Pharmacy

Ofatumumab (Arzerra)

Photo courtesy of GSK

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for ofatumumab (Arzerra^®).

The CHMP is recommending the drug be approved for use in combination with fludarabine and cyclophosphamide to treat adults with relapsed chronic lymphocytic leukemia (CLL).

The CHMP’s recommendation will be reviewed by the European Commission.

A final decision is expected in the coming months.

Ofatumumab is a monoclonal antibody designed to target CD20. The drug is marketed under a collaboration agreement between Genmab and Novartis.

The European Commission has already approved ofatumumab for the following indications:

• As a single-agent to treat CLL patients who are refractory to fludarabine and alemtuzumab
• For use in combination with chlorambucil or bendamustine in CLL patients who

  have not received prior therapy and are not eligible for

  fludarabine-based therapy.

COMPLEMENT 2 trial

The CHMP’s recommendation to approve ofatumumab in combination with fludarabine and cyclophosphamide was based on results from the phase 3 COMPLEMENT 2 study. Novartis reported top-line results from this study last April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for ofatumumab (Arzerra^®).

The CHMP is recommending the drug be approved for use in combination with fludarabine and cyclophosphamide to treat adults with relapsed chronic lymphocytic leukemia (CLL).

The CHMP’s recommendation will be reviewed by the European Commission.

A final decision is expected in the coming months.

Ofatumumab is a monoclonal antibody designed to target CD20. The drug is marketed under a collaboration agreement between Genmab and Novartis.

The European Commission has already approved ofatumumab for the following indications:

• As a single-agent to treat CLL patients who are refractory to fludarabine and alemtuzumab
• For use in combination with chlorambucil or bendamustine in CLL patients who

  have not received prior therapy and are not eligible for

  fludarabine-based therapy.

COMPLEMENT 2 trial

The CHMP’s recommendation to approve ofatumumab in combination with fludarabine and cyclophosphamide was based on results from the phase 3 COMPLEMENT 2 study. Novartis reported top-line results from this study last April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved indication for ofatumumab (Arzerra^®).

The CHMP is recommending the drug be approved for use in combination with fludarabine and cyclophosphamide to treat adults with relapsed chronic lymphocytic leukemia (CLL).

The CHMP’s recommendation will be reviewed by the European Commission.

A final decision is expected in the coming months.

Ofatumumab is a monoclonal antibody designed to target CD20. The drug is marketed under a collaboration agreement between Genmab and Novartis.

The European Commission has already approved ofatumumab for the following indications:

• As a single-agent to treat CLL patients who are refractory to fludarabine and alemtuzumab
• For use in combination with chlorambucil or bendamustine in CLL patients who

  have not received prior therapy and are not eligible for

  fludarabine-based therapy.

COMPLEMENT 2 trial

The CHMP’s recommendation to approve ofatumumab in combination with fludarabine and cyclophosphamide was based on results from the phase 3 COMPLEMENT 2 study. Novartis reported top-line results from this study last April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Thrombus

Image by Andre E.X. Brown

Health Canada has approved edoxaban (Lixiana^®), an oral factor Xa inhibitor, for use in patients with venous thromboembolism (VTE) or nonvalvular atrial fibrillation (NVAF).

The drug can now be used to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE).

It can also be used to prevent stroke and systemic embolism in adults with NVAF in whom anticoagulation is appropriate.

Edoxaban was discovered and developed by Daiichi Sankyo Co., Ltd., but Servier Canada will market the drug in Canada.

Edoxaban has been approved in the US, European Union, Switzerland, Japan, South Korea, Taiwan, and Hong Kong. The drug is marketed as Savaysa^® in the US and as Lixiana^® elsewhere.

Health Canada’s approval of edoxaban is based on data from a pair of phase 3 trials, ENGAGE AF-TIMI 48 and Hokusai-VTE.

Hokusai-VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with DVT and 3319 with PE. 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).

In addition, the incidence of clinically relevant bleeding was significantly lower in the edoxaban arm than the warfarin arm—8.5% and 10.3%, respectively (P=0.004 for superiority).

ENGAGE-AF TIMI 48

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism 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 systemic embolism 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).

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).

Thrombus

Image by Andre E.X. Brown

Health Canada has approved edoxaban (Lixiana^®), an oral factor Xa inhibitor, for use in patients with venous thromboembolism (VTE) or nonvalvular atrial fibrillation (NVAF).

The drug can now be used to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE).

It can also be used to prevent stroke and systemic embolism in adults with NVAF in whom anticoagulation is appropriate.

Edoxaban was discovered and developed by Daiichi Sankyo Co., Ltd., but Servier Canada will market the drug in Canada.

Edoxaban has been approved in the US, European Union, Switzerland, Japan, South Korea, Taiwan, and Hong Kong. The drug is marketed as Savaysa^® in the US and as Lixiana^® elsewhere.

Health Canada’s approval of edoxaban is based on data from a pair of phase 3 trials, ENGAGE AF-TIMI 48 and Hokusai-VTE.

Hokusai-VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with DVT and 3319 with PE. 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).

In addition, the incidence of clinically relevant bleeding was significantly lower in the edoxaban arm than the warfarin arm—8.5% and 10.3%, respectively (P=0.004 for superiority).

ENGAGE-AF TIMI 48

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism 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 systemic embolism 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).

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).

Thrombus

Image by Andre E.X. Brown

Health Canada has approved edoxaban (Lixiana^®), an oral factor Xa inhibitor, for use in patients with venous thromboembolism (VTE) or nonvalvular atrial fibrillation (NVAF).

The drug can now be used to treat and prevent the recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE).

It can also be used to prevent stroke and systemic embolism in adults with NVAF in whom anticoagulation is appropriate.

Edoxaban was discovered and developed by Daiichi Sankyo Co., Ltd., but Servier Canada will market the drug in Canada.

Edoxaban has been approved in the US, European Union, Switzerland, Japan, South Korea, Taiwan, and Hong Kong. The drug is marketed as Savaysa^® in the US and as Lixiana^® elsewhere.

Health Canada’s approval of edoxaban is based on data from a pair of phase 3 trials, ENGAGE AF-TIMI 48 and Hokusai-VTE.

Hokusai-VTE

In the Hokusai-VTE trial, researchers evaluated edoxaban in 4921 patients with DVT and 3319 with PE. 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).

In addition, the incidence of clinically relevant bleeding was significantly lower in the edoxaban arm than the warfarin arm—8.5% and 10.3%, respectively (P=0.004 for superiority).

ENGAGE-AF TIMI 48

In the ENGAGE AF-TIMI 48 trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism 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 systemic embolism 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).

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).

Bivalirudin for Injection

Photo from Business Wire

Fresenius Kabi’s Bivalirudin for Injection, a generic alternative to The Medicines Company’s Angiomax, is now available in the US.

Bivalirudin is a direct thrombin inhibitor indicated for use as an anticoagulant.

Fresenius Kabi’s Bivalirudin for Injection was approved by the US Food and Drug Administration in October.

Bivalirudin for Injection is now available in single-dose vials, each containing 250 mg of bivalirudin.

Bivalirudin for Injection was developed and is manufactured in the US.

Bivalirudin for Injection is indicated for use in:

• Patients with unstable angina who are undergoing percutaneous transluminal coronary angioplasty (PTCA)
• Patients undergoing percutaneous coronary intervention (PCI) with provisional use of glycoprotein IIb/IIIa inhibitors, as in the REPLACE-2 study
• Patients with, or at risk of, heparin-induced thrombocytopenia or heparin-induced thrombocytopenia and thrombosis syndrome who are undergoing PCI.

Bivalirudin for Injection is intended for use with aspirin.

