HT Staff

Thrombus

Credit: Kevin MacKenzie

An intravenous (IV) bolus of the factor Xa inhibitor antidote andexanet alfa can significantly and immediately reverse the steady-state anticoagulation activity of rivaroxaban in healthy subjects, according to initial results of the phase 3 ANNEXA-R study.

Portola Pharmaceuticals, the company developing andexanet alfa, recently announced these results from the first part of the study.

The company expects to present the full data set on March 16 at the American College of Cardiology’s 64th Annual Scientific Session & Expo in San Diego.

The second part of the ANNEXA-R study, in which researchers are evaluating a bolus plus a continuous infusion of andexanet alfa to sustain reversal, is ongoing.

Portola is developing andexanet alfa as a universal antidote for patients treated with oral and injectable factor Xa inhibitors who are experiencing a major bleeding episode or who require emergency surgery.

Andexanet alfa acts as a factor Xa decoy that targets and sequesters both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

ANNEXA-R details

This randomized, double-blind, placebo-controlled study is an evaluation of andexanet alfa in reversing rivaroxaban-induced anticoagulation in healthy volunteers ages 50 to 75 years.

In the first part of the study, 41 subjects received rivaroxaban at 20 mg once daily for 4 days. Then, they were randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus (n=27) or to placebo (n=14).

Results showed that andexanet alfa significantly and immediately reversed the anticoagulation activity of rivaroxaban. Furthermore, andexanet alfa appeared to be well tolerated.

For the second part of the ANNEXA-R study, researchers plan to enroll about 40 healthy volunteers and give them rivaroxaban at 20 mg once daily for 4 days.

Then, subjects will be randomized to receive either placebo or andexanet alfa administered as an 800 mg IV bolus, followed by a continuous infusion of 8 mg/min for 120 minutes. Data from this part of the study are expected in mid-2015.

Andexanet alfa development

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

Portola is evaluating andexanet alfa in randomized, placebo-controlled phase 3 ANNEXA registration studies using pharmacodynamic endpoints agreed to with the US Food and Drug Administration (FDA), such as anti-factor Xa inhibitor units, to demonstrate efficacy.

Researchers recently reported statistically significant results from the first part of the phase 3 ANNEXA-A study, in which researchers evaluated andexanet alfa administered as a single IV bolus dose with the direct factor Xa inhibitor apixaban.

The second part of the study is ongoing. It’s an evaluation of an IV bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity.

“The statistically significant phase 3 ANNEXA-R study data, together with results presented previously with apixaban, provide compelling evidence that this ground-breaking agent could serve as a universal antidote for factor Xa inhibitor anticoagulants,” said John T. Curnutte, MD, PhD, executive vice president, research and development for Portola.

“Andexanet alfa is unique among the other reversal agents in development in that it has been the only agent to immediately and significantly reverse all of the key pharmacodynamic measurements of coagulation that have been agreed to with the FDA for accelerated approval. These include anti-factor Xa levels, thrombin generation, and unbound anticoagulant (free-fraction). This has been demonstrated with all of the factor Xa inhibitors studied to date—apixaban, rivaroxaban, edoxaban, and enoxaparin.”

Thrombus

Credit: Kevin MacKenzie

An intravenous (IV) bolus of the factor Xa inhibitor antidote andexanet alfa can significantly and immediately reverse the steady-state anticoagulation activity of rivaroxaban in healthy subjects, according to initial results of the phase 3 ANNEXA-R study.

Portola Pharmaceuticals, the company developing andexanet alfa, recently announced these results from the first part of the study.

The company expects to present the full data set on March 16 at the American College of Cardiology’s 64th Annual Scientific Session & Expo in San Diego.

The second part of the ANNEXA-R study, in which researchers are evaluating a bolus plus a continuous infusion of andexanet alfa to sustain reversal, is ongoing.

Portola is developing andexanet alfa as a universal antidote for patients treated with oral and injectable factor Xa inhibitors who are experiencing a major bleeding episode or who require emergency surgery.

Andexanet alfa acts as a factor Xa decoy that targets and sequesters both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

ANNEXA-R details

This randomized, double-blind, placebo-controlled study is an evaluation of andexanet alfa in reversing rivaroxaban-induced anticoagulation in healthy volunteers ages 50 to 75 years.

In the first part of the study, 41 subjects received rivaroxaban at 20 mg once daily for 4 days. Then, they were randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus (n=27) or to placebo (n=14).

Results showed that andexanet alfa significantly and immediately reversed the anticoagulation activity of rivaroxaban. Furthermore, andexanet alfa appeared to be well tolerated.

For the second part of the ANNEXA-R study, researchers plan to enroll about 40 healthy volunteers and give them rivaroxaban at 20 mg once daily for 4 days.

Then, subjects will be randomized to receive either placebo or andexanet alfa administered as an 800 mg IV bolus, followed by a continuous infusion of 8 mg/min for 120 minutes. Data from this part of the study are expected in mid-2015.

Andexanet alfa development

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

Portola is evaluating andexanet alfa in randomized, placebo-controlled phase 3 ANNEXA registration studies using pharmacodynamic endpoints agreed to with the US Food and Drug Administration (FDA), such as anti-factor Xa inhibitor units, to demonstrate efficacy.

Researchers recently reported statistically significant results from the first part of the phase 3 ANNEXA-A study, in which researchers evaluated andexanet alfa administered as a single IV bolus dose with the direct factor Xa inhibitor apixaban.

The second part of the study is ongoing. It’s an evaluation of an IV bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity.

“The statistically significant phase 3 ANNEXA-R study data, together with results presented previously with apixaban, provide compelling evidence that this ground-breaking agent could serve as a universal antidote for factor Xa inhibitor anticoagulants,” said John T. Curnutte, MD, PhD, executive vice president, research and development for Portola.

“Andexanet alfa is unique among the other reversal agents in development in that it has been the only agent to immediately and significantly reverse all of the key pharmacodynamic measurements of coagulation that have been agreed to with the FDA for accelerated approval. These include anti-factor Xa levels, thrombin generation, and unbound anticoagulant (free-fraction). This has been demonstrated with all of the factor Xa inhibitors studied to date—apixaban, rivaroxaban, edoxaban, and enoxaparin.”

Thrombus

Credit: Kevin MacKenzie

An intravenous (IV) bolus of the factor Xa inhibitor antidote andexanet alfa can significantly and immediately reverse the steady-state anticoagulation activity of rivaroxaban in healthy subjects, according to initial results of the phase 3 ANNEXA-R study.

Portola Pharmaceuticals, the company developing andexanet alfa, recently announced these results from the first part of the study.

The company expects to present the full data set on March 16 at the American College of Cardiology’s 64th Annual Scientific Session & Expo in San Diego.

The second part of the ANNEXA-R study, in which researchers are evaluating a bolus plus a continuous infusion of andexanet alfa to sustain reversal, is ongoing.

Portola is developing andexanet alfa as a universal antidote for patients treated with oral and injectable factor Xa inhibitors who are experiencing a major bleeding episode or who require emergency surgery.

Andexanet alfa acts as a factor Xa decoy that targets and sequesters both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.

ANNEXA-R details

This randomized, double-blind, placebo-controlled study is an evaluation of andexanet alfa in reversing rivaroxaban-induced anticoagulation in healthy volunteers ages 50 to 75 years.

In the first part of the study, 41 subjects received rivaroxaban at 20 mg once daily for 4 days. Then, they were randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus (n=27) or to placebo (n=14).

