary tract infection, pneumonia, and Candida infection of the tongue.

The only other complication was a case of disseminated intravascular coagulation, sepsis, and hemorrhagic shock in a patient who had undergone a revision (original procedure unspecified).

“Despite the concern that proper replacement factor therapy, applied before and after the surgery, may increase the risk for thromboembolic complications in patients with hemophilia undergoing joint replacement, our data show that prophylactic anticoagulation in this group of patients is not necessary,” the investigators concluded.

The study was internally funded. The investigators reported no conflicts of interest.

[email protected]

ORLANDO – In patients with hemophilia who have therapeutic factor levels at the time of joint replacement surgery, prophylaxis against venous thromboembolism (VTE) may be unnecessary.

In a cohort study of patients with hemophilia A or B who underwent total joint replacement surgery while being in proper hemostasis with therapeutic factor levels, there were no clinically evident episodes of venous thromboembolism, even though none of the patients had received perioperative anticoagulant prophylaxis, reported investigators from the National Hemophilia Center and Institute of Thrombosis and Hemostasis at the Sheba Medical Center in Tel Hashomer, Israel.

© pavlen/iStockphoto

The data should be reassuring to clinicians whose patients with hemophilia require major orthopedic procedures, said lead author Dr. Anna Seltser, an orthopedic resident at Sheba Medical Center, in an interview.

“We have a lot of hemophilia patients who are not well treated because they live in the desert or distant communities, and we also sometimes treat patients from the Palestinian side of the Gaza Strip who don’t have access to care and need this type of surgery,” she said.

“We collected what I think is the biggest series of patients until now, we didn’t give any of them VTE prophylaxis, and none of them had any DVT [deep vein thrombosis], PE [pulmonary embolism], or similar complication,” she said.

Skip the heparin?

VTE prophylaxis with low-molecular-weight heparin, warfarin, or other anticoagulant agents is a common practice following orthopedic surgery in patients without bleeding disorders. But for patients with severe hemophilia, who often require major joint replacement surgery following years of bleeding-induced arthropathy, it’s unclear whether perioperative anticoagulation is beneficial, the investigators noted in a scientific poster at the World Federation of Hemophilia World Congress.

Dr. Seltser and colleagues therefore conducted a prospective cohort study of 50 patients with hemophilia A or B treated with major joint surgery and subsequent revisions from 1988 through 2015 at their center. In all, 47 patients had severe hemophilia A, 2 had mild hemophilia A, and 1 had hemophilia B.

The authors analyzed data on demographics, comorbidities, type of surgery, use of factor concentrates therapy around the time of surgery, and complications during follow-up, including massive hemorrhage, infections, implant loosening, DVT, and PE.

The patients underwent a total of 74 primary joint replacements (16 hips, 52 knees, and 6 ankles) and 23 revision surgeries.

As noted, there were no episodes of either DVT or PE among any of the patients. All but one complication occurred among patients undergoing total knee replacement. These included three cases of hemarthrosis, three limited-range-of-motion cases requiring closed manipulations, four soft-tissue hematomas, and one case each of superficial wound infection, urinary tract infection, pneumonia, and Candida infection of the tongue.

The only other complication was a case of disseminated intravascular coagulation, sepsis, and hemorrhagic shock in a patient who had undergone a revision (original procedure unspecified).

“Despite the concern that proper replacement factor therapy, applied before and after the surgery, may increase the risk for thromboembolic complications in patients with hemophilia undergoing joint replacement, our data show that prophylactic anticoagulation in this group of patients is not necessary,” the investigators concluded.

The study was internally funded. The investigators reported no conflicts of interest.

[email protected]

ORLANDO – In patients with hemophilia who have therapeutic factor levels at the time of joint replacement surgery, prophylaxis against venous thromboembolism (VTE) may be unnecessary.

In a cohort study of patients with hemophilia A or B who underwent total joint replacement surgery while being in proper hemostasis with therapeutic factor levels, there were no clinically evident episodes of venous thromboembolism, even though none of the patients had received perioperative anticoagulant prophylaxis, reported investigators from the National Hemophilia Center and Institute of Thrombosis and Hemostasis at the Sheba Medical Center in Tel Hashomer, Israel.

© pavlen/iStockphoto

The data should be reassuring to clinicians whose patients with hemophilia require major orthopedic procedures, said lead author Dr. Anna Seltser, an orthopedic resident at Sheba Medical Center, in an interview.

“We have a lot of hemophilia patients who are not well treated because they live in the desert or distant communities, and we also sometimes treat patients from the Palestinian side of the Gaza Strip who don’t have access to care and need this type of surgery,” she said.

“We collected what I think is the biggest series of patients until now, we didn’t give any of them VTE prophylaxis, and none of them had any DVT [deep vein thrombosis], PE [pulmonary embolism], or similar complication,” she said.

Skip the heparin?

VTE prophylaxis with low-molecular-weight heparin, warfarin, or other anticoagulant agents is a common practice following orthopedic surgery in patients without bleeding disorders. But for patients with severe hemophilia, who often require major joint replacement surgery following years of bleeding-induced arthropathy, it’s unclear whether perioperative anticoagulation is beneficial, the investigators noted in a scientific poster at the World Federation of Hemophilia World Congress.

Dr. Seltser and colleagues therefore conducted a prospective cohort study of 50 patients with hemophilia A or B treated with major joint surgery and subsequent revisions from 1988 through 2015 at their center. In all, 47 patients had severe hemophilia A, 2 had mild hemophilia A, and 1 had hemophilia B.

The authors analyzed data on demographics, comorbidities, type of surgery, use of factor concentrates therapy around the time of surgery, and complications during follow-up, including massive hemorrhage, infections, implant loosening, DVT, and PE.

The patients underwent a total of 74 primary joint replacements (16 hips, 52 knees, and 6 ankles) and 23 revision surgeries.

As noted, there were no episodes of either DVT or PE among any of the patients. All but one complication occurred among patients undergoing total knee replacement. These included three cases of hemarthrosis, three limited-range-of-motion cases requiring closed manipulations, four soft-tissue hematomas, and one case each of superficial wound infection, urinary tract infection, pneumonia, and Candida infection of the tongue.

The only other complication was a case of disseminated intravascular coagulation, sepsis, and hemorrhagic shock in a patient who had undergone a revision (original procedure unspecified).

“Despite the concern that proper replacement factor therapy, applied before and after the surgery, may increase the risk for thromboembolic complications in patients with hemophilia undergoing joint replacement, our data show that prophylactic anticoagulation in this group of patients is not necessary,” the investigators concluded.

The study was internally funded. The investigators reported no conflicts of interest.

[email protected]

ORLANDO – Screening urinalysis should be a part of routine care for children and young adults with hemophilia, although the clinical significance of the finding is still unclear, investigators say.

Among 93 boys and young men with hemophilia A or B followed at a hemophilia treatment center, nearly half were found to have hematuria on routine screening, a possible indicator for future renal problems, said Kyle Davis, MD, and Amy Dunn, MD, from the division of hematology at Nationwide Children’s Hospital in Columbus, Ohio.

Neil Osterweil/Frontline Medical News

“It’s not routine for all centers to screen for hematuria, so there is likely a large number of patients that are underrecognized, who have hematuria but we don’t even know it,” Dr. Davis said in an interview at the World Federation of Hemophilia World Congress.

Hematuria is a recognized complication in patients with hemophilia A and B, second only to joint damage in frequency. In addition, adults with hemophilia have been shown to have a higher prevalence of renal disease than the general population, suggesting that hematuria might be a marker or harbinger of later renal disease, the authors proposed in a scientific poster.

The investigators conducted their study as part of a quality improvement program at their center aimed at increasing the frequency of urine screening in patients with hemophilia during annual comprehensive visits.

