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ITI protects against bleeding in hemophilia A with factor VIII inhibitors
Immune tolerance induction, or ITI, in hemophilia A patients with inhibitor development against factor VIII (FVIII) appears to provide some protection against bleeding, as bleeding during ITI in patients from the PedNet registry was dependent on inhibitor titer and ITI regimen, according to Kathelijn Fischer, MD.
Of 218 registry patients who were born during 1990-2009 and who had clinically relevant inhibitors and available data on joint bleeding, 157 had bleeding for at least 3 months. They were followed for a median of 26 months starting at age 16 months, and most had high titer inhibitors (52% had titers of 5-199 BU, and 32% had titers greater than 200 BU).
The bleeding rates in 12 patients without ITI who were on prophylaxis were similar to those in 89 such patients without prophylaxis (0.3 and 0.4 bleeds/month, respectively); no significant difference was seen between the groups based on inhibitor titer, Dr. Fischer of University Medical Center Utrecht, The Netherlands reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Similarly, the bleeding rate during ITI among those on prophylaxis did not differ significantly from the rate in those without prophylaxis (0.4 vs. 0.3/month, respectively), but the rate did increase significantly according to inhibitor titer: The rate increased from 0.05/month in the group with less than 5 BU, to 0.2/month in those with 5-199 BU, and to 0.5/month in the group with greater than 200 BU.
Further, while ITI dose did not affect bleeding, dosing frequency had a strong effect. The median rate with nondaily dosing in 36 patients vs. daily dosing in 63 patients was 0.4/month vs. 0.2/month, respectively, Dr. Fischer said.
She reported having no disclosures.
Immune tolerance induction, or ITI, in hemophilia A patients with inhibitor development against factor VIII (FVIII) appears to provide some protection against bleeding, as bleeding during ITI in patients from the PedNet registry was dependent on inhibitor titer and ITI regimen, according to Kathelijn Fischer, MD.
Of 218 registry patients who were born during 1990-2009 and who had clinically relevant inhibitors and available data on joint bleeding, 157 had bleeding for at least 3 months. They were followed for a median of 26 months starting at age 16 months, and most had high titer inhibitors (52% had titers of 5-199 BU, and 32% had titers greater than 200 BU).
The bleeding rates in 12 patients without ITI who were on prophylaxis were similar to those in 89 such patients without prophylaxis (0.3 and 0.4 bleeds/month, respectively); no significant difference was seen between the groups based on inhibitor titer, Dr. Fischer of University Medical Center Utrecht, The Netherlands reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Similarly, the bleeding rate during ITI among those on prophylaxis did not differ significantly from the rate in those without prophylaxis (0.4 vs. 0.3/month, respectively), but the rate did increase significantly according to inhibitor titer: The rate increased from 0.05/month in the group with less than 5 BU, to 0.2/month in those with 5-199 BU, and to 0.5/month in the group with greater than 200 BU.
Further, while ITI dose did not affect bleeding, dosing frequency had a strong effect. The median rate with nondaily dosing in 36 patients vs. daily dosing in 63 patients was 0.4/month vs. 0.2/month, respectively, Dr. Fischer said.
She reported having no disclosures.
Immune tolerance induction, or ITI, in hemophilia A patients with inhibitor development against factor VIII (FVIII) appears to provide some protection against bleeding, as bleeding during ITI in patients from the PedNet registry was dependent on inhibitor titer and ITI regimen, according to Kathelijn Fischer, MD.
Of 218 registry patients who were born during 1990-2009 and who had clinically relevant inhibitors and available data on joint bleeding, 157 had bleeding for at least 3 months. They were followed for a median of 26 months starting at age 16 months, and most had high titer inhibitors (52% had titers of 5-199 BU, and 32% had titers greater than 200 BU).
The bleeding rates in 12 patients without ITI who were on prophylaxis were similar to those in 89 such patients without prophylaxis (0.3 and 0.4 bleeds/month, respectively); no significant difference was seen between the groups based on inhibitor titer, Dr. Fischer of University Medical Center Utrecht, The Netherlands reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Similarly, the bleeding rate during ITI among those on prophylaxis did not differ significantly from the rate in those without prophylaxis (0.4 vs. 0.3/month, respectively), but the rate did increase significantly according to inhibitor titer: The rate increased from 0.05/month in the group with less than 5 BU, to 0.2/month in those with 5-199 BU, and to 0.5/month in the group with greater than 200 BU.
Further, while ITI dose did not affect bleeding, dosing frequency had a strong effect. The median rate with nondaily dosing in 36 patients vs. daily dosing in 63 patients was 0.4/month vs. 0.2/month, respectively, Dr. Fischer said.
She reported having no disclosures.
FROM EAHAD 2017
Key clinical point:
Major finding: Median bleeding rate with nondaily vs. daily ITI dosing was 0.4/month vs. 0.2/month, respectively.
Data source: An analysis of 218 patients from the PedNet registry.
Disclosures: Dr. Fischer reported having no disclosures.
Study: No link between vaccines, inhibitor development
The administration of pediatric vaccinations in close proximity to factor VIII (FVIII) exposure was not associated with inhibitor development in previously untreated patients with severe hemophilia A in the PedNet Registry.
Similarly, no association was seen between recurrent vaccinations and inhibitor development, Dr. van den Berg reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Inhibitor development in this patient population is a multifactorial event, but these findings show no association between vaccinations administered early in life and increased inhibitor risk, she concluded.
Dr. van den Berg received grant/research support from Bayer, Baxalta, Pfizer, CSI, and Grifols.
The administration of pediatric vaccinations in close proximity to factor VIII (FVIII) exposure was not associated with inhibitor development in previously untreated patients with severe hemophilia A in the PedNet Registry.
Similarly, no association was seen between recurrent vaccinations and inhibitor development, Dr. van den Berg reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Inhibitor development in this patient population is a multifactorial event, but these findings show no association between vaccinations administered early in life and increased inhibitor risk, she concluded.
Dr. van den Berg received grant/research support from Bayer, Baxalta, Pfizer, CSI, and Grifols.
The administration of pediatric vaccinations in close proximity to factor VIII (FVIII) exposure was not associated with inhibitor development in previously untreated patients with severe hemophilia A in the PedNet Registry.
Similarly, no association was seen between recurrent vaccinations and inhibitor development, Dr. van den Berg reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.
Inhibitor development in this patient population is a multifactorial event, but these findings show no association between vaccinations administered early in life and increased inhibitor risk, she concluded.
Dr. van den Berg received grant/research support from Bayer, Baxalta, Pfizer, CSI, and Grifols.
FROM EAHAD 2017
Key clinical point:
Major finding: The adjusted hazard ratio for any inhibitor development related to vaccinations in close proximity to FVIII was 0.65.
Data source: A review of data from 375 children in the PedNet Registry.
Disclosures: Dr. van den Berg received grant/research support from Bayer, Baxalta, Pfizer, CSI, and Grifols.
AHEAD studies establish bleed rate benchmarks
The findings from a large cohort study of patients with moderate and severe hemophilia A have supplied benchmarks that can be used in developing new treatments, Alessandro Gringeri, MD, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.*
More than 37% of 869 patients with moderate or severe hemophilia A who were on prophylaxis and who were enrolled in the noninterventional, prospective, long-term AHEAD international and German cohort studies experienced less than one bleed per year on average, and 50% had an annual bleed rate of less than two.
Furthermore, a median of 56% of those on prophylaxis had an annual joint bleed rate (AJBR) of less than one, and nearly 70% had an AJBR of less than two. Study subjects were enrolled from 22 countries at a mean age at screening of 23.4 years. Most (67%) had severe hemophilia A, and 79% were on prophylaxis, said Dr. Gringeri of Global Medical Affairs Hematology, Shire, Austria.