The safety and effectiveness of Bivalirudin for Injection has not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.

Bivalirudin for Injection

Photo from Business Wire

Fresenius Kabi’s Bivalirudin for Injection, a generic alternative to The Medicines Company’s Angiomax, is now available in the US.

Bivalirudin is a direct thrombin inhibitor indicated for use as an anticoagulant.

Fresenius Kabi’s Bivalirudin for Injection was approved by the US Food and Drug Administration in October.

Bivalirudin for Injection is now available in single-dose vials, each containing 250 mg of bivalirudin.

Bivalirudin for Injection was developed and is manufactured in the US.

Bivalirudin for Injection is indicated for use in:

• Patients with unstable angina who are undergoing percutaneous transluminal coronary angioplasty (PTCA)
• Patients undergoing percutaneous coronary intervention (PCI) with provisional use of glycoprotein IIb/IIIa inhibitors, as in the REPLACE-2 study
• Patients with, or at risk of, heparin-induced thrombocytopenia or heparin-induced thrombocytopenia and thrombosis syndrome who are undergoing PCI.

Bivalirudin for Injection is intended for use with aspirin.

The safety and effectiveness of Bivalirudin for Injection has not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.

Bivalirudin for Injection

Photo from Business Wire

Fresenius Kabi’s Bivalirudin for Injection, a generic alternative to The Medicines Company’s Angiomax, is now available in the US.

Bivalirudin is a direct thrombin inhibitor indicated for use as an anticoagulant.

Fresenius Kabi’s Bivalirudin for Injection was approved by the US Food and Drug Administration in October.

Bivalirudin for Injection is now available in single-dose vials, each containing 250 mg of bivalirudin.

Bivalirudin for Injection was developed and is manufactured in the US.

Bivalirudin for Injection is indicated for use in:

• Patients with unstable angina who are undergoing percutaneous transluminal coronary angioplasty (PTCA)
• Patients undergoing percutaneous coronary intervention (PCI) with provisional use of glycoprotein IIb/IIIa inhibitors, as in the REPLACE-2 study
• Patients with, or at risk of, heparin-induced thrombocytopenia or heparin-induced thrombocytopenia and thrombosis syndrome who are undergoing PCI.

Bivalirudin for Injection is intended for use with aspirin.

The safety and effectiveness of Bivalirudin for Injection has not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.

Syringes filled with Zarxio

(filgrastim-sndz), the first

biosimilar approved in the US

© Sandoz Inc. 2015

WASHINGTON, DC—A survey of roughly 1200 US physicians has revealed gaps in their knowledge about biosimilars.

The results showed that some physicians had difficulty defining biosimilars, did not fully understand how the US Food and Drug Administration (FDA) approves biosimilars, and may not know how to prescribe biosimilars appropriately.

The results were published in Advances in Therapy and presented at the DIA Biosimilars 2016 conference.

The 19-question survey was created by the Biosimilars Forum and conducted by SERMO, a global social network organization for physicians, from November 20, 2015, to January 4, 2016.

Responses were obtained from 1201 US physicians across specialties that are high prescribers of biologics, including hematologist-oncologists, dermatologists, gastroenterologists, medical oncologists, nephrologists, and rheumatologists.

Knowledge gaps

The survey revealed 5 major knowledge gaps regarding biosimilars:

1. Defining biologics, biosimilars, and biosimilarity¹
2. Understanding the approval process and the FDA’s use of “totality of evidence” to evaluate biosimilars
3. Understanding that the safety profile of a biosimilar is expected to be the same as that of the originator biologic
4. Understanding how decisions are made by the FDA for extrapolation² of indications
5. Defining interchangeability³ and the related rules regarding pharmacy-level substitution.

“With 4 biosimilars approved by the FDA and more than 60 in development, the survey highlights the need for greater biosimilars education for physicians and healthcare professionals,” said study author Hillel Cohen, PhD, executive director of scientific affairs at Sandoz Inc.

“Education will help physicians and healthcare professionals have a better understanding and knowledge of biosimilars so that they feel comfortable about administering biosimilars to patients when appropriate.”

FDA approval

Most of the physicians surveyed did not clearly understand the concept of extrapolation as applied to biosimilars. Only 12% of survey respondents said they trust extrapolation of the studied biosimilar indication(s) as the basis to obtain approval of other licensed indications of the originator product.

Almost 60% of respondents correctly understood that, to be approved as “interchangeable” with the originator, a biosimilar must be shown to be safe and effective for back-and-forth switching, with no negative impacts to safety or efficacy.

However, almost 80% of respondents did not agree, or potentially did not realize, that an FDA designation of “interchangeable” may enable a pharmacist to switch between the originator biologic and biosimilar and vice versa.

A little more than half of physicians surveyed knew that, for a biosimilar to be approved, the FDA must find the biosimilar to be equally effective (62.3%) and safe (57.2%) when compared to the originator biologic.

Most physicians surveyed (74.5%) said they trust the FDA’s biosimilar approval decisions.

Biosimilar use

Fewer than half of the survey respondents (44.8%) believed that biosimilars will be safe and appropriate for use in existing patients as well as naïve patients.

Overall, respondents expressed a general agreement that switching an existing patient to a biosimilar may be appropriate, with 9 in 10 (91%) saying they would consider switching a patient from an originator biologic to a biosimilar as an effective alternative to the originator if it would help the patient have better access to his/her medications.

In addition, 82.2% of respondents believed biosimilars will expand treatment options and provide savings to patients and the healthcare system.

“The Biosimilars Forum launched the Partnership for Biosimilar Education and Access to provide evidence-based education for healthcare professionals, patients, and the public,” Dr Cohen said. “The forum will use the survey results to provide education on the key concepts of biosimilars as we advance our mission to encourage awareness, access, and adoption of these important medicines.”

The Biosimilars Forum intends to conduct a similar survey in 2 to 3 years with the same design in order to monitor trends in the awareness, knowledge, and perceptions of biosimilars over time.

1. A biosimilar medicine is a biologic that is highly similar to an FDA-approved biological medicine, known as an originator biologic. A biosimilar must (1) be highly similar to the originator biologic, notwithstanding minor differences in clinically inactive components, and (2) have no clinically meaningful differences in safety or effectiveness compared to the originator biologic. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf

2. Extrapolation is the process by which a biosimilar may be approved for one or more indications for which its reference biological product is licensed but for which there was no head-to-head clinical comparison. This approval is based on the extrapolation of the totality of data obtained with the biosimilar molecule in direct comparison to the originator biologic. Every indication for which extrapolation is sought must be scientifically justified. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf

3. An interchangeable biologic is a biosimilar that has been demonstrated to produce the same clinical result as its originator biologic in any given patient. In addition, for a product that is administered multiple times to an individual, the risk in terms of safety or diminished efficacy of alternating between use of the interchangeable biologic and its originator biologic is not greater than the risk of using the originator biologic alone. Designation of interchangeability requires additional supporting evidence, which will be further defined by the FDA. An interchangeable biologic may be substituted by a pharmacist for the originator biologic or vice-versa without the intervention of the healthcare professional who wrote the prescription. State laws govern the substitution process, and communication to the healthcare provider who wrote the prescription may be required after the product is dispensed. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf

Syringes filled with Zarxio

(filgrastim-sndz), the first

biosimilar approved in the US

© Sandoz Inc. 2015

WASHINGTON, DC—A survey of roughly 1200 US physicians has revealed gaps in their knowledge about biosimilars.

The results showed that some physicians had difficulty defining biosimilars, did not fully understand how the US Food and Drug Administration (FDA) approves biosimilars, and may not know how to prescribe biosimilars appropriately.

