Anemia

Lurie Children’s photographer

The gene therapy LentiGlobin can reduce or eliminate transfusion dependence in patients with β-thalassemia, according to a pair of phase 1/2 studies.

Fifteen of the 22 patients in these trials were able to discontinue red blood cell (RBC) transfusions after receiving LentiGlobin.

In the 9 patients with severe transfusion-dependent β-thalassemia (TDT), LentiGlobin reduced the transfusion volume by 73%.

There were 5 adverse events (AEs) considered possibly or probably related to LentiGlobin, all them grade 1.

“These study results exceeded our expectations, with clinical benefit for nearly all patients . . . ,” said Alexis Thompson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois.

“Since we saw such positive results, we are now enrolling patients as young as 5 years old on a phase 3 trial of gene therapy for transfusion-dependent thalassemia.”

Dr Thompson and her colleagues reported results from the phase 1/2 trials—known as HGB-204 and HGB-205—in NEJM. The studies were sponsored by Bluebird Bio, the company developing LentiGlobin.

Patients in HGB-204

HGB-204 (also known as Northstar) is a multicenter study that was recently completed. It included 18 patients with TDT. They had a median age of 20 (range, 12 to 35) at baseline, and 72% were female. Seventy-eight percent were Asian, and 22% were white.

Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 13.6 ml/kg (range, 10.4 to 21.8). The median age at which patients started regular transfusions was 3.5 years (range, 0 to 26.0). Six patients had undergone splenectomy.

Patients in HGB-205

HGB-205 is an ongoing study being conducted at a single site in France. It was designed to evaluate LentiGlobin in patients with TDT or severe sickle cell disease.

The NEJM paper includes 4 patients with TDT from this study. They had a median age of 18 (range, 16 to 19) at baseline, and half were female. Half were Asian, and the other half were white.

Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 15.2 ml/kg (range, 11.6 to 15.7). The median age at which patients started regular transfusions was 1.8 years (range, 0 to 14.0). Three patients had undergone splenectomy.

Treatment

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients.

CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA^T87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced RBC transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 AEs considered possibly or probably related to LentiGlobin. These included abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs, including 2 episodes of grade 3 veno-occlusive liver disease that were attributed to busulfan.

The remaining serious AEs were Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis (all grade 3), as well as device-related thrombosis and infectious diarrhea (both grade 2).

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin.

The 3 serious AEs were tooth infection and major depression (both grade 3), as well as pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) in HGB-204 and 23.0 days (range, 20.0 to 26.0) in HGB-205.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

At the last study visit (12 to 36 months post-treatment), the median HbA^T87Q level in these patients was 6.0 g/dL (range, 3.4 to 10.0), and the median total hemoglobin was 11.2 g/dL (range, 8.2 to 13.7).

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin infusion.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.

At their most recent study visit (12 months to 30 months), these 3 patients had median HbA^T87Q levels of 8.2 g/dL, 6.8 g/dL, and 6.6 g/dL, respectively. Their median total hemoglobin levels were 9.0 g/dL, 10.2 g/dL, and 8.3 g/dL, respectively.

For the 6 patients with a β0/β0 genotype who continued to receive RBC transfusions, the median HbA^T87Q level was 4.2 g/dL (range, 0.3 to 8.7) at the last study visit.

“There is room for improvement, as we’d like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease,” said study author Philippe Leboulch, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But there is also hope with protocol modifications we have introduced in our phase 3 trials.”

Lurie Children’s photographer

The gene therapy LentiGlobin can reduce or eliminate transfusion dependence in patients with β-thalassemia, according to a pair of phase 1/2 studies.

Fifteen of the 22 patients in these trials were able to discontinue red blood cell (RBC) transfusions after receiving LentiGlobin.

In the 9 patients with severe transfusion-dependent β-thalassemia (TDT), LentiGlobin reduced the transfusion volume by 73%.

There were 5 adverse events (AEs) considered possibly or probably related to LentiGlobin, all them grade 1.

“These study results exceeded our expectations, with clinical benefit for nearly all patients . . . ,” said Alexis Thompson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois.

“Since we saw such positive results, we are now enrolling patients as young as 5 years old on a phase 3 trial of gene therapy for transfusion-dependent thalassemia.”

Dr Thompson and her colleagues reported results from the phase 1/2 trials—known as HGB-204 and HGB-205—in NEJM. The studies were sponsored by Bluebird Bio, the company developing LentiGlobin.

Patients in HGB-204

HGB-204 (also known as Northstar) is a multicenter study that was recently completed. It included 18 patients with TDT. They had a median age of 20 (range, 12 to 35) at baseline, and 72% were female. Seventy-eight percent were Asian, and 22% were white.

Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 13.6 ml/kg (range, 10.4 to 21.8). The median age at which patients started regular transfusions was 3.5 years (range, 0 to 26.0). Six patients had undergone splenectomy.

Patients in HGB-205

HGB-205 is an ongoing study being conducted at a single site in France. It was designed to evaluate LentiGlobin in patients with TDT or severe sickle cell disease.

The NEJM paper includes 4 patients with TDT from this study. They had a median age of 18 (range, 16 to 19) at baseline, and half were female. Half were Asian, and the other half were white.

Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 15.2 ml/kg (range, 11.6 to 15.7). The median age at which patients started regular transfusions was 1.8 years (range, 0 to 14.0). Three patients had undergone splenectomy.

Treatment

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients.

CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA^T87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced RBC transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 AEs considered possibly or probably related to LentiGlobin. These included abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs, including 2 episodes of grade 3 veno-occlusive liver disease that were attributed to busulfan.

The remaining serious AEs were Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis (all grade 3), as well as device-related thrombosis and infectious diarrhea (both grade 2).

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin.

The 3 serious AEs were tooth infection and major depression (both grade 3), as well as pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) in HGB-204 and 23.0 days (range, 20.0 to 26.0) in HGB-205.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

At the last study visit (12 to 36 months post-treatment), the median HbA^T87Q level in these patients was 6.0 g/dL (range, 3.4 to 10.0), and the median total hemoglobin was 11.2 g/dL (range, 8.2 to 13.7).

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin infusion.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.

At their most recent study visit (12 months to 30 months), these 3 patients had median HbA^T87Q levels of 8.2 g/dL, 6.8 g/dL, and 6.6 g/dL, respectively. Their median total hemoglobin levels were 9.0 g/dL, 10.2 g/dL, and 8.3 g/dL, respectively.

For the 6 patients with a β0/β0 genotype who continued to receive RBC transfusions, the median HbA^T87Q level was 4.2 g/dL (range, 0.3 to 8.7) at the last study visit.

“There is room for improvement, as we’d like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease,” said study author Philippe Leboulch, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But there is also hope with protocol modifications we have introduced in our phase 3 trials.”

Lurie Children’s photographer

The gene therapy LentiGlobin can reduce or eliminate transfusion dependence in patients with β-thalassemia, according to a pair of phase 1/2 studies.

Fifteen of the 22 patients in these trials were able to discontinue red blood cell (RBC) transfusions after receiving LentiGlobin.

In the 9 patients with severe transfusion-dependent β-thalassemia (TDT), LentiGlobin reduced the transfusion volume by 73%.

There were 5 adverse events (AEs) considered possibly or probably related to LentiGlobin, all them grade 1.

“These study results exceeded our expectations, with clinical benefit for nearly all patients . . . ,” said Alexis Thompson, MD, of Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois.

“Since we saw such positive results, we are now enrolling patients as young as 5 years old on a phase 3 trial of gene therapy for transfusion-dependent thalassemia.”

Dr Thompson and her colleagues reported results from the phase 1/2 trials—known as HGB-204 and HGB-205—in NEJM. The studies were sponsored by Bluebird Bio, the company developing LentiGlobin.

Patients in HGB-204

HGB-204 (also known as Northstar) is a multicenter study that was recently completed. It included 18 patients with TDT. They had a median age of 20 (range, 12 to 35) at baseline, and 72% were female. Seventy-eight percent were Asian, and 22% were white.

Eight patients had a β0/β0 genotype, 6 had a βE/β0 genotype, and 4 had other genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 13.6 ml/kg (range, 10.4 to 21.8). The median age at which patients started regular transfusions was 3.5 years (range, 0 to 26.0). Six patients had undergone splenectomy.

