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Avapritinib yields high response rate in patients with systemic mastocytosis
ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.
that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.
Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.
The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.
This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.
The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.
Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.
The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”
More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.
A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.
Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.
ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.
that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.
Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.
The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.
This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.
The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.
Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.
The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”
More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.
A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.
Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.
ATLANTA – An oral investigational drug with specific activity against a mutation frequently found in advanced systemic mastocytosis (ASM) produced clinical responses in the majority treated patients, according to preliminary data presented at the annual meeting of the American Society of Hematology.
that included a 56% rate of complete or partial response, according to lead study author Daniel J. DeAngelo, MD, PhD, director of clinical and translational research at Dana-Farber Cancer Institute, Boston.
Currently, midostaurin, a multikinase inhibitor, is the only Food and Drug Administration–approved drug for the treatment of systemic mastocytosis. That approval, announced in April 2017, was based in part on a 17% rate of complete or partial response, Dr. DeAngelo noted at a press briefing.
The primary goal of the phase 1 trial was to evaluate the safety profile and establish a maximum-tolerated dose for once-daily oral avapritinib administration. Treatment-emergent side effects were primarily grade 1-2, according to Dr. DeAngelo. Most hematologic toxicities were mild to moderate, and the most common grade 3 nonhematologic toxicities were periorbital edema and fatigue.
This part of the phase 1 trial enrolled 18 patients with ASM, systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and mantle cell lymphoma (MCL). Efficacy of avapritinib was assessed on International Working Group criteria for response rate in myelodysplasia.
The overall response rate was 72% (13 of 18 patients saw complete response, partial response, or clinical improvement), and a 56% rate of complete and partial response (10 of 18 patients), Dr. DeAngelo said.
Avapritinib was active in all ASM subtypes evaluated, including in patients who had previously been treated with midostaurin or chemotherapy, according to the investigators.
The data on avapritinib suggests the drug “has a potent and clinically important activity in systemic mastocytosis,” he said. “It has been a wonderful success in terms of getting the majority of patients into complete and partial remissions, and so as this evolves, having better targeted agents, I think, can improve the outcome for these patients.”
More patients are being enrolled as the phase 1 study continues into the dose-expansion phase at 300 mg once daily, and 30 of 32 patients remain on treatment with median duration of 9 months, Dr. DeAngelo said.
A phase 2 study in advanced systemic mastocytosis is planned for 2018, as well as phase 1 and phase 2 studies that will include patients with indolent or smoldering disease, he added.
Avapritinib is manufactured by Blueprint Medicines, which also supported the study. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
SOURCE: DeAngelo D et al. ASH 2017 Abstract 2.
REPORTING FROM ASH 2017
Key clinical point: Avapritinib produced complete or partial responses in the majority of patients with advanced systemic mastocytosis.
Major finding: The overall response rate was 72%, including a 56% rate of complete or partial response.
Data source: Phase 1 dose-escalation study of 18 patients with advanced systemic mastocytosis.
Disclosures: The study was supported by Blueprint Medicines. Dr. DeAngelo reported disclosures from Blueprint and several other companies in the hematologic space.
Source: DeAngelo D et al. ASH 2017 Abstract 2
FDA grants drug orphan designation for AML, MDS
The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.
Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.
According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.
AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.
In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.
About orphan designation
The FDA grants orphan designation to products 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. 
The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.
Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.
According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.
AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.
In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.
About orphan designation
The FDA grants orphan designation to products 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.
The US Food and Drug Administration (FDA) has granted orphan drug designation to AMV564, a CD33/CD3 bispecific antibody, for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
AMV564 is a T-cell engager, derived from human protein sequences, that binds both CD33 and CD3 to mediate T-cell directed lysis of CD33-positive cancer cells.
Amphivena Therapeutics Inc., is currently conducting a phase 1 trial of AMV564 in relapsed or refractory AML. The company plans to launch a phase 1 trial in patients with MDS in early 2018.
According to Amphivena, AMV564 has demonstrated “potent activity” in AML patient samples, and that activity was independent of CD33 expression level, disease stage, and cytogenetic risk.
AMV564 also eliminated nearly all blasts from the bone marrow and spleen in a stringent AML patient-derived xenograft murine model.
In addition, Amphivena established a therapeutic window for AMV564 in cynomolgus monkeys, with rapid and sustained elimination of CD33-expressing cells during AMV564 dosing and rapid hematopoietic recovery following dosing.
About orphan designation
The FDA grants orphan designation to products 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.
Rigosertib produces better OS in MDS than tAML
Rigosertib has demonstrated activity and tolerability in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia transformed from MDS (tAML), according to researchers.
In a phase 1/2 study, rigosertib produced responses in a quarter of MDS/tAML patients and enabled stable disease in another quarter.
Overall survival (OS) was about a year longer for responders than for non-responders.