The results were published in Advances in Therapy and presented at the DIA Biosimilars 2016 conference.

The 19-question survey was created by the Biosimilars Forum and conducted by SERMO, a global social network organization for physicians, from November 20, 2015, to January 4, 2016.

Responses were obtained from 1201 US physicians across specialties that are high prescribers of biologics, including hematologist-oncologists, dermatologists, gastroenterologists, medical oncologists, nephrologists, and rheumatologists.

Knowledge gaps

The survey revealed 5 major knowledge gaps regarding biosimilars:

1. Defining biologics, biosimilars, and biosimilarity¹
2. Understanding the approval process and the FDA’s use of “totality of evidence” to evaluate biosimilars
3. Understanding that the safety profile of a biosimilar is expected to be the same as that of the originator biologic
4. Understanding how decisions are made by the FDA for extrapolation² of indications
5. Defining interchangeability³ and the related rules regarding pharmacy-level substitution.

“With 4 biosimilars approved by the FDA and more than 60 in development, the survey highlights the need for greater biosimilars education for physicians and healthcare professionals,” said study author Hillel Cohen, PhD, executive director of scientific affairs at Sandoz Inc.

“Education will help physicians and healthcare professionals have a better understanding and knowledge of biosimilars so that they feel comfortable about administering biosimilars to patients when appropriate.”

FDA approval

Most of the physicians surveyed did not clearly understand the concept of extrapolation as applied to biosimilars. Only 12% of survey respondents said they trust extrapolation of the studied biosimilar indication(s) as the basis to obtain approval of other licensed indications of the originator product.

Almost 60% of respondents correctly understood that, to be approved as “interchangeable” with the originator, a biosimilar must be shown to be safe and effective for back-and-forth switching, with no negative impacts to safety or efficacy.

However, almost 80% of respondents did not agree, or potentially did not realize, that an FDA designation of “interchangeable” may enable a pharmacist to switch between the originator biologic and biosimilar and vice versa.

A little more than half of physicians surveyed knew that, for a biosimilar to be approved, the FDA must find the biosimilar to be equally effective (62.3%) and safe (57.2%) when compared to the originator biologic.

Most physicians surveyed (74.5%) said they trust the FDA’s biosimilar approval decisions.

Biosimilar use

Fewer than half of the survey respondents (44.8%) believed that biosimilars will be safe and appropriate for use in existing patients as well as naïve patients.

Overall, respondents expressed a general agreement that switching an existing patient to a biosimilar may be appropriate, with 9 in 10 (91%) saying they would consider switching a patient from an originator biologic to a biosimilar as an effective alternative to the originator if it would help the patient have better access to his/her medications.

In addition, 82.2% of respondents believed biosimilars will expand treatment options and provide savings to patients and the healthcare system.

“The Biosimilars Forum launched the Partnership for Biosimilar Education and Access to provide evidence-based education for healthcare professionals, patients, and the public,” Dr Cohen said. “The forum will use the survey results to provide education on the key concepts of biosimilars as we advance our mission to encourage awareness, access, and adoption of these important medicines.”

The Biosimilars Forum intends to conduct a similar survey in 2 to 3 years with the same design in order to monitor trends in the awareness, knowledge, and perceptions of biosimilars over time.

1. A biosimilar medicine is a biologic that is highly similar to an FDA-approved biological medicine, known as an originator biologic. A biosimilar must (1) be highly similar to the originator biologic, notwithstanding minor differences in clinically inactive components, and (2) have no clinically meaningful differences in safety or effectiveness compared to the originator biologic. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf

2. Extrapolation is the process by which a biosimilar may be approved for one or more indications for which its reference biological product is licensed but for which there was no head-to-head clinical comparison. This approval is based on the extrapolation of the totality of data obtained with the biosimilar molecule in direct comparison to the originator biologic. Every indication for which extrapolation is sought must be scientifically justified. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf

3. An interchangeable biologic is a biosimilar that has been demonstrated to produce the same clinical result as its originator biologic in any given patient. In addition, for a product that is administered multiple times to an individual, the risk in terms of safety or diminished efficacy of alternating between use of the interchangeable biologic and its originator biologic is not greater than the risk of using the originator biologic alone. Designation of interchangeability requires additional supporting evidence, which will be further defined by the FDA. An interchangeable biologic may be substituted by a pharmacist for the originator biologic or vice-versa without the intervention of the healthcare professional who wrote the prescription. State laws govern the substitution process, and communication to the healthcare provider who wrote the prescription may be required after the product is dispensed. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf

Syringes filled with Zarxio

(filgrastim-sndz), the first

biosimilar approved in the US

© Sandoz Inc. 2015

WASHINGTON, DC—A survey of roughly 1200 US physicians has revealed gaps in their knowledge about biosimilars.

The results showed that some physicians had difficulty defining biosimilars, did not fully understand how the US Food and Drug Administration (FDA) approves biosimilars, and may not know how to prescribe biosimilars appropriately.

The results were published in Advances in Therapy and presented at the DIA Biosimilars 2016 conference.

The 19-question survey was created by the Biosimilars Forum and conducted by SERMO, a global social network organization for physicians, from November 20, 2015, to January 4, 2016.

Responses were obtained from 1201 US physicians across specialties that are high prescribers of biologics, including hematologist-oncologists, dermatologists, gastroenterologists, medical oncologists, nephrologists, and rheumatologists.

Knowledge gaps

The survey revealed 5 major knowledge gaps regarding biosimilars:

1. Defining biologics, biosimilars, and biosimilarity¹
2. Understanding the approval process and the FDA’s use of “totality of evidence” to evaluate biosimilars
3. Understanding that the safety profile of a biosimilar is expected to be the same as that of the originator biologic
4. Understanding how decisions are made by the FDA for extrapolation² of indications
5. Defining interchangeability³ and the related rules regarding pharmacy-level substitution.

“With 4 biosimilars approved by the FDA and more than 60 in development, the survey highlights the need for greater biosimilars education for physicians and healthcare professionals,” said study author Hillel Cohen, PhD, executive director of scientific affairs at Sandoz Inc.

“Education will help physicians and healthcare professionals have a better understanding and knowledge of biosimilars so that they feel comfortable about administering biosimilars to patients when appropriate.”

FDA approval

Most of the physicians surveyed did not clearly understand the concept of extrapolation as applied to biosimilars. Only 12% of survey respondents said they trust extrapolation of the studied biosimilar indication(s) as the basis to obtain approval of other licensed indications of the originator product.

Almost 60% of respondents correctly understood that, to be approved as “interchangeable” with the originator, a biosimilar must be shown to be safe and effective for back-and-forth switching, with no negative impacts to safety or efficacy.

However, almost 80% of respondents did not agree, or potentially did not realize, that an FDA designation of “interchangeable” may enable a pharmacist to switch between the originator biologic and biosimilar and vice versa.

A little more than half of physicians surveyed knew that, for a biosimilar to be approved, the FDA must find the biosimilar to be equally effective (62.3%) and safe (57.2%) when compared to the originator biologic.

Most physicians surveyed (74.5%) said they trust the FDA’s biosimilar approval decisions.

Biosimilar use

Fewer than half of the survey respondents (44.8%) believed that biosimilars will be safe and appropriate for use in existing patients as well as naïve patients.

Overall, respondents expressed a general agreement that switching an existing patient to a biosimilar may be appropriate, with 9 in 10 (91%) saying they would consider switching a patient from an originator biologic to a biosimilar as an effective alternative to the originator if it would help the patient have better access to his/her medications.

In addition, 82.2% of respondents believed biosimilars will expand treatment options and provide savings to patients and the healthcare system.