Results showed that andexanet alfa significantly and immediately reversed the anticoagulation activity of rivaroxaban. Furthermore, andexanet alfa appeared to be well tolerated.

For the second part of the ANNEXA-R study, researchers plan to enroll about 40 healthy volunteers and give them rivaroxaban at 20 mg once daily for 4 days.

Then, subjects will be randomized to receive either placebo or andexanet alfa administered as an 800 mg IV bolus, followed by a continuous infusion of 8 mg/min for 120 minutes. Data from this part of the study are expected in mid-2015.

Andexanet alfa development

Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.

Portola is evaluating andexanet alfa in randomized, placebo-controlled phase 3 ANNEXA registration studies using pharmacodynamic endpoints agreed to with the US Food and Drug Administration (FDA), such as anti-factor Xa inhibitor units, to demonstrate efficacy.

Researchers recently reported statistically significant results from the first part of the phase 3 ANNEXA-A study, in which researchers evaluated andexanet alfa administered as a single IV bolus dose with the direct factor Xa inhibitor apixaban.

The second part of the study is ongoing. It’s an evaluation of an IV bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity.

“The statistically significant phase 3 ANNEXA-R study data, together with results presented previously with apixaban, provide compelling evidence that this ground-breaking agent could serve as a universal antidote for factor Xa inhibitor anticoagulants,” said John T. Curnutte, MD, PhD, executive vice president, research and development for Portola.

“Andexanet alfa is unique among the other reversal agents in development in that it has been the only agent to immediately and significantly reverse all of the key pharmacodynamic measurements of coagulation that have been agreed to with the FDA for accelerated approval. These include anti-factor Xa levels, thrombin generation, and unbound anticoagulant (free-fraction). This has been demonstrated with all of the factor Xa inhibitors studied to date—apixaban, rivaroxaban, edoxaban, and enoxaparin.”

Drug production

Credit: FDA

The US Food and Drug Administration (FDA) has approved the oral, direct factor Xa inhibitor edoxaban (Savaysa) for use in two patient populations.

The anticoagulant is now approved to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and to treat venous thromboembolism (VTE) in patients who have already received parenteral anticoagulation for 5 to 10 days.

The drug has been approved with a Boxed Warning.

The warning states that edoxaban is less effective in NVAF patients with a creatinine clearance greater than 95 mL/min. Patients with creatinine clearance above this limit have an increased risk of stroke if they receive edoxaban (compared to the risk with warfarin), so these patients should not receive edoxaban.

The warning also states that premature discontinuation of edoxaban increases the risk of stroke. Furthermore, spinal or epidural hematomas may occur in patients on edoxaban who are receiving anesthesia injected around the spine or undergoing spinal puncture.

Edoxaban for VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with deep vein thrombosis and 3319 with pulmonary embolism. Patients received initial treatment with low-molecular-weight heparin and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Overall, edoxaban proved as effective as warfarin. Recurrent, symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for non-inferiority).

Edoxaban proved superior when it came to the primary safety outcome. Clinically relevant bleeding occurred in 8.5% of edoxaban-treated patients and 10.3% of warfarin-treated patients (P=0.004 for superiority).

In the edoxaban arm, there were 2 fatal bleeds and 13 non-fatal bleeds in a critical site. With warfarin, there were 10 fatal bleeds and 25 non-fatal bleeds in a critical site.

Edoxaban in NVAF

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with NVAF.

The trial included 21,105 patients who were randomized to receive warfarin (n=7036), edoxaban at 60 mg (n=7035), or edoxaban at 30 mg (n=7034).

Edoxaban was at least non-inferior to warfarin with regard to efficacy. The annual incidence of stroke or SEE was 1.50% with warfarin, 1.18% with edoxaban at 60 mg (P<0.001 for non-inferiority), and 1.61% with edoxaban at 30 mg (P=0.005 for non-inferiority).

Annualized rates for the secondary composite endpoint of stroke, SEE, and cardiovascular death were 4.43% with warfarin, 3.85% with edoxaban at 60 mg (P=0.005), and 4.23% with edoxaban at 30 mg (P=0.32).

In addition, edoxaban was associated with a significantly lower rate of major and fatal bleeding. The annual incidence of major bleeding was 3.43% with warfarin, 2.75% with edoxaban at 60 mg (P<0.001), and 1.61% with edoxaban at 30 mg (P<0.001).

Fatal bleeds occurred at an annual rate of 0.38% with warfarin, 0.21% with edoxaban at 60 mg (P=0.006), and 0.13% with edoxaban at 30 mg (P<0.001).

Edoxaban is under development by Daiichi Sankyo Co., Ltd.

Drug production

Credit: FDA

The US Food and Drug Administration (FDA) has approved the oral, direct factor Xa inhibitor edoxaban (Savaysa) for use in two patient populations.

The anticoagulant is now approved to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and to treat venous thromboembolism (VTE) in patients who have already received parenteral anticoagulation for 5 to 10 days.

The drug has been approved with a Boxed Warning.

The warning states that edoxaban is less effective in NVAF patients with a creatinine clearance greater than 95 mL/min. Patients with creatinine clearance above this limit have an increased risk of stroke if they receive edoxaban (compared to the risk with warfarin), so these patients should not receive edoxaban.

The warning also states that premature discontinuation of edoxaban increases the risk of stroke. Furthermore, spinal or epidural hematomas may occur in patients on edoxaban who are receiving anesthesia injected around the spine or undergoing spinal puncture.

Edoxaban for VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with deep vein thrombosis and 3319 with pulmonary embolism. Patients received initial treatment with low-molecular-weight heparin and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Overall, edoxaban proved as effective as warfarin. Recurrent, symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for non-inferiority).

Edoxaban proved superior when it came to the primary safety outcome. Clinically relevant bleeding occurred in 8.5% of edoxaban-treated patients and 10.3% of warfarin-treated patients (P=0.004 for superiority).

In the edoxaban arm, there were 2 fatal bleeds and 13 non-fatal bleeds in a critical site. With warfarin, there were 10 fatal bleeds and 25 non-fatal bleeds in a critical site.

Edoxaban in NVAF

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with NVAF.

The trial included 21,105 patients who were randomized to receive warfarin (n=7036), edoxaban at 60 mg (n=7035), or edoxaban at 30 mg (n=7034).

Edoxaban was at least non-inferior to warfarin with regard to efficacy. The annual incidence of stroke or SEE was 1.50% with warfarin, 1.18% with edoxaban at 60 mg (P<0.001 for non-inferiority), and 1.61% with edoxaban at 30 mg (P=0.005 for non-inferiority).

Annualized rates for the secondary composite endpoint of stroke, SEE, and cardiovascular death were 4.43% with warfarin, 3.85% with edoxaban at 60 mg (P=0.005), and 4.23% with edoxaban at 30 mg (P=0.32).

In addition, edoxaban was associated with a significantly lower rate of major and fatal bleeding. The annual incidence of major bleeding was 3.43% with warfarin, 2.75% with edoxaban at 60 mg (P<0.001), and 1.61% with edoxaban at 30 mg (P<0.001).

Fatal bleeds occurred at an annual rate of 0.38% with warfarin, 0.21% with edoxaban at 60 mg (P=0.006), and 0.13% with edoxaban at 30 mg (P<0.001).

Edoxaban is under development by Daiichi Sankyo Co., Ltd.

Drug production

Credit: FDA

The US Food and Drug Administration (FDA) has approved the oral, direct factor Xa inhibitor edoxaban (Savaysa) for use in two patient populations.