MDS patients were more likely to respond to rigosertib and therefore enjoyed longer OS than tAML patients.
Overall, rigosertib was considered well-tolerated. There were no treatment-related deaths, though 18% of patients experienced treatment-related serious adverse events (AEs).
Lewis Silverman, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues described these results in Leukemia Research.
The study was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
Rigosertib is an inhibitor of Ras-effector pathways that interacts with the Ras binding domains common to several signaling proteins, including Raf and PI3 kinase.
Dr Silverman and his colleagues tested intravenous rigosertib in a dose-escalation, phase 1/2 study of 22 patients. Patients had tAML (n=13), high-risk MDS (n=6), intermediate-2-risk MDS (n=2), or chronic myelomonocytic leukemia (n=1).
All patients had relapsed or were refractory to standard therapy and had no approved options for second-line therapies. The patients’ median age was 78 (range, 59-84), and 90% were male.
Patients received 3- to 7-day continuous infusions of rigosertib at doses ranging from 650 mg/m2/day to 1700 mg/m2/day in 14-day cycles.
The mean number of treatment cycles was 5.6 ± 5.8 (range, 1-23). The maximum tolerated dose of rigosertib was 1700 mg/m2/day, and the recommended phase 2 dose was 1375 mg/m2/day.
Safety
All patients had at least 1 AE. The most common AEs of any grade were fatigue (n=16, 73%), diarrhea (n=12, 55%), pyrexia (n=12, 55%), dyspnea (n=11, 50%), insomnia (n=11, 50%), anemia (n=10, 46%), constipation (n=9, 41%), nausea (n=9, 41%), cough (n=9, 41%), and decreased appetite (n=9, 41%).
The most common grade 3 or higher AEs were anemia (n=9, 41%), thrombocytopenia (n=5, 23%), pneumonia (n=5, 23%), hypoglycemia (n=4, 18%), hyponatremia (n=4, 18%), and hypophosphatemia (n=4, 18%).
Four patients (18%) had treatment-related serious AEs. This included hematuria and pollakiuria (n=1), dysuria and pollakiuria (n=1), asthenia (n=1), and dyspnea (n=1). Thirteen patients (59%) stopped treatment due to AEs.
Ten patients, who remained on study from 1 to 19 months, died within 30 days of stopping rigosertib. There were no treatment-related deaths.
Efficacy
Nineteen patients were evaluable for efficacy.
Five patients responded to treatment. Four patients with MDS had a marrow complete response, and 1 with tAML had a marrow partial response. Two of the patients with marrow complete response also had hematologic improvements.
Five patients had stable disease, 3 with MDS and 2 with tAML.
The median OS was 15.7 months for responders and 2.0 months for non-responders (P=0.0070). The median OS was 12.0 months for MDS patients and 2.0 months for tAML patients (P<0.0001).
“The publication of results from this historical study provides support of the relationship between bone marrow blast response and improvement in overall survival in this group of patients with MDS and acute myeloid leukemia for whom no FDA-approved treatments are currently available,” said Ramesh Kumar, president and chief executive officer of Onconova Therapeutics, Inc.
He added that these data are “fundamental to the rationale” of ongoing studies of rigosertib in high-risk MDS patients.
Rigosertib has demonstrated activity and tolerability in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia transformed from MDS (tAML), according to researchers.
In a phase 1/2 study, rigosertib produced responses in a quarter of MDS/tAML patients and enabled stable disease in another quarter.
Overall survival (OS) was about a year longer for responders than for non-responders.
MDS patients were more likely to respond to rigosertib and therefore enjoyed longer OS than tAML patients.
Overall, rigosertib was considered well-tolerated. There were no treatment-related deaths, though 18% of patients experienced treatment-related serious adverse events (AEs).
Lewis Silverman, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues described these results in Leukemia Research.
The study was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
Rigosertib is an inhibitor of Ras-effector pathways that interacts with the Ras binding domains common to several signaling proteins, including Raf and PI3 kinase.
Dr Silverman and his colleagues tested intravenous rigosertib in a dose-escalation, phase 1/2 study of 22 patients. Patients had tAML (n=13), high-risk MDS (n=6), intermediate-2-risk MDS (n=2), or chronic myelomonocytic leukemia (n=1).
All patients had relapsed or were refractory to standard therapy and had no approved options for second-line therapies. The patients’ median age was 78 (range, 59-84), and 90% were male.
Patients received 3- to 7-day continuous infusions of rigosertib at doses ranging from 650 mg/m2/day to 1700 mg/m2/day in 14-day cycles.
The mean number of treatment cycles was 5.6 ± 5.8 (range, 1-23). The maximum tolerated dose of rigosertib was 1700 mg/m2/day, and the recommended phase 2 dose was 1375 mg/m2/day.