“The Biosimilars Forum launched the Partnership for Biosimilar Education and Access to provide evidence-based education for healthcare professionals, patients, and the public,” Dr Cohen said. “The forum will use the survey results to provide education on the key concepts of biosimilars as we advance our mission to encourage awareness, access, and adoption of these important medicines.”

The Biosimilars Forum intends to conduct a similar survey in 2 to 3 years with the same design in order to monitor trends in the awareness, knowledge, and perceptions of biosimilars over time.

1. A biosimilar medicine is a biologic that is highly similar to an FDA-approved biological medicine, known as an originator biologic. A biosimilar must (1) be highly similar to the originator biologic, notwithstanding minor differences in clinically inactive components, and (2) have no clinically meaningful differences in safety or effectiveness compared to the originator biologic. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf

2. Extrapolation is the process by which a biosimilar may be approved for one or more indications for which its reference biological product is licensed but for which there was no head-to-head clinical comparison. This approval is based on the extrapolation of the totality of data obtained with the biosimilar molecule in direct comparison to the originator biologic. Every indication for which extrapolation is sought must be scientifically justified. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf

3. An interchangeable biologic is a biosimilar that has been demonstrated to produce the same clinical result as its originator biologic in any given patient. In addition, for a product that is administered multiple times to an individual, the risk in terms of safety or diminished efficacy of alternating between use of the interchangeable biologic and its originator biologic is not greater than the risk of using the originator biologic alone. Designation of interchangeability requires additional supporting evidence, which will be further defined by the FDA. An interchangeable biologic may be substituted by a pharmacist for the originator biologic or vice-versa without the intervention of the healthcare professional who wrote the prescription. State laws govern the substitution process, and communication to the healthcare provider who wrote the prescription may be required after the product is dispensed. Biosimilars Forum. (2016, March 28). Frequently Asked Questions. Retrieved from: http://www.biosimilarsforum.org/sites/default/files/uploads/biosimilars_faqs_032816opt_0.pdf

Eftrenonacog alfa

Photo courtesy of Biogen

The Swiss Agency for Therapeutic Products, Swissmedic, has approved eftrenonacog alfa (Alprolix®) for the treatment of hemophilia B.

Eftrenonacog alfa is a recombinant factor IX Fc fusion protein indicated for both on-demand treatment and prophylaxis in previously treated patients with hemophilia B.

For prophylaxis, 1 dose of eftrenonacog alfa can be given every 7 days or every 10 days, with the ability to adjust the dosing interval based on individual response.

Eftrenonacog alfa is the only recombinant factor IX Fc fusion protein therapy approved in Switzerland for the treatment of hemophilia B.

“The Swiss approval of Alprolix is an important milestone for the hemophilia community, offering the opportunity for people with hemophilia B to experience prolonged protection from bleeds,” said Krassimir Mitchev, MD, PhD, vice president and medical therapeutic area head of hemophilia at Sobi, the company developing eftrenonacog alfa in collaboration with Biogen.

“We will now focus on ensuring timely and sustainable access to Alprolix in Switzerland.”

About eftrenonacog alfa

Eftrenonacog alfa is a recombinant clotting factor therapy developed by fusing factor IX to the Fc portion of immunoglobulin G subclass 1 (IgG1). This enables eftrenonacog alfa to use a naturally occurring pathway to prolong the time the therapy remains in the body.

Eftrenonacog alfa is currently approved for the treatment of hemophilia B in the European Economic Area, the US, Canada, Japan, Australia, New Zealand, and other countries.

Sobi and Biogen collaborate on the development and commercialization of eftrenonacog alfa.

The product has been evaluated in two phase 3 trials of patients with hemophilia B: the B-LONG study and the Kids B-LONG study.

B-LONG study

The B-LONG study included 123 male subjects with severe hemophilia B who were 12 years of age or older. They had no current or previous factor IX inhibitors and a history of 100 or more documented prior exposure days to factor IX products.

Patients received eftrenonacog alfa in 1 of 4 treatment arms:

1. Weekly prophylaxis starting at 50 IU/kg, with pharmacokinetic (PK)-driven dose adjustments (n=63)
2. Individualized interval prophylaxis starting at 100 IU/kg every 10 days, with PK-driven interval adjustments (n=29)
3. On-demand treatment at 20 IU/kg to 100 IU/kg (n=27)
4. Perioperative management (n=12, including 8 from arms 1-3).

Researchers assessed control of bleeding in all patients who experienced

a bleeding episode while on study. In total, 90.4% of bleeding episodes

were controlled by a single injection of eftrenonacog alfa.

The overall median annualized bleeding rates (ABRs)—including spontaneous and traumatic bleeds—were 2.95 in the weekly prophylaxis arm, 1.38 in the individualized interval prophylaxis arm, and 17.69 in the episodic treatment arm.

The perioperative management arm consisted of 12 patients undergoing 14 major surgical procedures. The treating physicians rated the hemostatic efficacy of eftrenonacog alfa as “excellent” or “good” in all surgeries.

Eftrenonacog alfa was considered generally well-tolerated. None of the patients developed inhibitors, and none reported anaphylaxis.

The most common adverse events—with an incidence of 5% or greater—occurring outside of the perioperative management arm were nasopharyngitis, influenza, arthralgia, upper respiratory infection, hypertension, and headache.

One serious adverse event may have been drug-related. The patient experienced obstructive uropathy in the setting of hematuria. However, he continued to receive eftrenonacog alfa, and the event resolved with medical management.

Kids B-LONG

In Kids B-LONG, researchers tested eftrenonacog alfa in 30 previously treated children younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Children who received eftrenonacog alfa prophylactically had an overall median ABR of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of eftrenonacog alfa.

None of the patients developed inhibitors. Researchers said there were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events.

None of the patients discontinued the study due to an adverse event. One adverse event—decreased appetite occurring in 1 patient—was considered related to eftrenonacog alfa.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the B-LONG study.

Eftrenonacog alfa

Photo courtesy of Biogen

The Swiss Agency for Therapeutic Products, Swissmedic, has approved eftrenonacog alfa (Alprolix®) for the treatment of hemophilia B.

Eftrenonacog alfa is a recombinant factor IX Fc fusion protein indicated for both on-demand treatment and prophylaxis in previously treated patients with hemophilia B.

For prophylaxis, 1 dose of eftrenonacog alfa can be given every 7 days or every 10 days, with the ability to adjust the dosing interval based on individual response.

Eftrenonacog alfa is the only recombinant factor IX Fc fusion protein therapy approved in Switzerland for the treatment of hemophilia B.

“The Swiss approval of Alprolix is an important milestone for the hemophilia community, offering the opportunity for people with hemophilia B to experience prolonged protection from bleeds,” said Krassimir Mitchev, MD, PhD, vice president and medical therapeutic area head of hemophilia at Sobi, the company developing eftrenonacog alfa in collaboration with Biogen.

“We will now focus on ensuring timely and sustainable access to Alprolix in Switzerland.”

About eftrenonacog alfa

Eftrenonacog alfa is a recombinant clotting factor therapy developed by fusing factor IX to the Fc portion of immunoglobulin G subclass 1 (IgG1). This enables eftrenonacog alfa to use a naturally occurring pathway to prolong the time the therapy remains in the body.

Eftrenonacog alfa is currently approved for the treatment of hemophilia B in the European Economic Area, the US, Canada, Japan, Australia, New Zealand, and other countries.

Sobi and Biogen collaborate on the development and commercialization of eftrenonacog alfa.

The product has been evaluated in two phase 3 trials of patients with hemophilia B: the B-LONG study and the Kids B-LONG study.