Patients in HGB-205

HGB-205 is an ongoing study being conducted at a single site in France. It was designed to evaluate LentiGlobin in patients with TDT or severe sickle cell disease.

The NEJM paper includes 4 patients with TDT from this study. They had a median age of 18 (range, 16 to 19) at baseline, and half were female. Half were Asian, and the other half were white.

Three patients had a βE/β0 genotype. The remaining patient was homozygous for the IVS1-110 mutation and had a severe clinical presentation similar to that seen in β0/β0 genotypes.

The patients’ median monthly transfusion volume for 2 years before study enrollment was 15.2 ml/kg (range, 11.6 to 15.7). The median age at which patients started regular transfusions was 1.8 years (range, 0 to 14.0). Three patients had undergone splenectomy.

Treatment

For both studies, the researchers harvested hematopoietic stem and progenitor cells (mobilized with filgrastim and plerixafor) from the patients.

CD34+ cells were transduced ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA^T87Q).

The patients underwent myeloablative conditioning with busulfan, and the final LentiGlobin product was infused into patients after a 72-hour washout period.

In HGB-205 only, patients received enhanced RBC transfusions for at least 3 months before stem cell mobilization and harvest to maintain a hemoglobin level of more than 11.0 g/dL.

Safety

In HGB-204, there were 5 grade 1 AEs considered possibly or probably related to LentiGlobin. These included abdominal pain (n=2), dyspnea (n=1), hot flush (n=1), and non-cardiac chest pain (n=1).

There were 9 serious AEs, including 2 episodes of grade 3 veno-occlusive liver disease that were attributed to busulfan.

The remaining serious AEs were Klebsiella infection, cardiac ventricular thrombosis, cellulitis, hyperglycemia, and gastroenteritis (all grade 3), as well as device-related thrombosis and infectious diarrhea (both grade 2).

In HGB-205, there were no AEs considered possibly or probably related to LentiGlobin.

The 3 serious AEs were tooth infection and major depression (both grade 3), as well as pneumonia (grade 2).

Efficacy

The median time to neutrophil engraftment was 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

The median time to platelet engraftment was 39.5 days (range, 19.0 to 191.0) in HGB-204 and 23.0 days (range, 20.0 to 26.0) in HGB-205.

In both studies, the median follow-up was 26 months (range, 15 to 42) after LentiGlobin infusion.

At last follow-up, all but 1 of the 13 patients with a non-β0/β0 genotype had stopped receiving RBC transfusions.

At the last study visit (12 to 36 months post-treatment), the median HbA^T87Q level in these patients was 6.0 g/dL (range, 3.4 to 10.0), and the median total hemoglobin was 11.2 g/dL (range, 8.2 to 13.7).

In the 8 patients with a β0/β0 genotype and the 1 patient with 2 copies of the IVS1-110 mutation, the median annualized transfusion volume decreased by 73% after LentiGlobin infusion.

Two patients with a β0/β0 genotype were able to stop receiving RBC transfusions, as was the patient with 2 copies of the IVS1-110 mutation.

At their most recent study visit (12 months to 30 months), these 3 patients had median HbA^T87Q levels of 8.2 g/dL, 6.8 g/dL, and 6.6 g/dL, respectively. Their median total hemoglobin levels were 9.0 g/dL, 10.2 g/dL, and 8.3 g/dL, respectively.

For the 6 patients with a β0/β0 genotype who continued to receive RBC transfusions, the median HbA^T87Q level was 4.2 g/dL (range, 0.3 to 8.7) at the last study visit.

“There is room for improvement, as we’d like to see the elimination of dependency on transfusion even for patients with the most severe form of the disease,” said study author Philippe Leboulch, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.

“But there is also hope with protocol modifications we have introduced in our phase 3 trials.”

Red blood cells

In studying Diamond-Blackfan anemia (DBA), researchers have found evidence to suggest that ribosome levels play a key role in hematopoiesis.

The researchers found that a reduction in ribosomes is responsible for the disruption in red blood cell production observed in patients with DBA.

This reduction in ribosomes impairs the translation of certain messenger RNAs (mRNAs), which inhibits erythroid lineage commitment in hematopoietic stem and progenitor cells (HSCPs).

The researchers said this work has provided insight into how lineage commitment functions normally and in the setting of DBA.

Vijay Sankaran, MD, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues described these findings in Cell.

The team noted that most cases of DBA are caused by heterozygous loss-of-function mutations in ribosomal protein (RP) genes, which result in RP haploinsufficiency.

Past research revealed DBA-causing mutations in the transcription factor GATA1. Subsequent work showed that RP haploinsufficiency results in reduced translation of GATA1 mRNA, and increasing GATA1 protein levels can reduce the erythroid defects in DBA cells.

However, the mechanisms underlying these phenomena were unclear.

In the current study, the researchers found that DBA-associated perturbations reduced ribosome levels but did not affect the composition of ribosomes.

“There has been controversy over whether a ribosomal protein mutation changes the composition of the ribosomes or the quantity of the ribosomes,” Dr Sankaran said. “We know now that it is the latter.”

The researchers said the reduction of ribosome levels was largely promoted through reduced translation of RP mRNAs.

The team identified 525 transcripts with translation efficiencies that were downregulated by RP haploinsufficiency. They said a subset of these transcripts, including GATA1, have proven essential for hematopoietic cell growth and are upregulated during early erythropoiesis.

The researchers confirmed their prior findings that translation of GATA1 mRNA is decreased by about 2-fold in differentiating HSPCs with RP haploinsufficiency.

The team also found that GATA1 has “unique” 5’ untranslated region features that confer sensitivity to ribosome levels.

Taken together, these findings suggest the presence of GATA1 proteins in HSPCs helps prime them for erythroid lineage commitment. Without enough ribosomes to produce enough GATA1 proteins, the HSPCs never receive the signal to become red blood cells.

“This raises the question of whether we can design a gene therapy to overcome the GATA1 deficiency,” Dr Sankaran said. “We now have a tremendous interest in this approach and believe it can be done.”

Red blood cells

In studying Diamond-Blackfan anemia (DBA), researchers have found evidence to suggest that ribosome levels play a key role in hematopoiesis.

The researchers found that a reduction in ribosomes is responsible for the disruption in red blood cell production observed in patients with DBA.

This reduction in ribosomes impairs the translation of certain messenger RNAs (mRNAs), which inhibits erythroid lineage commitment in hematopoietic stem and progenitor cells (HSCPs).

The researchers said this work has provided insight into how lineage commitment functions normally and in the setting of DBA.

Vijay Sankaran, MD, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues described these findings in Cell.

The team noted that most cases of DBA are caused by heterozygous loss-of-function mutations in ribosomal protein (RP) genes, which result in RP haploinsufficiency.

Past research revealed DBA-causing mutations in the transcription factor GATA1. Subsequent work showed that RP haploinsufficiency results in reduced translation of GATA1 mRNA, and increasing GATA1 protein levels can reduce the erythroid defects in DBA cells.

However, the mechanisms underlying these phenomena were unclear.

In the current study, the researchers found that DBA-associated perturbations reduced ribosome levels but did not affect the composition of ribosomes.

“There has been controversy over whether a ribosomal protein mutation changes the composition of the ribosomes or the quantity of the ribosomes,” Dr Sankaran said. “We know now that it is the latter.”

The researchers said the reduction of ribosome levels was largely promoted through reduced translation of RP mRNAs.

The team identified 525 transcripts with translation efficiencies that were downregulated by RP haploinsufficiency. They said a subset of these transcripts, including GATA1, have proven essential for hematopoietic cell growth and are upregulated during early erythropoiesis.

The researchers confirmed their prior findings that translation of GATA1 mRNA is decreased by about 2-fold in differentiating HSPCs with RP haploinsufficiency.

The team also found that GATA1 has “unique” 5’ untranslated region features that confer sensitivity to ribosome levels.

Taken together, these findings suggest the presence of GATA1 proteins in HSPCs helps prime them for erythroid lineage commitment. Without enough ribosomes to produce enough GATA1 proteins, the HSPCs never receive the signal to become red blood cells.

“This raises the question of whether we can design a gene therapy to overcome the GATA1 deficiency,” Dr Sankaran said. “We now have a tremendous interest in this approach and believe it can be done.”

Red blood cells

In studying Diamond-Blackfan anemia (DBA), researchers have found evidence to suggest that ribosome levels play a key role in hematopoiesis.