The anticoagulant is now approved to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and to treat venous thromboembolism (VTE) in patients who have already received parenteral anticoagulation for 5 to 10 days.

The drug has been approved with a Boxed Warning.

The warning states that edoxaban is less effective in NVAF patients with a creatinine clearance greater than 95 mL/min. Patients with creatinine clearance above this limit have an increased risk of stroke if they receive edoxaban (compared to the risk with warfarin), so these patients should not receive edoxaban.

The warning also states that premature discontinuation of edoxaban increases the risk of stroke. Furthermore, spinal or epidural hematomas may occur in patients on edoxaban who are receiving anesthesia injected around the spine or undergoing spinal puncture.

Edoxaban for VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with deep vein thrombosis and 3319 with pulmonary embolism. Patients received initial treatment with low-molecular-weight heparin and were then randomized to receive edoxaban or warfarin daily for 3 to 12 months.

Overall, edoxaban proved as effective as warfarin. Recurrent, symptomatic VTE occurred in 3.2% and 3.5% of patients, respectively (P<0.001 for non-inferiority).

Edoxaban proved superior when it came to the primary safety outcome. Clinically relevant bleeding occurred in 8.5% of edoxaban-treated patients and 10.3% of warfarin-treated patients (P=0.004 for superiority).

In the edoxaban arm, there were 2 fatal bleeds and 13 non-fatal bleeds in a critical site. With warfarin, there were 10 fatal bleeds and 25 non-fatal bleeds in a critical site.

Edoxaban in NVAF

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin for the prevention of stroke or systemic embolic events (SEE) in patients with NVAF.

The trial included 21,105 patients who were randomized to receive warfarin (n=7036), edoxaban at 60 mg (n=7035), or edoxaban at 30 mg (n=7034).

Edoxaban was at least non-inferior to warfarin with regard to efficacy. The annual incidence of stroke or SEE was 1.50% with warfarin, 1.18% with edoxaban at 60 mg (P<0.001 for non-inferiority), and 1.61% with edoxaban at 30 mg (P=0.005 for non-inferiority).

Annualized rates for the secondary composite endpoint of stroke, SEE, and cardiovascular death were 4.43% with warfarin, 3.85% with edoxaban at 60 mg (P=0.005), and 4.23% with edoxaban at 30 mg (P=0.32).

In addition, edoxaban was associated with a significantly lower rate of major and fatal bleeding. The annual incidence of major bleeding was 3.43% with warfarin, 2.75% with edoxaban at 60 mg (P<0.001), and 1.61% with edoxaban at 30 mg (P<0.001).

Fatal bleeds occurred at an annual rate of 0.38% with warfarin, 0.21% with edoxaban at 60 mg (P=0.006), and 0.13% with edoxaban at 30 mg (P<0.001).

Edoxaban is under development by Daiichi Sankyo Co., Ltd.

Micrograph showing

mycosis fungoides

The US Food and Drug Administration (FDA) has granted fast track designation to SGX301 as a first-line treatment for cutaneous T-cell lymphoma (CTCL).

SGX301 is a photodynamic therapy utilizing safe, visible light for activation. The active ingredient in SGX301 is synthetic hypericin, a photosensitizer that is applied to skin lesions and then activated by fluorescent light 16 to 24 hours later.

Combined with photoactivation, hypericin has demonstrated significant antiproliferative effects on activated, normal human lymphoid cells and inhibited the growth of malignant T cells isolated from CTCL patients. Topical hypericin has also proven safe in a phase 1 study of healthy volunteers.

In a phase 2 trial of patients with CTCL (mycosis fungoides only) or psoriasis, topical hypericin conferred a significant improvement over placebo. Among CTCL patients, the treatment prompted a response rate of 58.3%, compared to an 8.3% response rate for placebo (P≤0.04).

Topical hypericin was also well tolerated in this trial. There were no deaths or serious adverse events related to the treatment. However, there were reports of mild to moderate burning, itching, erythema, and pruritus at the application site.

A phase 3 trial of SGX301 is set to begin in the first half of this year. In addition to its new fast track status, SGX301 also has orphan designation from the FDA.

About fast track designation

The FDA grants fast track designation to a drug that is intended to treat a serious or life-threatening condition and that demonstrates the potential to address an unmet medical need for the condition.

Fast track designation is designed to facilitate the development and expedite the review of new drugs. For instance, Soligenix, Inc., the company developing SGX301, is eligible to submit a new drug application (NDA) for SGX301 on a rolling basis, allowing the FDA to review sections of the NDA prior to receiving the complete submission.

Additionally, NDAs for fast track development programs ordinarily will be eligible for priority review, which imparts an abbreviated review time of approximately 6 months.

Micrograph showing

mycosis fungoides

The US Food and Drug Administration (FDA) has granted fast track designation to SGX301 as a first-line treatment for cutaneous T-cell lymphoma (CTCL).

SGX301 is a photodynamic therapy utilizing safe, visible light for activation. The active ingredient in SGX301 is synthetic hypericin, a photosensitizer that is applied to skin lesions and then activated by fluorescent light 16 to 24 hours later.

Combined with photoactivation, hypericin has demonstrated significant antiproliferative effects on activated, normal human lymphoid cells and inhibited the growth of malignant T cells isolated from CTCL patients. Topical hypericin has also proven safe in a phase 1 study of healthy volunteers.

In a phase 2 trial of patients with CTCL (mycosis fungoides only) or psoriasis, topical hypericin conferred a significant improvement over placebo. Among CTCL patients, the treatment prompted a response rate of 58.3%, compared to an 8.3% response rate for placebo (P≤0.04).

Topical hypericin was also well tolerated in this trial. There were no deaths or serious adverse events related to the treatment. However, there were reports of mild to moderate burning, itching, erythema, and pruritus at the application site.

A phase 3 trial of SGX301 is set to begin in the first half of this year. In addition to its new fast track status, SGX301 also has orphan designation from the FDA.

About fast track designation

The FDA grants fast track designation to a drug that is intended to treat a serious or life-threatening condition and that demonstrates the potential to address an unmet medical need for the condition.

Fast track designation is designed to facilitate the development and expedite the review of new drugs. For instance, Soligenix, Inc., the company developing SGX301, is eligible to submit a new drug application (NDA) for SGX301 on a rolling basis, allowing the FDA to review sections of the NDA prior to receiving the complete submission.

Additionally, NDAs for fast track development programs ordinarily will be eligible for priority review, which imparts an abbreviated review time of approximately 6 months.

Micrograph showing

mycosis fungoides

The US Food and Drug Administration (FDA) has granted fast track designation to SGX301 as a first-line treatment for cutaneous T-cell lymphoma (CTCL).

SGX301 is a photodynamic therapy utilizing safe, visible light for activation. The active ingredient in SGX301 is synthetic hypericin, a photosensitizer that is applied to skin lesions and then activated by fluorescent light 16 to 24 hours later.

Combined with photoactivation, hypericin has demonstrated significant antiproliferative effects on activated, normal human lymphoid cells and inhibited the growth of malignant T cells isolated from CTCL patients. Topical hypericin has also proven safe in a phase 1 study of healthy volunteers.

In a phase 2 trial of patients with CTCL (mycosis fungoides only) or psoriasis, topical hypericin conferred a significant improvement over placebo. Among CTCL patients, the treatment prompted a response rate of 58.3%, compared to an 8.3% response rate for placebo (P≤0.04).