B-LONG study

The B-LONG study included 123 male subjects with severe hemophilia B who were 12 years of age or older. They had no current or previous factor IX inhibitors and a history of 100 or more documented prior exposure days to factor IX products.

Patients received eftrenonacog alfa in 1 of 4 treatment arms:

1. Weekly prophylaxis starting at 50 IU/kg, with pharmacokinetic (PK)-driven dose adjustments (n=63)
2. Individualized interval prophylaxis starting at 100 IU/kg every 10 days, with PK-driven interval adjustments (n=29)
3. On-demand treatment at 20 IU/kg to 100 IU/kg (n=27)
4. Perioperative management (n=12, including 8 from arms 1-3).

Researchers assessed control of bleeding in all patients who experienced

a bleeding episode while on study. In total, 90.4% of bleeding episodes

were controlled by a single injection of eftrenonacog alfa.

The overall median annualized bleeding rates (ABRs)—including spontaneous and traumatic bleeds—were 2.95 in the weekly prophylaxis arm, 1.38 in the individualized interval prophylaxis arm, and 17.69 in the episodic treatment arm.

The perioperative management arm consisted of 12 patients undergoing 14 major surgical procedures. The treating physicians rated the hemostatic efficacy of eftrenonacog alfa as “excellent” or “good” in all surgeries.

Eftrenonacog alfa was considered generally well-tolerated. None of the patients developed inhibitors, and none reported anaphylaxis.

The most common adverse events—with an incidence of 5% or greater—occurring outside of the perioperative management arm were nasopharyngitis, influenza, arthralgia, upper respiratory infection, hypertension, and headache.

One serious adverse event may have been drug-related. The patient experienced obstructive uropathy in the setting of hematuria. However, he continued to receive eftrenonacog alfa, and the event resolved with medical management.

Kids B-LONG

In Kids B-LONG, researchers tested eftrenonacog alfa in 30 previously treated children younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Children who received eftrenonacog alfa prophylactically had an overall median ABR of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of eftrenonacog alfa.

None of the patients developed inhibitors. Researchers said there were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events.

None of the patients discontinued the study due to an adverse event. One adverse event—decreased appetite occurring in 1 patient—was considered related to eftrenonacog alfa.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the B-LONG study.

Eftrenonacog alfa

Photo courtesy of Biogen

The Swiss Agency for Therapeutic Products, Swissmedic, has approved eftrenonacog alfa (Alprolix®) for the treatment of hemophilia B.

Eftrenonacog alfa is a recombinant factor IX Fc fusion protein indicated for both on-demand treatment and prophylaxis in previously treated patients with hemophilia B.

For prophylaxis, 1 dose of eftrenonacog alfa can be given every 7 days or every 10 days, with the ability to adjust the dosing interval based on individual response.

Eftrenonacog alfa is the only recombinant factor IX Fc fusion protein therapy approved in Switzerland for the treatment of hemophilia B.

“The Swiss approval of Alprolix is an important milestone for the hemophilia community, offering the opportunity for people with hemophilia B to experience prolonged protection from bleeds,” said Krassimir Mitchev, MD, PhD, vice president and medical therapeutic area head of hemophilia at Sobi, the company developing eftrenonacog alfa in collaboration with Biogen.

“We will now focus on ensuring timely and sustainable access to Alprolix in Switzerland.”

About eftrenonacog alfa

Eftrenonacog alfa is a recombinant clotting factor therapy developed by fusing factor IX to the Fc portion of immunoglobulin G subclass 1 (IgG1). This enables eftrenonacog alfa to use a naturally occurring pathway to prolong the time the therapy remains in the body.

Eftrenonacog alfa is currently approved for the treatment of hemophilia B in the European Economic Area, the US, Canada, Japan, Australia, New Zealand, and other countries.

Sobi and Biogen collaborate on the development and commercialization of eftrenonacog alfa.

The product has been evaluated in two phase 3 trials of patients with hemophilia B: the B-LONG study and the Kids B-LONG study.

B-LONG study

The B-LONG study included 123 male subjects with severe hemophilia B who were 12 years of age or older. They had no current or previous factor IX inhibitors and a history of 100 or more documented prior exposure days to factor IX products.

Patients received eftrenonacog alfa in 1 of 4 treatment arms:

1. Weekly prophylaxis starting at 50 IU/kg, with pharmacokinetic (PK)-driven dose adjustments (n=63)
2. Individualized interval prophylaxis starting at 100 IU/kg every 10 days, with PK-driven interval adjustments (n=29)
3. On-demand treatment at 20 IU/kg to 100 IU/kg (n=27)
4. Perioperative management (n=12, including 8 from arms 1-3).

Researchers assessed control of bleeding in all patients who experienced

a bleeding episode while on study. In total, 90.4% of bleeding episodes

were controlled by a single injection of eftrenonacog alfa.

The overall median annualized bleeding rates (ABRs)—including spontaneous and traumatic bleeds—were 2.95 in the weekly prophylaxis arm, 1.38 in the individualized interval prophylaxis arm, and 17.69 in the episodic treatment arm.

The perioperative management arm consisted of 12 patients undergoing 14 major surgical procedures. The treating physicians rated the hemostatic efficacy of eftrenonacog alfa as “excellent” or “good” in all surgeries.

Eftrenonacog alfa was considered generally well-tolerated. None of the patients developed inhibitors, and none reported anaphylaxis.

The most common adverse events—with an incidence of 5% or greater—occurring outside of the perioperative management arm were nasopharyngitis, influenza, arthralgia, upper respiratory infection, hypertension, and headache.

One serious adverse event may have been drug-related. The patient experienced obstructive uropathy in the setting of hematuria. However, he continued to receive eftrenonacog alfa, and the event resolved with medical management.

Kids B-LONG

In Kids B-LONG, researchers tested eftrenonacog alfa in 30 previously treated children younger than 12 who had severe hemophilia B. Patients had at least 50 prior exposure days to factor IX therapies.

Children who received eftrenonacog alfa prophylactically had an overall median ABR of 1.97. The median ABR for spontaneous joint bleeds was 0.

Approximately 33% of patients did not experience any bleeding episodes. About 92% of bleeding episodes were controlled by 1 or 2 injections of eftrenonacog alfa.

None of the patients developed inhibitors. Researchers said there were no treatment-related serious adverse events and no cases of serious allergic reactions or vascular thrombotic events.

None of the patients discontinued the study due to an adverse event. One adverse event—decreased appetite occurring in 1 patient—was considered related to eftrenonacog alfa.

The pattern of treatment-emergent adverse events in this study was generally consistent with results seen in adolescents and adults in the B-LONG study.

Micrograph showing sickled

and normal red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending that LJPC-401 receive orphan designation as a treatment for patients with sickle cell disease (SCD).

LJPC-401 is a formulation of synthetic human hepcidin.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload, which can occur in SCD and other diseases.

LJPC-401 already has orphan designation in the European Union as a treatment for patients with beta-thalassemia intermedia and major.

La Jolla recently reported positive results from a phase 1 study of LJPC-401 in patients at risk of iron overload suffering from hereditary hemochromatosis, thalassemia, or SCD. Fifteen patients received LJPC-401 at escalating dose levels ranging from 1 mg to 20 mg.

The researchers observed a dose-dependent, statistically significant reduction in serum iron (P=0.008 for dose response; not adjusted for multiple comparisons).

At the 20 mg dose level, LJPC-401 reduced serum iron by an average of 58.1% from baseline to hour 8 (P=0.001; not adjusted for potential regression to the mean effect), and serum iron had not returned to baseline through day 7 (21.2% reduction from baseline to the end of day 7).

