Rare Daily Staff

The Annual Meeting of the American Society of Hematology, running in Orlando, Florida from December 7 through December 10, has become a place for visibility into several rare disease therapies in development. Below are some highlights from the conference.

Sangamo and Pfizer Say Hemophilia Gene Therapy Provides Stable and Durable Factor VIII Levels
Sangamo Therapeutics and Pfizer updated follow-up results from the phase 1/2 Alta study evaluating their experimental hemophilia A gene therapy SB-525 that showed it was generally well tolerated and demonstrated sustained increased factor VIII levels following treatment through 44 weeks, the extent of follow-up for the longest treated patient in the high-dose cohort.

People living with hemophilia A lack enough factor VIII protein to help their blood clot and are at risk for painful and potentially life-threatening bleeds from even modest injuries. In cases where the condition is severe, people with hemophilia A experience painful, spontaneous bleeds into their muscles or joints. Even with the use of replacement factor VIII therapy, many people continue to experience bleeds, resulting in progressive and debilitating joint damage, which can have a major impact on their quality of life.

Data from 11 patients treated with SB-525 were featured in a poster presentation December 7 at the ASH meeting.

All five patients in the high dose cohort rapidly achieved normal levels of factor VIII, and factor VIII levels have been stable and durable in the normal range for the first two patients up to 44 and 37 weeks following treatment respectively, with no bleeding events or factor usage up to a follow-up of 44 weeks in the longest treated patient.

“It is important to continue to follow these patients to determine whether these results are sustained in the longer term as the combination of a favorable safety profile coupled with sustained expression at a level that prevents bleeding and allows normal activity will be the hallmark of a successful gene therapy for hemophilia A,” said Barbara Konkle, Bloodworks Northwest, professor of medicine at University of Washington and a principal investigator of the Alta study.

Bluebird Bio Reports New Data from Ongoing Trial of SCD Gene Therapy
Bluebird bio said new data from its ongoing phase 1/2 HGB-206 study of experimental LentiGlobin gene therapy for sickle cell disease showed that the 17 patients in the highest dose cohort experienced high levels of gene-therapy derived anti-sickling hemoglobin and with up to four years of follow up, have not experienced any episodes of acute chest syndrome or serious vaso-occlusive crises following treatment.

Sickle cell disease (SCD) is a serious, progressive and debilitating genetic disease caused by a mutation in the β-globin gene that leads to the production of abnormal sickle hemoglobin, causing red blood cells to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and painful vaso-occlusive crises. For people living with SCD, this means unpredictable episodes of severe pain due to vaso-occlusion as well as other acute complications—such as acute chest syndrome, and stroke and infections, which can contribute to early mortality in these patients.

LentiGlobin for SCD was designed to add functional copies of a modified form of the β-globin gene into a patient’s own hematopoietic stem cells. Once patients have the gene, their red blood cells can produce anti-sickling hemoglobin that decreases the proportion of sickled hemoglobin, with the goal of reducing sickled red blood cells, hemolysis, and other complications.

Patients in two lower dose cohorts experienced a reduction, but not complete elimination of vaso-occlusion and acute chest syndrome events. The company said that suggests the levels of gene therapy-derived hemoglobin may have been sufficient to reduce but not eliminate continued sickle-related disease manifestations.

The safety data from all patients in HGB-206 showed there were no serious adverse events related to LentiGlobin for SCD. One mild, non-serious event of hot flush was reported that the investigator considered to be related to LentiGlobin for SCD. That event occurred and resolved on the day of infusion and did not require treatment.

Agios Says Phase 2 Study Established Proof-of-Concept for Thalassemia Therapy
Agios Pharmaceuticals said that a phase 2 study of mitapivat, it’s experimental therapy for patients with non-transfusion-dependent thalassemia, established proof-of-concept.

Thalassemia is an inherited blood disorder in which the body produces malformed or an inadequate amount of hemoglobin, a protein in red blood cells that carry oxygen. The condition leads to anemia.

Mitapivat is a first-in-class, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase-R (PKR) enzymes.