Among patients in the international arm and the German arm of the study, the median annual bleed rates, respectively, were 1.2 and 2.5 in year 1, 1.2 and 2.2 in year 2, and 1.9 in each arm in year 3. Median AJBRs were 0.9 in each arm in year 1, 0.9 and 0 in year 2, and 1.0 and 0.8 in year 3.
The data provide a valid benchmark for new products and therapeutic approaches, Dr. Gringeri concluded.
Dr. Gringeri is an employee of Shire.
CORRECTION 2/11/17: An earlier version of this article misstated the presenting author's name.
The findings from a large cohort study of patients with moderate and severe hemophilia A have supplied benchmarks that can be used in developing new treatments, Alessandro Gringeri, MD, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.*
More than 37% of 869 patients with moderate or severe hemophilia A who were on prophylaxis and who were enrolled in the noninterventional, prospective, long-term AHEAD international and German cohort studies experienced less than one bleed per year on average, and 50% had an annual bleed rate of less than two.
Furthermore, a median of 56% of those on prophylaxis had an annual joint bleed rate (AJBR) of less than one, and nearly 70% had an AJBR of less than two. Study subjects were enrolled from 22 countries at a mean age at screening of 23.4 years. Most (67%) had severe hemophilia A, and 79% were on prophylaxis, said Dr. Gringeri of Global Medical Affairs Hematology, Shire, Austria.
Among patients in the international arm and the German arm of the study, the median annual bleed rates, respectively, were 1.2 and 2.5 in year 1, 1.2 and 2.2 in year 2, and 1.9 in each arm in year 3. Median AJBRs were 0.9 in each arm in year 1, 0.9 and 0 in year 2, and 1.0 and 0.8 in year 3.
The data provide a valid benchmark for new products and therapeutic approaches, Dr. Gringeri concluded.
Dr. Gringeri is an employee of Shire.
CORRECTION 2/11/17: An earlier version of this article misstated the presenting author's name.
The findings from a large cohort study of patients with moderate and severe hemophilia A have supplied benchmarks that can be used in developing new treatments, Alessandro Gringeri, MD, reported at the annual meeting of the European Association for Haemophilia and Allied Disorders.*
More than 37% of 869 patients with moderate or severe hemophilia A who were on prophylaxis and who were enrolled in the noninterventional, prospective, long-term AHEAD international and German cohort studies experienced less than one bleed per year on average, and 50% had an annual bleed rate of less than two.
Furthermore, a median of 56% of those on prophylaxis had an annual joint bleed rate (AJBR) of less than one, and nearly 70% had an AJBR of less than two. Study subjects were enrolled from 22 countries at a mean age at screening of 23.4 years. Most (67%) had severe hemophilia A, and 79% were on prophylaxis, said Dr. Gringeri of Global Medical Affairs Hematology, Shire, Austria.
Among patients in the international arm and the German arm of the study, the median annual bleed rates, respectively, were 1.2 and 2.5 in year 1, 1.2 and 2.2 in year 2, and 1.9 in each arm in year 3. Median AJBRs were 0.9 in each arm in year 1, 0.9 and 0 in year 2, and 1.0 and 0.8 in year 3.
The data provide a valid benchmark for new products and therapeutic approaches, Dr. Gringeri concluded.
Dr. Gringeri is an employee of Shire.
CORRECTION 2/11/17: An earlier version of this article misstated the presenting author's name.
FROM EAHAD 2017
Key clinical point:
Major finding: 37% of hemophilia A patients on prophylaxis experienced less than one bleed per year on average.
Data source: The prospective long-term AHEAD cohort studies, including 869 patients.
Disclosures: Dr. Gringeri is an employee of Shire.
Sickle cell trait artificially lowers HbA1c
African Americans who have sickle cell trait show lower hemoglobin A1c levels at any given concentration of fasting glucose than do those who don’t have sickle cell trait, according to a report published online Feb. 7 in JAMA.
This suggests that HbA1c levels systematically underestimate glucose levels in black patients who carry the trait, who comprise approximately 10% of the African American population, said Mary E. Lacy, a doctoral candidate in the department of epidemiology, Brown University School of Public Health, Providence, R.I., and her associates.
The investigators examined a possible link between HbA1c and sickle cell trait, which affects hemoglobin even though it doesn’t confer sickle cell disease, by analyzing data from two cohort studies involving African American adults. They focused on 4,620 participants who underwent serial HbA1c and plasma glucose measurements during 5-25 years of follow-up. A total of 367 of them had sickle cell trait.
Analysis of 9,062 concurrent assessments of fasting glucose and HbA1c plus 2,001 concurrent assessments of 2-hour postprandial glucose and HbA1c showed mean HbA1c was consistently significantly lower in people with sickle cell trait (mean level, 5.7%) than in those without the trait (mean level, 6%) despite similar glucose values.
“Our results suggest that currently accepted clinical measures of HbA1c do not reflect recent past glycemia in the same way in African Americans with and without sickle cell trait,” Ms. Lacy and her associates said (JAMA 2017 Feb 7. doi: 10.1001/jama.2016.21035).
When used as a screen for prediabetes or diabetes, HbA1c values “systematically underestimate long-term glucose levels,” which means a significant proportion of African American patients will miss the opportunity for treatment. In this study, “using standard clinical HbA1c criteria to identify prediabetes and diabetes resulted in identifying 40% fewer cases of prediabetes and 48% fewer cases of diabetes among participants with sickle cell trait, compared to those without sickle cell trait,” the investigators noted.
“Because black people typically have a higher prevalence of diabetes and experience a number of diabetic complications at higher rates than [those of] white people, the cost of inaccurately assessing risk and treatment response is high,” they added.
The National Heart, Lung, and Blood Institute, the National Institute on Aging, the National Institute on Minority Health Disparities, the Providence VA Medical Center, and the National Institute of Diabetes and Digestive and Kidney Diseases supported the study. Ms. Lacy and her associates reported having no relevant financial disclosures.
The findings of Lacy et al. indicate that clinicians must be alert that black patients with diabetes who don’t have sickle cell trait may be more vulnerable to treatment-related hypoglycemia and require slightly higher HbA1c targets.
The study results also imply that black patients without sickle cell trait are more likely to be misdiagnosed as having prediabetes or diabetes when they don’t actually have these disorders. This would have serious medical and psychosocial implications: In addition to subjecting such patients to unnecessary tests, medications, and health care visits, a diabetes misdiagnosis (like an accurate diabetes diagnosis) makes the purchase of health and life insurance prohibitively expensive.
Anthony J. Bleyer, MD, is in the section on nephrology, and Joseph A. Aloi, MD, is in the section on endocrinology, at Wake Forest University, Winston-Salem, N.C. They made these remarks in an editorial accompanying Ms. Lacy’s report (JAMA 2017;317:481-2), and reported having no relevant financial disclosures.
The findings of Lacy et al. indicate that clinicians must be alert that black patients with diabetes who don’t have sickle cell trait may be more vulnerable to treatment-related hypoglycemia and require slightly higher HbA1c targets.
The study results also imply that black patients without sickle cell trait are more likely to be misdiagnosed as having prediabetes or diabetes when they don’t actually have these disorders. This would have serious medical and psychosocial implications: In addition to subjecting such patients to unnecessary tests, medications, and health care visits, a diabetes misdiagnosis (like an accurate diabetes diagnosis) makes the purchase of health and life insurance prohibitively expensive.
