Piper Jaffray analyst Joseph Catanzaro notes that ImmunoGen presented updates from the Phase I trials of both IMGN632 and IMGN779in r/r AML and BPDCN at ASH this weekend. While the aanalyst acknowledges that some may be disappointed with the slight dip in CR/CRi rate for ‘632 and the lack of dose response, he finds the clear anti-leukemic activity at the lower, more tolerable doses notable and sees this as a positive first full look for this program. ‘779 still looks to be struggling to find an active dose, Catanzarro contends, adding that he is unsure whether higher doses will elicit enough of an increase in activity without increased toxicity that would warrant further monotherapy development. He reiterates an Overweight rating and $14 price target on the shares.
Sunday, December 2, 2018
MDS case bad for Bluebird Bio, likely others, says Piper Jaffray
Piper Jaffray analyst Tyler Van Buren notes that Bluebird Bio presented at ASH long-term follow up from the Phase I HGB-206 study for the original cohort of LentiGlobin sickle cell patients and the efficacy update was positive and showed encouraging reductions in VOEs. However, one patient who received LentiGlobin approximately 3 years ago developed myelodysplastic syndrome, he contends. The analyst adds that while this appears unrelated to LentiGlobin drug product, it is likely due to the intensive conditioning regimen, or in other words, the procedure. This highlights the simple fact that there are significant risks with procedures involving intensive conditioning of any kind, Van Buren points out, adding that he continues to “wonder how many non-malignant heme patients will be willing to accept these risks, which now quite obviously may include cancer.” The analyst has an Overweight rating and $240 price target on the shares.
Alpine Immune Sciences Data to be Included in ASH Oral Presentation
Alpine Immune Sciences, Inc. (NASDAQ:ALPN), a leading immunotherapy company focused on developing innovative treatments for cancer, autoimmune/inflammatory, and other diseases, today announced pre-clinical data from its lead autoimmune/inflammatory program, ALPN-101, will be included in an oral presentation at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition on Sunday, December 2, 2018 at 9:30am PT in San Diego, CA.
The presentation highlights the novel role ICOS ligand (ICOS-L) plays in acute GvHD, extending what is currently understood about the CD28/B7 protein family in disease pathogenesis. In particular, there is a strong correlation with ICOS-L positive plasmacytoid dendritic cells and the gastrointestinal manifestations of GvHD that may act as a biomarker for identification of patients. There are no current therapies in development blocking both the CD28 and ICOS pathways. The oral presentation will include data evaluating ALPN-101, a highly potent and effective first in class dual blocker of both the ICOS and CD28 pathways, in GvHD and discuss its potential role and mechanism. It will be delivered by Dr. Djamilatou Adom from the Indiana University School of Medicine laboratory of Dr. Sophie Paczesny.
“I’m excited about the potential of ALPN-101 in GvHD given its dual CD28/ICOS mechanism of action,” said Dr. Paczesny, Professor of Immunology and Pediatrics at Indiana University School of Medicine and lead of the Biomarkers Stem Cell Transplantation Program, and one of Alpine’s research collaborators. “Targeting the ICOS/ICOSL and CD28/B7 pathways may represent a new avenue to treat or prevent GvHD, and early biomarker development could identify patients at risk and support ALPN-101 as an early intervention in this patient population.”
Oral Presentation
- Title: ICOSL+ Plasmacytoid Dendritic Cells As Biomarker and Inducer of Graft-Versus-Host Disease
- Session Name: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Biomarkers and the Microbiome
- Date and Time: Sunday, December 2, 2018 at 9:30-9:45 a.m. PT
- Location: Grand Hall A of the Manchester Grand Hyatt San Diego.
Editas Data Supports Novel Sickle Cell, Beta-Thalassemia Therapy at ASH
Editas Medicine, Inc.EDIT, +3.49% a leading genome editing company, today announced results from experiments to demonstrate expanded CRISPR genome editing strategies in hematopoietic stem cells for the treatment of sickle cell disease and beta-thalassemia. In these experiments, the Company demonstrated HBG1/2 promoter-edited CD34+ cells robustly engrafted in mice without lineage skewing of red blood cell precursors. The Company reported these data today in an oral presentation at the 60 [th] Annual Meeting of the American Society of Hematology (ASH) in San Diego.