They looked at urinalysis results collected from all male patients older than 2 years with hemophilia A or B seen at their center from August 2011 through September 2015. They defined hematuria as the presence of three or more red blood cells on at least one urinalysis sample.

They also performed univariate logistic regression to evaluate the association of hematuria with patient age, race, hemophilia type and severity, treatment regimen, and history of inhibitory antibodies.

A total of 93 patients, 67 with hemophilia A and 26 with hemophilia B, were included. In all, 43 patients (47%) were identified as having hematuria, with a median of seven red cells. Hematuria was seen in 37 patients with hemophilia A (55%), and in 6 patients with hemophilia B (23%).

Characteristics associated with risk for hematuria included older age and hemophilia A.

Imaging studies available on 24 of the 93 patients showed renal calculi in 3 patients, minor pelviectasis in 1, and congenital dysplastic left kidney, ureterocele, and right hydroureter in 1 patient.

Dr. Davis and Dr. Dunn said that while screening urinalysis could be considered as a part of routine hemophilia, additional studies are needed to replicate the finding in other treatment centers and to determine whether urinalysis results can be predictive of future renal disease, and if so, whether interventions might help.

“For example, there is the potential that if you recognize hematuria in a patient and that patient is currently on an on-demand treatment process, should we switch to prophylaxis?” Dr Davis said.

Dr. Dunn noted that “certainly there are high-risk populations who should be screened, like our patients who have an active inhibitor or even a tolerized inhibitor. Our data suggest that we ought to be looking a bit more closely at those patients, and perhaps that will help us tease out the cause of this. Can we blame it all on hemophilia, or is there something else going on?”

The study was internally funded. Dr. Davis and Dr. Dunn reported no relevant disclosures.

ORLANDO – Screening urinalysis should be a part of routine care for children and young adults with hemophilia, although the clinical significance of the finding is still unclear, investigators say.

Among 93 boys and young men with hemophilia A or B followed at a hemophilia treatment center, nearly half were found to have hematuria on routine screening, a possible indicator for future renal problems, said Kyle Davis, MD, and Amy Dunn, MD, from the division of hematology at Nationwide Children’s Hospital in Columbus, Ohio.

Neil Osterweil/Frontline Medical News

“It’s not routine for all centers to screen for hematuria, so there is likely a large number of patients that are underrecognized, who have hematuria but we don’t even know it,” Dr. Davis said in an interview at the World Federation of Hemophilia World Congress.

Hematuria is a recognized complication in patients with hemophilia A and B, second only to joint damage in frequency. In addition, adults with hemophilia have been shown to have a higher prevalence of renal disease than the general population, suggesting that hematuria might be a marker or harbinger of later renal disease, the authors proposed in a scientific poster.

The investigators conducted their study as part of a quality improvement program at their center aimed at increasing the frequency of urine screening in patients with hemophilia during annual comprehensive visits.

They looked at urinalysis results collected from all male patients older than 2 years with hemophilia A or B seen at their center from August 2011 through September 2015. They defined hematuria as the presence of three or more red blood cells on at least one urinalysis sample.

They also performed univariate logistic regression to evaluate the association of hematuria with patient age, race, hemophilia type and severity, treatment regimen, and history of inhibitory antibodies.

A total of 93 patients, 67 with hemophilia A and 26 with hemophilia B, were included. In all, 43 patients (47%) were identified as having hematuria, with a median of seven red cells. Hematuria was seen in 37 patients with hemophilia A (55%), and in 6 patients with hemophilia B (23%).

Characteristics associated with risk for hematuria included older age and hemophilia A.

Imaging studies available on 24 of the 93 patients showed renal calculi in 3 patients, minor pelviectasis in 1, and congenital dysplastic left kidney, ureterocele, and right hydroureter in 1 patient.

Dr. Davis and Dr. Dunn said that while screening urinalysis could be considered as a part of routine hemophilia, additional studies are needed to replicate the finding in other treatment centers and to determine whether urinalysis results can be predictive of future renal disease, and if so, whether interventions might help.

“For example, there is the potential that if you recognize hematuria in a patient and that patient is currently on an on-demand treatment process, should we switch to prophylaxis?” Dr Davis said.

Dr. Dunn noted that “certainly there are high-risk populations who should be screened, like our patients who have an active inhibitor or even a tolerized inhibitor. Our data suggest that we ought to be looking a bit more closely at those patients, and perhaps that will help us tease out the cause of this. Can we blame it all on hemophilia, or is there something else going on?”

The study was internally funded. Dr. Davis and Dr. Dunn reported no relevant disclosures.

ORLANDO – Screening urinalysis should be a part of routine care for children and young adults with hemophilia, although the clinical significance of the finding is still unclear, investigators say.

Among 93 boys and young men with hemophilia A or B followed at a hemophilia treatment center, nearly half were found to have hematuria on routine screening, a possible indicator for future renal problems, said Kyle Davis, MD, and Amy Dunn, MD, from the division of hematology at Nationwide Children’s Hospital in Columbus, Ohio.

Neil Osterweil/Frontline Medical News

“It’s not routine for all centers to screen for hematuria, so there is likely a large number of patients that are underrecognized, who have hematuria but we don’t even know it,” Dr. Davis said in an interview at the World Federation of Hemophilia World Congress.

Hematuria is a recognized complication in patients with hemophilia A and B, second only to joint damage in frequency. In addition, adults with hemophilia have been shown to have a higher prevalence of renal disease than the general population, suggesting that hematuria might be a marker or harbinger of later renal disease, the authors proposed in a scientific poster.

The investigators conducted their study as part of a quality improvement program at their center aimed at increasing the frequency of urine screening in patients with hemophilia during annual comprehensive visits.

They looked at urinalysis results collected from all male patients older than 2 years with hemophilia A or B seen at their center from August 2011 through September 2015. They defined hematuria as the presence of three or more red blood cells on at least one urinalysis sample.

They also performed univariate logistic regression to evaluate the association of hematuria with patient age, race, hemophilia type and severity, treatment regimen, and history of inhibitory antibodies.

A total of 93 patients, 67 with hemophilia A and 26 with hemophilia B, were included. In all, 43 patients (47%) were identified as having hematuria, with a median of seven red cells. Hematuria was seen in 37 patients with hemophilia A (55%), and in 6 patients with hemophilia B (23%).

Characteristics associated with risk for hematuria included older age and hemophilia A.

Imaging studies available on 24 of the 93 patients showed renal calculi in 3 patients, minor pelviectasis in 1, and congenital dysplastic left kidney, ureterocele, and right hydroureter in 1 patient.

Dr. Davis and Dr. Dunn said that while screening urinalysis could be considered as a part of routine hemophilia, additional studies are needed to replicate the finding in other treatment centers and to determine whether urinalysis results can be predictive of future renal disease, and if so, whether interventions might help.

“For example, there is the potential that if you recognize hematuria in a patient and that patient is currently on an on-demand treatment process, should we switch to prophylaxis?” Dr Davis said.

Dr. Dunn noted that “certainly there are high-risk populations who should be screened, like our patients who have an active inhibitor or even a tolerized inhibitor. Our data suggest that we ought to be looking a bit more closely at those patients, and perhaps that will help us tease out the cause of this. Can we blame it all on hemophilia, or is there something else going on?”

The study was internally funded. Dr. Davis and Dr. Dunn reported no relevant disclosures.

ORLANDO – Conventional wisdom holds that persons with hemophilia are at lower risk for death from cardiovascular events than the general population, but there are conflicting data from studies attempting to confirm or refute this notion.

In a prospective, multicenter European study of more than 500 patients with hemophilia, the predicted cardiovascular disease (CVD) event rate was less than half of what was expected, reported Paul R. van der Valk, MD, from University Medical Center in Utrecht, the Netherlands, and colleagues.