Topical hypericin was also well tolerated in this trial. There were no deaths or serious adverse events related to the treatment. However, there were reports of mild to moderate burning, itching, erythema, and pruritus at the application site.

A phase 3 trial of SGX301 is set to begin in the first half of this year. In addition to its new fast track status, SGX301 also has orphan designation from the FDA.

About fast track designation

The FDA grants fast track designation to a drug that is intended to treat a serious or life-threatening condition and that demonstrates the potential to address an unmet medical need for the condition.

Fast track designation is designed to facilitate the development and expedite the review of new drugs. For instance, Soligenix, Inc., the company developing SGX301, is eligible to submit a new drug application (NDA) for SGX301 on a rolling basis, allowing the FDA to review sections of the NDA prior to receiving the complete submission.

Additionally, NDAs for fast track development programs ordinarily will be eligible for priority review, which imparts an abbreviated review time of approximately 6 months.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).

Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).

The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.

“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.

In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor combos in MM

In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.

The study included 9 evaluable patients who received selinexor at 45 mg/m² twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.

The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.

The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.

During the dose-evaluation part of the study, the 60 mg/m² selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m² is the recommended future study dose.

In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.

The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).

Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).

The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.

“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.

In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor combos in MM

In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.

The study included 9 evaluable patients who received selinexor at 45 mg/m² twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.

The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.

The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.

During the dose-evaluation part of the study, the 60 mg/m² selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m² is the recommended future study dose.

In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.

The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.

Micrograph showing MM

The US Food and Drug Administration (FDA) has granted selinexor (KPT-330) orphan drug designation to treat multiple myeloma (MM).

Selinexor already has orphan designation from the FDA to treat acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL).

The drug has also received orphan designation from the European Medicines Agency (EMA) to treat MM, AML, DLBCL, and chronic lymphocytic leukemia/small lymphocytic lymphoma, including Richter’s transformation.

“Orphan drug designation by the FDA for multiple myeloma is another significant milestone in the selinexor development program,” said Sharon Shacham, PhD, President and Chief Scientific Officer of Karyopharm Therapeutics, Inc., the company developing selinexor.

In the US, orphan designation qualifies a company for certain benefits, including an accelerated approval process, 7 years of market exclusivity following the drug’s approval, tax credits on US clinical trials, eligibility for orphan drug grants, and a waiver of certain administrative fees.

About selinexor

Selinexor (KPT-330) is a first-in-class, oral, selective inhibitor of nuclear export compound. The drug functions by inhibiting the nuclear export protein XPO1 (also called CRM1).

This leads to the accumulation of tumor suppressor proteins in the cell nucleus, which subsequently reinitiates and amplifies their tumor suppressor function. This is thought to prompt apoptosis in cancer cells while largely sparing normal cells.

Selinexor combos in MM

In a poster presented at the 2014 ASH Annual Meeting (4773), researchers reported results observed with selinexor plus dexamethasone in preclinical models and in patients with heavily pretreated, refractory MM.

The study included 9 evaluable patients who received selinexor at 45 mg/m² twice weekly and dexamethasone at 20 mg twice weekly. The combination prompted an overall response rate of 67%, with one stringent complete response (11%) and 5 partial responses (56%), as well as a clinical benefit rate of 89%.

The combination demonstrated a reduction in nausea grades and very little weight loss compared with selinexor alone. The most common grade 1/2 adverse events were nausea, fatigue, anorexia, and vomiting.

The combination was also associated with an increase in time on study relative to selinexor alone. Sixty-six percent of patients remained on study for at least 16 weeks, including one patient for 28 weeks and one for 43 weeks as of December 1, 2014.

During the dose-evaluation part of the study, the 60 mg/m² selinexor dose was deemed intolerable in this heavily pretreated patient population. So 45 mg/m² is the recommended future study dose.

In another poster presented at the 2014 ASH Annual Meeting (3443), researchers described the activity of selinexor in combination with carfilzomib. This preclinical study revealed a novel, intracellular, membrane-embedded mechanism of caspase activation.

The results suggested a model of synergy wherein the selinexor-carfilzomib combination promotes caspase activation, likely by induced proximity, cleavage of other caspases, and subsequent apoptosis as well as autophagy.

Sleeping newborn

Credit: Vera Kratochvil

Results of a new study indicate that current guidelines for exchange transfusions in infants can successfully prevent kernicterus, a rare and life-threatening type of cerebral palsy triggered by escalating bilirubin that injures the brain.

However, the research also showed that only infants whose levels of bilirubin were well above the level for exchange transfusion actually developed kernicterus. And those infants all had additional risk factors for brain damage.

This suggests perhaps the threshold for exchange transfusion could safely be raised for infants with high bilirubin levels who have no other risk factors for brain injury, according to Yvonne W. Wu, MD, of the University of California, San Francisco (UCSF).

Dr Wu and her colleagues evaluated the health records of two groups of infants selected from 525,409 births. The children had been born at 15 hospitals within the Kaiser Permanente Northern California region from 1995 through 2011.

One group comprised 1833 newborns with levels of bilirubin above the level at which the American Academy of Pediatrics (AAP) recommends exchange transfusions.

The second group was made up of 104,716 randomly sampled newborns, born at at least 35 weeks’ gestation with lower levels of bilirubin. The two groups were followed for an average of 7 and 6 years, respectively.

The researchers confirmed 3 cases of kernicterus based on the brain MRIs of children with cerebral palsy. All 3 cases had occurred in newborns with the highest levels of bilirubin. But further study revealed that each child had 2 or more risk factors for brain damage.

”We found that cerebral palsy consistent with kernicterus did not occur in a single infant with high bilirubin without the presence of additional risk factors for neurotoxicity, such as prematurity, sepsis, and the hereditary blood disorder G6PD deficiency,” said Michael W. Kuzniewicz, MD, of UCSF. “This was the case even in infants with very high bilirubin.”

In 2004, the AAP published a guideline for treating infants whose bilirubin remained high despite phototherapy. It recommended exchange transfusions based on the level of bilirubin, the age of the infant, and other risk factors for brain damage.

“Our study was the first to evaluate how well the exchange transfusion guidelines predicted risk of cerebral palsy and kernicterus in babies with jaundice,” said Thomas B. Newman, MD, of UCSF.

“It was reassuring that brain injury due to high bilirubin was rare and that only those infants whose levels were well above exchange transfusion guidelines developed kernicterus.”

“Based on our study, the current guidelines for when to perform exchange transfusions have been quite successful in preventing kernicterus,” Dr Wu added. “However, our study also raises the question whether the threshold for exchange transfusion could be higher for infants with high bilirubin levels who are otherwise healthy and who have no other risk factors for brain injury.”

This is especially important, she noted, because exchange transfusions pose risks such as blood clot formation, blood pressure instability, bleeding, and changes in blood chemistry.

Dr Wu and her colleagues described this research in JAMA Pediatrics.

Sleeping newborn

Credit: Vera Kratochvil

Results of a new study indicate that current guidelines for exchange transfusions in infants can successfully prevent kernicterus, a rare and life-threatening type of cerebral palsy triggered by escalating bilirubin that injures the brain.

However, the research also showed that only infants whose levels of bilirubin were well above the level for exchange transfusion actually developed kernicterus. And those infants all had additional risk factors for brain damage.

This suggests perhaps the threshold for exchange transfusion could safely be raised for infants with high bilirubin levels who have no other risk factors for brain injury, according to Yvonne W. Wu, MD, of the University of California, San Francisco (UCSF).