Anthony J. Bleyer, MD, is in the section on nephrology, and Joseph A. Aloi, MD, is in the section on endocrinology, at Wake Forest University, Winston-Salem, N.C. They made these remarks in an editorial accompanying Ms. Lacy’s report (JAMA 2017;317:481-2), and reported having no relevant financial disclosures.
The findings of Lacy et al. indicate that clinicians must be alert that black patients with diabetes who don’t have sickle cell trait may be more vulnerable to treatment-related hypoglycemia and require slightly higher HbA1c targets.
The study results also imply that black patients without sickle cell trait are more likely to be misdiagnosed as having prediabetes or diabetes when they don’t actually have these disorders. This would have serious medical and psychosocial implications: In addition to subjecting such patients to unnecessary tests, medications, and health care visits, a diabetes misdiagnosis (like an accurate diabetes diagnosis) makes the purchase of health and life insurance prohibitively expensive.
Anthony J. Bleyer, MD, is in the section on nephrology, and Joseph A. Aloi, MD, is in the section on endocrinology, at Wake Forest University, Winston-Salem, N.C. They made these remarks in an editorial accompanying Ms. Lacy’s report (JAMA 2017;317:481-2), and reported having no relevant financial disclosures.
African Americans who have sickle cell trait show lower hemoglobin A1c levels at any given concentration of fasting glucose than do those who don’t have sickle cell trait, according to a report published online Feb. 7 in JAMA.
This suggests that HbA1c levels systematically underestimate glucose levels in black patients who carry the trait, who comprise approximately 10% of the African American population, said Mary E. Lacy, a doctoral candidate in the department of epidemiology, Brown University School of Public Health, Providence, R.I., and her associates.
The investigators examined a possible link between HbA1c and sickle cell trait, which affects hemoglobin even though it doesn’t confer sickle cell disease, by analyzing data from two cohort studies involving African American adults. They focused on 4,620 participants who underwent serial HbA1c and plasma glucose measurements during 5-25 years of follow-up. A total of 367 of them had sickle cell trait.
Analysis of 9,062 concurrent assessments of fasting glucose and HbA1c plus 2,001 concurrent assessments of 2-hour postprandial glucose and HbA1c showed mean HbA1c was consistently significantly lower in people with sickle cell trait (mean level, 5.7%) than in those without the trait (mean level, 6%) despite similar glucose values.
“Our results suggest that currently accepted clinical measures of HbA1c do not reflect recent past glycemia in the same way in African Americans with and without sickle cell trait,” Ms. Lacy and her associates said (JAMA 2017 Feb 7. doi: 10.1001/jama.2016.21035).
When used as a screen for prediabetes or diabetes, HbA1c values “systematically underestimate long-term glucose levels,” which means a significant proportion of African American patients will miss the opportunity for treatment. In this study, “using standard clinical HbA1c criteria to identify prediabetes and diabetes resulted in identifying 40% fewer cases of prediabetes and 48% fewer cases of diabetes among participants with sickle cell trait, compared to those without sickle cell trait,” the investigators noted.
“Because black people typically have a higher prevalence of diabetes and experience a number of diabetic complications at higher rates than [those of] white people, the cost of inaccurately assessing risk and treatment response is high,” they added.
The National Heart, Lung, and Blood Institute, the National Institute on Aging, the National Institute on Minority Health Disparities, the Providence VA Medical Center, and the National Institute of Diabetes and Digestive and Kidney Diseases supported the study. Ms. Lacy and her associates reported having no relevant financial disclosures.
African Americans who have sickle cell trait show lower hemoglobin A1c levels at any given concentration of fasting glucose than do those who don’t have sickle cell trait, according to a report published online Feb. 7 in JAMA.
This suggests that HbA1c levels systematically underestimate glucose levels in black patients who carry the trait, who comprise approximately 10% of the African American population, said Mary E. Lacy, a doctoral candidate in the department of epidemiology, Brown University School of Public Health, Providence, R.I., and her associates.
The investigators examined a possible link between HbA1c and sickle cell trait, which affects hemoglobin even though it doesn’t confer sickle cell disease, by analyzing data from two cohort studies involving African American adults. They focused on 4,620 participants who underwent serial HbA1c and plasma glucose measurements during 5-25 years of follow-up. A total of 367 of them had sickle cell trait.
Analysis of 9,062 concurrent assessments of fasting glucose and HbA1c plus 2,001 concurrent assessments of 2-hour postprandial glucose and HbA1c showed mean HbA1c was consistently significantly lower in people with sickle cell trait (mean level, 5.7%) than in those without the trait (mean level, 6%) despite similar glucose values.
“Our results suggest that currently accepted clinical measures of HbA1c do not reflect recent past glycemia in the same way in African Americans with and without sickle cell trait,” Ms. Lacy and her associates said (JAMA 2017 Feb 7. doi: 10.1001/jama.2016.21035).
When used as a screen for prediabetes or diabetes, HbA1c values “systematically underestimate long-term glucose levels,” which means a significant proportion of African American patients will miss the opportunity for treatment. In this study, “using standard clinical HbA1c criteria to identify prediabetes and diabetes resulted in identifying 40% fewer cases of prediabetes and 48% fewer cases of diabetes among participants with sickle cell trait, compared to those without sickle cell trait,” the investigators noted.
“Because black people typically have a higher prevalence of diabetes and experience a number of diabetic complications at higher rates than [those of] white people, the cost of inaccurately assessing risk and treatment response is high,” they added.
The National Heart, Lung, and Blood Institute, the National Institute on Aging, the National Institute on Minority Health Disparities, the Providence VA Medical Center, and the National Institute of Diabetes and Digestive and Kidney Diseases supported the study. Ms. Lacy and her associates reported having no relevant financial disclosures.
FROM JAMA
Key clinical point: African Americans who have sickle cell trait show lower HbA1c levels at any given concentration of fasting glucose than do those without the trait.
Major finding: Mean HbA1c was consistently significantly lower in people with sickle cell trait (mean level, 5.7%) than in those without the trait (mean level, 6%) despite similar glucose values.
Data source: A secondary, retrospective analysis of data pooled from two large cohorts of African American adults involving a total of 4,620 participants.
Disclosures: The National Heart, Lung, and Blood Institute, the National Institute on Aging, the National Institute on Minority Health Disparities, the Providence VA Medical Center, and the National Institute of Diabetes and Digestive and Kidney Diseases supported the study. Ms. Lacy and her associates reported having no relevant financial disclosures.
Ruxolitinib beats best available care for hematocrit control in polycythemia
For patients with polycythemia vera without splenomegaly who had inadequate responses to hydroxyurea, targeted therapy with the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) offered better control of hematocrit and better improvement of symptoms than did the best available therapy, according to results of a multinational randomized phase IIIb trial.
Among 74 patients randomly assigned to receive ruxolitinib, 46 (62%) achieved hematocrit control, compared with 14 of 75 patients (19%) assigned to receive one of several different options lumped into the best available therapy category, noted investigators led by Francesco Passamonti, MD, of the University of Insubria in Varese, Italy.
“Ruxolitinib also led to an improved symptom burden and quality of life. Patients treated with ruxolitinib experienced improvements in all polycythemia vera–associated symptoms, including pruritus, whereas patients treated with best available therapy experienced worsening of most symptoms,” they wrote.
Unlike cytoreductive therapies such as hydroxyurea or pegylated interferon, ruxolitinib works by inhibition of JAK1 and JAK2 signaling. A majority of patients with polycythemia vera have an activating JAK2 mutation that leads to overactivation of the JAK-STAT signaling pathway, resulting in erythrocytosis, the hallmark symptom of polycythemia vera, and associated vascular complications.