In these experiments, NBSGW mice received an infusion of human CD34+ cells which had been edited either at the BCL11A erythroid enhancer (BCL11Ae) site or at the HBG1/2 promoter site. Analysis of bone marrow collected eight to 16 weeks post-infusion demonstrated that robust fetal hemoglobin induction was achieved when targeting HBG1/2 promoters. Notably, editing HBG1/2 promoters upregulated fetal hemoglobin with superior repopulation of red blood cell precursors as compared to editing the BCL11Ae site. The red blood cell precursors from bone marrow edited at the BCL11Ae site had lower productive editing rates compared to other lineages and showed increased level of apoptosis, or programmed cell death, in erythroid culture compared to HBG1/2 promoter-edited cells.
Increased production of fetal hemoglobin can be beneficial to patients with sickle cell disease or beta-thalassemia. Editing at the HBG1/2 site is a differentiated approach for development of a human therapeutic for the treatment of sickle cell disease and beta-thalassemia as compared to other medicines currently under development that edit at the BCL11Ae site.
“We are encouraged by these preclinical results demonstrating cells edited at the HBG1/2 promoters repopulated all lineages of the blood system including, importantly, the red blood cell precursors. Editing at this site met our preclinical goals including robust, long-term induction of fetal hemoglobin and maintenance of normal hematopoietic stem/progenitor cell function,” said Charles Albright, Ph.D., Chief Scientific Officer, Editas Medicine. “These findings further support our novel approach to developing a medicine for the potential treatment of sickle cell disease and beta-thalassemia. If these preclinical results translate to humans, we believe our editing approach for hemoglobinopathies may yield a safer and more effective medicine.”
Novel Therapies Offer Hope in Sickle Cell Disease
New approaches to stem cell transplantation and gene therapy showed promise in treating, and possibly even reversing, sickle cell disease (SCD), researchers said here.
In one study, a parental-donor transplant technique seemed to provide SCD patients with more options for finding suitable allogeneic transplant donors, reported Mitchell Cairo, MD, of New York Medical College in Valhalla, New York, and colleagues, in a presentation at the American Society of Hematology annual meeting.
Currently, the only cure available for SCD is a stem cell transplant using cells donated by a sibling who doesn’t have SCD, who has the same tissue type, and has the same mother and father. With these restrictions, only about 15% of patients with SCD has a sibling who is a suitable donor.
Cairo and colleagues investigated the possibility of a haploidentical transplant, a modified form of stem cell transplant in which a healthy first-degree relative — such as a parent — could be a suitable donor.
The problem with this type of transplant has been a high failure rate. To counter that, Cairo’s group enriched stem cells with a protein called CD34, with the understanding it promotes the acceptance of transplanted blood-forming cells. They also added back the patients’ T cells after the transplant because these cells also promote acceptance of blood-forming cells, but don’t increase rates of graft-versus-host-disease (GVHD).
The authors transplanted parental stem cells into 19 patients (mean age 13.1 years) who had frequent or severe SCD symptoms.
Engraftment, where the recipient’s body accepts the new stem cells and they begin to produce new blood and immune cells, occurred in all 19 patients, while chimerism, which is a measure of the durability of engraftment, was at a 97% rate 1 year after transplant.
One patient developed GVHD disease within 100 days of transplant, while another developed it >100 days post-transplant.
In follow-up testing 2 years after the transplant, patients had improved heart and lung function, no evidence of stroke or inflammation of blood vessels, and improved or stable intellectual functioning, memory, language, and executive function.
Physical and emotional quality of life were also significantly improved at 2 years.
After 3 years of follow-up, “there are no patients who have signs of sickle cell disease, or sickle symptoms, and they are all off immunosuppressive therapy, and off all other drugs,” Cairo stated.
Most importantly, patients with high-risk SCD features who have a living parent “now have a potential allogeneic donor in the family,” he added.
In a second study, a novel approach to gene therapy showed promise in helping patients stop producing sickle hemoglobin and produce fetal hemoglobin instead, reported Erica Esrick, MD, of Boston Children’s Hospital, and colleagues.
Fetal hemoglobin inhibits the development sickle hemoglobin polymers, Esrick explained.
Esrick’s group targeted a protein called BCL11A. Previous research has shown that silencing BCL11A can reactivate fetal hemoglobin production, effectively reversing SCD.
The technique, devised by co-author David Williams, MD, also of Boston Children’s Hospital, involves the use of a lentiviral vector in a patient’s own stem cells to reintroduce the capacity to make fetal hemoglobin.