In patients with hemophilia, “the leading cause of death seems to be malignancy related and intracranial hemorrhage. Atrial fibrillation is quite common,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

But a second study of 100 patients with hemophilia showed that the bleeding disorder did not appear to offer protection against cardiovascular or thrombotic adverse events, Beatriz Delgado, MD, and colleagues at the Centro Hospitalar São João in Porto, Portugal, also presented in a poster session.

Risk scores considered

The prospective study by Dr. van der Valk and colleagues was designed to assess the incidence of CVD in patients with hemophilia in the Netherlands and the United Kingdom, compared with the general population. They used the QRISK2 cardiovascular risk score (2011 version). This instrument is used to calculate risk of CVD events in adults from 30 to 84 with no history of CVD or statin use.

Among 557 patients with a calculable QRISK2 score at 2 years of follow-up, there were four CVD events, including two cases of ischemic heart disease, one ischemic stroke, and one intracranial hemorrhage. The median 2-year QRISK2 score was 1.7%, and the 10-year risk was 9.0%, which translated in to an expected 9.5 CVD events during 2 years of follow-up.

Among the additional 104 patients who could not have a QRISK2 score calculated because of age over 84, statin use, or history of CVD, there were four CVD events: ischemic heart disease, transient ischemic attack/carotid artery stenosis, myocardial infarction, and intracranial hemorrhage.

Other CVD events occurring in both groups included atrial fibrillation in eight patients, other arrhythmia in three, and, in one patient each, aortic valve pathology, pericarditis, and carotid artery plaque.

Portuguese experience

Dr, Delgado and colleagues noted that although hemophilia has traditionally been regarded as protective against ischemic heart disease or thrombotic events, modern management “has prolonged life expectancy of people with hemophilia and consequently, an associated increase in incidence and prevalence of conditions that affect the general older population, such as cardiovascular disease and hypertension, are expected.”

They conducted a retrospective analysis of 100 adults (69 with hemophilia A, and 31 with hemophilia B) treated at their center. Overall, 29 patients had severe hemophilia A, 20 moderate hemophilia A, and 20 mild hemophilia A. Among patients with hemophilia B, 11 had severe, 15 moderate, and 5 mild disease.­

Two patients (one with moderate and one with severe hemophilia) had angina episodes with coronary artery disease and underwent multiple coronary bypass grafts. The patient with severe disease had a disabling ischemic stroke during recovery from bypass surgery, and the patient with moderate hemophilia had an acute myocardial infarction prior to bypass surgery.

Two other patients had transient ischemic strokes from which they recovered without disability.

The main cardiovascular risk factors identified in this population were hypertension, diabetes mellitus, heavy smoking, obesity, and dyslipidemia. All patients were screened for prothrombotic risk, and all patients had negative test results.

“Hemophilia does not seem to have a protective effect against thrombotic/cardiovascular events, mainly in [patients with] coronary artery disease,” the investigators wrote.

Endothelial function

In a study presented in an oral abstract session, Shannon Jackson, MD, of the University of British Columbia in Vancouver found that men with hemophilia appear to have better macrovascular endothelial function but worse microvascular endothelial function than did men with normal clotting parameters.

“Based on endothelial function, contemporary hemophilia cohorts may have a different profile of cardiovascular risk than healthy controls,” she said.

Although they do not have an obvious mechanistic explanation for the differences in microvascular function among patients with hemophilia vs. healthy controls, there is evidence to show that microvascular function is predictive of cardiovascular events independent of other risk factors in otherwise healthy people. Their findings indicate that further study of the association between endothelial function, cardiovascular risk factors, and atherosclerosis among patients with hemophilia is warranted, she said.

Dr. van der Valk and colleagues and Dr. Delgado and colleagues did not disclose funding or conflicts of interest. The study by Dr. Jackson and colleagues was supported by the Canadian Hemophilia Society and Pfizer. She disclosed honoraria for speaking engagements for Biogen, Baxalta, and Pfizer and for participating in scientific advisory boards for Bayer, Pfizer, Baxalta, CLS Behring, and Novo Nordisk.

ORLANDO – Conventional wisdom holds that persons with hemophilia are at lower risk for death from cardiovascular events than the general population, but there are conflicting data from studies attempting to confirm or refute this notion.

In a prospective, multicenter European study of more than 500 patients with hemophilia, the predicted cardiovascular disease (CVD) event rate was less than half of what was expected, reported Paul R. van der Valk, MD, from University Medical Center in Utrecht, the Netherlands, and colleagues.

In patients with hemophilia, “the leading cause of death seems to be malignancy related and intracranial hemorrhage. Atrial fibrillation is quite common,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

But a second study of 100 patients with hemophilia showed that the bleeding disorder did not appear to offer protection against cardiovascular or thrombotic adverse events, Beatriz Delgado, MD, and colleagues at the Centro Hospitalar São João in Porto, Portugal, also presented in a poster session.

Risk scores considered

The prospective study by Dr. van der Valk and colleagues was designed to assess the incidence of CVD in patients with hemophilia in the Netherlands and the United Kingdom, compared with the general population. They used the QRISK2 cardiovascular risk score (2011 version). This instrument is used to calculate risk of CVD events in adults from 30 to 84 with no history of CVD or statin use.

Among 557 patients with a calculable QRISK2 score at 2 years of follow-up, there were four CVD events, including two cases of ischemic heart disease, one ischemic stroke, and one intracranial hemorrhage. The median 2-year QRISK2 score was 1.7%, and the 10-year risk was 9.0%, which translated in to an expected 9.5 CVD events during 2 years of follow-up.

Among the additional 104 patients who could not have a QRISK2 score calculated because of age over 84, statin use, or history of CVD, there were four CVD events: ischemic heart disease, transient ischemic attack/carotid artery stenosis, myocardial infarction, and intracranial hemorrhage.

Other CVD events occurring in both groups included atrial fibrillation in eight patients, other arrhythmia in three, and, in one patient each, aortic valve pathology, pericarditis, and carotid artery plaque.

Portuguese experience

Dr, Delgado and colleagues noted that although hemophilia has traditionally been regarded as protective against ischemic heart disease or thrombotic events, modern management “has prolonged life expectancy of people with hemophilia and consequently, an associated increase in incidence and prevalence of conditions that affect the general older population, such as cardiovascular disease and hypertension, are expected.”

They conducted a retrospective analysis of 100 adults (69 with hemophilia A, and 31 with hemophilia B) treated at their center. Overall, 29 patients had severe hemophilia A, 20 moderate hemophilia A, and 20 mild hemophilia A. Among patients with hemophilia B, 11 had severe, 15 moderate, and 5 mild disease.­

Two patients (one with moderate and one with severe hemophilia) had angina episodes with coronary artery disease and underwent multiple coronary bypass grafts. The patient with severe disease had a disabling ischemic stroke during recovery from bypass surgery, and the patient with moderate hemophilia had an acute myocardial infarction prior to bypass surgery.

Two other patients had transient ischemic strokes from which they recovered without disability.

The main cardiovascular risk factors identified in this population were hypertension, diabetes mellitus, heavy smoking, obesity, and dyslipidemia. All patients were screened for prothrombotic risk, and all patients had negative test results.

“Hemophilia does not seem to have a protective effect against thrombotic/cardiovascular events, mainly in [patients with] coronary artery disease,” the investigators wrote.

Endothelial function

In a study presented in an oral abstract session, Shannon Jackson, MD, of the University of British Columbia in Vancouver found that men with hemophilia appear to have better macrovascular endothelial function but worse microvascular endothelial function than did men with normal clotting parameters.

“Based on endothelial function, contemporary hemophilia cohorts may have a different profile of cardiovascular risk than healthy controls,” she said.