“In some patients, conventional therapies can lose effectiveness over time. Although hydroxyurea is well tolerated in most patients, about 15%-20% of patients become resistant or intolerant, with hydroxyurea resistance affecting survival and increasing the risk of progression to myelofibrosis. Additionally, patients who are intolerant of hydroxyurea can have adverse side effects, such as drug-induced fever, mouth ulcers, leg ulcers, and skin malignancies, which necessitate discontinuation of first-line therapy,” the investigators noted.
RESPONSE trials
Ruxolitinib had previously been shown in the RESPONSE study to be superior to the best available therapy for controlling hematocrit and for improving splenomegaly and other symptoms in patients with polycythemia vera and disease-associated splenomegaly who had an inadequate response or unacceptable toxicities from treatment with hydroxyurea.
In the currently reported study, dubbed RESPONSE-2, patients 18 and older with polycythemia vera with no palpable splenomegaly who were intolerant of hydroxyurea or had disease that was resistant to it were randomized to receive either oral ruxolitinib 10 mg twice daily, or best available therapy at the investigators’ discretion. Best available therapy consisted of either hydroxyurea at the maximum tolerated dose, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment.
As noted, hematocrit control at week 28, the primary endpoint, was significantly higher among patients on ruxolitinib, with an odds ratio (OR) of 7.28 (P less than .0001).
Hematocrit levels among patients on ruxolitinib group decreased from a mean of 42.8% at baseline to 40.2% at week 28. In contrast, hematocrit in the best available therapy group increased from a mean of 42.7% to 44.9% at week 28.
Fewer patients on ruxolitinib required phlebotomy procedures during the 28 weeks of the study compared with patients on best available therapy, and of those patients who did undergo phlebotomy, fewer of those in the ruxolitinib group underwent more than two procedures. There were a total of 98 phlebotomies among best available care patients, vs. 19 among ruxolitinib patients.
Complete hematologic remissions, a secondary endpoint, occurred in 23% of patients on ruxolitinib, compared with 5% of those on best available care (OR 5.58, P = .0019).
The most frequent hematologic adverse events of any grade were anemia, which occurred in 10 patients on ruxolitinib (none grade 3 or greater) vs. two on best available therapy (one grade 3), and thrombocytopenia occurring in two (both grade 1 or 2) and six patients (three grade 1 or 2, two grade 3, and one grade 4) respectively.
Grade 3 or 4 nonhematologic adverse events included hypertension in five patients on ruxolitinib vs. three on best available care, and pruritus in none vs. two, respectively.
Two patients died; both were in the best available therapy group.
“Although the short follow-up of this study precludes any conclusions about vascular complications, an important finding is that patients treated with ruxolitinib in both RESPONSE and RESPONSE-2 had fewer thromboembolic events compared with those given best available therapy; there were two thromboembolic events with ruxolitinib (one in each study) versus nine with best available therapy across both studies (six in RESPONSE and three in RESPONSE-2). This finding could have been attributable to better control of hematocrit or white blood cell count with ruxolitinib, given that baseline risk factors were similar in both treatment groups,” the investigators wrote.
The findings from the two studies support the use of ruxolitinib as a standard of care for second-line therapy of patients with polycythemia vera following treatment with hydroxyurea, they contended.
Several coauthors disclosed ties to Novartis, which supported the study. Two are Novartis employees; one was previously employed by the company.
Ruxolitinib has now been assessed in two clinical trials in polycythemia vera without myelofibrosis. Francesco Passamonti and colleagues report the results of RESPONSE-2, a randomized, open-label, phase IIIb trial of ruxolitinib in patients with polycythemia vera without splenomegaly, who were intolerant of or unresponsive to hydroxyurea, versus the best available therapy (usually hydroxyurea), making this trial – like the previous RESPONSE trial, in which the effect of ruxolitinib was examined in hydroxyurea-intolerant or unresponsive patients with polycythemia vera with splenomegaly – a referendum on hydroxyurea. On the basis of their age, most RESPONSE-2 patients were defined as so-called high-risk patients, and were phlebotomy dependent.
Unsurprisingly, for the primary endpoint of patients achieving hematocrit control, ruxolitinib was superior to best available therapy (46 [62%] of 74 patients in the ruxolitinib group vs. 14 [19%] of 75 in the best available therapy group; odds ratio, 7.28 [95% CI 3.43–15.45]; P less than .0001), and also for the key secondary endpoint for patients achieving complete hematologic remission (23% vs .5%).
Symptom control, including pruritus, was superior in the ruxolitinib group, and adverse events were more common in the best available therapy group. The authors concluded that ruxolitinib “could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population”
However, I challenge this conclusion. First, the consensus that hydroxyurea is first-line therapy for polycythemia vera is not evidence based. Indeed, a trial using hydroxyurea in patients with polycythemia vera to achieve European LeukemiaNet criteria for complete hematologic remission did not result in better survival or less thrombosis compared with the expected survival of patients with similar disease characteristics.
Second, the primary endpoint of RESPONSE-2 was phlebotomy control but the appropriate control group (a phlebotomy-only group) was not included, nor was phlebotomy control or hematologic remission achieved with ruxolitinib in all patients. Ruxolitinib is an expensive drug, but phlebotomy is an inexpensive and immediately effective procedure, and it is unlikely that insurers would support the use of ruxolitinib in polycythemia vera for hematocrit control without proof of greater efficacy than phlebotomy therapy.
Third, no study of ruxolitinib in polycythemia vera has capitalized on the observation, based on both clinical and gene-expression data, that patients with polycythemia vera are not all alike; male and female patients differ clinically and in gene expression, and the disease is indolent in some patients and aggressive in others, who also differ in gene expression. Thus, it should not be presumed that all patients with polycythemia vera will require ruxolitinib therapy or that all patients who do receive this treatment will respond similarly. Finally, polycythemia vera is an hematopoietic stem-cell disorder and, so far, ruxolitinib does not seem to affect hematopoietic stem cell behavior. At present, pegylated interferon is the only drug that targets hematopoietic stem cells and produces hematologic and molecular remission, although not in all patients and, like ruxolitinib, we still do not know how best to use it. Thus, following the data recorded in the RESPONSE trials we now have access to two non-myelotoxic therapies (ruxolitinib and pegylated interferon) to treat a disease whose natural history is measured in decades but whose patients do not all have the same genetic background or require the same level of myelosuppression – a setting most appropriate for precision medicine.
Jerry L. Spivak, MD, is with Johns Hopkins University in Baltimore. His remarks were excerpted from an accompanying editorial.
Ruxolitinib has now been assessed in two clinical trials in polycythemia vera without myelofibrosis. Francesco Passamonti and colleagues report the results of RESPONSE-2, a randomized, open-label, phase IIIb trial of ruxolitinib in patients with polycythemia vera without splenomegaly, who were intolerant of or unresponsive to hydroxyurea, versus the best available therapy (usually hydroxyurea), making this trial – like the previous RESPONSE trial, in which the effect of ruxolitinib was examined in hydroxyurea-intolerant or unresponsive patients with polycythemia vera with splenomegaly – a referendum on hydroxyurea. On the basis of their age, most RESPONSE-2 patients were defined as so-called high-risk patients, and were phlebotomy dependent.
Unsurprisingly, for the primary endpoint of patients achieving hematocrit control, ruxolitinib was superior to best available therapy (46 [62%] of 74 patients in the ruxolitinib group vs. 14 [19%] of 75 in the best available therapy group; odds ratio, 7.28 [95% CI 3.43–15.45]; P less than .0001), and also for the key secondary endpoint for patients achieving complete hematologic remission (23% vs .5%).