Safety
All patients had at least 1 AE. The most common AEs of any grade were fatigue (n=16, 73%), diarrhea (n=12, 55%), pyrexia (n=12, 55%), dyspnea (n=11, 50%), insomnia (n=11, 50%), anemia (n=10, 46%), constipation (n=9, 41%), nausea (n=9, 41%), cough (n=9, 41%), and decreased appetite (n=9, 41%).
The most common grade 3 or higher AEs were anemia (n=9, 41%), thrombocytopenia (n=5, 23%), pneumonia (n=5, 23%), hypoglycemia (n=4, 18%), hyponatremia (n=4, 18%), and hypophosphatemia (n=4, 18%).
Four patients (18%) had treatment-related serious AEs. This included hematuria and pollakiuria (n=1), dysuria and pollakiuria (n=1), asthenia (n=1), and dyspnea (n=1). Thirteen patients (59%) stopped treatment due to AEs.
Ten patients, who remained on study from 1 to 19 months, died within 30 days of stopping rigosertib. There were no treatment-related deaths.
Efficacy
Nineteen patients were evaluable for efficacy.
Five patients responded to treatment. Four patients with MDS had a marrow complete response, and 1 with tAML had a marrow partial response. Two of the patients with marrow complete response also had hematologic improvements.
Five patients had stable disease, 3 with MDS and 2 with tAML.
The median OS was 15.7 months for responders and 2.0 months for non-responders (P=0.0070). The median OS was 12.0 months for MDS patients and 2.0 months for tAML patients (P<0.0001).
“The publication of results from this historical study provides support of the relationship between bone marrow blast response and improvement in overall survival in this group of patients with MDS and acute myeloid leukemia for whom no FDA-approved treatments are currently available,” said Ramesh Kumar, president and chief executive officer of Onconova Therapeutics, Inc.
He added that these data are “fundamental to the rationale” of ongoing studies of rigosertib in high-risk MDS patients.
Rigosertib has demonstrated activity and tolerability in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia transformed from MDS (tAML), according to researchers.
In a phase 1/2 study, rigosertib produced responses in a quarter of MDS/tAML patients and enabled stable disease in another quarter.
Overall survival (OS) was about a year longer for responders than for non-responders.
MDS patients were more likely to respond to rigosertib and therefore enjoyed longer OS than tAML patients.
Overall, rigosertib was considered well-tolerated. There were no treatment-related deaths, though 18% of patients experienced treatment-related serious adverse events (AEs).
Lewis Silverman, MD, of Icahn School of Medicine at Mount Sinai in New York, New York, and his colleagues described these results in Leukemia Research.
The study was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.
Rigosertib is an inhibitor of Ras-effector pathways that interacts with the Ras binding domains common to several signaling proteins, including Raf and PI3 kinase.
Dr Silverman and his colleagues tested intravenous rigosertib in a dose-escalation, phase 1/2 study of 22 patients. Patients had tAML (n=13), high-risk MDS (n=6), intermediate-2-risk MDS (n=2), or chronic myelomonocytic leukemia (n=1).
All patients had relapsed or were refractory to standard therapy and had no approved options for second-line therapies. The patients’ median age was 78 (range, 59-84), and 90% were male.
Patients received 3- to 7-day continuous infusions of rigosertib at doses ranging from 650 mg/m2/day to 1700 mg/m2/day in 14-day cycles.
The mean number of treatment cycles was 5.6 ± 5.8 (range, 1-23). The maximum tolerated dose of rigosertib was 1700 mg/m2/day, and the recommended phase 2 dose was 1375 mg/m2/day.
Safety
All patients had at least 1 AE. The most common AEs of any grade were fatigue (n=16, 73%), diarrhea (n=12, 55%), pyrexia (n=12, 55%), dyspnea (n=11, 50%), insomnia (n=11, 50%), anemia (n=10, 46%), constipation (n=9, 41%), nausea (n=9, 41%), cough (n=9, 41%), and decreased appetite (n=9, 41%).
The most common grade 3 or higher AEs were anemia (n=9, 41%), thrombocytopenia (n=5, 23%), pneumonia (n=5, 23%), hypoglycemia (n=4, 18%), hyponatremia (n=4, 18%), and hypophosphatemia (n=4, 18%).
Four patients (18%) had treatment-related serious AEs. This included hematuria and pollakiuria (n=1), dysuria and pollakiuria (n=1), asthenia (n=1), and dyspnea (n=1). Thirteen patients (59%) stopped treatment due to AEs.
Ten patients, who remained on study from 1 to 19 months, died within 30 days of stopping rigosertib. There were no treatment-related deaths.
Efficacy
Nineteen patients were evaluable for efficacy.
Five patients responded to treatment. Four patients with MDS had a marrow complete response, and 1 with tAML had a marrow partial response. Two of the patients with marrow complete response also had hematologic improvements.