The researchers also said LJPC-401 was well tolerated, with no dose-limiting toxicities. Injection-site reactions were the most commonly reported adverse event. These were all mild or moderate in severity, self-limiting, and fully resolved.

Now, La Jolla is working to initiate a pivotal study of LJPC-401. This will be a randomized, controlled, multicenter study in beta-thalassemia patients suffering from iron overload. La Jolla plans to initiate this study in mid-2017.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

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

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

Micrograph showing sickled

and normal red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending that LJPC-401 receive orphan designation as a treatment for patients with sickle cell disease (SCD).

LJPC-401 is a formulation of synthetic human hepcidin.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload, which can occur in SCD and other diseases.

LJPC-401 already has orphan designation in the European Union as a treatment for patients with beta-thalassemia intermedia and major.

La Jolla recently reported positive results from a phase 1 study of LJPC-401 in patients at risk of iron overload suffering from hereditary hemochromatosis, thalassemia, or SCD. Fifteen patients received LJPC-401 at escalating dose levels ranging from 1 mg to 20 mg.

The researchers observed a dose-dependent, statistically significant reduction in serum iron (P=0.008 for dose response; not adjusted for multiple comparisons).

At the 20 mg dose level, LJPC-401 reduced serum iron by an average of 58.1% from baseline to hour 8 (P=0.001; not adjusted for potential regression to the mean effect), and serum iron had not returned to baseline through day 7 (21.2% reduction from baseline to the end of day 7).

The researchers also said LJPC-401 was well tolerated, with no dose-limiting toxicities. Injection-site reactions were the most commonly reported adverse event. These were all mild or moderate in severity, self-limiting, and fully resolved.

Now, La Jolla is working to initiate a pivotal study of LJPC-401. This will be a randomized, controlled, multicenter study in beta-thalassemia patients suffering from iron overload. La Jolla plans to initiate this study in mid-2017.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

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

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

Micrograph showing sickled

and normal red blood cells

Image by Graham Beards

The European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending that LJPC-401 receive orphan designation as a treatment for patients with sickle cell disease (SCD).

LJPC-401 is a formulation of synthetic human hepcidin.

La Jolla Pharmaceutical Company is developing LJPC-401 for the treatment of iron overload, which can occur in SCD and other diseases.

LJPC-401 already has orphan designation in the European Union as a treatment for patients with beta-thalassemia intermedia and major.

La Jolla recently reported positive results from a phase 1 study of LJPC-401 in patients at risk of iron overload suffering from hereditary hemochromatosis, thalassemia, or SCD. Fifteen patients received LJPC-401 at escalating dose levels ranging from 1 mg to 20 mg.

The researchers observed a dose-dependent, statistically significant reduction in serum iron (P=0.008 for dose response; not adjusted for multiple comparisons).

At the 20 mg dose level, LJPC-401 reduced serum iron by an average of 58.1% from baseline to hour 8 (P=0.001; not adjusted for potential regression to the mean effect), and serum iron had not returned to baseline through day 7 (21.2% reduction from baseline to the end of day 7).

The researchers also said LJPC-401 was well tolerated, with no dose-limiting toxicities. Injection-site reactions were the most commonly reported adverse event. These were all mild or moderate in severity, self-limiting, and fully resolved.

Now, La Jolla is working to initiate a pivotal study of LJPC-401. This will be a randomized, controlled, multicenter study in beta-thalassemia patients suffering from iron overload. La Jolla plans to initiate this study in mid-2017.

About orphan designation

The EMA’s COMP adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision.

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

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

Micrograph showing CTCL

The US Food and Drug Administration (FDA) has granted orphan drug designation to TLC178 for the treatment of cutaneous T-cell lymphoma (CTCL).

TLC178 is a liposomal-encapsulated formulation of the chemotherapy drug vinorelbine, which is FDA approved to treat non-small cell lung cancer.

The goal with TLC178 is to improve the efficacy and decrease the toxicity of vinorelbine to extend the indication beyond solid tumors into lymphoma.

A proprietary technology known as NanoX™ is used to load vinorelbine into liposomes designed to target tumor-specific cell-surface epitopes, extend the circulation time of the drug, increase the concentation of drug delivered to tumor cells, and decrease side effects.

TLC178 is being developed by Taiwan Liposome Company.

The company recently received US FDA approval for its phase 1/2 study (NCT02925000) investigating TLC178 in patients with advanced cancers, including CTCL and other lymphomas.

This trial is planned for sites in Taiwan and the US. The trial will be initiated in Taiwan once approval is granted by the Taiwan FDA.

About orphan designation

The US FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CTCL

The US Food and Drug Administration (FDA) has granted orphan drug designation to TLC178 for the treatment of cutaneous T-cell lymphoma (CTCL).

TLC178 is a liposomal-encapsulated formulation of the chemotherapy drug vinorelbine, which is FDA approved to treat non-small cell lung cancer.

The goal with TLC178 is to improve the efficacy and decrease the toxicity of vinorelbine to extend the indication beyond solid tumors into lymphoma.

A proprietary technology known as NanoX™ is used to load vinorelbine into liposomes designed to target tumor-specific cell-surface epitopes, extend the circulation time of the drug, increase the concentation of drug delivered to tumor cells, and decrease side effects.

TLC178 is being developed by Taiwan Liposome Company.

The company recently received US FDA approval for its phase 1/2 study (NCT02925000) investigating TLC178 in patients with advanced cancers, including CTCL and other lymphomas.

This trial is planned for sites in Taiwan and the US. The trial will be initiated in Taiwan once approval is granted by the Taiwan FDA.

About orphan designation

The US FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CTCL

The US Food and Drug Administration (FDA) has granted orphan drug designation to TLC178 for the treatment of cutaneous T-cell lymphoma (CTCL).

TLC178 is a liposomal-encapsulated formulation of the chemotherapy drug vinorelbine, which is FDA approved to treat non-small cell lung cancer.

The goal with TLC178 is to improve the efficacy and decrease the toxicity of vinorelbine to extend the indication beyond solid tumors into lymphoma.

A proprietary technology known as NanoX™ is used to load vinorelbine into liposomes designed to target tumor-specific cell-surface epitopes, extend the circulation time of the drug, increase the concentation of drug delivered to tumor cells, and decrease side effects.

TLC178 is being developed by Taiwan Liposome Company.

The company recently received US FDA approval for its phase 1/2 study (NCT02925000) investigating TLC178 in patients with advanced cancers, including CTCL and other lymphomas.

This trial is planned for sites in Taiwan and the US. The trial will be initiated in Taiwan once approval is granted by the Taiwan FDA.

About orphan designation

The US FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Iclusig (ponatinib)

Photo from Business Wire

A pair of US legislators are questioning why ARIAD Pharmaceuticals, Inc. has increased the price of its leukemia drug Iclusig (ponatinib) by more than $80,000 over the last several years.

ARIAD raised the price of Iclusig 4 times in 2016. The drug now costs nearly $199,000 a year.

Senator Bernie Sanders (Vermont) and Congressman Elijah Cummings (Maryland) sent a letter to ARIAD last week requesting information about these price increases.

Cummings and Sanders are also investigating whether ARIAD took additional steps to boost profits by discontinuing sales of certain dosages and quantities of Iclusig in order to charge patients and insurers more in exchange for less medicine.

“These outrageous sales tactics indicate that ARIAD is more concerned with its profit than with its patients,” Sanders and Cummings wrote in the letter.

The US Food and Drug Administration (FDA) approved Iclusig in December 2012 to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

In late 2013, the FDA suspended sales and clinical trials of the drug due to reports of serious adverse events.