Symptom control, including pruritus, was superior in the ruxolitinib group, and adverse events were more common in the best available therapy group. The authors concluded that ruxolitinib “could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population”
However, I challenge this conclusion. First, the consensus that hydroxyurea is first-line therapy for polycythemia vera is not evidence based. Indeed, a trial using hydroxyurea in patients with polycythemia vera to achieve European LeukemiaNet criteria for complete hematologic remission did not result in better survival or less thrombosis compared with the expected survival of patients with similar disease characteristics.
Second, the primary endpoint of RESPONSE-2 was phlebotomy control but the appropriate control group (a phlebotomy-only group) was not included, nor was phlebotomy control or hematologic remission achieved with ruxolitinib in all patients. Ruxolitinib is an expensive drug, but phlebotomy is an inexpensive and immediately effective procedure, and it is unlikely that insurers would support the use of ruxolitinib in polycythemia vera for hematocrit control without proof of greater efficacy than phlebotomy therapy.
Third, no study of ruxolitinib in polycythemia vera has capitalized on the observation, based on both clinical and gene-expression data, that patients with polycythemia vera are not all alike; male and female patients differ clinically and in gene expression, and the disease is indolent in some patients and aggressive in others, who also differ in gene expression. Thus, it should not be presumed that all patients with polycythemia vera will require ruxolitinib therapy or that all patients who do receive this treatment will respond similarly. Finally, polycythemia vera is an hematopoietic stem-cell disorder and, so far, ruxolitinib does not seem to affect hematopoietic stem cell behavior. At present, pegylated interferon is the only drug that targets hematopoietic stem cells and produces hematologic and molecular remission, although not in all patients and, like ruxolitinib, we still do not know how best to use it. Thus, following the data recorded in the RESPONSE trials we now have access to two non-myelotoxic therapies (ruxolitinib and pegylated interferon) to treat a disease whose natural history is measured in decades but whose patients do not all have the same genetic background or require the same level of myelosuppression – a setting most appropriate for precision medicine.
Jerry L. Spivak, MD, is with Johns Hopkins University in Baltimore. His remarks were excerpted from an accompanying editorial.
Ruxolitinib has now been assessed in two clinical trials in polycythemia vera without myelofibrosis. Francesco Passamonti and colleagues report the results of RESPONSE-2, a randomized, open-label, phase IIIb trial of ruxolitinib in patients with polycythemia vera without splenomegaly, who were intolerant of or unresponsive to hydroxyurea, versus the best available therapy (usually hydroxyurea), making this trial – like the previous RESPONSE trial, in which the effect of ruxolitinib was examined in hydroxyurea-intolerant or unresponsive patients with polycythemia vera with splenomegaly – a referendum on hydroxyurea. On the basis of their age, most RESPONSE-2 patients were defined as so-called high-risk patients, and were phlebotomy dependent.
Unsurprisingly, for the primary endpoint of patients achieving hematocrit control, ruxolitinib was superior to best available therapy (46 [62%] of 74 patients in the ruxolitinib group vs. 14 [19%] of 75 in the best available therapy group; odds ratio, 7.28 [95% CI 3.43–15.45]; P less than .0001), and also for the key secondary endpoint for patients achieving complete hematologic remission (23% vs .5%).
Symptom control, including pruritus, was superior in the ruxolitinib group, and adverse events were more common in the best available therapy group. The authors concluded that ruxolitinib “could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population”
However, I challenge this conclusion. First, the consensus that hydroxyurea is first-line therapy for polycythemia vera is not evidence based. Indeed, a trial using hydroxyurea in patients with polycythemia vera to achieve European LeukemiaNet criteria for complete hematologic remission did not result in better survival or less thrombosis compared with the expected survival of patients with similar disease characteristics.
Second, the primary endpoint of RESPONSE-2 was phlebotomy control but the appropriate control group (a phlebotomy-only group) was not included, nor was phlebotomy control or hematologic remission achieved with ruxolitinib in all patients. Ruxolitinib is an expensive drug, but phlebotomy is an inexpensive and immediately effective procedure, and it is unlikely that insurers would support the use of ruxolitinib in polycythemia vera for hematocrit control without proof of greater efficacy than phlebotomy therapy.
Third, no study of ruxolitinib in polycythemia vera has capitalized on the observation, based on both clinical and gene-expression data, that patients with polycythemia vera are not all alike; male and female patients differ clinically and in gene expression, and the disease is indolent in some patients and aggressive in others, who also differ in gene expression. Thus, it should not be presumed that all patients with polycythemia vera will require ruxolitinib therapy or that all patients who do receive this treatment will respond similarly. Finally, polycythemia vera is an hematopoietic stem-cell disorder and, so far, ruxolitinib does not seem to affect hematopoietic stem cell behavior. At present, pegylated interferon is the only drug that targets hematopoietic stem cells and produces hematologic and molecular remission, although not in all patients and, like ruxolitinib, we still do not know how best to use it. Thus, following the data recorded in the RESPONSE trials we now have access to two non-myelotoxic therapies (ruxolitinib and pegylated interferon) to treat a disease whose natural history is measured in decades but whose patients do not all have the same genetic background or require the same level of myelosuppression – a setting most appropriate for precision medicine.
Jerry L. Spivak, MD, is with Johns Hopkins University in Baltimore. His remarks were excerpted from an accompanying editorial.
For patients with polycythemia vera without splenomegaly who had inadequate responses to hydroxyurea, targeted therapy with the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) offered better control of hematocrit and better improvement of symptoms than did the best available therapy, according to results of a multinational randomized phase IIIb trial.
Among 74 patients randomly assigned to receive ruxolitinib, 46 (62%) achieved hematocrit control, compared with 14 of 75 patients (19%) assigned to receive one of several different options lumped into the best available therapy category, noted investigators led by Francesco Passamonti, MD, of the University of Insubria in Varese, Italy.
“Ruxolitinib also led to an improved symptom burden and quality of life. Patients treated with ruxolitinib experienced improvements in all polycythemia vera–associated symptoms, including pruritus, whereas patients treated with best available therapy experienced worsening of most symptoms,” they wrote.
Unlike cytoreductive therapies such as hydroxyurea or pegylated interferon, ruxolitinib works by inhibition of JAK1 and JAK2 signaling. A majority of patients with polycythemia vera have an activating JAK2 mutation that leads to overactivation of the JAK-STAT signaling pathway, resulting in erythrocytosis, the hallmark symptom of polycythemia vera, and associated vascular complications.
“In some patients, conventional therapies can lose effectiveness over time. Although hydroxyurea is well tolerated in most patients, about 15%-20% of patients become resistant or intolerant, with hydroxyurea resistance affecting survival and increasing the risk of progression to myelofibrosis. Additionally, patients who are intolerant of hydroxyurea can have adverse side effects, such as drug-induced fever, mouth ulcers, leg ulcers, and skin malignancies, which necessitate discontinuation of first-line therapy,” the investigators noted.
RESPONSE trials
Ruxolitinib had previously been shown in the RESPONSE study to be superior to the best available therapy for controlling hematocrit and for improving splenomegaly and other symptoms in patients with polycythemia vera and disease-associated splenomegaly who had an inadequate response or unacceptable toxicities from treatment with hydroxyurea.
In the currently reported study, dubbed RESPONSE-2, patients 18 and older with polycythemia vera with no palpable splenomegaly who were intolerant of hydroxyurea or had disease that was resistant to it were randomized to receive either oral ruxolitinib 10 mg twice daily, or best available therapy at the investigators’ discretion. Best available therapy consisted of either hydroxyurea at the maximum tolerated dose, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment.
As noted, hematocrit control at week 28, the primary endpoint, was significantly higher among patients on ruxolitinib, with an odds ratio (OR) of 7.28 (P less than .0001).