Five patients had stable disease, 3 with MDS and 2 with tAML.
The median OS was 15.7 months for responders and 2.0 months for non-responders (P=0.0070). The median OS was 12.0 months for MDS patients and 2.0 months for tAML patients (P<0.0001).
“The publication of results from this historical study provides support of the relationship between bone marrow blast response and improvement in overall survival in this group of patients with MDS and acute myeloid leukemia for whom no FDA-approved treatments are currently available,” said Ramesh Kumar, president and chief executive officer of Onconova Therapeutics, Inc.
He added that these data are “fundamental to the rationale” of ongoing studies of rigosertib in high-risk MDS patients.
Generic azacitidine approved in Canada
Health Canada has approved Dr. Reddy’s Laboratories Ltd.’s Azacitidine for Injection 100 mg/vial, a bioequivalent generic version of VIDAZA® (azacitidine for injection).
The generic drug is approved for the same indications as VIDAZA®.
This includes treating adults with intermediate-2 or high-risk myelodysplastic syndromes (according to the International Prognostic Scoring System) who are not eligible for hematopoietic stem cell transplant.
It also includes treating adults who have acute myeloid leukemia with 20% to 30% blasts and multi-lineage dysplasia (according to World Health Organization classification) who are not eligible for hematopoietic stem cell transplant.
“The approval and launch of Azacitidine for Injection is an important milestone for Dr. Reddy’s in Canada,” said Vinod Ramachandran, PhD, country manager, Dr. Reddy’s Canada.
“The launch of the first generic azacitidine for injection is another step in our long-term commitment to bring more cost-effective options to Canadian patients.”
Health Canada has approved Dr. Reddy’s Laboratories Ltd.’s Azacitidine for Injection 100 mg/vial, a bioequivalent generic version of VIDAZA® (azacitidine for injection).
The generic drug is approved for the same indications as VIDAZA®.
This includes treating adults with intermediate-2 or high-risk myelodysplastic syndromes (according to the International Prognostic Scoring System) who are not eligible for hematopoietic stem cell transplant.
It also includes treating adults who have acute myeloid leukemia with 20% to 30% blasts and multi-lineage dysplasia (according to World Health Organization classification) who are not eligible for hematopoietic stem cell transplant.
“The approval and launch of Azacitidine for Injection is an important milestone for Dr. Reddy’s in Canada,” said Vinod Ramachandran, PhD, country manager, Dr. Reddy’s Canada.
“The launch of the first generic azacitidine for injection is another step in our long-term commitment to bring more cost-effective options to Canadian patients.”
Health Canada has approved Dr. Reddy’s Laboratories Ltd.’s Azacitidine for Injection 100 mg/vial, a bioequivalent generic version of VIDAZA® (azacitidine for injection).
The generic drug is approved for the same indications as VIDAZA®.
This includes treating adults with intermediate-2 or high-risk myelodysplastic syndromes (according to the International Prognostic Scoring System) who are not eligible for hematopoietic stem cell transplant.
It also includes treating adults who have acute myeloid leukemia with 20% to 30% blasts and multi-lineage dysplasia (according to World Health Organization classification) who are not eligible for hematopoietic stem cell transplant.
“The approval and launch of Azacitidine for Injection is an important milestone for Dr. Reddy’s in Canada,” said Vinod Ramachandran, PhD, country manager, Dr. Reddy’s Canada.
“The launch of the first generic azacitidine for injection is another step in our long-term commitment to bring more cost-effective options to Canadian patients.”
FDA approves first Erdheim-Chester disease treatment
The kinase inhibitor – marketed as Zelboraf – was approved on Nov. 6. It is the first approved treatment for ECD and is already on the market as a treatment for patients with unresectable or metastatic melanoma with BRAF V600E mutation.
The FDA expedited approval of the drug under the Priority Review and Breakthrough Therapy programs. The drug also received an orphan status designation, which makes the sponsor eligible for incentives such as tax credits for clinical testing.
The agency based its approval on results from 22 patients with BRAF-V600-mutation positive ECD. Half of the patients (11) experienced a partial reduction in tumor size and 1 patient experienced a complete response, according to the FDA. Initial results from the phase 2, open-label VE-BASKET study were published in 2015 (N Engl J Med. 2015 Aug 20;373[8]:726-36).
Common side effects of vemurafenib include arthralgias, maculopapular rash, alopecia, fatigue, prolonged QT interval, and papilloma. Severe side effects include development of new cancers, growth of tumors in patients with BRAF wild-type melanoma, anaphylaxis and DRESS syndrome, severe skin reactions, heart abnormalities, hepatotoxicity, photosensitivity, uveitis, radiation sensitization and radiation recall, and Dupuytren’s contracture and plantar fascial fibromatosis. The drug is also considered teratogenic and women should be advised to use contraception while taking it, according to the FDA.