Dr Wu and her colleagues evaluated the health records of two groups of infants selected from 525,409 births. The children had been born at 15 hospitals within the Kaiser Permanente Northern California region from 1995 through 2011.

One group comprised 1833 newborns with levels of bilirubin above the level at which the American Academy of Pediatrics (AAP) recommends exchange transfusions.

The second group was made up of 104,716 randomly sampled newborns, born at at least 35 weeks’ gestation with lower levels of bilirubin. The two groups were followed for an average of 7 and 6 years, respectively.

The researchers confirmed 3 cases of kernicterus based on the brain MRIs of children with cerebral palsy. All 3 cases had occurred in newborns with the highest levels of bilirubin. But further study revealed that each child had 2 or more risk factors for brain damage.

”We found that cerebral palsy consistent with kernicterus did not occur in a single infant with high bilirubin without the presence of additional risk factors for neurotoxicity, such as prematurity, sepsis, and the hereditary blood disorder G6PD deficiency,” said Michael W. Kuzniewicz, MD, of UCSF. “This was the case even in infants with very high bilirubin.”

In 2004, the AAP published a guideline for treating infants whose bilirubin remained high despite phototherapy. It recommended exchange transfusions based on the level of bilirubin, the age of the infant, and other risk factors for brain damage.

“Our study was the first to evaluate how well the exchange transfusion guidelines predicted risk of cerebral palsy and kernicterus in babies with jaundice,” said Thomas B. Newman, MD, of UCSF.

“It was reassuring that brain injury due to high bilirubin was rare and that only those infants whose levels were well above exchange transfusion guidelines developed kernicterus.”

“Based on our study, the current guidelines for when to perform exchange transfusions have been quite successful in preventing kernicterus,” Dr Wu added. “However, our study also raises the question whether the threshold for exchange transfusion could be higher for infants with high bilirubin levels who are otherwise healthy and who have no other risk factors for brain injury.”

This is especially important, she noted, because exchange transfusions pose risks such as blood clot formation, blood pressure instability, bleeding, and changes in blood chemistry.

Dr Wu and her colleagues described this research in JAMA Pediatrics.

Sleeping newborn

Credit: Vera Kratochvil

Results of a new study indicate that current guidelines for exchange transfusions in infants can successfully prevent kernicterus, a rare and life-threatening type of cerebral palsy triggered by escalating bilirubin that injures the brain.

However, the research also showed that only infants whose levels of bilirubin were well above the level for exchange transfusion actually developed kernicterus. And those infants all had additional risk factors for brain damage.

This suggests perhaps the threshold for exchange transfusion could safely be raised for infants with high bilirubin levels who have no other risk factors for brain injury, according to Yvonne W. Wu, MD, of the University of California, San Francisco (UCSF).

Dr Wu and her colleagues evaluated the health records of two groups of infants selected from 525,409 births. The children had been born at 15 hospitals within the Kaiser Permanente Northern California region from 1995 through 2011.

One group comprised 1833 newborns with levels of bilirubin above the level at which the American Academy of Pediatrics (AAP) recommends exchange transfusions.

The second group was made up of 104,716 randomly sampled newborns, born at at least 35 weeks’ gestation with lower levels of bilirubin. The two groups were followed for an average of 7 and 6 years, respectively.

The researchers confirmed 3 cases of kernicterus based on the brain MRIs of children with cerebral palsy. All 3 cases had occurred in newborns with the highest levels of bilirubin. But further study revealed that each child had 2 or more risk factors for brain damage.

”We found that cerebral palsy consistent with kernicterus did not occur in a single infant with high bilirubin without the presence of additional risk factors for neurotoxicity, such as prematurity, sepsis, and the hereditary blood disorder G6PD deficiency,” said Michael W. Kuzniewicz, MD, of UCSF. “This was the case even in infants with very high bilirubin.”

In 2004, the AAP published a guideline for treating infants whose bilirubin remained high despite phototherapy. It recommended exchange transfusions based on the level of bilirubin, the age of the infant, and other risk factors for brain damage.

“Our study was the first to evaluate how well the exchange transfusion guidelines predicted risk of cerebral palsy and kernicterus in babies with jaundice,” said Thomas B. Newman, MD, of UCSF.

“It was reassuring that brain injury due to high bilirubin was rare and that only those infants whose levels were well above exchange transfusion guidelines developed kernicterus.”

“Based on our study, the current guidelines for when to perform exchange transfusions have been quite successful in preventing kernicterus,” Dr Wu added. “However, our study also raises the question whether the threshold for exchange transfusion could be higher for infants with high bilirubin levels who are otherwise healthy and who have no other risk factors for brain injury.”

This is especially important, she noted, because exchange transfusions pose risks such as blood clot formation, blood pressure instability, bleeding, and changes in blood chemistry.

Dr Wu and her colleagues described this research in JAMA Pediatrics.

Cord blood donation

Credit: NHS

The US Food and Drug Administration (FDA) has granted orphan designation to a cord blood product called NiCord for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and myelodysplastic syndromes (MDS).

NiCord consists of cells from a single cord blood unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The FDA’s orphan drug designation for NiCord coincides with the positive opinion of the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products regarding NiCord as a treatment for AML. Gamida Cell, the company developing NiCord, intends to file for orphan drug status with the EMA for other indications as well.

“Receipt of orphan drug status for NiCord in the US and Europe advances Gamida Cell’s commercialization plans a major step further, as both afford significant advantages,” said Yael Margolin, President and CEO of Gamida Cell.

Orphan drug designation provides various regulatory and economic benefits, including 7 years of market exclusivity upon product approval in the US and 10 years in the European Union.

Trials of NiCord

NiCord is currently being tested in a phase 1/2 study as an investigational therapeutic treatment for hematologic malignancies. In this study, NiCord is being used as the sole stem cell source.

In a previous study, presented at the 11th Annual International Cord Blood Symposium, researchers transplanted a NiCord unit and an unmanipulated cord blood unit in patients with ALL, AML, MDS, HL, or non-Hodgkin lymphoma.

A majority of patients in this small, phase 1/2 study achieved early platelet and neutrophil engraftment. And, in some patients, that engraftment persisted for 2 years.

Eight of the 11 patients enrolled achieved engraftment with the NiCord unit, and 2 engrafted with the unmanipulated cord blood unit. One patient had primary graft failure.

There were no adverse events attributable to the NiCord unit, but 4 patients developed grade 1-2 acute GVHD, and 1 patient developed limited chronic GVHD.

For more information on NiCord, visit the Gamida Cell website.

Cord blood donation

Credit: NHS

The US Food and Drug Administration (FDA) has granted orphan designation to a cord blood product called NiCord for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and myelodysplastic syndromes (MDS).

NiCord consists of cells from a single cord blood unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The FDA’s orphan drug designation for NiCord coincides with the positive opinion of the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products regarding NiCord as a treatment for AML. Gamida Cell, the company developing NiCord, intends to file for orphan drug status with the EMA for other indications as well.

“Receipt of orphan drug status for NiCord in the US and Europe advances Gamida Cell’s commercialization plans a major step further, as both afford significant advantages,” said Yael Margolin, President and CEO of Gamida Cell.

Orphan drug designation provides various regulatory and economic benefits, including 7 years of market exclusivity upon product approval in the US and 10 years in the European Union.

Trials of NiCord

NiCord is currently being tested in a phase 1/2 study as an investigational therapeutic treatment for hematologic malignancies. In this study, NiCord is being used as the sole stem cell source.