The researchers found that a reduction in ribosomes is responsible for the disruption in red blood cell production observed in patients with DBA.

This reduction in ribosomes impairs the translation of certain messenger RNAs (mRNAs), which inhibits erythroid lineage commitment in hematopoietic stem and progenitor cells (HSCPs).

The researchers said this work has provided insight into how lineage commitment functions normally and in the setting of DBA.

Vijay Sankaran, MD, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues described these findings in Cell.

The team noted that most cases of DBA are caused by heterozygous loss-of-function mutations in ribosomal protein (RP) genes, which result in RP haploinsufficiency.

Past research revealed DBA-causing mutations in the transcription factor GATA1. Subsequent work showed that RP haploinsufficiency results in reduced translation of GATA1 mRNA, and increasing GATA1 protein levels can reduce the erythroid defects in DBA cells.

However, the mechanisms underlying these phenomena were unclear.

In the current study, the researchers found that DBA-associated perturbations reduced ribosome levels but did not affect the composition of ribosomes.

“There has been controversy over whether a ribosomal protein mutation changes the composition of the ribosomes or the quantity of the ribosomes,” Dr Sankaran said. “We know now that it is the latter.”

The researchers said the reduction of ribosome levels was largely promoted through reduced translation of RP mRNAs.

The team identified 525 transcripts with translation efficiencies that were downregulated by RP haploinsufficiency. They said a subset of these transcripts, including GATA1, have proven essential for hematopoietic cell growth and are upregulated during early erythropoiesis.

The researchers confirmed their prior findings that translation of GATA1 mRNA is decreased by about 2-fold in differentiating HSPCs with RP haploinsufficiency.

The team also found that GATA1 has “unique” 5’ untranslated region features that confer sensitivity to ribosome levels.

Taken together, these findings suggest the presence of GATA1 proteins in HSPCs helps prime them for erythroid lineage commitment. Without enough ribosomes to produce enough GATA1 proteins, the HSPCs never receive the signal to become red blood cells.

“This raises the question of whether we can design a gene therapy to overcome the GATA1 deficiency,” Dr Sankaran said. “We now have a tremendous interest in this approach and believe it can be done.”

Lab mouse

Preclinical results support clinical testing of an experimental agent in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to researchers.

The agent, ALRN-6924, was shown to combat AML and MDS by restoring activity of the tumor-suppressing protein p53.

ALRN-6924 exhibited antileukemic activity in AML cells and mouse models of the disease, as well as in a patient with MDS and excess leukemic blasts who received the drug on a compassionate-use basis.

These results, published in Science Translational Medicine, have led to a phase 1 trial of ALRN-6924 in patients with AML or MDS.

ALRN-6924 was developed by Aileron Therapeutics Inc., to target p53 by inhibiting 2 naturally occurring proteins, MDMX and MDM2. Overexpression of these proteins inactivates p53, allowing cancer cells to multiply unchecked.

In the current study, researchers set out to confirm ALRN-6924’s mechanism of action and determine the efficacy of the drug in AML/MDS. This work was supported, in part, by grants from Aileron Therapeutics Inc., and the National Institutes of Health.

The researchers did find that ALRN-6924 targets both MDMX and MDM2, blocking their interaction with p53 in AML cells.

The team said ALRN-6924 inhibited proliferation by inducing cell-cycle arrest and apoptosis in AML cell lines and AML patient cells, including leukemic stem cell-enriched populations.

“This is important because AML is driven by stem cells, and, if you don’t target stem cells, the disease will come back very quickly,” said study author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York.

The researchers also found that ALRN-6924 greatly increased survival in a mouse model of AML. The median survival was 34 days in vehicle-treated control mice, 83 days in mice that received ALRN-6924 at 20 mg/kg twice a week, and 151 days in mice that received ALRN-6924 at 20 mg/kg three times a week.

“This is a very striking response,” Dr Steidl said. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease-free more than 1 year after treatment, essentially a lifetime for a mouse.”

Finally, the researchers assessed the effects of ALRN-6924 in a patient who had high-risk MDS with excess leukemic blasts.

The team found the p53 protein “was rapidly induced” in CD34+ leukemic blasts but not in healthy lymphocytes. And ALRN-6924 reduced the number of malignant cells circulating in the blood.

“This test was not designed to assess the efficacy of the drug in humans,” Dr Steidl noted. “That has to be done in a proper clinical trial. Our goal was to determine whether it can hit the desired target in human cells in a clinical setting, which it did in this individual.”

ALRN-6924 is a stapled alpha-helical peptide, a class of drugs whose helical structure is stabilized using hydrocarbon “staples.” The stapling prevents the peptides from being degraded by enzymes before reaching their intended target. ALRN-6924 is the first stapled peptide therapeutic to be tested in patients.

In the phase 1 trial (NCT02909972), researchers are testing ALRN-6924 in patients with relapsed/refractory AML or advanced MDS.

Lab mouse

Preclinical results support clinical testing of an experimental agent in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to researchers.

The agent, ALRN-6924, was shown to combat AML and MDS by restoring activity of the tumor-suppressing protein p53.

ALRN-6924 exhibited antileukemic activity in AML cells and mouse models of the disease, as well as in a patient with MDS and excess leukemic blasts who received the drug on a compassionate-use basis.

These results, published in Science Translational Medicine, have led to a phase 1 trial of ALRN-6924 in patients with AML or MDS.

ALRN-6924 was developed by Aileron Therapeutics Inc., to target p53 by inhibiting 2 naturally occurring proteins, MDMX and MDM2. Overexpression of these proteins inactivates p53, allowing cancer cells to multiply unchecked.

In the current study, researchers set out to confirm ALRN-6924’s mechanism of action and determine the efficacy of the drug in AML/MDS. This work was supported, in part, by grants from Aileron Therapeutics Inc., and the National Institutes of Health.

The researchers did find that ALRN-6924 targets both MDMX and MDM2, blocking their interaction with p53 in AML cells.

The team said ALRN-6924 inhibited proliferation by inducing cell-cycle arrest and apoptosis in AML cell lines and AML patient cells, including leukemic stem cell-enriched populations.

“This is important because AML is driven by stem cells, and, if you don’t target stem cells, the disease will come back very quickly,” said study author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York.

The researchers also found that ALRN-6924 greatly increased survival in a mouse model of AML. The median survival was 34 days in vehicle-treated control mice, 83 days in mice that received ALRN-6924 at 20 mg/kg twice a week, and 151 days in mice that received ALRN-6924 at 20 mg/kg three times a week.

“This is a very striking response,” Dr Steidl said. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease-free more than 1 year after treatment, essentially a lifetime for a mouse.”

Finally, the researchers assessed the effects of ALRN-6924 in a patient who had high-risk MDS with excess leukemic blasts.

The team found the p53 protein “was rapidly induced” in CD34+ leukemic blasts but not in healthy lymphocytes. And ALRN-6924 reduced the number of malignant cells circulating in the blood.

“This test was not designed to assess the efficacy of the drug in humans,” Dr Steidl noted. “That has to be done in a proper clinical trial. Our goal was to determine whether it can hit the desired target in human cells in a clinical setting, which it did in this individual.”

ALRN-6924 is a stapled alpha-helical peptide, a class of drugs whose helical structure is stabilized using hydrocarbon “staples.” The stapling prevents the peptides from being degraded by enzymes before reaching their intended target. ALRN-6924 is the first stapled peptide therapeutic to be tested in patients.

In the phase 1 trial (NCT02909972), researchers are testing ALRN-6924 in patients with relapsed/refractory AML or advanced MDS.

Lab mouse

Preclinical results support clinical testing of an experimental agent in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), according to researchers.

The agent, ALRN-6924, was shown to combat AML and MDS by restoring activity of the tumor-suppressing protein p53.

ALRN-6924 exhibited antileukemic activity in AML cells and mouse models of the disease, as well as in a patient with MDS and excess leukemic blasts who received the drug on a compassionate-use basis.

These results, published in Science Translational Medicine, have led to a phase 1 trial of ALRN-6924 in patients with AML or MDS.

ALRN-6924 was developed by Aileron Therapeutics Inc., to target p53 by inhibiting 2 naturally occurring proteins, MDMX and MDM2. Overexpression of these proteins inactivates p53, allowing cancer cells to multiply unchecked.