Four patients enrolled in the pilot study, one of who has already received gene therapy. Prior to transplant, that patient required monthly transfusions to alleviate SCD symptoms, but post-study, required one transplant in the following 6 months, according to Esrick.
In addition, while blood tests show high levels of fetal hemoglobin in this patient, and he has not experienced any of the complications associated with SCD, such as pain, anemia, and respiratory or neurological events.
“Targeting BCL11A using gene therapy looks to be a promising approach to increase fetal hemoglobin,” Esrick stated.
Cairo disclosed a relevant relationship with Janssen. Co-authors disclosed multiple relevant relationships with industry.
Esrick and many co-authors disclosed relevant relationships with Bluebird Bio. Some co-authors are company employees.
Primary Source
American Society of Hematology
Secondary Source
American Society of Hematology
ASH: Hemophilia Meds Elocta, Alprolix Efficacious, Safe Over 4 Years
Orphan Biovitrum AB (publ) (Sobi™) and Bioverativ Inc., a Sanofi-company, today announced the final results of ASPIRE and B-YOND, the most comprehensive long-term studies of extended half-life factor therapies in haemophilia. The data from both studies confirm the established safety and sustained efficacy of Elocta® (efmoroctocog alfa), marketed as ELOCTATE® in the United Statesand other countries, and Alprolix® (eftrenonacog alfa) over four years of treatment in previously treated adult, adolescent, and paediatric patients with severe haemophilia A and B, respectively. These results were presented at the 60th Annual Meeting of the American Society of Hematology (ASH).
Factor replacement therapy is the cornerstone of haemophilia care and results from ASPIRE and B-YOND demonstrated that long-term prophylactic treatment with efmoroctocog alfa and eftrenonacog alfa consistently improved annualised bleed rates, including joint bleeds, across all patient populations studied and at extended dosing intervals. No inhibitors were observed in subjects enrolled in either of the two extension studies and the overall safety profile was consistent with the pivotal phase 3 studies. Inhibitor development has been observed with efmoroctocog alfa and eftrenonacog alfa post market.
“These data add to a significant body of evidence showing that efmoroctocog alfa and eftrenonacog alfa provide protection from all types of haemophilia-related bleeds with individualised and flexible dosing regimens across all study populations,” said Tim Harris, Ph.D. DSc., Executive Vice President, Research and Development at Bioverativ. “We remain focused on and committed to providing complete protection for people with haemophilia.”
Debilitating joint disease, which is caused by repeated bleeds into joints over time, is one of the most common complications for people with haemophilia. In ASPIRE and B-YOND, subjects on prophylactic treatment experienced low joint and spontaneous joint annualised bleed rates (ABRs) across all dosing regimens. These results support that prophylactic dosing with efmoroctocog alfa and eftrenonacog alfa can effectively manage and control all types of joint bleeds.
“Joint protection remains a significant challenge in the long-term treatment of haemophilia keeping individuals from living a life without constraints of their disease and these results confirm that our therapies can play a role in the effective prevention of joint bleeds,” said Milan Zdravkovic, Head of Research & Development and Chief Medical Officer at Sobi. “In addition to providing the clinical evidence to support the long-term use of our therapies, we continue to explore the impact of Fc fusion on joint health.”
An interim, post-hoc analysis of ASPIRE published in Haemophilia found that a prophylactic regimen of efmoroctocog alfa can lead to continuous improvement in joint health, regardless of prior treatment regimen, severity of joint damage, or target joints. This retrospective study evaluated joint health in adult and adolescent participants (n=47) using a modified version of the Hemophilia Joint Health Score (mHJHS), a first-line assessment tool that grades joints by specific domains including swelling, muscle atrophy, alignment, range of motion, joint pain, strength and global gait. Additional studies will be needed to confirm these findings and the mHJHS will require further validation.
Efmoroctocog alfa and eftrenonacog alfa are leading extended half-life therapies in the United States and Europe. They have been proven to treat all types of bleeds and can be used in all treatment scenarios, including acute, surgical and emergency situations. The safety and efficacy of both therapies have been studied over hundreds of exposure days in adult, adolescent, and paediatric patients with haemophilia since 2010.