The full prescribing information is available at zelboraf.com.
[email protected]
On Twitter @maryellenny
The kinase inhibitor – marketed as Zelboraf – was approved on Nov. 6. It is the first approved treatment for ECD and is already on the market as a treatment for patients with unresectable or metastatic melanoma with BRAF V600E mutation.
The FDA expedited approval of the drug under the Priority Review and Breakthrough Therapy programs. The drug also received an orphan status designation, which makes the sponsor eligible for incentives such as tax credits for clinical testing.
The agency based its approval on results from 22 patients with BRAF-V600-mutation positive ECD. Half of the patients (11) experienced a partial reduction in tumor size and 1 patient experienced a complete response, according to the FDA. Initial results from the phase 2, open-label VE-BASKET study were published in 2015 (N Engl J Med. 2015 Aug 20;373[8]:726-36).
Common side effects of vemurafenib include arthralgias, maculopapular rash, alopecia, fatigue, prolonged QT interval, and papilloma. Severe side effects include development of new cancers, growth of tumors in patients with BRAF wild-type melanoma, anaphylaxis and DRESS syndrome, severe skin reactions, heart abnormalities, hepatotoxicity, photosensitivity, uveitis, radiation sensitization and radiation recall, and Dupuytren’s contracture and plantar fascial fibromatosis. The drug is also considered teratogenic and women should be advised to use contraception while taking it, according to the FDA.
The full prescribing information is available at zelboraf.com.
[email protected]
On Twitter @maryellenny
The kinase inhibitor – marketed as Zelboraf – was approved on Nov. 6. It is the first approved treatment for ECD and is already on the market as a treatment for patients with unresectable or metastatic melanoma with BRAF V600E mutation.
The FDA expedited approval of the drug under the Priority Review and Breakthrough Therapy programs. The drug also received an orphan status designation, which makes the sponsor eligible for incentives such as tax credits for clinical testing.
The agency based its approval on results from 22 patients with BRAF-V600-mutation positive ECD. Half of the patients (11) experienced a partial reduction in tumor size and 1 patient experienced a complete response, according to the FDA. Initial results from the phase 2, open-label VE-BASKET study were published in 2015 (N Engl J Med. 2015 Aug 20;373[8]:726-36).
Common side effects of vemurafenib include arthralgias, maculopapular rash, alopecia, fatigue, prolonged QT interval, and papilloma. Severe side effects include development of new cancers, growth of tumors in patients with BRAF wild-type melanoma, anaphylaxis and DRESS syndrome, severe skin reactions, heart abnormalities, hepatotoxicity, photosensitivity, uveitis, radiation sensitization and radiation recall, and Dupuytren’s contracture and plantar fascial fibromatosis. The drug is also considered teratogenic and women should be advised to use contraception while taking it, according to the FDA.
The full prescribing information is available at zelboraf.com.
[email protected]
On Twitter @maryellenny
Drug receives fast track designation for lower-risk MDS
The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.
The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).
Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.
Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.
Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.
Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.
The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.
As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.
Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.
The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).
Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.
Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.
Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.
Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.
The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.
As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.
Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
The US Food and Drug Administration (FDA) has granted fast track designation to the telomerase inhibitor imetelstat.
The designation is for imetelstat as a potential treatment for adults who have transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS), do not have 5q deletion, and are refractory or resistant to treatment with an erythropoiesis-stimulating agent (ESA).
Imetelstat was initially developed by Geron Corporation and exclusively licensed to Janssen Biotech, Inc.
Janssen sponsored the application for fast track designation using preliminary data from IMerge, a trial in which researchers are studying transfusion-dependent patients with low- or intermediate-1 risk MDS who have relapsed after or are refractory to treatment with an ESA.
Part 1 of IMerge is a phase 2, single-arm trial. Part 2 is a phase 3, randomized, placebo-controlled trial.
Thirty-two patients have been enrolled in part 1 of IMerge. However, this part of the trial is expanding to enroll approximately 20 additional patients who do not have 5q deletion and are naïve to treatment with a hypomethylating agent and lenalidomide.
The expansion is based on results observed in a subset of the original 32 patients who had not received prior treatment with a hypomethylating agent or lenalidomide and did not have 5q deletion.
As of May 2017, this 13-patient subset showed an increased durability and rate of red blood cell transfusion-independence compared to the overall trial population.
Results in these patients and the rest of the original 32 patients are expected to be presented at an upcoming medical conference.
About fast track designation
The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.
Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.
Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.
ATLG fights GVHD but reduces PFS, OS
Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.
In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.
However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.
On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.
These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.
The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.
Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.
In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).
Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m2 on day 1, then 10 mg/m2 on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.
Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:
- Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
- Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
- Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.
Overall results
Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).
However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).
In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).
In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).
Role of conditioning, ALC
The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.
For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).
For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).
For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).
The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 109/L, compared to less than 35% of patients who received busulfan-based conditioning.
ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 109/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.
ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.
Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.
In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.
However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.
On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.
These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.
The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.
Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.
In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).
Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m2 on day 1, then 10 mg/m2 on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.
Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:
- Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
- Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
- Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.
Overall results
Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).
However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).
In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).
In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).
Role of conditioning, ALC
The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.
For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).
For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).
For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).
The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 109/L, compared to less than 35% of patients who received busulfan-based conditioning.
ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 109/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.
ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.
Results of a phase 3 trial suggest rabbit anti-T lymphocyte globulin (ATLG) can reduce graft-versus-host disease (GVHD) but also decrease survival in patients who have received a hematopoietic stem cell transplant (HSCT) from a matched, unrelated donor.
In this randomized trial, ATLG significantly decreased the incidence of moderate-to-severe chronic GVHD and acute grade 2-4 GVHD, when compared to placebo.
However, patients who received ATLG also had significantly lower progression-free survival (PFS) and overall survival (OS) than placebo-treated patients.
On the other hand, the data also suggest that patients who receive conditioning regimens that do not lower absolute lymphocyte counts (ALCs) substantially may not experience a significant decrease in survival with ATLG.
These results were published in the Journal of Clinical Oncology. The study was sponsored by Neovii Pharmaceuticals AG, which is developing ATLG as Grafalon®.
The study was a prospective, randomized, double-blind trial conducted in North America and Australia (NCT01295710). It enrolled 254 patients, ages 18 to 65, who had acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndromes. All patients were undergoing myeloablative, HLA-matched, unrelated HSCT.
Patients were randomized in a 1:1 fashion to receive ATLG (given at 20 mg/kg/day, n=126) or placebo (250 ml of normal saline, n=128) on days -3, -2, and -1 prior to HSCT.
In addition, all patients received antihistamine and methylprednisolone (at 2 mg/kg on day -3 and 1 mg/kg on days -2 and -1).
Patients also received GVHD prophylaxis in the form of tacrolimus (with a target serum trough level of 5 to 15 ng/mL) and methotrexate (15 mg/m2 on day 1, then 10 mg/m2 on days 3, 6, and 11). If patients did not develop clinical GVHD, tacrolimus was tapered starting on day 50 or later over a minimum of 26 weeks and ultimately discontinued.
Patients received 1 of 3 conditioning regimens, which were declared prior to randomization and included:
- Cyclophosphamide at 120 mg/kg intravenously (IV) and fractionated total body irradiation (TBI, ≥12 Gy)
- Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and cyclophosphamide at 120 mg/kg IV
- Busulfan at 16 mg/kg orally or 12.8 mg/kg IV and fludarabine at 120 mg/m2 IV.
Overall results
Compared to placebo-treated patients, those who received ATLG had a significant reduction in grade 2-4 acute GVHD—23% and 40%, respectively (P=0.004)—and moderate-to-severe chronic GVHD—12% and 33%, respectively (P<0.001).
However, there was no significant difference between the ATLG and placebo arms with regard to moderate-severe chronic GVHD-free survival. The 2-year estimate was 48% and 44%, respectively (P=0.47).
In addition, PFS and OS were significantly lower in patients who received ATLG. The estimated 2-year PFS was 47% in the ATLG arm and 65% in the placebo arm (P=0.04). The estimated 2-year OS was 59% and 74%, respectively (P=0.034).
In a multivariable analysis, ATLG remained significantly associated with inferior PFS (hazard ratio [HR]=1.55, P=0.026) and OS (hazard ratio=1.74, P=0.01).
Role of conditioning, ALC
The researchers found evidence to suggest that conditioning regimen and ALC played a role in patient outcomes.
For patients who received cyclophosphamide and TBI, 2-year moderate-severe chronic GVHD-free survival was 61% in the placebo arm and 38% in the ATLG arm (P=0.080). Two-year OS was 88% and 48%, respectively (P=0.006). And 2-year PFS was 75% and 29%, respectively (P=0.007).
For patients who received busulfan and cyclophosphamide, 2-year moderate-severe chronic GVHD-free survival was 47% in the placebo arm and 53% in the ATLG arm (P=0.650). Two-year OS was 77% and 71%, respectively (P=0.350). And 2-year PFS was 73% and 60%, respectively (P=0.460).
For patients who received busulfan and fludarabine, 2-year moderate-severe chronic GVHD-free survival was 33% in the placebo arm and 49% in the ATLG arm (P=0.047). Two-year OS was 66% and 53%, respectively (P=0.520). And 2-year PFS was 58% and 48%, respectively (P=0.540).
The researchers noted that the choice of conditioning regimen had a “profound effect” on ALC at day -3 (the time of ATLG/placebo initiation). More than 70% of patients who received TBI had an ALC <0.1 x 109/L, compared to less than 35% of patients who received busulfan-based conditioning.