In a previous study, presented at the 11th Annual International Cord Blood Symposium, researchers transplanted a NiCord unit and an unmanipulated cord blood unit in patients with ALL, AML, MDS, HL, or non-Hodgkin lymphoma.

A majority of patients in this small, phase 1/2 study achieved early platelet and neutrophil engraftment. And, in some patients, that engraftment persisted for 2 years.

Eight of the 11 patients enrolled achieved engraftment with the NiCord unit, and 2 engrafted with the unmanipulated cord blood unit. One patient had primary graft failure.

There were no adverse events attributable to the NiCord unit, but 4 patients developed grade 1-2 acute GVHD, and 1 patient developed limited chronic GVHD.

For more information on NiCord, visit the Gamida Cell website.

Cord blood donation

Credit: NHS

The US Food and Drug Administration (FDA) has granted orphan designation to a cord blood product called NiCord for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma (HL), and myelodysplastic syndromes (MDS).

NiCord consists of cells from a single cord blood unit cultured in nicotinamide—a vitamin B derivative—and cytokines that are typically used for expansion—thrombopoietin, interleukin 6, FLT3 ligand, and stem cell factor.

The FDA’s orphan drug designation for NiCord coincides with the positive opinion of the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products regarding NiCord as a treatment for AML. Gamida Cell, the company developing NiCord, intends to file for orphan drug status with the EMA for other indications as well.

“Receipt of orphan drug status for NiCord in the US and Europe advances Gamida Cell’s commercialization plans a major step further, as both afford significant advantages,” said Yael Margolin, President and CEO of Gamida Cell.

Orphan drug designation provides various regulatory and economic benefits, including 7 years of market exclusivity upon product approval in the US and 10 years in the European Union.

Trials of NiCord

NiCord is currently being tested in a phase 1/2 study as an investigational therapeutic treatment for hematologic malignancies. In this study, NiCord is being used as the sole stem cell source.

In a previous study, presented at the 11th Annual International Cord Blood Symposium, researchers transplanted a NiCord unit and an unmanipulated cord blood unit in patients with ALL, AML, MDS, HL, or non-Hodgkin lymphoma.

A majority of patients in this small, phase 1/2 study achieved early platelet and neutrophil engraftment. And, in some patients, that engraftment persisted for 2 years.

Eight of the 11 patients enrolled achieved engraftment with the NiCord unit, and 2 engrafted with the unmanipulated cord blood unit. One patient had primary graft failure.

There were no adverse events attributable to the NiCord unit, but 4 patients developed grade 1-2 acute GVHD, and 1 patient developed limited chronic GVHD.

For more information on NiCord, visit the Gamida Cell website.

Neutrophil engulfing bacteria

Credit: Volker Brinkmann

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, according to research published in Cell Metabolism.

Working with mice, researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of neutrophils.

“The link between these enzymes and neutrophils was a big surprise,” said study author Irfan J. Lodhi, PhD, of the Washington University School of Medicine in St. Louis.

“We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking.”

In the study, mice that couldn’t make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

“This may be a pathway to limit inflammation,” said study author Clay F. Semenkovich, MD, also of the Washington University School of Medicine.

“If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis.”

Dr Semenkovich said the enzymes specifically target neutrophils without affecting other immune cells, “so ether lipids appear to be a very precise target.”

The researchers also learned that inactivating the enzymes didn’t harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient’s neutrophil count would gradually rise, allowing the immune system to return to normal.

Neutrophil engulfing bacteria

Credit: Volker Brinkmann

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, according to research published in Cell Metabolism.

Working with mice, researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of neutrophils.

“The link between these enzymes and neutrophils was a big surprise,” said study author Irfan J. Lodhi, PhD, of the Washington University School of Medicine in St. Louis.

“We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking.”

In the study, mice that couldn’t make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

“This may be a pathway to limit inflammation,” said study author Clay F. Semenkovich, MD, also of the Washington University School of Medicine.

“If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis.”

Dr Semenkovich said the enzymes specifically target neutrophils without affecting other immune cells, “so ether lipids appear to be a very precise target.”

The researchers also learned that inactivating the enzymes didn’t harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient’s neutrophil count would gradually rise, allowing the immune system to return to normal.

Neutrophil engulfing bacteria

Credit: Volker Brinkmann

Enzymes linked to diabetes and obesity appear to play key roles in arthritis and leukemia, according to research published in Cell Metabolism.

Working with mice, researchers discovered that the same enzymes involved in turning carbohydrates into the building blocks of fats also influence the health of neutrophils.

“The link between these enzymes and neutrophils was a big surprise,” said study author Irfan J. Lodhi, PhD, of the Washington University School of Medicine in St. Louis.

“We had never thought about treating rheumatoid arthritis or leukemia by targeting enzymes that produce fatty acids, but this work supports that line of thinking.”

In the study, mice that couldn’t make enzymes needed to produce a certain type of fat abruptly lost weight and developed extremely low white blood cell counts, with very few neutrophils. Without this fat, called an ether lipid, neutrophils died.

That discovery could lead to the targeting of ether lipids as a way to reduce the number of neutrophils in inflammatory diseases and leukemias. The researchers believe limiting, rather than eliminating, ether lipids may be the best approach because neutrophils are important infection fighters.

“This may be a pathway to limit inflammation,” said study author Clay F. Semenkovich, MD, also of the Washington University School of Medicine.

“If we could reduce the activity of these enzymes without eliminating them entirely, it could lower the levels of ether lipids and potentially help patients with leukemia and inflammatory diseases such as arthritis.”

Dr Semenkovich said the enzymes specifically target neutrophils without affecting other immune cells, “so ether lipids appear to be a very precise target.”

The researchers also learned that inactivating the enzymes didn’t harm the precursors of neutrophils; only mature neutrophils were killed.

That could mean strategies to limit the production of ether lipids might lower neutrophil levels only temporarily so that when treatment stops, a patient’s neutrophil count would gradually rise, allowing the immune system to return to normal.

Blood collection

Credit: Charles Haymond

The European Commission has granted KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, orphan designation to treat patients with diffuse large B-cell lymphoma (DLBCL) in the European Union (EU).

To create KTE-C19, a patient’s T cells are genetically modified using a gammaretroviral vector to express a CAR designed to target CD19, a protein expressed on B cells.

The product received orphan designation to treat DLBCL in the US last March.

“We are pleased with the approval of orphan drug designation for KTE-C19 in the EU, another important milestone for Kite Pharma and for the progress of our lead program,” said Arie Belldegrun, MD, President and CEO of Kite Pharma, Inc., the company developing KTE-C19.

Orphan designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the EU, and where no satisfactory treatment is available.

In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, and direct access to the centralized authorization procedure.

KTE-C19 in DLBCL

In a study published in the Journal of Clinical Oncology last year, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a complete response to treatment, 2 achieved a partial response, and 1 had stable disease. Three of the complete responses were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.

In the entire patient population, KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.

Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.

For more information on KTE-C19, visit Kite Pharma’s website.

Blood collection

Credit: Charles Haymond

The European Commission has granted KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, orphan designation to treat patients with diffuse large B-cell lymphoma (DLBCL) in the European Union (EU).

To create KTE-C19, a patient’s T cells are genetically modified using a gammaretroviral vector to express a CAR designed to target CD19, a protein expressed on B cells.

The product received orphan designation to treat DLBCL in the US last March.