Spark Updates Data on Ongoing Phase 1/2 Hemophilia A Trial at ASH
Preliminary Phase 1/2 data for investigational SPK-8011 for hemophilia A show dramatic reductions in bleeds and infusions for first 12 participants with an encouraging safety profile, as of Nov. 2, 2018, data cutoff
All five participants in the first two dose cohorts, the longest of whom is out 78 weeks post SPK-8011 infusion, have shown persistent, stable factor VIII activity levels in this ongoing study
Planning to initiate a Phase 3 run-in study by the end of 2018
Spark Therapeutics (NASDAQ:ONCE), a fully integrated, commercial gene therapy company dedicated to challenging the inevitability of genetic disease, today announced updated preliminary data on the first 12 participants in the ongoing Phase 1/2 clinical trial of investigational SPK-8011 in hemophilia A. These data were presented at the 60thAmerican Society of Hematology (ASH) Annual Meeting and Exposition in San Diego by Principal Investigator Lindsey A. George, M.D., assistant professor of pediatrics, The Perelman School of Medicine, University of Pennsylvania and attending physician in the Division of Hematology at Children’s Hospital of Philadelphia.
The 12 participants in the Phase 1/2 trial received a single administration of investigational SPK-8011, including two at a dose of 5×1011 vector genomes (vg)/kg body weight, three at a dose of 1×1012 vg/kg and seven at a dose of 2×1012 vg/kg. As of the Nov 2, 2018, data cutoff, no inhibitors, no thrombotic events and no persistent or unresolved transaminase elevations have been observed across a cumulative 9.7 years of data follow-up. Across all three doses, beginning four weeks after vector infusion, there has been a 94-percent reduction in bleeds and a 95-percent reduction in FVIII infusions.
Participants in the 5×1011 vg/kg and 1×1012 vg/kg dose cohorts have shown dramatic reductions in bleeds and infusions as well as stable FVIII activity with up to 78 weeks of follow-up, with observation ongoing.
Among the five participants treated in the 2×1012 vg/kg cohort who did not experience an immune response-associated decline in FVIII expression, beginning four weeks after vector infusion, there has been a 100-percent reduction in bleeds and a greater than 99-percent reduction in FVIII infusions, with up to 46 weeks of follow-up.
“These updated data continue to demonstrate impressive reductions in bleeds and infusions across all doses studied, including complete-elimination of bleeds in the five participants at 2×1012 vg/kg cohort who did not experience a deleterious immune response,” said Katherine A. High, M.D., president and head of research and development at Spark Therapeutics. “Moreover, the safety profile has been excellent, with no inhibitors, no prolonged transaminase elevations and no thromboembolic events for the 12 participants. Consistent with our expectations and aligned with prior results using Spark Therapeutics’ adeno-associated viral (AAV) technology platform, the participants in the first two dose cohorts have seen durable responses characterized by stable factor VIII activity levels out as long as one and a half years.”
Seven of the 12 participants received a tapering course of reactively administered oral steroids, including five in the 2×1012 vg/kg cohort, in response to an alanine aminotransferase (ALT) elevation above the patient’s baseline, declining FVIII levels and/or positive IFN-g enzyme-linked immunospots (ELISPOTs). For all participants, steroids led to rapid normalization of ALT and/or ELISPOTs.
All participants responded to vector infusion with an increase in circulating levels of FVIII. As previously disclosed, two participants in the 2×1012 vg/kg cohort had a suspected capsid immune response that caused their FVIII levels to decline to less than 5 percent. One of these participants did not rapidly respond to reactively administered oral steroids and was electively admitted to the hospital to receive two intravenous (IV) methylprednisolone infusions. The event subsequently resolved without sustained deleterious effects other than the decrease in FVIII activity. The admission to hospital for these infusions met the criteria for a serious adverse event (SAE).
Across the study through the data cutoff, the 12 participants demonstrated rapid clearance of vector from body fluids, with median time to clear vector DNA from saliva, semen and urine of two weeks.
“We expect to provide a further update of the Phase 1/2 study in mid-2019, which will include an additional 2×1012 vg/kg dose cohort of five to 10 participants dosed with material from our suspension manufacturing process and will also evaluate a prophylactic – rather than reactive – approach to steroid administration with the goal of reducing or eliminating immune responses,” added High.
Spark Therapeutics intends to initiate a Phase 3 run-in study by the end of 2018 to collect prospective observational data on trial participants.
Please see Dr. George’s presentation here.
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