Although they do not have an obvious mechanistic explanation for the differences in microvascular function among patients with hemophilia vs. healthy controls, there is evidence to show that microvascular function is predictive of cardiovascular events independent of other risk factors in otherwise healthy people. Their findings indicate that further study of the association between endothelial function, cardiovascular risk factors, and atherosclerosis among patients with hemophilia is warranted, she said.

Dr. van der Valk and colleagues and Dr. Delgado and colleagues did not disclose funding or conflicts of interest. The study by Dr. Jackson and colleagues was supported by the Canadian Hemophilia Society and Pfizer. She disclosed honoraria for speaking engagements for Biogen, Baxalta, and Pfizer and for participating in scientific advisory boards for Bayer, Pfizer, Baxalta, CLS Behring, and Novo Nordisk.

ORLANDO – Conventional wisdom holds that persons with hemophilia are at lower risk for death from cardiovascular events than the general population, but there are conflicting data from studies attempting to confirm or refute this notion.

In a prospective, multicenter European study of more than 500 patients with hemophilia, the predicted cardiovascular disease (CVD) event rate was less than half of what was expected, reported Paul R. van der Valk, MD, from University Medical Center in Utrecht, the Netherlands, and colleagues.

In patients with hemophilia, “the leading cause of death seems to be malignancy related and intracranial hemorrhage. Atrial fibrillation is quite common,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

But a second study of 100 patients with hemophilia showed that the bleeding disorder did not appear to offer protection against cardiovascular or thrombotic adverse events, Beatriz Delgado, MD, and colleagues at the Centro Hospitalar São João in Porto, Portugal, also presented in a poster session.

Risk scores considered

The prospective study by Dr. van der Valk and colleagues was designed to assess the incidence of CVD in patients with hemophilia in the Netherlands and the United Kingdom, compared with the general population. They used the QRISK2 cardiovascular risk score (2011 version). This instrument is used to calculate risk of CVD events in adults from 30 to 84 with no history of CVD or statin use.

Among 557 patients with a calculable QRISK2 score at 2 years of follow-up, there were four CVD events, including two cases of ischemic heart disease, one ischemic stroke, and one intracranial hemorrhage. The median 2-year QRISK2 score was 1.7%, and the 10-year risk was 9.0%, which translated in to an expected 9.5 CVD events during 2 years of follow-up.

Among the additional 104 patients who could not have a QRISK2 score calculated because of age over 84, statin use, or history of CVD, there were four CVD events: ischemic heart disease, transient ischemic attack/carotid artery stenosis, myocardial infarction, and intracranial hemorrhage.

Other CVD events occurring in both groups included atrial fibrillation in eight patients, other arrhythmia in three, and, in one patient each, aortic valve pathology, pericarditis, and carotid artery plaque.

Portuguese experience

Dr, Delgado and colleagues noted that although hemophilia has traditionally been regarded as protective against ischemic heart disease or thrombotic events, modern management “has prolonged life expectancy of people with hemophilia and consequently, an associated increase in incidence and prevalence of conditions that affect the general older population, such as cardiovascular disease and hypertension, are expected.”

They conducted a retrospective analysis of 100 adults (69 with hemophilia A, and 31 with hemophilia B) treated at their center. Overall, 29 patients had severe hemophilia A, 20 moderate hemophilia A, and 20 mild hemophilia A. Among patients with hemophilia B, 11 had severe, 15 moderate, and 5 mild disease.­

Two patients (one with moderate and one with severe hemophilia) had angina episodes with coronary artery disease and underwent multiple coronary bypass grafts. The patient with severe disease had a disabling ischemic stroke during recovery from bypass surgery, and the patient with moderate hemophilia had an acute myocardial infarction prior to bypass surgery.

Two other patients had transient ischemic strokes from which they recovered without disability.

The main cardiovascular risk factors identified in this population were hypertension, diabetes mellitus, heavy smoking, obesity, and dyslipidemia. All patients were screened for prothrombotic risk, and all patients had negative test results.

“Hemophilia does not seem to have a protective effect against thrombotic/cardiovascular events, mainly in [patients with] coronary artery disease,” the investigators wrote.

Endothelial function

In a study presented in an oral abstract session, Shannon Jackson, MD, of the University of British Columbia in Vancouver found that men with hemophilia appear to have better macrovascular endothelial function but worse microvascular endothelial function than did men with normal clotting parameters.

“Based on endothelial function, contemporary hemophilia cohorts may have a different profile of cardiovascular risk than healthy controls,” she said.

Although they do not have an obvious mechanistic explanation for the differences in microvascular function among patients with hemophilia vs. healthy controls, there is evidence to show that microvascular function is predictive of cardiovascular events independent of other risk factors in otherwise healthy people. Their findings indicate that further study of the association between endothelial function, cardiovascular risk factors, and atherosclerosis among patients with hemophilia is warranted, she said.

Dr. van der Valk and colleagues and Dr. Delgado and colleagues did not disclose funding or conflicts of interest. The study by Dr. Jackson and colleagues was supported by the Canadian Hemophilia Society and Pfizer. She disclosed honoraria for speaking engagements for Biogen, Baxalta, and Pfizer and for participating in scientific advisory boards for Bayer, Pfizer, Baxalta, CLS Behring, and Novo Nordisk.

ORLANDO – The frequency of prophylactic clotting factor infusions does not appear to adversely affect adherence to hemophilia therapy in children, but age seems to play a role in compliance to prescribed regimens, investigators in two separate studies report.

A study of pediatric patients with moderate to severe hemophilia A or B on bleeding prophylaxis showed no significant differences in adherence between patients receiving two clotting factor infusions per week and those receiving three or four per week, reported Karen Strike, a physiotherapist at McMaster Children’s Hospital in Hamilton, Ont., and colleagues.

“This study demonstrates that our patients have a very high degree of adherence, and it doesn’t appear to be related to infusion frequency,” she said in an interview at a scientific poster session at the World Federation of Hemophilia World Congress.

Although their sample size was small – just 23 patients – the median levels of adherence were high for both twice-weekly infusers (99.5%) and 3-4 times per week infusers (96%; P = .053).

Ms. Strike acknowledges that the borderline P value could be due to the small sample size instead of a lack of association. Additionally, because the patients are managed by a regional hemophilia treatment center, they tend to be more engaged and more likely to cooperate with clinician instructions, she said.

“Basically, patients are either going to do what’s prescribed or they’re not. What that actual prescription is doesn’t seem to matter. If they prescribe you twice a week or they prescribe me every other day, you’re going to be adherent to twice a week or you’re not.

The investigators have expanded their study to include adult patients on primary prophylaxis and to look at additional co-variates that might have an effect on adherence, including interactions with a health care team, geographical distance from a hemophilia treatment center, joint health status, and infusion delivery method (peripheral vs. port).

Age may be a factor

In a separate study, German investigators report that adherence appears to vary by age.

Wolfgang Miesbach, MD, from Goethe University Hospital in Frankfurt, Germany, and colleagues asked all members of the German hemophilia patient organization with moderate or severe hemophilia to fill out the VERITAS-PRO (Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis) questionnaire and compared scores across age groups.

Data were available on a total of 364 patients. The investigators found that among 131 children from birth to age 19, adherence to prescribed regimens was 100%. In contrast, the adherence rate among 189 adults aged 20-59 was 88.1%. After age 59, adherence rates began to improve as those 60 and older (44 patients) reported 93.9% adherence.

“Within the patients aged 20+, care by a hemophilia center was the only significant indicator for better adherence. The tendency of better adherence of patients aged greater than 60 compared to patients 20-59 may be explained by the significant association of the occurrence of pain with increasing age although a significant influence of pain on the adherence levels could not be demonstrated,” the investigators wrote.

Their findings point the way to possible interventions to facilitate adherence to prophylaxis among patients with hemophilia, they wrote.

Both studies were internally funded. The authors reported no relevant disclosures.