In the current study, researchers set out to confirm ALRN-6924’s mechanism of action and determine the efficacy of the drug in AML/MDS. This work was supported, in part, by grants from Aileron Therapeutics Inc., and the National Institutes of Health.

The researchers did find that ALRN-6924 targets both MDMX and MDM2, blocking their interaction with p53 in AML cells.

The team said ALRN-6924 inhibited proliferation by inducing cell-cycle arrest and apoptosis in AML cell lines and AML patient cells, including leukemic stem cell-enriched populations.

“This is important because AML is driven by stem cells, and, if you don’t target stem cells, the disease will come back very quickly,” said study author Ulrich Steidl, MD, PhD, of Albert Einstein College of Medicine in Bronx, New York.

The researchers also found that ALRN-6924 greatly increased survival in a mouse model of AML. The median survival was 34 days in vehicle-treated control mice, 83 days in mice that received ALRN-6924 at 20 mg/kg twice a week, and 151 days in mice that received ALRN-6924 at 20 mg/kg three times a week.

“This is a very striking response,” Dr Steidl said. “Most experimental drugs for leukemia achieve an increase in survival of only a few days in these preclinical models. Even more importantly, ALRN-6924 effectively cured about 40% of the treated mice, meaning they were disease-free more than 1 year after treatment, essentially a lifetime for a mouse.”

Finally, the researchers assessed the effects of ALRN-6924 in a patient who had high-risk MDS with excess leukemic blasts.

The team found the p53 protein “was rapidly induced” in CD34+ leukemic blasts but not in healthy lymphocytes. And ALRN-6924 reduced the number of malignant cells circulating in the blood.

“This test was not designed to assess the efficacy of the drug in humans,” Dr Steidl noted. “That has to be done in a proper clinical trial. Our goal was to determine whether it can hit the desired target in human cells in a clinical setting, which it did in this individual.”

ALRN-6924 is a stapled alpha-helical peptide, a class of drugs whose helical structure is stabilized using hydrocarbon “staples.” The stapling prevents the peptides from being degraded by enzymes before reaching their intended target. ALRN-6924 is the first stapled peptide therapeutic to be tested in patients.

In the phase 1 trial (NCT02909972), researchers are testing ALRN-6924 in patients with relapsed/refractory AML or advanced MDS.

Image by Spencer Phillips

New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).

Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.

The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.

Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.

The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.

This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.

The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.

Variants in recipients

Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.

Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.

The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.

Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.

Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.

The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.

Donor variants linked to OS

Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.

The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.

And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.

There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).

And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.

Donor variants linked to TRM and DRM

Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.

There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).

Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).

The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.

“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.

“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”

Image by Spencer Phillips

New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).

Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.

The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.

Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.

The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.

This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.

The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.

Variants in recipients

Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.

Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.

The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.

Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.

Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.

The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.

Donor variants linked to OS

Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.

The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.

And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.

There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).

And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.

Donor variants linked to TRM and DRM

Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.

There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).

Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).

The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.

“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.

“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”

Image by Spencer Phillips

New research has revealed a link between rare gene variants and survival after hematopoietic stem cell transplant (HSCT).

Researchers performed exome sequencing in nearly 2500 HSCT recipients and their matched, unrelated donors.

The sequencing revealed several gene variants—in both donors and recipients—that were significantly associated with overall survival (OS), transplant-related mortality (TRM), and disease-related mortality (DRM) after HSCT.

Qianqian Zhu, PhD, of Roswell Park Comprehensive Cancer Center in Buffalo, New York, and her colleagues described these findings in Blood.

The team performed exome sequencing—using the Illumina HumanExome BeadChip—in patients who participated in the DISCOVeRY-BMT study.

This included 2473 HSCT recipients who had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. It also included 2221 donors who were a 10/10 human leukocyte antigen match for each recipient.

The researchers looked at genetic variants in donors and recipients and assessed the variants’ associations with OS, TRM, and DRM.

Variants in recipients

Analyses revealed an increased risk of TRM when there was a mismatch between donors and recipients for a variant in TEX38—rs200092801. The increased risk was even more pronounced when either the recipient or the donor was female.

Among the recipients mismatched with their donors at rs200092801, every female recipient and every recipient with a female donor died from TRM. In comparison, 44% of the male recipients with male donors died from TRM.

The researchers said the rs200092801 variant may prompt the production of a mutant peptide that can be presented by MHC-I molecules to immune cells to trigger downstream immune response and TRM.

Dr Zhu and her colleagues also identified variants that appeared to have a positive impact on TRM and OS.

Recipients who had any of 6 variants in the gene OR51D1 had a decreased risk of TRM and improved OS.

The variants (rs138224979, rs148606808, rs141786655, rs61745314, rs200394876, and rs149135276) were not associated with DRM, so the researchers concluded that the improvement in OS was driven by protection against TRM.

Donor variants linked to OS

Donors had variants in 4 genes—ALPP, EMID1, SLC44A5, and LRP1—that were associated with OS but not TRM or DRM.

The 3 variants identified in ALPP (rs144454460, rs140078460, and rs142493383) were associated with improved OS.

And the 2 variants in SLC44A5 (rs143004355 and rs149696907) were associated with worse OS.

There were 2 variants in EMID1. One was associated with improved OS (rs34772704), and the other was associated with decreased OS (rs139996840).

And there were 27 variants in LRP1. Some had a positive association with OS, and others had a negative association.

Donor variants linked to TRM and DRM

Six variants in the HHAT gene were associated with TRM. Five of the variants appeared to have a protective effect against TRM (rs145455128, rs146916002, rs61744143, rs149597734, and rs145943928). For the other variant (rs141591165), the apparent effect was inconsistent between patient cohorts.

There were 3 variants in LYZL4 associated with DRM. Two were associated with an increased risk of DRM (rs147770623 and rs76947105), and 1 appeared to have a protective effect (rs181886204).

Six variants in NT5E appeared to have a protective effect against DRM (rs200250022, rs200369370, rs41271617, rs200648774, rs144719925, and rs145505137).

The researchers said the variants in NT5E probably reduce the enzyme activity of the gene. This supports preclinical findings showing that targeted blockade of NT5E can slow tumor growth.

“We have just started to uncover the biological relevance of these new and unexpected genes to a patient’s survival after [HSCT],” Dr Zhu said.

“Our findings shed light on new areas that were not considered before, but we need to further replicate and test our findings. We’re hoping that additional studies of this type will continue to discover novel genes leading to improved outcomes for patients.”

Red and white blood cells

A portable device could be used to monitor patients’ white blood cell (WBC) levels at home, without the need for blood samples, according to researchers.

The team created a prototype that records video of blood cells flowing through capillaries just below the skin surface at the base of the fingernail.

The group is developing a computer algorithm that, in early testing, has been able to analyze the videos and determine if WBC levels are too low.

The researchers believe this type of device could be used to prevent infections among chemotherapy recipients.

“Our vision is that patients will have this portable device that they can take home, and they can monitor daily how they are reacting to the treatment,” said Carlos Castro-Gonzalez, PhD, of the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts.

“If they go below the [safe WBC] threshold, then preventive treatment can be deployed.”

Dr Castro-Gonzalez and his colleagues described their prototype, and the testing of it, in Scientific Reports.

The device consists of a wide-field microscope that emits blue light, which penetrates about 50 to 150 microns below the skin and is reflected back to a video camera.

The researchers decided to image the skin at the base of the nail because the capillaries there are very close to the skin surface. These capillaries are so narrow that WBCs must squeeze through one at a time, making them easier to see.

The researchers tested the device in 11 patients at various points during their chemotherapy treatment.

The device does not provide precise WBC counts but allowed the team to differentiate cases of severe neutropenia (<500 neutrophils per μL) from non-neutropenic cases (>1500 neutrophils per μL).

To obtain enough data to make these classifications, the researchers recorded 1 minute of video per patient. Three blinded human assistants then watched the videos and noted whenever a WBC passed by.

However, since submitting their paper, the researchers have been developing a computer algorithm to perform the same task automatically.

“Based on the feature-set that our human raters identified, we are now developing an AI and machine-vision algorithm, with preliminary results that indicate the same accuracy as the raters,” said study author Aurélien Bourquard, PhD, of MIT.

The researchers have applied for patents on the technology and launched a company called Leuko, which is working on commercializing the technology with help from MIT.

To move the technology further toward commercialization, the researchers are building a new automated prototype.

“Automating the measurement process is key to making a viable home-use device,” said study author Ian Butterworth, of MIT. “The imaging needs to take place in the right spot on the patient’s finger, and the operation of the device must be straightforward.”