The FDA allowed ARIAD to resume selling Iclusig in December 2013, but only to CML/ALL patients who cannot tolerate, or whose disease is resistant to, other tyrosine kinase inhibitors.

“Despite this new evidence showing the drug posed a far greater safety risk to patients than was known when the drug came on the market, ARIAD nonetheless raised the price of Iclusig several times over the subsequent 4 years,” Sanders and Cummings wrote.

“In the interest of patients and taxpayers, we are interested in learning more about the impact that the escalating price and restrictions on product availability have had.”

ARIAD has released a statement acknowledging Cummings’ and Sanders’ letter and defending its decisions to increase the price of Iclusig.

The company said it “makes significant investments in research and development (R&D) to advance breakthrough treatments” for patients with rare cancers.

In fact, ARIAD has invested more than $1.3 billion in R&D and accumulated losses of approximately $1.4 billion, which have not been recovered. In 2015, ARIAD generated $119 million in total revenue and invested $171 million in R&D.

The company said it intends to respond to Cummings’ and Sanders’ request for information.

Iclusig (ponatinib)

Photo from Business Wire

A pair of US legislators are questioning why ARIAD Pharmaceuticals, Inc. has increased the price of its leukemia drug Iclusig (ponatinib) by more than $80,000 over the last several years.

ARIAD raised the price of Iclusig 4 times in 2016. The drug now costs nearly $199,000 a year.

Senator Bernie Sanders (Vermont) and Congressman Elijah Cummings (Maryland) sent a letter to ARIAD last week requesting information about these price increases.

Cummings and Sanders are also investigating whether ARIAD took additional steps to boost profits by discontinuing sales of certain dosages and quantities of Iclusig in order to charge patients and insurers more in exchange for less medicine.

“These outrageous sales tactics indicate that ARIAD is more concerned with its profit than with its patients,” Sanders and Cummings wrote in the letter.

The US Food and Drug Administration (FDA) approved Iclusig in December 2012 to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

In late 2013, the FDA suspended sales and clinical trials of the drug due to reports of serious adverse events.

The FDA allowed ARIAD to resume selling Iclusig in December 2013, but only to CML/ALL patients who cannot tolerate, or whose disease is resistant to, other tyrosine kinase inhibitors.

“Despite this new evidence showing the drug posed a far greater safety risk to patients than was known when the drug came on the market, ARIAD nonetheless raised the price of Iclusig several times over the subsequent 4 years,” Sanders and Cummings wrote.

“In the interest of patients and taxpayers, we are interested in learning more about the impact that the escalating price and restrictions on product availability have had.”

ARIAD has released a statement acknowledging Cummings’ and Sanders’ letter and defending its decisions to increase the price of Iclusig.

The company said it “makes significant investments in research and development (R&D) to advance breakthrough treatments” for patients with rare cancers.

In fact, ARIAD has invested more than $1.3 billion in R&D and accumulated losses of approximately $1.4 billion, which have not been recovered. In 2015, ARIAD generated $119 million in total revenue and invested $171 million in R&D.

The company said it intends to respond to Cummings’ and Sanders’ request for information.

Iclusig (ponatinib)

Photo from Business Wire

A pair of US legislators are questioning why ARIAD Pharmaceuticals, Inc. has increased the price of its leukemia drug Iclusig (ponatinib) by more than $80,000 over the last several years.

ARIAD raised the price of Iclusig 4 times in 2016. The drug now costs nearly $199,000 a year.

Senator Bernie Sanders (Vermont) and Congressman Elijah Cummings (Maryland) sent a letter to ARIAD last week requesting information about these price increases.

Cummings and Sanders are also investigating whether ARIAD took additional steps to boost profits by discontinuing sales of certain dosages and quantities of Iclusig in order to charge patients and insurers more in exchange for less medicine.

“These outrageous sales tactics indicate that ARIAD is more concerned with its profit than with its patients,” Sanders and Cummings wrote in the letter.

The US Food and Drug Administration (FDA) approved Iclusig in December 2012 to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).

In late 2013, the FDA suspended sales and clinical trials of the drug due to reports of serious adverse events.

The FDA allowed ARIAD to resume selling Iclusig in December 2013, but only to CML/ALL patients who cannot tolerate, or whose disease is resistant to, other tyrosine kinase inhibitors.

“Despite this new evidence showing the drug posed a far greater safety risk to patients than was known when the drug came on the market, ARIAD nonetheless raised the price of Iclusig several times over the subsequent 4 years,” Sanders and Cummings wrote.

“In the interest of patients and taxpayers, we are interested in learning more about the impact that the escalating price and restrictions on product availability have had.”

ARIAD has released a statement acknowledging Cummings’ and Sanders’ letter and defending its decisions to increase the price of Iclusig.

The company said it “makes significant investments in research and development (R&D) to advance breakthrough treatments” for patients with rare cancers.

In fact, ARIAD has invested more than $1.3 billion in R&D and accumulated losses of approximately $1.4 billion, which have not been recovered. In 2015, ARIAD generated $119 million in total revenue and invested $171 million in R&D.

The company said it intends to respond to Cummings’ and Sanders’ request for information.

Micrograph showing CLL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of venetoclax (Venclyxto™).

The CHMP is recommending that venetoclax receive conditional marketing authorization to treat adults with chronic lymphocytic leukemia (CLL) who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with an inhibitor of the B-cell receptor pathway.

The CHMP is also recommending the conditional authorization of venetoclax as a treatment for adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemo immunotherapy and treatment with an inhibitor of the B-cell receptor pathway.

The European Commission (EC) will review the CHMP’s opinion and is expected to make a final decision about venetoclax in late 2016.

If the EC follows the CHMP’s recommendations, venetoclax will become the first BCL-2 inhibitor approved for use in Europe. The authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, and Norway.

Conditional marketing authorization represents an expedited path for approval. The EC grants conditional marketing authorization to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.

Conditional marketing authorization is granted before pivotal registration studies of a product are completed, but the company developing the product is required to complete post-marketing studies showing that the product provides a clinical benefit.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Venetoclax is currently approved for use in Argentina, Canada, Puerto Rico, and the US. The drug is being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Phase 2 trial

Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.

Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.

At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.

Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.

At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

The incidence of serious adverse events was 55%. The most common of these were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Micrograph showing CLL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of venetoclax (Venclyxto™).

The CHMP is recommending that venetoclax receive conditional marketing authorization to treat adults with chronic lymphocytic leukemia (CLL) who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with an inhibitor of the B-cell receptor pathway.

The CHMP is also recommending the conditional authorization of venetoclax as a treatment for adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemo immunotherapy and treatment with an inhibitor of the B-cell receptor pathway.

The European Commission (EC) will review the CHMP’s opinion and is expected to make a final decision about venetoclax in late 2016.

If the EC follows the CHMP’s recommendations, venetoclax will become the first BCL-2 inhibitor approved for use in Europe. The authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, and Norway.

Conditional marketing authorization represents an expedited path for approval. The EC grants conditional marketing authorization to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.

Conditional marketing authorization is granted before pivotal registration studies of a product are completed, but the company developing the product is required to complete post-marketing studies showing that the product provides a clinical benefit.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Venetoclax is currently approved for use in Argentina, Canada, Puerto Rico, and the US. The drug is being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Phase 2 trial

Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.

Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.

At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.

Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.

At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

The incidence of serious adverse events was 55%. The most common of these were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Micrograph showing CLL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of venetoclax (Venclyxto™).

The CHMP is recommending that venetoclax receive conditional marketing authorization to treat adults with chronic lymphocytic leukemia (CLL) who have 17p deletion or TP53 mutation and are unsuitable for or have failed treatment with an inhibitor of the B-cell receptor pathway.