ORLANDO – The frequency of prophylactic clotting factor infusions does not appear to adversely affect adherence to hemophilia therapy in children, but age seems to play a role in compliance to prescribed regimens, investigators in two separate studies report.

A study of pediatric patients with moderate to severe hemophilia A or B on bleeding prophylaxis showed no significant differences in adherence between patients receiving two clotting factor infusions per week and those receiving three or four per week, reported Karen Strike, a physiotherapist at McMaster Children’s Hospital in Hamilton, Ont., and colleagues.

“This study demonstrates that our patients have a very high degree of adherence, and it doesn’t appear to be related to infusion frequency,” she said in an interview at a scientific poster session at the World Federation of Hemophilia World Congress.

Although their sample size was small – just 23 patients – the median levels of adherence were high for both twice-weekly infusers (99.5%) and 3-4 times per week infusers (96%; P = .053).

Ms. Strike acknowledges that the borderline P value could be due to the small sample size instead of a lack of association. Additionally, because the patients are managed by a regional hemophilia treatment center, they tend to be more engaged and more likely to cooperate with clinician instructions, she said.

“Basically, patients are either going to do what’s prescribed or they’re not. What that actual prescription is doesn’t seem to matter. If they prescribe you twice a week or they prescribe me every other day, you’re going to be adherent to twice a week or you’re not.

The investigators have expanded their study to include adult patients on primary prophylaxis and to look at additional co-variates that might have an effect on adherence, including interactions with a health care team, geographical distance from a hemophilia treatment center, joint health status, and infusion delivery method (peripheral vs. port).

Age may be a factor

In a separate study, German investigators report that adherence appears to vary by age.

Wolfgang Miesbach, MD, from Goethe University Hospital in Frankfurt, Germany, and colleagues asked all members of the German hemophilia patient organization with moderate or severe hemophilia to fill out the VERITAS-PRO (Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis) questionnaire and compared scores across age groups.

Data were available on a total of 364 patients. The investigators found that among 131 children from birth to age 19, adherence to prescribed regimens was 100%. In contrast, the adherence rate among 189 adults aged 20-59 was 88.1%. After age 59, adherence rates began to improve as those 60 and older (44 patients) reported 93.9% adherence.

“Within the patients aged 20+, care by a hemophilia center was the only significant indicator for better adherence. The tendency of better adherence of patients aged greater than 60 compared to patients 20-59 may be explained by the significant association of the occurrence of pain with increasing age although a significant influence of pain on the adherence levels could not be demonstrated,” the investigators wrote.

Their findings point the way to possible interventions to facilitate adherence to prophylaxis among patients with hemophilia, they wrote.

Both studies were internally funded. The authors reported no relevant disclosures.

ORLANDO – The frequency of prophylactic clotting factor infusions does not appear to adversely affect adherence to hemophilia therapy in children, but age seems to play a role in compliance to prescribed regimens, investigators in two separate studies report.

A study of pediatric patients with moderate to severe hemophilia A or B on bleeding prophylaxis showed no significant differences in adherence between patients receiving two clotting factor infusions per week and those receiving three or four per week, reported Karen Strike, a physiotherapist at McMaster Children’s Hospital in Hamilton, Ont., and colleagues.

“This study demonstrates that our patients have a very high degree of adherence, and it doesn’t appear to be related to infusion frequency,” she said in an interview at a scientific poster session at the World Federation of Hemophilia World Congress.

Although their sample size was small – just 23 patients – the median levels of adherence were high for both twice-weekly infusers (99.5%) and 3-4 times per week infusers (96%; P = .053).

Ms. Strike acknowledges that the borderline P value could be due to the small sample size instead of a lack of association. Additionally, because the patients are managed by a regional hemophilia treatment center, they tend to be more engaged and more likely to cooperate with clinician instructions, she said.

“Basically, patients are either going to do what’s prescribed or they’re not. What that actual prescription is doesn’t seem to matter. If they prescribe you twice a week or they prescribe me every other day, you’re going to be adherent to twice a week or you’re not.

The investigators have expanded their study to include adult patients on primary prophylaxis and to look at additional co-variates that might have an effect on adherence, including interactions with a health care team, geographical distance from a hemophilia treatment center, joint health status, and infusion delivery method (peripheral vs. port).

Age may be a factor

In a separate study, German investigators report that adherence appears to vary by age.

Wolfgang Miesbach, MD, from Goethe University Hospital in Frankfurt, Germany, and colleagues asked all members of the German hemophilia patient organization with moderate or severe hemophilia to fill out the VERITAS-PRO (Validated Hemophilia Regimen Treatment Adherence Scale-Prophylaxis) questionnaire and compared scores across age groups.

Data were available on a total of 364 patients. The investigators found that among 131 children from birth to age 19, adherence to prescribed regimens was 100%. In contrast, the adherence rate among 189 adults aged 20-59 was 88.1%. After age 59, adherence rates began to improve as those 60 and older (44 patients) reported 93.9% adherence.

“Within the patients aged 20+, care by a hemophilia center was the only significant indicator for better adherence. The tendency of better adherence of patients aged greater than 60 compared to patients 20-59 may be explained by the significant association of the occurrence of pain with increasing age although a significant influence of pain on the adherence levels could not be demonstrated,” the investigators wrote.

Their findings point the way to possible interventions to facilitate adherence to prophylaxis among patients with hemophilia, they wrote.

Both studies were internally funded. The authors reported no relevant disclosures.

Structure of RNA

ORLANDO—Results from an ongoing phase 1 study suggest fitusiran, a small interfering RNA therapeutic targeting antithrombin (AT), can restore hemostasis and prevent bleeding in patients with hemophilia A or B, with or without inhibitors.

In patients with inhibitors, fitusiran exhibited preliminary evidence of reduced bleeding. In patients without inhibitors, fitusiran reduced the median estimated annualized bleeding rate (ABR) to 0.

In addition, researchers said fitusiran was generally well tolerated, and none of the patients developed anti-drug antibodies.

These results were presented at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Alnylam Pharmaceuticals, Inc.

Study design

This phase 1 trial consists of 4 parts. Part A enrolled healthy volunteers who were randomized 3:1 to fitusiran or placebo. This part of the study was completed after the first dose cohort received a single subcutaneous dose of fitusiran at 30 mcg/kg.

Part B, which is also complete, enrolled 12 patients with severe hemophilia A or B. Patients received 3 weekly subcutaneous injections of fitusiran at doses of 15, 45, or 75 mcg/kg.

Part C, in which dosing is complete, enrolled 18 patients with moderate or severe hemophilia A or B without inhibitors. Twelve patients received 3 monthly subcutaneous doses of fitusiran at 225, 450, 900, or 1800 mcg/kg. Six patients received 3 fixed monthly subcutaneous doses of fitusiran at 80 mg.

Part D is designed to enroll up to 18 patients with inhibitors. The first cohort of 6 patients received a 50 mg, fixed, once-monthly, subcutaneous dose. The second cohort has completed enrollment, with 6 patients receiving an 80 mg, fixed, once-monthly, subcutaneous dose.

Results from Parts C and D were presented at the meeting.

Part C results

Treatment with fitusiran resulted in a dose-dependent, statistically significant decrease in AT and increase in thrombin generation. At the 80 mg monthly dose, fitusiran achieved 87±1% mean maximal AT lowering with low inter-patient variability.

Researchers assessed the association between AT lowering and increased thrombin generation in a post-hoc exploratory analysis in which AT lowering was grouped by 25% increments for completed patients in Parts B (n=12) and C (n=17) of the study.

In the highest quartile of ≥75% AT lowering (n=16), fitusiran administration resulted in mean increases in thrombin generation of approximately 290% relative to baseline (P<0.001, as compared to the lowest AT-lowering quartile).

There was a significant, AT-lowering-dependent reduction in bleeding frequency as well.