Using this new prototype, the researchers plan to test the device with additional cancer patients. And the team is investigating whether they can get accurate results with shorter lengths of video.

They also plan to adapt the technology so it can generate more precise WBC counts, which would make it useful for monitoring bone marrow transplant recipients or people with certain infectious diseases, Dr Castro-Gonzalez said.

This could also make it possible to determine whether chemotherapy patients can receive their next dose sooner than usual.

“There is a balancing act that oncologists must do,” said study author Alvaro Sanchez-Ferro, MD, of Centro Integral en Neurociencias A.C. HM CINAC in Madrid, Spain.

“Normally, doctors want to make chemotherapy as intensive as possible but without getting people too immunosuppressed. Current 21-day cycles are based on statistics of what most patients can take, but if you are ready early, then they can potentially bring you back early, and that can translate into better survival.”

Red and white blood cells

A portable device could be used to monitor patients’ white blood cell (WBC) levels at home, without the need for blood samples, according to researchers.

The team created a prototype that records video of blood cells flowing through capillaries just below the skin surface at the base of the fingernail.

The group is developing a computer algorithm that, in early testing, has been able to analyze the videos and determine if WBC levels are too low.

The researchers believe this type of device could be used to prevent infections among chemotherapy recipients.

“Our vision is that patients will have this portable device that they can take home, and they can monitor daily how they are reacting to the treatment,” said Carlos Castro-Gonzalez, PhD, of the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts.

“If they go below the [safe WBC] threshold, then preventive treatment can be deployed.”

Dr Castro-Gonzalez and his colleagues described their prototype, and the testing of it, in Scientific Reports.

The device consists of a wide-field microscope that emits blue light, which penetrates about 50 to 150 microns below the skin and is reflected back to a video camera.

The researchers decided to image the skin at the base of the nail because the capillaries there are very close to the skin surface. These capillaries are so narrow that WBCs must squeeze through one at a time, making them easier to see.

The researchers tested the device in 11 patients at various points during their chemotherapy treatment.

The device does not provide precise WBC counts but allowed the team to differentiate cases of severe neutropenia (<500 neutrophils per μL) from non-neutropenic cases (>1500 neutrophils per μL).

To obtain enough data to make these classifications, the researchers recorded 1 minute of video per patient. Three blinded human assistants then watched the videos and noted whenever a WBC passed by.

However, since submitting their paper, the researchers have been developing a computer algorithm to perform the same task automatically.

“Based on the feature-set that our human raters identified, we are now developing an AI and machine-vision algorithm, with preliminary results that indicate the same accuracy as the raters,” said study author Aurélien Bourquard, PhD, of MIT.

The researchers have applied for patents on the technology and launched a company called Leuko, which is working on commercializing the technology with help from MIT.

To move the technology further toward commercialization, the researchers are building a new automated prototype.

“Automating the measurement process is key to making a viable home-use device,” said study author Ian Butterworth, of MIT. “The imaging needs to take place in the right spot on the patient’s finger, and the operation of the device must be straightforward.”

Using this new prototype, the researchers plan to test the device with additional cancer patients. And the team is investigating whether they can get accurate results with shorter lengths of video.

They also plan to adapt the technology so it can generate more precise WBC counts, which would make it useful for monitoring bone marrow transplant recipients or people with certain infectious diseases, Dr Castro-Gonzalez said.

This could also make it possible to determine whether chemotherapy patients can receive their next dose sooner than usual.

“There is a balancing act that oncologists must do,” said study author Alvaro Sanchez-Ferro, MD, of Centro Integral en Neurociencias A.C. HM CINAC in Madrid, Spain.

“Normally, doctors want to make chemotherapy as intensive as possible but without getting people too immunosuppressed. Current 21-day cycles are based on statistics of what most patients can take, but if you are ready early, then they can potentially bring you back early, and that can translate into better survival.”

Red and white blood cells

A portable device could be used to monitor patients’ white blood cell (WBC) levels at home, without the need for blood samples, according to researchers.

The team created a prototype that records video of blood cells flowing through capillaries just below the skin surface at the base of the fingernail.

The group is developing a computer algorithm that, in early testing, has been able to analyze the videos and determine if WBC levels are too low.

The researchers believe this type of device could be used to prevent infections among chemotherapy recipients.

“Our vision is that patients will have this portable device that they can take home, and they can monitor daily how they are reacting to the treatment,” said Carlos Castro-Gonzalez, PhD, of the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts.

“If they go below the [safe WBC] threshold, then preventive treatment can be deployed.”

Dr Castro-Gonzalez and his colleagues described their prototype, and the testing of it, in Scientific Reports.

The device consists of a wide-field microscope that emits blue light, which penetrates about 50 to 150 microns below the skin and is reflected back to a video camera.

The researchers decided to image the skin at the base of the nail because the capillaries there are very close to the skin surface. These capillaries are so narrow that WBCs must squeeze through one at a time, making them easier to see.

The researchers tested the device in 11 patients at various points during their chemotherapy treatment.

The device does not provide precise WBC counts but allowed the team to differentiate cases of severe neutropenia (<500 neutrophils per μL) from non-neutropenic cases (>1500 neutrophils per μL).

To obtain enough data to make these classifications, the researchers recorded 1 minute of video per patient. Three blinded human assistants then watched the videos and noted whenever a WBC passed by.

However, since submitting their paper, the researchers have been developing a computer algorithm to perform the same task automatically.

“Based on the feature-set that our human raters identified, we are now developing an AI and machine-vision algorithm, with preliminary results that indicate the same accuracy as the raters,” said study author Aurélien Bourquard, PhD, of MIT.

The researchers have applied for patents on the technology and launched a company called Leuko, which is working on commercializing the technology with help from MIT.

To move the technology further toward commercialization, the researchers are building a new automated prototype.

“Automating the measurement process is key to making a viable home-use device,” said study author Ian Butterworth, of MIT. “The imaging needs to take place in the right spot on the patient’s finger, and the operation of the device must be straightforward.”

Using this new prototype, the researchers plan to test the device with additional cancer patients. And the team is investigating whether they can get accurate results with shorter lengths of video.

They also plan to adapt the technology so it can generate more precise WBC counts, which would make it useful for monitoring bone marrow transplant recipients or people with certain infectious diseases, Dr Castro-Gonzalez said.

This could also make it possible to determine whether chemotherapy patients can receive their next dose sooner than usual.

“There is a balancing act that oncologists must do,” said study author Alvaro Sanchez-Ferro, MD, of Centro Integral en Neurociencias A.C. HM CINAC in Madrid, Spain.

“Normally, doctors want to make chemotherapy as intensive as possible but without getting people too immunosuppressed. Current 21-day cycles are based on statistics of what most patients can take, but if you are ready early, then they can potentially bring you back early, and that can translate into better survival.”

Photo by Don Boomer

New research indicates that non-muscle myosin II-A (NMIIA) plays a key role in maintaining red blood cell (RBC) shape and deformability.

Researchers found evidence to suggest that NMIIA forms filaments in RBCs, and specialized regions at both ends of the filaments can pull on actin to control the stiffness of the cell membrane.

“You need active contraction on the cell membrane, similar to how muscles contract,” explained study author Velia Fowler, PhD, of The Scripps Research Institute in La Jolla, California.

“The myosin pulls on the actin to provide tension in the membrane, and then that tension maintains the biconcave shape.”

Dr Fowler and her colleagues described these findings in PNAS.

The researchers noted that RBC shape and deformability depend upon the membrane skeleton—a network of actin filaments (F-actin) cross-linked by spectrin tetramers.

And although NMII motors are known to exert force on F-actin networks to control cell shapes, no one had investigated a function for NMII contractility in the spectrin–F-actin network of RBCs. So Dr Fowler and her colleagues did just that.

The researchers said their work suggests NMIIA is the predominant RBC NMII isoform, and NMIIA motor activity regulates interactions with the spectrin–F-actin network to control RBCs’ shape and deformability.

Specifically, NMIIA forms bipolar filaments in RBCs, and these filaments associate with F-actins via their motor domains. It is through these interactions that NMIIA contractile forces promote membrane tension to maintain RBC shape and deformability.

To test these findings, the researchers treated RBCs with a compound called blebbistatin, which inhibits NMII motor activity.