ALC, in turn, had an impact on PFS and OS. In patients with an ALC ≥ 0.1 x 109/L on day -3, ATLG did not compromise PFS or OS, but PFS and OS were negatively affected in patients with an ALC < 0.1.
ATLG recipients with an ALC < 0.1 had significantly worse OS (HR=4.13, P<0.001) and PFS (HR=3.19, P<0.001) than patients with an ALC ≥ 0.1.
Drug receives orphan designation for treatment of MDS
The European Commission has granted orphan designation to asunercept (APG101) for the treatment of myelodysplastic syndromes (MDS).
Asunercept is a fully human fusion protein that consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG1 antibody.
Asunercept binds to the CD95 ligand and blocks activation of the CD95 receptor.
Excessive stimulation of the CD95 receptor on hematopoietic precursors inhibits erythropoiesis in MDS patients.
As a result, the patients develop transfusion-dependent anemia that is refractory to erythropoiesis-stimulating agents (ESAs).
Treatment with asunercept, by inhibiting the CD95 system, stimulates the production of red blood cells and decreases transfusion dependency.
Asunercept has been evaluated in a phase 1 trial, the results of which were presented at the 2016 ASH Annual Meeting.
The trial enrolled 20 patients with low- to intermediate-risk MDS. All patients had anemia resulting in a high transfusion burden, had hemoglobin levels of less than 10 g/dL, and were refractory to ESAs.
Patients received once-weekly asunercept infusions for 12 weeks. Eight of the 20 patients (40%) experienced a reduction in transfusion frequency for 6 months.
Asunercept was considered generally well tolerated, with no grade 3 or higher treatment-related adverse events reported. The most common treatment-emergent adverse events were peripheral edema (n=6), urinary tract infection (n=4), and oral herpes (n=3).
One patient developed acute myeloid leukemia, and 1 patient died from sepsis due to pre-existing neutropenia.
“We are highly encouraged by the data from our clinical phase 1 trial with asunercept in these patients and are currently preparing to initiate a clinical phase 2 proof-of-concept trial to further evaluate the efficacy of asunercept in MDS,” said Harald Fricke, chief medical officer of Apogenix AG, the company developing asunercept.
About orphan designation
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 European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Commission has granted orphan designation to asunercept (APG101) for the treatment of myelodysplastic syndromes (MDS).
Asunercept is a fully human fusion protein that consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG1 antibody.
Asunercept binds to the CD95 ligand and blocks activation of the CD95 receptor.
Excessive stimulation of the CD95 receptor on hematopoietic precursors inhibits erythropoiesis in MDS patients.
As a result, the patients develop transfusion-dependent anemia that is refractory to erythropoiesis-stimulating agents (ESAs).
Treatment with asunercept, by inhibiting the CD95 system, stimulates the production of red blood cells and decreases transfusion dependency.
Asunercept has been evaluated in a phase 1 trial, the results of which were presented at the 2016 ASH Annual Meeting.
The trial enrolled 20 patients with low- to intermediate-risk MDS. All patients had anemia resulting in a high transfusion burden, had hemoglobin levels of less than 10 g/dL, and were refractory to ESAs.
Patients received once-weekly asunercept infusions for 12 weeks. Eight of the 20 patients (40%) experienced a reduction in transfusion frequency for 6 months.
Asunercept was considered generally well tolerated, with no grade 3 or higher treatment-related adverse events reported. The most common treatment-emergent adverse events were peripheral edema (n=6), urinary tract infection (n=4), and oral herpes (n=3).
One patient developed acute myeloid leukemia, and 1 patient died from sepsis due to pre-existing neutropenia.
“We are highly encouraged by the data from our clinical phase 1 trial with asunercept in these patients and are currently preparing to initiate a clinical phase 2 proof-of-concept trial to further evaluate the efficacy of asunercept in MDS,” said Harald Fricke, chief medical officer of Apogenix AG, the company developing asunercept.
About orphan designation
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 European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
The European Commission has granted orphan designation to asunercept (APG101) for the treatment of myelodysplastic syndromes (MDS).
Asunercept is a fully human fusion protein that consists of the extracellular domain of the CD95 receptor and the Fc domain of an IgG1 antibody.
Asunercept binds to the CD95 ligand and blocks activation of the CD95 receptor.
Excessive stimulation of the CD95 receptor on hematopoietic precursors inhibits erythropoiesis in MDS patients.
As a result, the patients develop transfusion-dependent anemia that is refractory to erythropoiesis-stimulating agents (ESAs).
Treatment with asunercept, by inhibiting the CD95 system, stimulates the production of red blood cells and decreases transfusion dependency.
Asunercept has been evaluated in a phase 1 trial, the results of which were presented at the 2016 ASH Annual Meeting.