Hematocrit levels among patients on ruxolitinib group decreased from a mean of 42.8% at baseline to 40.2% at week 28. In contrast, hematocrit in the best available therapy group increased from a mean of 42.7% to 44.9% at week 28.
Fewer patients on ruxolitinib required phlebotomy procedures during the 28 weeks of the study compared with patients on best available therapy, and of those patients who did undergo phlebotomy, fewer of those in the ruxolitinib group underwent more than two procedures. There were a total of 98 phlebotomies among best available care patients, vs. 19 among ruxolitinib patients.
Complete hematologic remissions, a secondary endpoint, occurred in 23% of patients on ruxolitinib, compared with 5% of those on best available care (OR 5.58, P = .0019).
The most frequent hematologic adverse events of any grade were anemia, which occurred in 10 patients on ruxolitinib (none grade 3 or greater) vs. two on best available therapy (one grade 3), and thrombocytopenia occurring in two (both grade 1 or 2) and six patients (three grade 1 or 2, two grade 3, and one grade 4) respectively.
Grade 3 or 4 nonhematologic adverse events included hypertension in five patients on ruxolitinib vs. three on best available care, and pruritus in none vs. two, respectively.
Two patients died; both were in the best available therapy group.
“Although the short follow-up of this study precludes any conclusions about vascular complications, an important finding is that patients treated with ruxolitinib in both RESPONSE and RESPONSE-2 had fewer thromboembolic events compared with those given best available therapy; there were two thromboembolic events with ruxolitinib (one in each study) versus nine with best available therapy across both studies (six in RESPONSE and three in RESPONSE-2). This finding could have been attributable to better control of hematocrit or white blood cell count with ruxolitinib, given that baseline risk factors were similar in both treatment groups,” the investigators wrote.
The findings from the two studies support the use of ruxolitinib as a standard of care for second-line therapy of patients with polycythemia vera following treatment with hydroxyurea, they contended.
Several coauthors disclosed ties to Novartis, which supported the study. Two are Novartis employees; one was previously employed by the company.
For patients with polycythemia vera without splenomegaly who had inadequate responses to hydroxyurea, targeted therapy with the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) offered better control of hematocrit and better improvement of symptoms than did the best available therapy, according to results of a multinational randomized phase IIIb trial.
Among 74 patients randomly assigned to receive ruxolitinib, 46 (62%) achieved hematocrit control, compared with 14 of 75 patients (19%) assigned to receive one of several different options lumped into the best available therapy category, noted investigators led by Francesco Passamonti, MD, of the University of Insubria in Varese, Italy.
“Ruxolitinib also led to an improved symptom burden and quality of life. Patients treated with ruxolitinib experienced improvements in all polycythemia vera–associated symptoms, including pruritus, whereas patients treated with best available therapy experienced worsening of most symptoms,” they wrote.
Unlike cytoreductive therapies such as hydroxyurea or pegylated interferon, ruxolitinib works by inhibition of JAK1 and JAK2 signaling. A majority of patients with polycythemia vera have an activating JAK2 mutation that leads to overactivation of the JAK-STAT signaling pathway, resulting in erythrocytosis, the hallmark symptom of polycythemia vera, and associated vascular complications.
“In some patients, conventional therapies can lose effectiveness over time. Although hydroxyurea is well tolerated in most patients, about 15%-20% of patients become resistant or intolerant, with hydroxyurea resistance affecting survival and increasing the risk of progression to myelofibrosis. Additionally, patients who are intolerant of hydroxyurea can have adverse side effects, such as drug-induced fever, mouth ulcers, leg ulcers, and skin malignancies, which necessitate discontinuation of first-line therapy,” the investigators noted.
RESPONSE trials
Ruxolitinib had previously been shown in the RESPONSE study to be superior to the best available therapy for controlling hematocrit and for improving splenomegaly and other symptoms in patients with polycythemia vera and disease-associated splenomegaly who had an inadequate response or unacceptable toxicities from treatment with hydroxyurea.
In the currently reported study, dubbed RESPONSE-2, patients 18 and older with polycythemia vera with no palpable splenomegaly who were intolerant of hydroxyurea or had disease that was resistant to it were randomized to receive either oral ruxolitinib 10 mg twice daily, or best available therapy at the investigators’ discretion. Best available therapy consisted of either hydroxyurea at the maximum tolerated dose, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment.
As noted, hematocrit control at week 28, the primary endpoint, was significantly higher among patients on ruxolitinib, with an odds ratio (OR) of 7.28 (P less than .0001).
Hematocrit levels among patients on ruxolitinib group decreased from a mean of 42.8% at baseline to 40.2% at week 28. In contrast, hematocrit in the best available therapy group increased from a mean of 42.7% to 44.9% at week 28.
Fewer patients on ruxolitinib required phlebotomy procedures during the 28 weeks of the study compared with patients on best available therapy, and of those patients who did undergo phlebotomy, fewer of those in the ruxolitinib group underwent more than two procedures. There were a total of 98 phlebotomies among best available care patients, vs. 19 among ruxolitinib patients.
Complete hematologic remissions, a secondary endpoint, occurred in 23% of patients on ruxolitinib, compared with 5% of those on best available care (OR 5.58, P = .0019).
The most frequent hematologic adverse events of any grade were anemia, which occurred in 10 patients on ruxolitinib (none grade 3 or greater) vs. two on best available therapy (one grade 3), and thrombocytopenia occurring in two (both grade 1 or 2) and six patients (three grade 1 or 2, two grade 3, and one grade 4) respectively.
Grade 3 or 4 nonhematologic adverse events included hypertension in five patients on ruxolitinib vs. three on best available care, and pruritus in none vs. two, respectively.
Two patients died; both were in the best available therapy group.
“Although the short follow-up of this study precludes any conclusions about vascular complications, an important finding is that patients treated with ruxolitinib in both RESPONSE and RESPONSE-2 had fewer thromboembolic events compared with those given best available therapy; there were two thromboembolic events with ruxolitinib (one in each study) versus nine with best available therapy across both studies (six in RESPONSE and three in RESPONSE-2). This finding could have been attributable to better control of hematocrit or white blood cell count with ruxolitinib, given that baseline risk factors were similar in both treatment groups,” the investigators wrote.
The findings from the two studies support the use of ruxolitinib as a standard of care for second-line therapy of patients with polycythemia vera following treatment with hydroxyurea, they contended.
Several coauthors disclosed ties to Novartis, which supported the study. Two are Novartis employees; one was previously employed by the company.
FROM LANCET ONCOLOGY
Key clinical point: Ruxolitinib was superior to best available care for hematocrit control among patients with polycythemia vera without splenomegaly.
Major finding: In the ruxolitinib group, 62% had control of hematocrit at week 28, vs. 19% on best available care.
Data source: Randomized trial of 149 adults with polycythemia vera in the absence of palpable splenomegaly.
Disclosures: Several coauthors disclosed ties to Novartis, which supported the study. Two are Novartis employees; one was previously employed by the company.
Drug granted fast track designation for PNH
The US Food and Drug Administration (FDA) has granted fast track designation for the complement C3 inhibitor APL-2.
The designation applies to APL-2 in the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) who continue to experience hemolysis and require red blood cell transfusions despite receiving therapy with eculizumab.
APL-2 is also being developed as a treatment for PNH patients not previously treated with eculizumab.
The company developing APL-2 is Apellis Pharmaceuticals, Inc.
APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).
According to Apellis, this comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH.
Results from a pair of phase 1 studies of APL-2 in healthy volunteers were recently presented at the 2016 ASH Annual Meeting (abstract 1251).
Now, Apellis is evaluating APL-2 in a pair of phase 1b clinical trials of patients with PNH.
In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.
In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA. 