To obtain a comprehensive assessment of fitusiran’s potential effects on bleeding, researchers performed a post-hoc analysis in evaluable patients from Part C (n=17).

The team compared bleeding events that occurred over the 6-month period prior to study entry, bleeding events that were assessed prospectively during days 0-28 following the initial fitusiran dose (the onset period), and bleeding events that occurred beyond day 29 up to day 112 (the observation period).

Prior to study entry, the estimated median ABR was 28 for patients receiving on-demand factor therapy (n=4) and 2 for patients receiving prophylactic factor therapy (n=13).

The estimated median ABR was 13 among all evaluable patients during the onset period and 0 during the observation period.

In all Part C dose cohorts during the observation period, 53% of patients (9/17) were bleed-free, and 82% of patients reported no spontaneous bleeds.

Part D results

Prior to study entry, all patients in Part D utilized bypass agents, including recombinant factor VIIa and activated prothrombin complex concentrate, to manage their bleeds. They had a pre-study ABR of up to 80.

The first cohort (n=6) of patients received a once-monthly, fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal AT lowering of 81±2% and a mean maximal thrombin generation increase of approximately 368%.

In addition, there was preliminary evidence of reduced bleeding, with a 49% to 100% reduction in estimated ABR during the observation period compared with pre-study values.

Safety results

As of July 11, 2016, fitusiran appears to be generally well tolerated in hemophilia patients, with or without inhibitors (n=31, with 5 patients participating in both Parts B and C).

There have been no serious adverse events related to the drug and no thromboembolic events or laboratory evidence of pathologic clot formation.

One non-inhibitor patient in Part C treated with the 80 mg fixed dose discontinued treatment due to an adverse event that was considered severe and possibly related to the study drug.

This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT (10x upper limit of normal), AST (8x upper limit of normal), C-reactive protein, and D-dimer, without an increase in total bilirubin. The event resolved with symptomatic management, including antacids and analgesics.

Eleven patients (35%) reported mild, drug-related injection site reactions, which were mostly pain or erythema at the injection site.

Additional adverse events reported in at least 10% of patients included upper respiratory tract infection (10%) and arthralgia (10%). The majority of these events were mild or moderate in severity.

*Pasi K J et al, A Subcutaneously Administered Investigational RNAi Therapeutic, Fitusiran (ALN- AT3), Targeting Antithrombin for Treatment of Hemophilia: Interim Results in Patients with Hemophilia A or B, WFH 2016 World Congress, July 2016.

Structure of RNA

ORLANDO—Results from an ongoing phase 1 study suggest fitusiran, a small interfering RNA therapeutic targeting antithrombin (AT), can restore hemostasis and prevent bleeding in patients with hemophilia A or B, with or without inhibitors.

In patients with inhibitors, fitusiran exhibited preliminary evidence of reduced bleeding. In patients without inhibitors, fitusiran reduced the median estimated annualized bleeding rate (ABR) to 0.

In addition, researchers said fitusiran was generally well tolerated, and none of the patients developed anti-drug antibodies.

These results were presented at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Alnylam Pharmaceuticals, Inc.

Study design

This phase 1 trial consists of 4 parts. Part A enrolled healthy volunteers who were randomized 3:1 to fitusiran or placebo. This part of the study was completed after the first dose cohort received a single subcutaneous dose of fitusiran at 30 mcg/kg.

Part B, which is also complete, enrolled 12 patients with severe hemophilia A or B. Patients received 3 weekly subcutaneous injections of fitusiran at doses of 15, 45, or 75 mcg/kg.

Part C, in which dosing is complete, enrolled 18 patients with moderate or severe hemophilia A or B without inhibitors. Twelve patients received 3 monthly subcutaneous doses of fitusiran at 225, 450, 900, or 1800 mcg/kg. Six patients received 3 fixed monthly subcutaneous doses of fitusiran at 80 mg.

Part D is designed to enroll up to 18 patients with inhibitors. The first cohort of 6 patients received a 50 mg, fixed, once-monthly, subcutaneous dose. The second cohort has completed enrollment, with 6 patients receiving an 80 mg, fixed, once-monthly, subcutaneous dose.

Results from Parts C and D were presented at the meeting.

Part C results

Treatment with fitusiran resulted in a dose-dependent, statistically significant decrease in AT and increase in thrombin generation. At the 80 mg monthly dose, fitusiran achieved 87±1% mean maximal AT lowering with low inter-patient variability.

Researchers assessed the association between AT lowering and increased thrombin generation in a post-hoc exploratory analysis in which AT lowering was grouped by 25% increments for completed patients in Parts B (n=12) and C (n=17) of the study.

In the highest quartile of ≥75% AT lowering (n=16), fitusiran administration resulted in mean increases in thrombin generation of approximately 290% relative to baseline (P<0.001, as compared to the lowest AT-lowering quartile).

There was a significant, AT-lowering-dependent reduction in bleeding frequency as well.

To obtain a comprehensive assessment of fitusiran’s potential effects on bleeding, researchers performed a post-hoc analysis in evaluable patients from Part C (n=17).

The team compared bleeding events that occurred over the 6-month period prior to study entry, bleeding events that were assessed prospectively during days 0-28 following the initial fitusiran dose (the onset period), and bleeding events that occurred beyond day 29 up to day 112 (the observation period).

Prior to study entry, the estimated median ABR was 28 for patients receiving on-demand factor therapy (n=4) and 2 for patients receiving prophylactic factor therapy (n=13).

The estimated median ABR was 13 among all evaluable patients during the onset period and 0 during the observation period.

In all Part C dose cohorts during the observation period, 53% of patients (9/17) were bleed-free, and 82% of patients reported no spontaneous bleeds.

Part D results

Prior to study entry, all patients in Part D utilized bypass agents, including recombinant factor VIIa and activated prothrombin complex concentrate, to manage their bleeds. They had a pre-study ABR of up to 80.

The first cohort (n=6) of patients received a once-monthly, fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal AT lowering of 81±2% and a mean maximal thrombin generation increase of approximately 368%.

In addition, there was preliminary evidence of reduced bleeding, with a 49% to 100% reduction in estimated ABR during the observation period compared with pre-study values.

Safety results

As of July 11, 2016, fitusiran appears to be generally well tolerated in hemophilia patients, with or without inhibitors (n=31, with 5 patients participating in both Parts B and C).

There have been no serious adverse events related to the drug and no thromboembolic events or laboratory evidence of pathologic clot formation.

One non-inhibitor patient in Part C treated with the 80 mg fixed dose discontinued treatment due to an adverse event that was considered severe and possibly related to the study drug.

This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT (10x upper limit of normal), AST (8x upper limit of normal), C-reactive protein, and D-dimer, without an increase in total bilirubin. The event resolved with symptomatic management, including antacids and analgesics.

Eleven patients (35%) reported mild, drug-related injection site reactions, which were mostly pain or erythema at the injection site.

Additional adverse events reported in at least 10% of patients included upper respiratory tract infection (10%) and arthralgia (10%). The majority of these events were mild or moderate in severity.

*Pasi K J et al, A Subcutaneously Administered Investigational RNAi Therapeutic, Fitusiran (ALN- AT3), Targeting Antithrombin for Treatment of Hemophilia: Interim Results in Patients with Hemophilia A or B, WFH 2016 World Congress, July 2016.

Structure of RNA

ORLANDO—Results from an ongoing phase 1 study suggest fitusiran, a small interfering RNA therapeutic targeting antithrombin (AT), can restore hemostasis and prevent bleeding in patients with hemophilia A or B, with or without inhibitors.

In patients with inhibitors, fitusiran exhibited preliminary evidence of reduced bleeding. In patients without inhibitors, fitusiran reduced the median estimated annualized bleeding rate (ABR) to 0.

In addition, researchers said fitusiran was generally well tolerated, and none of the patients developed anti-drug antibodies.