After treatment, the team observed a decrease in NMIIA filaments associated with the RBC membrane and evidence of decreased membrane tension. The treated RBCs became elongated and showed a reduction in biconcavity as well as an increase in deformability.

The researchers believe this work could have applications for diseases in which RBCs are deformed. In fact, the team thinks inhibiting NMIIA in RBCs might prove useful for treating patients with sickle cell disease, as it could restore some elasticity to the patients’ RBCs.

Going forward, the researchers hope to learn more about what regulates NMIIA’s activity in RBCs and other cells.

Photo by Don Boomer

New research indicates that non-muscle myosin II-A (NMIIA) plays a key role in maintaining red blood cell (RBC) shape and deformability.

Researchers found evidence to suggest that NMIIA forms filaments in RBCs, and specialized regions at both ends of the filaments can pull on actin to control the stiffness of the cell membrane.

“You need active contraction on the cell membrane, similar to how muscles contract,” explained study author Velia Fowler, PhD, of The Scripps Research Institute in La Jolla, California.

“The myosin pulls on the actin to provide tension in the membrane, and then that tension maintains the biconcave shape.”

Dr Fowler and her colleagues described these findings in PNAS.

The researchers noted that RBC shape and deformability depend upon the membrane skeleton—a network of actin filaments (F-actin) cross-linked by spectrin tetramers.

And although NMII motors are known to exert force on F-actin networks to control cell shapes, no one had investigated a function for NMII contractility in the spectrin–F-actin network of RBCs. So Dr Fowler and her colleagues did just that.

The researchers said their work suggests NMIIA is the predominant RBC NMII isoform, and NMIIA motor activity regulates interactions with the spectrin–F-actin network to control RBCs’ shape and deformability.

Specifically, NMIIA forms bipolar filaments in RBCs, and these filaments associate with F-actins via their motor domains. It is through these interactions that NMIIA contractile forces promote membrane tension to maintain RBC shape and deformability.

To test these findings, the researchers treated RBCs with a compound called blebbistatin, which inhibits NMII motor activity.

After treatment, the team observed a decrease in NMIIA filaments associated with the RBC membrane and evidence of decreased membrane tension. The treated RBCs became elongated and showed a reduction in biconcavity as well as an increase in deformability.

The researchers believe this work could have applications for diseases in which RBCs are deformed. In fact, the team thinks inhibiting NMIIA in RBCs might prove useful for treating patients with sickle cell disease, as it could restore some elasticity to the patients’ RBCs.

Going forward, the researchers hope to learn more about what regulates NMIIA’s activity in RBCs and other cells.

Photo by Don Boomer

New research indicates that non-muscle myosin II-A (NMIIA) plays a key role in maintaining red blood cell (RBC) shape and deformability.

Researchers found evidence to suggest that NMIIA forms filaments in RBCs, and specialized regions at both ends of the filaments can pull on actin to control the stiffness of the cell membrane.

“You need active contraction on the cell membrane, similar to how muscles contract,” explained study author Velia Fowler, PhD, of The Scripps Research Institute in La Jolla, California.

“The myosin pulls on the actin to provide tension in the membrane, and then that tension maintains the biconcave shape.”

Dr Fowler and her colleagues described these findings in PNAS.

The researchers noted that RBC shape and deformability depend upon the membrane skeleton—a network of actin filaments (F-actin) cross-linked by spectrin tetramers.

And although NMII motors are known to exert force on F-actin networks to control cell shapes, no one had investigated a function for NMII contractility in the spectrin–F-actin network of RBCs. So Dr Fowler and her colleagues did just that.

The researchers said their work suggests NMIIA is the predominant RBC NMII isoform, and NMIIA motor activity regulates interactions with the spectrin–F-actin network to control RBCs’ shape and deformability.

Specifically, NMIIA forms bipolar filaments in RBCs, and these filaments associate with F-actins via their motor domains. It is through these interactions that NMIIA contractile forces promote membrane tension to maintain RBC shape and deformability.

To test these findings, the researchers treated RBCs with a compound called blebbistatin, which inhibits NMII motor activity.

After treatment, the team observed a decrease in NMIIA filaments associated with the RBC membrane and evidence of decreased membrane tension. The treated RBCs became elongated and showed a reduction in biconcavity as well as an increase in deformability.

The researchers believe this work could have applications for diseases in which RBCs are deformed. In fact, the team thinks inhibiting NMIIA in RBCs might prove useful for treating patients with sickle cell disease, as it could restore some elasticity to the patients’ RBCs.

Going forward, the researchers hope to learn more about what regulates NMIIA’s activity in RBCs and other cells.

AML cells

The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.

The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).

When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.

Researchers said that, overall, the toxic effects of prexigebersen were manageable.

There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.

Still, the maximum tolerated dose of prexigebersen was not established.

These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.

Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.

In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.

There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.

All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.

For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).

In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).

Safety

Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.

One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.

There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.

The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).

In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.

There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.

Efficacy

According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.

Single-agent activity was observed in other patients as well.

Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.

Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy.  Two of these patients had AML, and 1 had MDS.

Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.

Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.

Deaths

There were a total of 8 deaths.

One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.

Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.

AML cells

The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.

The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).

When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.

Researchers said that, overall, the toxic effects of prexigebersen were manageable.

There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.

Still, the maximum tolerated dose of prexigebersen was not established.

These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.

Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.

In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.

There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.

All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.

For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).

In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).

Safety

Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.

One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.

There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.

The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).

In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.

There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.

Efficacy

According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.

Single-agent activity was observed in other patients as well.

Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.

Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy.  Two of these patients had AML, and 1 had MDS.

Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.

Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.

Deaths

There were a total of 8 deaths.

One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.

Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.

AML cells

The experimental agent prexigebersen (formerly BP1001) was considered well-tolerated and demonstrated early evidence of activity against relapsed/refractory hematologic disorders in a phase 1/1b trial.

The drug reduced blasts in the bone marrow and peripheral blood for patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS).

When given in combination with low-dose cytarabine, prexigebersen produced complete responses (CRs) in patients with AML.

Researchers said that, overall, the toxic effects of prexigebersen were manageable.

There was 1 patient who had dose-limiting toxicities, 1 who discontinued treatment due to possible drug-related toxic effects, and 1 treatment-related death.

Still, the maximum tolerated dose of prexigebersen was not established.

These results were published in The Lancet Haematology. The study was sponsored by Bio-Path Holdings, Inc., the company developing prexigebersen.

Prexigebersen is an anti-sense oligodeoxynucleotide developed to block Grb2 expression and function. Researchers tested the drug in a single-center, dose-escalation, phase 1/1b trial that enrolled and treated 39 patients.

In the phase 1 portion of the trial, patients received prexigebersen monotherapy. In the phase 1b portion, they received the drug in combination with low-dose cytarabine.

There were 32 patients in the phase 1 portion of the trial. Most (n=23) had AML, 5 had CML in blast phase, and 4 had MDS. The patients’ median age was 63 (range, 56-73), and they had received a median of 4 prior therapies.

All 7 patients in the phase 1b portion had AML. They had a median age of 72 (range, 70-76) and had all received 1 prior therapy.

For phase 1, prexigebersen was administered intravenously, twice weekly for 28 days at doses of 5 mg/m² in cohort 1 (n=13), 10 mg/m² in cohort 2 (n=6), 20 mg/m² in cohort 3 (n=3), 40 mg/m² in cohort 4 (n=3), 60 mg/m² in cohort 5 (n=3), and 90 mg/m² in cohort 6 (n=4).

In the phase 1b portion, patients received prexigebersen at 60 mg/m² (n=4) or 90 mg/m² (n=3) in combination with 20 mg of cytarabine (twice-daily subcutaneous injections).

Safety

Twenty-seven patients were evaluable for dose-limiting toxicity—21 from phase 1 and 6 from 1b.

One patient in cohort 1 developed mucositis and hand-foot syndrome, which were considered possibly related to prexigebersen and deemed dose-limiting toxicities. The patient was also receiving hydroxyurea (3 g/day) for CML and had a history of hydroxyurea-induced mucositis.

There were no other dose-limiting toxicities, and the researchers did not identify a maximum tolerated dose of prexigebersen.

The most common grade 3-4 adverse events (AEs) were cardiopulmonary disorders and fevers (including neutropenic fevers and infections).

In the monotherapy group, 17% of patients had grade 3-4 cardiopulmonary AEs, and 11% had fevers. In the prexigebersen-cytarabine combination group, 8% had grade 3-4 cardiopulmonary AEs, and 6% had fevers.