The CHMP is also recommending the conditional authorization of venetoclax as a treatment for adults with CLL who do not have 17p deletion or TP53 mutation but have failed both chemo immunotherapy and treatment with an inhibitor of the B-cell receptor pathway.

The European Commission (EC) will review the CHMP’s opinion and is expected to make a final decision about venetoclax in late 2016.

If the EC follows the CHMP’s recommendations, venetoclax will become the first BCL-2 inhibitor approved for use in Europe. The authorization will be valid in all member states of the European Union, as well as Iceland, Liechtenstein, and Norway.

Conditional marketing authorization represents an expedited path for approval. The EC grants conditional marketing authorization to products whose benefits are thought to outweigh their risks, products that address unmet needs, and products that are expected to provide a significant public health benefit.

Conditional marketing authorization is granted before pivotal registration studies of a product are completed, but the company developing the product is required to complete post-marketing studies showing that the product provides a clinical benefit.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Venetoclax is currently approved for use in Argentina, Canada, Puerto Rico, and the US. The drug is being evaluated in phase 3 trials for the treatment of relapsed, refractory, and previously untreated CLL.

Phase 2 trial

Results from a phase 2 trial of venetoclax in CLL (M13-982, NCT01889186) were published in The Lancet Oncology in June. The trial enrolled 107 patients with relapsed or refractory CLL and 17p deletion.

Patients received venetoclax at 400 mg once daily following a weekly ramp-up schedule for the first 5 weeks. The primary endpoint was overall response rate, as determined by an independent review committee.

At a median follow-up of 12.1 months, 85 patients had responded to treatment, for an overall response rate of 79%.

Eight patients (8%) achieved a complete response or complete response with incomplete count recovery, 3 (3%) had a near-partial response, and 74 (69%) had a partial response. Twenty-two patients (21%) did not respond.

At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival. The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%. The most frequent grade 3/4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%).

The incidence of serious adverse events was 55%. The most common of these were pyrexia (7%), autoimmune hemolytic anemia (7%), pneumonia (6%), and febrile neutropenia (5%).

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients during the ramp-up period only. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Zebrafish embryos

Image by Ian Johnston

Results of preclinical research explain the role endoglin plays in hematopoietic cell fate during embryogenesis.

Previous research showed that endoglin, a cell surface protein belonging to the TGF-beta receptor complex, is required for early hematopoietic lineage specification.

A new study shows that endoglin modulates the BMP and Wnt signaling pathways to encourage progenitor cells to develop into blood cells rather than cardiac cells.

This study was published in Nature Communications.

“During the early stages of development, cells have to make decisions very quickly,” said study author Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis.

“Fine-tuning of these early cell fate decisions can be easily disrupted by levels of key proteins within these cells. When one cell type is favored, this implies less of another. In this case, high levels of endoglin expression enhance the cell differentiation into blood cells, whereas cardiac cells are in deficit.”

Dr Perlingeiro and her colleagues made this discovery studying zebrafish and mouse models. The team wanted to pinpoint the mechanism underlying the dual function of endoglin in blood cell and cardiac cell fate.

The researchers found that endoglin is expressed in early mesoderm, and it marks both hematopoietic and cardiac progenitors.

Experiments showed that high levels of endoglin increase hematopoiesis while inhibiting cardiogenesis. And the levels of endoglin determine the activation of the BMP and Wnt signaling pathways.

With further investigation, the researchers identified JDP2, a member of the AP-1 transcription factor family, as an endoglin-dependent downstream target of Wnt signaling.

The team found that JDP2 expression is sufficient to establish blood cell fate when BMP and Wnt crosstalk is disturbed.

“The blood and heart systems are the first organs to develop in mammals, but the mechanisms regulating these earliest cell fate decisions are poorly understood,” Dr Perlingeiro said.

“By using multiple model systems, combined with specialized cell sorting technology and sequencing tools, our findings help uncover mechanisms previously unseen in the few cells engaged in these early development decisions.”

Zebrafish embryos

Image by Ian Johnston

Results of preclinical research explain the role endoglin plays in hematopoietic cell fate during embryogenesis.

Previous research showed that endoglin, a cell surface protein belonging to the TGF-beta receptor complex, is required for early hematopoietic lineage specification.

A new study shows that endoglin modulates the BMP and Wnt signaling pathways to encourage progenitor cells to develop into blood cells rather than cardiac cells.

This study was published in Nature Communications.

“During the early stages of development, cells have to make decisions very quickly,” said study author Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis.

“Fine-tuning of these early cell fate decisions can be easily disrupted by levels of key proteins within these cells. When one cell type is favored, this implies less of another. In this case, high levels of endoglin expression enhance the cell differentiation into blood cells, whereas cardiac cells are in deficit.”

Dr Perlingeiro and her colleagues made this discovery studying zebrafish and mouse models. The team wanted to pinpoint the mechanism underlying the dual function of endoglin in blood cell and cardiac cell fate.

The researchers found that endoglin is expressed in early mesoderm, and it marks both hematopoietic and cardiac progenitors.

Experiments showed that high levels of endoglin increase hematopoiesis while inhibiting cardiogenesis. And the levels of endoglin determine the activation of the BMP and Wnt signaling pathways.

With further investigation, the researchers identified JDP2, a member of the AP-1 transcription factor family, as an endoglin-dependent downstream target of Wnt signaling.

The team found that JDP2 expression is sufficient to establish blood cell fate when BMP and Wnt crosstalk is disturbed.

“The blood and heart systems are the first organs to develop in mammals, but the mechanisms regulating these earliest cell fate decisions are poorly understood,” Dr Perlingeiro said.

“By using multiple model systems, combined with specialized cell sorting technology and sequencing tools, our findings help uncover mechanisms previously unseen in the few cells engaged in these early development decisions.”

Zebrafish embryos

Image by Ian Johnston

Results of preclinical research explain the role endoglin plays in hematopoietic cell fate during embryogenesis.

Previous research showed that endoglin, a cell surface protein belonging to the TGF-beta receptor complex, is required for early hematopoietic lineage specification.

A new study shows that endoglin modulates the BMP and Wnt signaling pathways to encourage progenitor cells to develop into blood cells rather than cardiac cells.

This study was published in Nature Communications.

“During the early stages of development, cells have to make decisions very quickly,” said study author Rita Perlingeiro, PhD, of the University of Minnesota in Minneapolis.

“Fine-tuning of these early cell fate decisions can be easily disrupted by levels of key proteins within these cells. When one cell type is favored, this implies less of another. In this case, high levels of endoglin expression enhance the cell differentiation into blood cells, whereas cardiac cells are in deficit.”

Dr Perlingeiro and her colleagues made this discovery studying zebrafish and mouse models. The team wanted to pinpoint the mechanism underlying the dual function of endoglin in blood cell and cardiac cell fate.

The researchers found that endoglin is expressed in early mesoderm, and it marks both hematopoietic and cardiac progenitors.

Experiments showed that high levels of endoglin increase hematopoiesis while inhibiting cardiogenesis. And the levels of endoglin determine the activation of the BMP and Wnt signaling pathways.

With further investigation, the researchers identified JDP2, a member of the AP-1 transcription factor family, as an endoglin-dependent downstream target of Wnt signaling.

The team found that JDP2 expression is sufficient to establish blood cell fate when BMP and Wnt crosstalk is disturbed.

“The blood and heart systems are the first organs to develop in mammals, but the mechanisms regulating these earliest cell fate decisions are poorly understood,” Dr Perlingeiro said.

“By using multiple model systems, combined with specialized cell sorting technology and sequencing tools, our findings help uncover mechanisms previously unseen in the few cells engaged in these early development decisions.”