The US Food and Drug Administration (FDA) has granted fast track designation for the complement C3 inhibitor APL-2.
The designation applies to APL-2 in the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) who continue to experience hemolysis and require red blood cell transfusions despite receiving therapy with eculizumab.
APL-2 is also being developed as a treatment for PNH patients not previously treated with eculizumab.
The company developing APL-2 is Apellis Pharmaceuticals, Inc.
APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).
According to Apellis, this comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH.
Results from a pair of phase 1 studies of APL-2 in healthy volunteers were recently presented at the 2016 ASH Annual Meeting (abstract 1251).
Now, Apellis is evaluating APL-2 in a pair of phase 1b clinical trials of patients with PNH.
In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.
In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
The US Food and Drug Administration (FDA) has granted fast track designation for the complement C3 inhibitor APL-2.
The designation applies to APL-2 in the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) who continue to experience hemolysis and require red blood cell transfusions despite receiving therapy with eculizumab.
APL-2 is also being developed as a treatment for PNH patients not previously treated with eculizumab.
The company developing APL-2 is Apellis Pharmaceuticals, Inc.
APL-2 is a synthetic cyclic peptide conjugated to a polyethylene glycol polymer that binds specifically to C3 and C3b, blocking all 3 pathways of complement activation (classical, lectin, and alternative).
According to Apellis, this comprehensive inhibition of complement-mediated pathology may have the potential to control symptoms and modify underlying disease in patients with PNH.
Results from a pair of phase 1 studies of APL-2 in healthy volunteers were recently presented at the 2016 ASH Annual Meeting (abstract 1251).
Now, Apellis is evaluating APL-2 in a pair of phase 1b clinical trials of patients with PNH.
In PADDOCK (NCT02588833), researchers are assessing the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple doses of APL-2 administered by daily subcutaneous injection in patients with PNH who have not received the standard of care in the past.
In PHAROAH (NCT02264639), researchers are assessing the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of APL-2 administered by subcutaneous injection as an add-on to the standard of care in patients with PNH.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the FDA’s fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the biologic license application or new drug application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
VIDEO: Point-of-care microsensor prototype beats conventional coagulopathy tests
SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating both activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity by using a technique called dielectric spectroscopy, Evi X. Stavrou, MD, of Case Western Reserve University, Cleveland, said in a video interview at the annual meeting of the American Society of Hematology. It points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.
By plotting rates of true positives (patients with coagulopathies) against rates of true negatives (controls), the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.
Dr. Stavrou and her coinvestigators had no relevant financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating both activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity by using a technique called dielectric spectroscopy, Evi X. Stavrou, MD, of Case Western Reserve University, Cleveland, said in a video interview at the annual meeting of the American Society of Hematology. It points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.
By plotting rates of true positives (patients with coagulopathies) against rates of true negatives (controls), the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.
Dr. Stavrou and her coinvestigators had no relevant financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating both activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity by using a technique called dielectric spectroscopy, Evi X. Stavrou, MD, of Case Western Reserve University, Cleveland, said in a video interview at the annual meeting of the American Society of Hematology. It points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.
By plotting rates of true positives (patients with coagulopathies) against rates of true negatives (controls), the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.
Dr. Stavrou and her coinvestigators had no relevant financial disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2016
Microsensor perfectly distinguished coagulopathy patients from controls
SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in less than 15 minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating the results with both activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity using dielectric spectroscopy, Evi X. Stavrou, MD, said at the annual meeting of the American Society of Hematology. The development points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.
Existing point-of-care coagulation assays have several shortcomings, Dr. Stavrou, of Case Western Reserve University, Cleveland, said during a press briefing at the conference. They are relatively insensitive, fail to measure platelet activity, or are only approved for specific subgroups of patients, such as those on warfarin, she specified.
To develop an alternative, Dr. Stavrou and her associates added a parallel-plate capacitive sensing structure to an inexpensive, disposable microfluidic biochip designed to test 9 microliters (less than one drop) of blood. They built the microsensor from biocompatible and chemically inert materials to minimize the chances of artificial contact activation.
To test the device, the researchers used calcium dichloride to induce coagulation in whole blood samples from 11 controls with normal aPTT and PT values. Time curves of output from the microsensor showed that coagulation consistently peaked within 4.5 to 6 minutes.
Next, the investigators tested blood from 12 patients with coagulopathies, including hemophilia A, hemophilia B, acquired von Willebrand factor defect, and congenital hypodysfibrinogenemia. These samples all yielded abnormal curves, with prolonged times to peak that ranged between 7 and 15 minutes – significantly exceeding those of healthy controls (P = .0002).
By plotting rates of true positives against rates of true negatives, the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.
Finally, the researchers used the microsensor to measure coagulation activity in normal blood samples that they treated with prostaglandin E2 to inhibit platelet aggregation. Normalized permittivity (an electrical measure) was significantly lower than in untreated control samples (P = .03), but time to peak values were the same in both groups. This finding confirms that the chip can identify abnormal platelet function, Dr. Stavrou said. “ClotChip is sensitive to the complete hemostasis process, exhibits better sensitivity and specificity than conventional coagulation assays, and discriminates between coagulation and platelet defects,” she concluded.
The investigators are recruiting volunteers for an expanded round of testing for the device, and are working to optimize construction to further enhance its sensitivity.
Dr. Stavrou and her coinvestigators had no relevant financial disclosures.
SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in less than 15 minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating the results with both activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity using dielectric spectroscopy, Evi X. Stavrou, MD, said at the annual meeting of the American Society of Hematology. The development points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.
Existing point-of-care coagulation assays have several shortcomings, Dr. Stavrou, of Case Western Reserve University, Cleveland, said during a press briefing at the conference. They are relatively insensitive, fail to measure platelet activity, or are only approved for specific subgroups of patients, such as those on warfarin, she specified.
To develop an alternative, Dr. Stavrou and her associates added a parallel-plate capacitive sensing structure to an inexpensive, disposable microfluidic biochip designed to test 9 microliters (less than one drop) of blood. They built the microsensor from biocompatible and chemically inert materials to minimize the chances of artificial contact activation.
To test the device, the researchers used calcium dichloride to induce coagulation in whole blood samples from 11 controls with normal aPTT and PT values. Time curves of output from the microsensor showed that coagulation consistently peaked within 4.5 to 6 minutes.
Next, the investigators tested blood from 12 patients with coagulopathies, including hemophilia A, hemophilia B, acquired von Willebrand factor defect, and congenital hypodysfibrinogenemia. These samples all yielded abnormal curves, with prolonged times to peak that ranged between 7 and 15 minutes – significantly exceeding those of healthy controls (P = .0002).
By plotting rates of true positives against rates of true negatives, the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.
Finally, the researchers used the microsensor to measure coagulation activity in normal blood samples that they treated with prostaglandin E2 to inhibit platelet aggregation. Normalized permittivity (an electrical measure) was significantly lower than in untreated control samples (P = .03), but time to peak values were the same in both groups. This finding confirms that the chip can identify abnormal platelet function, Dr. Stavrou said. “ClotChip is sensitive to the complete hemostasis process, exhibits better sensitivity and specificity than conventional coagulation assays, and discriminates between coagulation and platelet defects,” she concluded.
The investigators are recruiting volunteers for an expanded round of testing for the device, and are working to optimize construction to further enhance its sensitivity.
Dr. Stavrou and her coinvestigators had no relevant financial disclosures.
SAN DIEGO – Using less than a drop of blood, a portable microsensor provided a comprehensive coagulation profile in less than 15 minutes and perfectly distinguished various coagulopathies from normal blood samples – handily beating the results with both activated partial thromboplastin time (aPTT) and prothrombin time (PT).