“We are pleased with the approval of orphan drug designation for KTE-C19 in the EU, another important milestone for Kite Pharma and for the progress of our lead program,” said Arie Belldegrun, MD, President and CEO of Kite Pharma, Inc., the company developing KTE-C19.

Orphan designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the EU, and where no satisfactory treatment is available.

In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, and direct access to the centralized authorization procedure.

KTE-C19 in DLBCL

In a study published in the Journal of Clinical Oncology last year, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a complete response to treatment, 2 achieved a partial response, and 1 had stable disease. Three of the complete responses were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.

In the entire patient population, KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.

Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.

For more information on KTE-C19, visit Kite Pharma’s website.

Blood collection

Credit: Charles Haymond

The European Commission has granted KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy, orphan designation to treat patients with diffuse large B-cell lymphoma (DLBCL) in the European Union (EU).

To create KTE-C19, a patient’s T cells are genetically modified using a gammaretroviral vector to express a CAR designed to target CD19, a protein expressed on B cells.

The product received orphan designation to treat DLBCL in the US last March.

“We are pleased with the approval of orphan drug designation for KTE-C19 in the EU, another important milestone for Kite Pharma and for the progress of our lead program,” said Arie Belldegrun, MD, President and CEO of Kite Pharma, Inc., the company developing KTE-C19.

Orphan designation by the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the EU, and where no satisfactory treatment is available.

In addition to a 10-year period of marketing exclusivity in the EU after product approval, orphan drug designation provides incentives for companies seeking protocol assistance from the European Medicines Agency during the product development phase, and direct access to the centralized authorization procedure.

KTE-C19 in DLBCL

In a study published in the Journal of Clinical Oncology last year, researchers evaluated KTE-C19 in 15 patients with advanced B-cell malignancies.

The patients received a conditioning regimen of cyclophosphamide and fludarabine, followed 1 day later by a single infusion of KTE-C19. The researchers noted that the conditioning regimen is known to be active against B-cell malignancies and could have made a direct contribution to patient responses.

Of the 7 patients with chemotherapy-refractory DLBCL, 4 achieved a complete response to treatment, 2 achieved a partial response, and 1 had stable disease. Three of the complete responses were ongoing at the time of publication, with the duration ranging from 9 months to 22 months.

In the entire patient population, KTE-C19 elicited a number of adverse events, including fever, hypotension, delirium, and other neurologic toxicities. All but 2 patients experienced grade 3/4 adverse events.

Three patients developed unexpected neurologic abnormalities. One patient experienced aphasia and right-sided facial paresis. One patient developed aphasia, confusion, and severe, generalized myoclonus. And 1 patient had aphasia, confusion, hemifacial spasms, apraxia, and gait disturbances.

For more information on KTE-C19, visit Kite Pharma’s website.

Lab mouse

Sepsis may have an Achilles heel that would allow for more effective treatment of the condition, according to research published in The FASEB Journal.

The study showed that CD39, an enzyme capable of clearing high levels of adenosine triphosphate (ATP) from the bloodstream, significantly improved survival of mice with severe sepsis.

Based on this finding, the researchers speculate that CD39 may also be used in other diseases associated with inflammation.

“Although we have come a long way in the treatment of sepsis since it was first described by Hippocrates in the fourth century BC, about 250,000 Americans still die from sepsis each year,” said study author Gyorgy Hasko, PhD, of Rutgers New Jersey Medical School in Newark.

“A drug that could cure patients with sepsis would not only save the lives of many, it would also decrease the enormous costs associated with treating septic patients in the intensive care unit and would help unburden the healthcare system.”

To make their discovery, Dr Hasko and his colleagues compared mice lacking the CD39 gene to wild-type mice. When sepsis was induced in both sets of mice, those without CD39 had worse survival.

With this information in hand, the researchers then performed another experiment with two more groups of normal mice that were septic.

The first group was injected with CD39 and the other with placebo. The mice that received CD39 had improved survival compared to those injected with placebo.

“Finding a more effective treatment for sepsis would be a major step forward since far too many people still die from overwhelming microbial infection,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “If CD39 proves to be as critical a factor in humans as in mice, this is a major discovery.”

Lab mouse

Sepsis may have an Achilles heel that would allow for more effective treatment of the condition, according to research published in The FASEB Journal.

The study showed that CD39, an enzyme capable of clearing high levels of adenosine triphosphate (ATP) from the bloodstream, significantly improved survival of mice with severe sepsis.

Based on this finding, the researchers speculate that CD39 may also be used in other diseases associated with inflammation.

“Although we have come a long way in the treatment of sepsis since it was first described by Hippocrates in the fourth century BC, about 250,000 Americans still die from sepsis each year,” said study author Gyorgy Hasko, PhD, of Rutgers New Jersey Medical School in Newark.

“A drug that could cure patients with sepsis would not only save the lives of many, it would also decrease the enormous costs associated with treating septic patients in the intensive care unit and would help unburden the healthcare system.”

To make their discovery, Dr Hasko and his colleagues compared mice lacking the CD39 gene to wild-type mice. When sepsis was induced in both sets of mice, those without CD39 had worse survival.

With this information in hand, the researchers then performed another experiment with two more groups of normal mice that were septic.

The first group was injected with CD39 and the other with placebo. The mice that received CD39 had improved survival compared to those injected with placebo.

“Finding a more effective treatment for sepsis would be a major step forward since far too many people still die from overwhelming microbial infection,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “If CD39 proves to be as critical a factor in humans as in mice, this is a major discovery.”

Lab mouse

Sepsis may have an Achilles heel that would allow for more effective treatment of the condition, according to research published in The FASEB Journal.

The study showed that CD39, an enzyme capable of clearing high levels of adenosine triphosphate (ATP) from the bloodstream, significantly improved survival of mice with severe sepsis.

Based on this finding, the researchers speculate that CD39 may also be used in other diseases associated with inflammation.

“Although we have come a long way in the treatment of sepsis since it was first described by Hippocrates in the fourth century BC, about 250,000 Americans still die from sepsis each year,” said study author Gyorgy Hasko, PhD, of Rutgers New Jersey Medical School in Newark.

“A drug that could cure patients with sepsis would not only save the lives of many, it would also decrease the enormous costs associated with treating septic patients in the intensive care unit and would help unburden the healthcare system.”

To make their discovery, Dr Hasko and his colleagues compared mice lacking the CD39 gene to wild-type mice. When sepsis was induced in both sets of mice, those without CD39 had worse survival.

With this information in hand, the researchers then performed another experiment with two more groups of normal mice that were septic.

The first group was injected with CD39 and the other with placebo. The mice that received CD39 had improved survival compared to those injected with placebo.

“Finding a more effective treatment for sepsis would be a major step forward since far too many people still die from overwhelming microbial infection,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “If CD39 proves to be as critical a factor in humans as in mice, this is a major discovery.”

Blood for transfusion

Credit: UAB Hospital

The process of pathogen inactivation does not compromise the quality of red blood cells (RBCs), results of a phase 3 study suggest.

Researchers compared untreated RBCs and RBCs treated with the INTERCEPT Blood System, a pathogen inactivation system.

The two sets of RBCs, which were given to cardiovascular surgery patients with acute anemia, had comparable hemoglobin content and in vitro quality, according to Cerus Corporation, makers of the INTERCEPT system.

Cerus recently announced these results, and the researchers plan to submit data from this study for presentation at upcoming scientific congresses.