These results were presented at the World Federation of Hemophilia 2016 World Congress.* The study was sponsored by Alnylam Pharmaceuticals, Inc.

Study design

This phase 1 trial consists of 4 parts. Part A enrolled healthy volunteers who were randomized 3:1 to fitusiran or placebo. This part of the study was completed after the first dose cohort received a single subcutaneous dose of fitusiran at 30 mcg/kg.

Part B, which is also complete, enrolled 12 patients with severe hemophilia A or B. Patients received 3 weekly subcutaneous injections of fitusiran at doses of 15, 45, or 75 mcg/kg.

Part C, in which dosing is complete, enrolled 18 patients with moderate or severe hemophilia A or B without inhibitors. Twelve patients received 3 monthly subcutaneous doses of fitusiran at 225, 450, 900, or 1800 mcg/kg. Six patients received 3 fixed monthly subcutaneous doses of fitusiran at 80 mg.

Part D is designed to enroll up to 18 patients with inhibitors. The first cohort of 6 patients received a 50 mg, fixed, once-monthly, subcutaneous dose. The second cohort has completed enrollment, with 6 patients receiving an 80 mg, fixed, once-monthly, subcutaneous dose.

Results from Parts C and D were presented at the meeting.

Part C results

Treatment with fitusiran resulted in a dose-dependent, statistically significant decrease in AT and increase in thrombin generation. At the 80 mg monthly dose, fitusiran achieved 87±1% mean maximal AT lowering with low inter-patient variability.

Researchers assessed the association between AT lowering and increased thrombin generation in a post-hoc exploratory analysis in which AT lowering was grouped by 25% increments for completed patients in Parts B (n=12) and C (n=17) of the study.

In the highest quartile of ≥75% AT lowering (n=16), fitusiran administration resulted in mean increases in thrombin generation of approximately 290% relative to baseline (P<0.001, as compared to the lowest AT-lowering quartile).

There was a significant, AT-lowering-dependent reduction in bleeding frequency as well.

To obtain a comprehensive assessment of fitusiran’s potential effects on bleeding, researchers performed a post-hoc analysis in evaluable patients from Part C (n=17).

The team compared bleeding events that occurred over the 6-month period prior to study entry, bleeding events that were assessed prospectively during days 0-28 following the initial fitusiran dose (the onset period), and bleeding events that occurred beyond day 29 up to day 112 (the observation period).

Prior to study entry, the estimated median ABR was 28 for patients receiving on-demand factor therapy (n=4) and 2 for patients receiving prophylactic factor therapy (n=13).

The estimated median ABR was 13 among all evaluable patients during the onset period and 0 during the observation period.

In all Part C dose cohorts during the observation period, 53% of patients (9/17) were bleed-free, and 82% of patients reported no spontaneous bleeds.

Part D results

Prior to study entry, all patients in Part D utilized bypass agents, including recombinant factor VIIa and activated prothrombin complex concentrate, to manage their bleeds. They had a pre-study ABR of up to 80.

The first cohort (n=6) of patients received a once-monthly, fixed subcutaneous dose of 50 mg. Fitusiran achieved a mean maximal AT lowering of 81±2% and a mean maximal thrombin generation increase of approximately 368%.

In addition, there was preliminary evidence of reduced bleeding, with a 49% to 100% reduction in estimated ABR during the observation period compared with pre-study values.

Safety results

As of July 11, 2016, fitusiran appears to be generally well tolerated in hemophilia patients, with or without inhibitors (n=31, with 5 patients participating in both Parts B and C).

There have been no serious adverse events related to the drug and no thromboembolic events or laboratory evidence of pathologic clot formation.

One non-inhibitor patient in Part C treated with the 80 mg fixed dose discontinued treatment due to an adverse event that was considered severe and possibly related to the study drug.

This event was described as non-cardiac chest pain and was accompanied by transient elevations of ALT (10x upper limit of normal), AST (8x upper limit of normal), C-reactive protein, and D-dimer, without an increase in total bilirubin. The event resolved with symptomatic management, including antacids and analgesics.

Eleven patients (35%) reported mild, drug-related injection site reactions, which were mostly pain or erythema at the injection site.

Additional adverse events reported in at least 10% of patients included upper respiratory tract infection (10%) and arthralgia (10%). The majority of these events were mild or moderate in severity.

*Pasi K J et al, A Subcutaneously Administered Investigational RNAi Therapeutic, Fitusiran (ALN- AT3), Targeting Antithrombin for Treatment of Hemophilia: Interim Results in Patients with Hemophilia A or B, WFH 2016 World Congress, July 2016.

DNA helices

Image courtesy of NIGMS

ORLANDO—The gene therapy AMT-060 can reduce the need for factor IX (FIX) prophylaxis in patients with severe hemophilia B, results of a phase 1/2 study suggest.

All of the patients treated in the low-dose cohort of this study have had sustained improvements in their disease phenotype and continue to maintain durable levels of FIX gene activity for up to 39 weeks post-treatment.

Four of the 5 patients were able to discontinue prophylactic FIX infusions.

In addition, AMT-060 was considered well-tolerated. There were 2 serious adverse events, but both were temporary. And none of the patients developed FIX inhibitors.

These data were presented at the World Federation of Hemophilia 2016 World Congress.* The research is sponsored by uniQure.

“I am very encouraged by the stability of increased FIX activity of AMT-060 and the significant reduction in required infusions of factor replacement,” said study investigator Wolfgang Miesbach, MD, of the University of Frankfurt in Germany.

“This effect is particularly important because it is seen in severe patients with established joint disease who experienced a high frequency of joint bleeds despite intense use of prophylactic FIX prior to study entry.”

Patients and treatment

AMT-060 consists of a codon-optimized wild-type FIX gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform.

In this phase 1/2 trial, Dr Miesbach and his colleagues are testing AMT-060 in 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.

Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5x10¹² gc/kg, and 5 received AMT-060 at 2x10¹³ gc/kg.

Dr Miesbach presented results observed in the low-dose cohort. Patients in the high-dose cohort are still in the early stages of follow-up.

Most patients in the low-dose cohort were older than 50 years of age (range, 35-72). Four patients had severe hemophilia B, and 4 had advanced joint disease. All of the patients had frequent bleeding episodes, despite receiving once- or twice-weekly FIX prophylaxis.

Efficacy

For all 5 patients in the low-dose cohort, the mean annualized total FIX usage declined 75% after treatment with AMT-060.

“The majority of patients in this low-dose cohort of AMT-060 are showing FIX activity in the range of 5% of normal, and clinical experience has shown that patients in this range generally do not require prophylactic factor replacement and have a very low frequency of spontaneous joint bleeding episodes,” Dr Miesbach said.

Four patients discontinued prophylactic therapy. The 1 patient who remained on prophylactic therapy has sustained an improved disease phenotype and also required materially less FIX concentrate after treatment with AMT-060.

Through up to 9 months of follow-up, the mean steady-state FIX activity for the 4 patients who discontinued prophylactic FIX therapy was 5.4% of normal, with a range from 3.1% to 6.7% of normal.  These patients had a mean reduction in annualized total FIX usage of 82%.

Safety and immunogenicity

Two patients experienced serious adverse events. One patient had self-limiting fever in the first 24 hours after receiving AMT-060.

The other patient had a transient elevation of alanine aminotransferase (ALT) that was responsive to tapering prednisolone (60 mg/day start dose) without loss of FIX activity. At baseline, this patient’s ALT was 26 IU/L. It hit a peak of 61 IU/L at week 10, but values returned to baseline levels within 2 weeks of treatment.

As expected, all of the patients developed anti-AAV5 antibodies after week 1. None of the patients developed inhibitory antibodies against FIX.

There was no evidence of sustained AAV5 capsid-specific T-cell activation, although 1 patient had transient T-cell activation slightly above the positive threshold at 1 time point. This patient did not have ALT elevation.