Dubbed ClotChip, the disposable device detects coagulation factors and platelet activity using dielectric spectroscopy, Evi X. Stavrou, MD, said at the annual meeting of the American Society of Hematology. The development points the way for comprehensive, rapid, point-of-care assessment of critically ill or severely injured patients and those who need ongoing monitoring to evaluate response to anticoagulant therapy, she added.
Existing point-of-care coagulation assays have several shortcomings, Dr. Stavrou, of Case Western Reserve University, Cleveland, said during a press briefing at the conference. They are relatively insensitive, fail to measure platelet activity, or are only approved for specific subgroups of patients, such as those on warfarin, she specified.
To develop an alternative, Dr. Stavrou and her associates added a parallel-plate capacitive sensing structure to an inexpensive, disposable microfluidic biochip designed to test 9 microliters (less than one drop) of blood. They built the microsensor from biocompatible and chemically inert materials to minimize the chances of artificial contact activation.
To test the device, the researchers used calcium dichloride to induce coagulation in whole blood samples from 11 controls with normal aPTT and PT values. Time curves of output from the microsensor showed that coagulation consistently peaked within 4.5 to 6 minutes.
Next, the investigators tested blood from 12 patients with coagulopathies, including hemophilia A, hemophilia B, acquired von Willebrand factor defect, and congenital hypodysfibrinogenemia. These samples all yielded abnormal curves, with prolonged times to peak that ranged between 7 and 15 minutes – significantly exceeding those of healthy controls (P = .0002).
By plotting rates of true positives against rates of true negatives, the researchers obtained areas under the receiver operating curves of 100% for ClotChip, 78% for aPTT, and 57% for PT. In other words, ClotChip correctly identified all cases and controls in this small patient cohort, which neither aPTT or PT did.
Finally, the researchers used the microsensor to measure coagulation activity in normal blood samples that they treated with prostaglandin E2 to inhibit platelet aggregation. Normalized permittivity (an electrical measure) was significantly lower than in untreated control samples (P = .03), but time to peak values were the same in both groups. This finding confirms that the chip can identify abnormal platelet function, Dr. Stavrou said. “ClotChip is sensitive to the complete hemostasis process, exhibits better sensitivity and specificity than conventional coagulation assays, and discriminates between coagulation and platelet defects,” she concluded.
The investigators are recruiting volunteers for an expanded round of testing for the device, and are working to optimize construction to further enhance its sensitivity.
Dr. Stavrou and her coinvestigators had no relevant financial disclosures.
AT ASH 2016
Key clinical point: A prototype point-of-care microsensor perfectly distinguished patients with various coagulopathies from healthy controls.
Major finding: The area under the receiver operating characteristic curve was 100%, compared with 78% for aPTT and 59% for PT.
Data source: Oral and poster sessions at ASH 2016.
Disclosures: None of the investigators had relevant financial disclosures.
VIDEO: Artificial blood cells clear first phase of animal testing
SAN DIEGO – An artificial red blood cell has come close to emulating the key functions of natural cells and does not appear to be associated with the side effects such as vasospasm and poor response to changes in blood pH that hampered the development of previous artificial blood products, Allan Doctor, MD, reported at the annual meeting of the American Society of Hematology.
The bio-synthetic cells, called ErythroMer, are about 1/50th the size of natural red blood cells. They can be stored at room temperature and reconstituted with water when needed for use.
In a mouse model, the ErythroMer cells were shown to capture oxygen in the lungs and release it to tissue in a pattern that was nearly identical to blood transfusion. In a rat model of shock, ErythroMer was effective for resuscitation.
In a video interview, Dr. Doctor of Washington University in St. Louis discussed the pharmacokinetics of ErythroMer, the need for a readily available blood substitute for treating trauma patients, other potential uses for artificial blood cells, and next steps for testing the product.
Dr. Doctor has equity ownership in KaloCyte, the company developing ErythroMer. He receives research funding from Children’s Discovery Institute and the National Institutes of Health.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – An artificial red blood cell has come close to emulating the key functions of natural cells and does not appear to be associated with the side effects such as vasospasm and poor response to changes in blood pH that hampered the development of previous artificial blood products, Allan Doctor, MD, reported at the annual meeting of the American Society of Hematology.
The bio-synthetic cells, called ErythroMer, are about 1/50th the size of natural red blood cells. They can be stored at room temperature and reconstituted with water when needed for use.
In a mouse model, the ErythroMer cells were shown to capture oxygen in the lungs and release it to tissue in a pattern that was nearly identical to blood transfusion. In a rat model of shock, ErythroMer was effective for resuscitation.
In a video interview, Dr. Doctor of Washington University in St. Louis discussed the pharmacokinetics of ErythroMer, the need for a readily available blood substitute for treating trauma patients, other potential uses for artificial blood cells, and next steps for testing the product.
Dr. Doctor has equity ownership in KaloCyte, the company developing ErythroMer. He receives research funding from Children’s Discovery Institute and the National Institutes of Health.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – An artificial red blood cell has come close to emulating the key functions of natural cells and does not appear to be associated with the side effects such as vasospasm and poor response to changes in blood pH that hampered the development of previous artificial blood products, Allan Doctor, MD, reported at the annual meeting of the American Society of Hematology.
The bio-synthetic cells, called ErythroMer, are about 1/50th the size of natural red blood cells. They can be stored at room temperature and reconstituted with water when needed for use.
In a mouse model, the ErythroMer cells were shown to capture oxygen in the lungs and release it to tissue in a pattern that was nearly identical to blood transfusion. In a rat model of shock, ErythroMer was effective for resuscitation.
In a video interview, Dr. Doctor of Washington University in St. Louis discussed the pharmacokinetics of ErythroMer, the need for a readily available blood substitute for treating trauma patients, other potential uses for artificial blood cells, and next steps for testing the product.
Dr. Doctor has equity ownership in KaloCyte, the company developing ErythroMer. He receives research funding from Children’s Discovery Institute and the National Institutes of Health.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2016
VIDEO: Hemophilia B gene therapy maintains factor IX levels averaging 28%
SAN DIEGO – Patients with hemophilia B who received a single infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.
All nine patients treated to date have exceeded the steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, reported at the American Society of Hematology. There have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product. Two patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels. Tapering doses of corticosteroids halted the immune response and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor.
Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. She discussed the trial in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Patients with hemophilia B who received a single infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.
All nine patients treated to date have exceeded the steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, reported at the American Society of Hematology. There have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product. Two patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels. Tapering doses of corticosteroids halted the immune response and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor.
Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. She discussed the trial in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN DIEGO – Patients with hemophilia B who received a single infusion of the gene transfer therapy SPK-9001 achieved steady-state factor IX activity levels averaging 28% and persisting over 1,650 cumulative days of observation, according to updated results from a phase I/II trial.
All nine patients treated to date have exceeded the steady-state factor IX activity level typically needed to prevent breakthrough bleeds, Katherine A. High, MD, reported at the American Society of Hematology. There have been no confirmed bleeds, all patients remain off prophylactic factor IX, none have developed factor IX inhibitory antibodies, and Enzyme-Linked ImmunoSpot testing has uncovered no evidence of emergent reactivity to the gene product. Two patients developed an immune response to the viral capsid in the product, with a corresponding drop in factor IX activity levels. Tapering doses of corticosteroids halted the immune response and patients maintained sufficient levels of factor IX activity to prevent breakthrough bleeds or the need for replacement factor.
Spark Therapeutics Inc. and Pfizer sponsored the work. Dr. High is president and chief scientific officer of Spark. She discussed the trial in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ASH 2016