There were 5 grade 5 AEs in 4 patients, all of whom received monotherapy. These included cardiopulmonary disorders (n=2), fevers (n=2), and multi-organ failure (n=1). One patient had both fever (sepsis) and multi-organ failure.

Efficacy

According to the researchers’ assessments, 22% of phase 1 patients (7/32) benefited from prexigebersen monotherapy and therefore received more than 1 cycle of treatment. Five of these patients had AML, and 2 had MDS.

Single-agent activity was observed in other patients as well.

Thirty-three percent (9/27) of patients who had peripheral blood blasts at baseline saw their blasts reduced by 50% or more while receiving monotherapy. One of these patients had CML, and the rest had AML.

Ten percent (3/29) of patients with bone marrow blasts at baseline had a reduction in blasts of 50% or more while receiving monotherapy.  Two of these patients had AML, and 1 had MDS.

Of the 7 patients receiving prexigebersen with cytarabine, 2 achieved a CR, and 1 had a CR with incomplete hematological recovery.

Two of the patients had stable disease, and the remaining 2 patients progressed. One of the patients with progressive disease withdrew from the study, and the other died.

Deaths

There were a total of 8 deaths.

One death was considered treatment-related. This patient had progressive CML in blast phase and died of multiple organ failure. This was the first patient treated on the trial, who also had the only dose-limiting toxicities.

Two patients with AML and 1 with MDS died of disease progression. Three AML patients died of sepsis, pneumonia, and cardiac arrest. And a CML patient died of respiratory distress.

Image by Betty Pace

The European Commission (EC) has granted orphan designation to Altemia (formerly SC411) for the treatment of pediatric patients with sickle cell disease (SCD).

Altemia gelatin capsules are designed to replenish the lipids destroyed by sickle hemoglobin.

Altemia is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.

Altemia consists of a mixture of fatty acids, primarily in the form of Ethyl Cervonate (a proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface active agents formulated using Advanced Lipid Technologies.

Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used by Sancilio Pharmaceuticals Company, Inc. (SPCI) to create lipophilic drug products.

Last November, SPCI reported topline data from its phase 2 study of Altemia, the SCOT trial (NCT02973360). The trial included pediatric patients, ages 5 to 17, with SCD.

The study’s primary endpoint was the change from baseline in blood cell membranes’ fatty acids concentration. SPCI said Altemia showed a significant improvement in this endpoint, compared to placebo, within 4 weeks of treatment initiation.

Patients who received Altemia also had significant improvements in markers of coagulation (D-dimer), inflammation (C-reactive protein), and adhesion (E-selectin) after 8 weeks of treatment.

And patients treated with Altemia had a “clinically meaningful” reduction in vaso-occlusive events, according to SPCI.

There were no treatment-related serious adverse events reported.

Ninety-four percent of patients completed the study, and most have chosen to participate in the open-label extension phase, in which researchers will continue monitoring the safety and effectiveness of Altemia.

SPCI said additional analyses of SCOT data are ongoing, and the company plans to present detailed data from the study in journals and at upcoming scientific conferences.

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.

Image by Betty Pace

The European Commission (EC) has granted orphan designation to Altemia (formerly SC411) for the treatment of pediatric patients with sickle cell disease (SCD).

Altemia gelatin capsules are designed to replenish the lipids destroyed by sickle hemoglobin.

Altemia is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.

Altemia consists of a mixture of fatty acids, primarily in the form of Ethyl Cervonate (a proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface active agents formulated using Advanced Lipid Technologies.

Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used by Sancilio Pharmaceuticals Company, Inc. (SPCI) to create lipophilic drug products.

Last November, SPCI reported topline data from its phase 2 study of Altemia, the SCOT trial (NCT02973360). The trial included pediatric patients, ages 5 to 17, with SCD.

The study’s primary endpoint was the change from baseline in blood cell membranes’ fatty acids concentration. SPCI said Altemia showed a significant improvement in this endpoint, compared to placebo, within 4 weeks of treatment initiation.

Patients who received Altemia also had significant improvements in markers of coagulation (D-dimer), inflammation (C-reactive protein), and adhesion (E-selectin) after 8 weeks of treatment.

And patients treated with Altemia had a “clinically meaningful” reduction in vaso-occlusive events, according to SPCI.

There were no treatment-related serious adverse events reported.

Ninety-four percent of patients completed the study, and most have chosen to participate in the open-label extension phase, in which researchers will continue monitoring the safety and effectiveness of Altemia.

SPCI said additional analyses of SCOT data are ongoing, and the company plans to present detailed data from the study in journals and at upcoming scientific conferences.

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.

Image by Betty Pace

The European Commission (EC) has granted orphan designation to Altemia (formerly SC411) for the treatment of pediatric patients with sickle cell disease (SCD).

Altemia gelatin capsules are designed to replenish the lipids destroyed by sickle hemoglobin.

Altemia is intended to be taken once daily to reduce vaso-occlusive crises, anemia, organ damage, and other complications of SCD.

Altemia consists of a mixture of fatty acids, primarily in the form of Ethyl Cervonate (a proprietary blend of docosahexaenoic acid and other omega-3 fatty acids), and surface active agents formulated using Advanced Lipid Technologies.

Advanced Lipid Technologies are proprietary formulation and manufacturing techniques used by Sancilio Pharmaceuticals Company, Inc. (SPCI) to create lipophilic drug products.

Last November, SPCI reported topline data from its phase 2 study of Altemia, the SCOT trial (NCT02973360). The trial included pediatric patients, ages 5 to 17, with SCD.

The study’s primary endpoint was the change from baseline in blood cell membranes’ fatty acids concentration. SPCI said Altemia showed a significant improvement in this endpoint, compared to placebo, within 4 weeks of treatment initiation.

Patients who received Altemia also had significant improvements in markers of coagulation (D-dimer), inflammation (C-reactive protein), and adhesion (E-selectin) after 8 weeks of treatment.

And patients treated with Altemia had a “clinically meaningful” reduction in vaso-occlusive events, according to SPCI.

There were no treatment-related serious adverse events reported.

Ninety-four percent of patients completed the study, and most have chosen to participate in the open-label extension phase, in which researchers will continue monitoring the safety and effectiveness of Altemia.

SPCI said additional analyses of SCOT data are ongoing, and the company plans to present detailed data from the study in journals and at upcoming scientific conferences.

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.

Platelet-rich plasma

HIT Confirm, a test used to diagnose heparin-induced thrombocytopenia (HIT), has received the CE mark.

This means the test meets regulatory requirements and health, safety, and environmental protection standards for products sold within the European Economic Area.

HIT Confirm is a flow cytometry-based test developed by Emosis. The test can be performed on any flow cytometer and provides results within 30 minutes.

HIT Confirm requires a low-volume sample (microliters) of platelet-rich plasma to confirm the presence of HIT antibodies that lead to the formation of a heparin-antibody-PF4 complex that will bind to platelets and activate them.

HIT Confirm requires a single incubation with 2 fluorophores against a marker of platelets (CD41) and a marker of activated platelets (CD62).

After 30 minutes of incubation with 2 dose levels of heparin (0.3 U/mL and 100 U/mL), the proportion of activated platelets is obtained via flow cytometry.

Results are interpreted using a platelet activation index called HEPLA, which was developed by Emosis.

Research presented at the 2017 ISTH Congress (abstract OC 34.3*) indicated that HIT Confirm produces results comparable to those provided by the serotonin release assay (SRA).

Researchers tested the sensitivity and specificity of SRA and HIT Confirm when analyzing plasma from 290 patients—131 of whom were deemed HIT-positive by experts.

When compared to expert opinion, HIT Confirm provided 90% sensitivity and 94% specificity. SRA provided 80% sensitivity and 94% specificity compared to expert opinion.

For more information on HIT Confirm, visit the Emosis website.

*Data in the abstract differ from data provided by Emosis. The data used here were provided by Emosis.

Platelet-rich plasma

HIT Confirm, a test used to diagnose heparin-induced thrombocytopenia (HIT), has received the CE mark.

This means the test meets regulatory requirements and health, safety, and environmental protection standards for products sold within the European Economic Area.

HIT Confirm is a flow cytometry-based test developed by Emosis. The test can be performed on any flow cytometer and provides results within 30 minutes.