*Miesbach W et al, Updated results from a dose escalating study in adult patients with haemophilia B treated with AMT-060 (AAV5-hFIX) gene therapy, WFH 2016 World

Congress, July 2016.

DNA helices

Image courtesy of NIGMS

ORLANDO—The gene therapy AMT-060 can reduce the need for factor IX (FIX) prophylaxis in patients with severe hemophilia B, results of a phase 1/2 study suggest.

All of the patients treated in the low-dose cohort of this study have had sustained improvements in their disease phenotype and continue to maintain durable levels of FIX gene activity for up to 39 weeks post-treatment.

Four of the 5 patients were able to discontinue prophylactic FIX infusions.

In addition, AMT-060 was considered well-tolerated. There were 2 serious adverse events, but both were temporary. And none of the patients developed FIX inhibitors.

These data were presented at the World Federation of Hemophilia 2016 World Congress.* The research is sponsored by uniQure.

“I am very encouraged by the stability of increased FIX activity of AMT-060 and the significant reduction in required infusions of factor replacement,” said study investigator Wolfgang Miesbach, MD, of the University of Frankfurt in Germany.

“This effect is particularly important because it is seen in severe patients with established joint disease who experienced a high frequency of joint bleeds despite intense use of prophylactic FIX prior to study entry.”

Patients and treatment

AMT-060 consists of a codon-optimized wild-type FIX gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform.

In this phase 1/2 trial, Dr Miesbach and his colleagues are testing AMT-060 in 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.

Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5x10¹² gc/kg, and 5 received AMT-060 at 2x10¹³ gc/kg.

Dr Miesbach presented results observed in the low-dose cohort. Patients in the high-dose cohort are still in the early stages of follow-up.

Most patients in the low-dose cohort were older than 50 years of age (range, 35-72). Four patients had severe hemophilia B, and 4 had advanced joint disease. All of the patients had frequent bleeding episodes, despite receiving once- or twice-weekly FIX prophylaxis.

Efficacy

For all 5 patients in the low-dose cohort, the mean annualized total FIX usage declined 75% after treatment with AMT-060.

“The majority of patients in this low-dose cohort of AMT-060 are showing FIX activity in the range of 5% of normal, and clinical experience has shown that patients in this range generally do not require prophylactic factor replacement and have a very low frequency of spontaneous joint bleeding episodes,” Dr Miesbach said.

Four patients discontinued prophylactic therapy. The 1 patient who remained on prophylactic therapy has sustained an improved disease phenotype and also required materially less FIX concentrate after treatment with AMT-060.

Through up to 9 months of follow-up, the mean steady-state FIX activity for the 4 patients who discontinued prophylactic FIX therapy was 5.4% of normal, with a range from 3.1% to 6.7% of normal.  These patients had a mean reduction in annualized total FIX usage of 82%.

Safety and immunogenicity

Two patients experienced serious adverse events. One patient had self-limiting fever in the first 24 hours after receiving AMT-060.

The other patient had a transient elevation of alanine aminotransferase (ALT) that was responsive to tapering prednisolone (60 mg/day start dose) without loss of FIX activity. At baseline, this patient’s ALT was 26 IU/L. It hit a peak of 61 IU/L at week 10, but values returned to baseline levels within 2 weeks of treatment.

As expected, all of the patients developed anti-AAV5 antibodies after week 1. None of the patients developed inhibitory antibodies against FIX.

There was no evidence of sustained AAV5 capsid-specific T-cell activation, although 1 patient had transient T-cell activation slightly above the positive threshold at 1 time point. This patient did not have ALT elevation.

*Miesbach W et al, Updated results from a dose escalating study in adult patients with haemophilia B treated with AMT-060 (AAV5-hFIX) gene therapy, WFH 2016 World

Congress, July 2016.

DNA helices

Image courtesy of NIGMS

ORLANDO—The gene therapy AMT-060 can reduce the need for factor IX (FIX) prophylaxis in patients with severe hemophilia B, results of a phase 1/2 study suggest.

All of the patients treated in the low-dose cohort of this study have had sustained improvements in their disease phenotype and continue to maintain durable levels of FIX gene activity for up to 39 weeks post-treatment.

Four of the 5 patients were able to discontinue prophylactic FIX infusions.

In addition, AMT-060 was considered well-tolerated. There were 2 serious adverse events, but both were temporary. And none of the patients developed FIX inhibitors.

These data were presented at the World Federation of Hemophilia 2016 World Congress.* The research is sponsored by uniQure.

“I am very encouraged by the stability of increased FIX activity of AMT-060 and the significant reduction in required infusions of factor replacement,” said study investigator Wolfgang Miesbach, MD, of the University of Frankfurt in Germany.

“This effect is particularly important because it is seen in severe patients with established joint disease who experienced a high frequency of joint bleeds despite intense use of prophylactic FIX prior to study entry.”

Patients and treatment

AMT-060 consists of a codon-optimized wild-type FIX gene cassette, the LP1 liver promoter, and an AAV5 viral vector manufactured by uniQure using its proprietary insect cell-based technology platform.

In this phase 1/2 trial, Dr Miesbach and his colleagues are testing AMT-060 in 10 patients. All patients had severe or moderately severe hemophilia at baseline, including documented FIX levels less than 1% to 2% of normal, and required chronic infusions of prophylactic or on-demand FIX therapy at the time of enrollment.

Each patient received a 1-time, 30-minute, intravenous dose of AMT-060, without the use of corticosteroids. Five patients received AMT-060 at 5x10¹² gc/kg, and 5 received AMT-060 at 2x10¹³ gc/kg.

Dr Miesbach presented results observed in the low-dose cohort. Patients in the high-dose cohort are still in the early stages of follow-up.

Most patients in the low-dose cohort were older than 50 years of age (range, 35-72). Four patients had severe hemophilia B, and 4 had advanced joint disease. All of the patients had frequent bleeding episodes, despite receiving once- or twice-weekly FIX prophylaxis.

Efficacy

For all 5 patients in the low-dose cohort, the mean annualized total FIX usage declined 75% after treatment with AMT-060.

“The majority of patients in this low-dose cohort of AMT-060 are showing FIX activity in the range of 5% of normal, and clinical experience has shown that patients in this range generally do not require prophylactic factor replacement and have a very low frequency of spontaneous joint bleeding episodes,” Dr Miesbach said.

Four patients discontinued prophylactic therapy. The 1 patient who remained on prophylactic therapy has sustained an improved disease phenotype and also required materially less FIX concentrate after treatment with AMT-060.

Through up to 9 months of follow-up, the mean steady-state FIX activity for the 4 patients who discontinued prophylactic FIX therapy was 5.4% of normal, with a range from 3.1% to 6.7% of normal.  These patients had a mean reduction in annualized total FIX usage of 82%.

Safety and immunogenicity

Two patients experienced serious adverse events. One patient had self-limiting fever in the first 24 hours after receiving AMT-060.

The other patient had a transient elevation of alanine aminotransferase (ALT) that was responsive to tapering prednisolone (60 mg/day start dose) without loss of FIX activity. At baseline, this patient’s ALT was 26 IU/L. It hit a peak of 61 IU/L at week 10, but values returned to baseline levels within 2 weeks of treatment.

As expected, all of the patients developed anti-AAV5 antibodies after week 1. None of the patients developed inhibitory antibodies against FIX.

There was no evidence of sustained AAV5 capsid-specific T-cell activation, although 1 patient had transient T-cell activation slightly above the positive threshold at 1 time point. This patient did not have ALT elevation.

*Miesbach W et al, Updated results from a dose escalating study in adult patients with haemophilia B treated with AMT-060 (AAV5-hFIX) gene therapy, WFH 2016 World

Congress, July 2016.