The trial enrolled 20 patients with low- to intermediate-risk MDS. All patients had anemia resulting in a high transfusion burden, had hemoglobin levels of less than 10 g/dL, and were refractory to ESAs.
Patients received once-weekly asunercept infusions for 12 weeks. Eight of the 20 patients (40%) experienced a reduction in transfusion frequency for 6 months.
Asunercept was considered generally well tolerated, with no grade 3 or higher treatment-related adverse events reported. The most common treatment-emergent adverse events were peripheral edema (n=6), urinary tract infection (n=4), and oral herpes (n=3).
One patient developed acute myeloid leukemia, and 1 patient died from sepsis due to pre-existing neutropenia.
“We are highly encouraged by the data from our clinical phase 1 trial with asunercept in these patients and are currently preparing to initiate a clinical phase 2 proof-of-concept trial to further evaluate the efficacy of asunercept in MDS,” said Harald Fricke, chief medical officer of Apogenix AG, the company developing asunercept.
About orphan designation
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 European Medicines Agency during the product development phase and direct access to the centralized authorization procedure.
Mutations impact outcomes in AML, MDS
Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.
The results showed no additional benefit with the combination, when compared to azacitidine alone.
However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.
“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.
“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”
Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.
Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.
To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.
The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.
Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).
In both arms, azacitidine was given at 75 mg/m2 on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.
Results
The combination did not significantly improve response rates or survival times.
The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).
The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).
The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).
Impact of mutations
In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).
In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.
The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.
The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.
And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.
The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.
The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.
Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.
The results showed no additional benefit with the combination, when compared to azacitidine alone.
However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.
“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.
“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”
Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.
Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.
To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.
The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.
Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).
In both arms, azacitidine was given at 75 mg/m2 on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.
Results
The combination did not significantly improve response rates or survival times.
The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).
The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).
The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).
Impact of mutations
In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).
In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.
The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.
The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.
And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.
The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.
The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.
Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.
The results showed no additional benefit with the combination, when compared to azacitidine alone.
However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.
“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.
“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”
Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.
Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.
To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.
The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.
Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).
In both arms, azacitidine was given at 75 mg/m2 on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.
Results
The combination did not significantly improve response rates or survival times.
The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).
The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).
The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).
Impact of mutations
In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).
In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.
The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.
The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.
And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.
The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.
The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.
FDA grants RMAT designation to HSCT adjunct
The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).
ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.
Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.
Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.
The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.
About RMAT designation
The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.
Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.
A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.
“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.
“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”
ATIR101 trials
Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.
Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.
None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.
A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.
The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.
The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).
ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.
Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.
Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.
The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.
About RMAT designation
The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.
Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.
A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.
“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.
“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”
ATIR101 trials
Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.
Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.
None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.
A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.
The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.
The US Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation to ATIR101™, which is intended to be used as an adjunct to haploidentical hematopoietic stem cell transplant (HSCT).
ATIR101 is a personalized T-cell immunotherapy—a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.
Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with TH9402 (a rhodamide-like dye), which is selectively retained in activated T cells.
Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.
The final product is infused after CD34-selected haploidentical HSCT with the goal of preventing infectious complications, graft-versus-host disease (GVHD), and relapse.
About RMAT designation
The RMAT pathway is analogous to the breakthrough therapy designation designed for traditional drug candidates and medical devices. RMAT designation was specifically created by the US Congress in 2016 in the hopes of getting new cell therapies and advanced medicinal products to patients earlier.
Just like breakthrough designation, RMAT designation allows companies developing regenerative medicine therapies to interact with the FDA more frequently in the clinical testing process. In addition, RMAT-designated products may be eligible for priority review and accelerated approval.
A regenerative medicine is eligible for RMAT designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and if preliminary clinical evidence indicates the treatment has the potential to address unmet medical needs for such a disease or condition.
“To receive the RMAT designation from the FDA is an important milestone for Kiadis Pharma and a recognition by the FDA of the significant potential for ATIR101 to help patients receive safer and more effective bone marrow transplantations,” said Arthur Lahr, CEO of Kiadis Pharma, the company developing ATIR101.
“We are now going to work even closer with the FDA to agree a path to make this cell therapy treatment available for patients in the US as soon as possible. In Europe, ATIR101 was filed for registration in April 2017, and we continue to prepare the company for the potential European launch in 2019.”
ATIR101 trials
Results of a phase 2 trial of ATIR101 were presented at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation in 2016.
Patients who received ATIR101 after haploidentical HSCT had significant improvements in transplant-related mortality and overall survival when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.
None of the patients who received ATIR101 developed grade 3-4 GVHD, but a few patients did develop grade 2 GVHD.
A phase 3 trial of ATIR101 is now underway. The trial is expected to enroll 200 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome.
The patients will receive a haploidentical HSCT with either a T-cell-depleted graft and adjunctive treatment with ATIR101 or a T-cell-replete graft and post-transplant cyclophosphamide.