HIT Confirm requires a low-volume sample (microliters) of platelet-rich plasma to confirm the presence of HIT antibodies that lead to the formation of a heparin-antibody-PF4 complex that will bind to platelets and activate them.

HIT Confirm requires a single incubation with 2 fluorophores against a marker of platelets (CD41) and a marker of activated platelets (CD62).

After 30 minutes of incubation with 2 dose levels of heparin (0.3 U/mL and 100 U/mL), the proportion of activated platelets is obtained via flow cytometry.

Results are interpreted using a platelet activation index called HEPLA, which was developed by Emosis.

Research presented at the 2017 ISTH Congress (abstract OC 34.3*) indicated that HIT Confirm produces results comparable to those provided by the serotonin release assay (SRA).

Researchers tested the sensitivity and specificity of SRA and HIT Confirm when analyzing plasma from 290 patients—131 of whom were deemed HIT-positive by experts.

When compared to expert opinion, HIT Confirm provided 90% sensitivity and 94% specificity. SRA provided 80% sensitivity and 94% specificity compared to expert opinion.

For more information on HIT Confirm, visit the Emosis website.

*Data in the abstract differ from data provided by Emosis. The data used here were provided by Emosis.

Platelet-rich plasma

HIT Confirm, a test used to diagnose heparin-induced thrombocytopenia (HIT), has received the CE mark.

This means the test meets regulatory requirements and health, safety, and environmental protection standards for products sold within the European Economic Area.

HIT Confirm is a flow cytometry-based test developed by Emosis. The test can be performed on any flow cytometer and provides results within 30 minutes.

HIT Confirm requires a low-volume sample (microliters) of platelet-rich plasma to confirm the presence of HIT antibodies that lead to the formation of a heparin-antibody-PF4 complex that will bind to platelets and activate them.

HIT Confirm requires a single incubation with 2 fluorophores against a marker of platelets (CD41) and a marker of activated platelets (CD62).

After 30 minutes of incubation with 2 dose levels of heparin (0.3 U/mL and 100 U/mL), the proportion of activated platelets is obtained via flow cytometry.

Results are interpreted using a platelet activation index called HEPLA, which was developed by Emosis.

Research presented at the 2017 ISTH Congress (abstract OC 34.3*) indicated that HIT Confirm produces results comparable to those provided by the serotonin release assay (SRA).

Researchers tested the sensitivity and specificity of SRA and HIT Confirm when analyzing plasma from 290 patients—131 of whom were deemed HIT-positive by experts.

When compared to expert opinion, HIT Confirm provided 90% sensitivity and 94% specificity. SRA provided 80% sensitivity and 94% specificity compared to expert opinion.

For more information on HIT Confirm, visit the Emosis website.

*Data in the abstract differ from data provided by Emosis. The data used here were provided by Emosis.

Photo from UNSW

Researchers have used CRISPR-Cas9 gene editing to reproduce naturally occurring mutations that boost the production of fetal hemoglobin.

The mutations are associated with hereditary persistence of fetal hemoglobin (HPFH), and the researchers believe that introducing these mutations into erythroid cells could be a safe way to treat β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia.

This research was published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders, including β-thalassemia and sickle cell anemia,” said study author Merlin Crossley, DPhil, of the University of New South Wales in Sydney, Australia.

“It is organic because no new DNA is introduced into the cells; rather, we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions. It should prove to be a safe and effective therapy, although more research would be needed to scale the processes up into effective treatments.”

Dr Crossley and his colleagues noted that reactivating fetal hemoglobin production has long been a therapeutic goal for SCD and β-thalassemia.

“The fetal hemoglobin gene is naturally silenced after birth,” Dr Crossley explained. “For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. Our study, which is the culmination of many years of work, solves that mystery.”

“We have found that 2 genes, called BCL11A and ZBTB7A, switch off the fetal hemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the 2 sites where these 2 genes bind.”

The “beneficial mutations,” which cause some forms of HPFH, are point mutations in the γ-globin gene promoter at -115 and -200 bp upstream of the transcription start site.

Dr Crossley and his colleagues found that BCL11A31 and ZBTB7A23—2 well-established fetal globin repressors—bind these regions of the γ-globin gene proximal promoter, and mutations at –115 and –200 bp disrupt the binding.

The researchers used CRISPR-Cas9 to introduce the HPFH-associated mutations into erythroid cells and observed both disruption of repressor binding and increased γ-globin gene expression.

“This landmark finding not only contributes to our appreciation of how these globin genes are regulated,” Dr Crossley said. “It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”

Photo from UNSW

Researchers have used CRISPR-Cas9 gene editing to reproduce naturally occurring mutations that boost the production of fetal hemoglobin.

The mutations are associated with hereditary persistence of fetal hemoglobin (HPFH), and the researchers believe that introducing these mutations into erythroid cells could be a safe way to treat β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia.

This research was published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders, including β-thalassemia and sickle cell anemia,” said study author Merlin Crossley, DPhil, of the University of New South Wales in Sydney, Australia.

“It is organic because no new DNA is introduced into the cells; rather, we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions. It should prove to be a safe and effective therapy, although more research would be needed to scale the processes up into effective treatments.”

Dr Crossley and his colleagues noted that reactivating fetal hemoglobin production has long been a therapeutic goal for SCD and β-thalassemia.

“The fetal hemoglobin gene is naturally silenced after birth,” Dr Crossley explained. “For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. Our study, which is the culmination of many years of work, solves that mystery.”

“We have found that 2 genes, called BCL11A and ZBTB7A, switch off the fetal hemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the 2 sites where these 2 genes bind.”

The “beneficial mutations,” which cause some forms of HPFH, are point mutations in the γ-globin gene promoter at -115 and -200 bp upstream of the transcription start site.

Dr Crossley and his colleagues found that BCL11A31 and ZBTB7A23—2 well-established fetal globin repressors—bind these regions of the γ-globin gene proximal promoter, and mutations at –115 and –200 bp disrupt the binding.

The researchers used CRISPR-Cas9 to introduce the HPFH-associated mutations into erythroid cells and observed both disruption of repressor binding and increased γ-globin gene expression.

“This landmark finding not only contributes to our appreciation of how these globin genes are regulated,” Dr Crossley said. “It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”

Photo from UNSW

Researchers have used CRISPR-Cas9 gene editing to reproduce naturally occurring mutations that boost the production of fetal hemoglobin.

The mutations are associated with hereditary persistence of fetal hemoglobin (HPFH), and the researchers believe that introducing these mutations into erythroid cells could be a safe way to treat β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia.

This research was published in Nature Genetics.

“Our new approach can be seen as a forerunner to ‘organic gene therapy’ for a range of common inherited blood disorders, including β-thalassemia and sickle cell anemia,” said study author Merlin Crossley, DPhil, of the University of New South Wales in Sydney, Australia.

“It is organic because no new DNA is introduced into the cells; rather, we engineer in naturally occurring, benign mutations that are known to be beneficial to people with these conditions. It should prove to be a safe and effective therapy, although more research would be needed to scale the processes up into effective treatments.”

Dr Crossley and his colleagues noted that reactivating fetal hemoglobin production has long been a therapeutic goal for SCD and β-thalassemia.

“The fetal hemoglobin gene is naturally silenced after birth,” Dr Crossley explained. “For 50 years, researchers have been competing furiously to find out how it is switched off, so it can be turned back on. Our study, which is the culmination of many years of work, solves that mystery.”

“We have found that 2 genes, called BCL11A and ZBTB7A, switch off the fetal hemoglobin gene by binding directly to it. And the beneficial mutations work by disrupting the 2 sites where these 2 genes bind.”

The “beneficial mutations,” which cause some forms of HPFH, are point mutations in the γ-globin gene promoter at -115 and -200 bp upstream of the transcription start site.

Dr Crossley and his colleagues found that BCL11A31 and ZBTB7A23—2 well-established fetal globin repressors—bind these regions of the γ-globin gene proximal promoter, and mutations at –115 and –200 bp disrupt the binding.

The researchers used CRISPR-Cas9 to introduce the HPFH-associated mutations into erythroid cells and observed both disruption of repressor binding and increased γ-globin gene expression.

“This landmark finding not only contributes to our appreciation of how these globin genes are regulated,” Dr Crossley said. “It means we can now shift our focus to developing therapies for these genetic diseases using CRISPR to target precise changes in the genome.”