“In our prior US phase 3 study in a similar patient population, INTERCEPT red cells were shown to be noninferior to control red cells in 148 patients based on a composite endpoint of myocardial infarction, renal failure, and death,” said Laurence Corash, MD, Cerus’s chief medical officer.

“The data from the recent phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. We believe that the successful results from this study, combined with data from the prior phase 3 study, support the safety and efficacy of the INTERCEPT RBC system for CE Mark registration.”

In the current trial, researchers evaluated the efficacy of the INTERCEPT system to process RBCs with quality and mean hemoglobin content (> 40 g) suitable to support transfusion according to the European Directorate for the Quality of Medicines.

The blood components were transfused in 51 cardiovascular surgery patients at 2 German trial sites. Patients undergoing procedures for coronary artery bypass grafting, valve repair, or combined procedures received transfusions during a 7-day treatment period that included the day of surgery and 6 days post-operatively.

The patients received either INTERCEPT-treated RBCs or control RBCs not treated for pathogen inactivation. RBC components for both clinical sites were manufactured at the German Red Cross blood center in Frankfurt, and the RBCs were stored for up to 35 days prior to transfusion.

The primary endpoint was the equivalence of mean hemoglobin content between INTERCEPT-treated RBCs and conventional RBCs. The mean hemoglobin content of INTERCEPT-treated RBCs on day 35 of storage (53.1 g) fell within the protocol-specified 5g equivalence margin, when compared to control RBCs (55.8 g).

The secondary efficacy endpoints also suggested INTERCEPT-treated RBCs were suitable for transfusion based on mean hematocrit of 60.4% (acceptance range: 55%-70%) and mean end-of-storage hemolysis rate of 0.28% (acceptance range < 0.8%).

There were no statistical differences in the adverse event rates between recipients of INTERCEPT-treated RBCs and control RBCs. There were no clinically relevant trends in severe or serious treatment-related adverse events by system organ class.

The observed adverse events were within the expected spectrum of comorbidity and mortality for patients of similar age and with advanced cardiovascular diseases undergoing cardiovascular surgery requiring RBC transfusion. And none of the patients exhibited an immune response to INTERCEPT-treated RBCs.

Blood for transfusion

Credit: UAB Hospital

The process of pathogen inactivation does not compromise the quality of red blood cells (RBCs), results of a phase 3 study suggest.

Researchers compared untreated RBCs and RBCs treated with the INTERCEPT Blood System, a pathogen inactivation system.

The two sets of RBCs, which were given to cardiovascular surgery patients with acute anemia, had comparable hemoglobin content and in vitro quality, according to Cerus Corporation, makers of the INTERCEPT system.

Cerus recently announced these results, and the researchers plan to submit data from this study for presentation at upcoming scientific congresses.

“In our prior US phase 3 study in a similar patient population, INTERCEPT red cells were shown to be noninferior to control red cells in 148 patients based on a composite endpoint of myocardial infarction, renal failure, and death,” said Laurence Corash, MD, Cerus’s chief medical officer.

“The data from the recent phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. We believe that the successful results from this study, combined with data from the prior phase 3 study, support the safety and efficacy of the INTERCEPT RBC system for CE Mark registration.”

In the current trial, researchers evaluated the efficacy of the INTERCEPT system to process RBCs with quality and mean hemoglobin content (> 40 g) suitable to support transfusion according to the European Directorate for the Quality of Medicines.

The blood components were transfused in 51 cardiovascular surgery patients at 2 German trial sites. Patients undergoing procedures for coronary artery bypass grafting, valve repair, or combined procedures received transfusions during a 7-day treatment period that included the day of surgery and 6 days post-operatively.

The patients received either INTERCEPT-treated RBCs or control RBCs not treated for pathogen inactivation. RBC components for both clinical sites were manufactured at the German Red Cross blood center in Frankfurt, and the RBCs were stored for up to 35 days prior to transfusion.

The primary endpoint was the equivalence of mean hemoglobin content between INTERCEPT-treated RBCs and conventional RBCs. The mean hemoglobin content of INTERCEPT-treated RBCs on day 35 of storage (53.1 g) fell within the protocol-specified 5g equivalence margin, when compared to control RBCs (55.8 g).

The secondary efficacy endpoints also suggested INTERCEPT-treated RBCs were suitable for transfusion based on mean hematocrit of 60.4% (acceptance range: 55%-70%) and mean end-of-storage hemolysis rate of 0.28% (acceptance range < 0.8%).

There were no statistical differences in the adverse event rates between recipients of INTERCEPT-treated RBCs and control RBCs. There were no clinically relevant trends in severe or serious treatment-related adverse events by system organ class.

The observed adverse events were within the expected spectrum of comorbidity and mortality for patients of similar age and with advanced cardiovascular diseases undergoing cardiovascular surgery requiring RBC transfusion. And none of the patients exhibited an immune response to INTERCEPT-treated RBCs.

Blood for transfusion

Credit: UAB Hospital

The process of pathogen inactivation does not compromise the quality of red blood cells (RBCs), results of a phase 3 study suggest.

Researchers compared untreated RBCs and RBCs treated with the INTERCEPT Blood System, a pathogen inactivation system.

The two sets of RBCs, which were given to cardiovascular surgery patients with acute anemia, had comparable hemoglobin content and in vitro quality, according to Cerus Corporation, makers of the INTERCEPT system.

Cerus recently announced these results, and the researchers plan to submit data from this study for presentation at upcoming scientific congresses.

“In our prior US phase 3 study in a similar patient population, INTERCEPT red cells were shown to be noninferior to control red cells in 148 patients based on a composite endpoint of myocardial infarction, renal failure, and death,” said Laurence Corash, MD, Cerus’s chief medical officer.

“The data from the recent phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. We believe that the successful results from this study, combined with data from the prior phase 3 study, support the safety and efficacy of the INTERCEPT RBC system for CE Mark registration.”

In the current trial, researchers evaluated the efficacy of the INTERCEPT system to process RBCs with quality and mean hemoglobin content (> 40 g) suitable to support transfusion according to the European Directorate for the Quality of Medicines.

The blood components were transfused in 51 cardiovascular surgery patients at 2 German trial sites. Patients undergoing procedures for coronary artery bypass grafting, valve repair, or combined procedures received transfusions during a 7-day treatment period that included the day of surgery and 6 days post-operatively.

The patients received either INTERCEPT-treated RBCs or control RBCs not treated for pathogen inactivation. RBC components for both clinical sites were manufactured at the German Red Cross blood center in Frankfurt, and the RBCs were stored for up to 35 days prior to transfusion.

The primary endpoint was the equivalence of mean hemoglobin content between INTERCEPT-treated RBCs and conventional RBCs. The mean hemoglobin content of INTERCEPT-treated RBCs on day 35 of storage (53.1 g) fell within the protocol-specified 5g equivalence margin, when compared to control RBCs (55.8 g).

The secondary efficacy endpoints also suggested INTERCEPT-treated RBCs were suitable for transfusion based on mean hematocrit of 60.4% (acceptance range: 55%-70%) and mean end-of-storage hemolysis rate of 0.28% (acceptance range < 0.8%).

There were no statistical differences in the adverse event rates between recipients of INTERCEPT-treated RBCs and control RBCs. There were no clinically relevant trends in severe or serious treatment-related adverse events by system organ class.

The observed adverse events were within the expected spectrum of comorbidity and mortality for patients of similar age and with advanced cardiovascular diseases undergoing cardiovascular surgery requiring RBC transfusion. And none of the patients exhibited an immune response to INTERCEPT-treated RBCs.