The phase 2 study has enrolled 12 of the intended 17 patients (nine with β-thalassemia and three with α-thalassemia). As of the November 14, 2019 data cut-off date, eight patients, all with β-thalassemia, were evaluable for the primary endpoint of a hemoglobin increase of 1.0 g/dL from baseline in at least one assessment during Weeks 4-12.

Seven of eight efficacy evaluable patients achieved a hemoglobin increase of 1.0 g/dL, and for responders the mean hemoglobin increase from baseline was 1.76 g/dL (range, 0.9–3.3 g/dL) during weeks 4-12.

The company said the safety and tolerability profile observed in the trial and in adults with pyruvate kinase deficiency supports the continued study of mitapivat treatment. Updated results from the phase 2 thalassemia study will be presented at a medical meeting in the first half of 2020.

In addition to the thalassemia phase 2 study, mitapivat is being studied in sickle cell disease under a Cooperative Research and Development Agreement with the U.S. National Institutes of Health.

Mustang Bio Updates Clinical Data on MB-107 Lentiviral Gene Therapy for Patients with X-Linked SCID
Mustang Bio said that updated phase 1/2 clinical data for MB-107 lentiviral gene therapy for X-linked severe combined immunodeficiency by St. Jude Children’s Research Hospital and the National Institutes of Health show the “curative potential” of the therapy.

X-linked severe combined immunodeficiency is a rare genetic disorder that is characterized by the absence or lack of function of key immune cells, resulting in a severely compromised immune system and death by 1 year of age if untreated. Patients with XSCID have no T cells or natural killer cells. Although their B cells are normal in number, they are not functional. As a result, XSCID patients are usually affected by severe bacterial, viral or fungal infections early in life and often present with interstitial lung disease, chronic diarrhea, and failure to thrive.

MB-107 is currently being assessed in two phase 1/2 clinical trials for XSCID: the first in newly diagnosed infants under the age of two at St. Jude, and the second in patients over the age of two who have received prior hematopoietic stem cell transplantation at the National Institutes of Health.

Under a licensing partnership with St. Jude, Mustang intends to develop the lentiviral gene therapy for commercial use as MB-107. The U.S. Food and Drug Administration (FDA) granted Regenerative Medicine Advanced Therapy designation to MB-107 for the treatment of XSCID in August 2019.

“The updated clinical data presented at the 2019 ASH Annual Meeting underscore the curative potential of MB-107 for newly diagnosed infants with XSCID, as well as its meaningful impact on older XSCID patients who received prior hematopoietic stem cell transplantation,” said Manuel Litchman, president and CEO of Mustang.

Interim data from the multicenter phase 1/2 clinical trial for infants under the age of two treated with the lentiviral gene therapy preceded by low exposure-targeted busulfan conditioning were published in the New England Journal of Medicine. Updated data presented at the 2019 ASH Annual Meeting include three more patients, eight months additional median follow up, more extensive analysis of T and B cell functional recovery, and detailed vector integration site studies.

Lentiviral gene therapy using low dose busulfan conditioning has been well tolerated, with no serious adverse events other than hematologic related to busulfan. All 11 patients had robust hematopoietic recovery within three to four weeks post cell infusion without blood product support.

Nine patients, with a follow up of greater than three months, achieved normal-for-age T-cell and natural killer-cell numbers within three to four months post gene therapy.

Five patients are off intravenous immunoglobulin (IVIG) therapy thus far, of whom three responded to vaccines.

Early outcome data for five older children and young adults with XSCID who received the lentivector gene therapy as salvage therapy after having previously received haplo-identical hematopoietic stem cell transplantation as infants without chemotherapy-based conditioning were previously reported and published in Science Translational Medicine.

By 2016, three additional patients were treated, and the cohort of eight patients (referred to as Cohort A) has now been followed for three to seven years. Among Cohort A, gradual clinical benefit in the clearance of chronic norovirus and associated improved abdominal complaints, malabsorption, growth and IgG production were observed, and four patients were able to cease immunoglobulin replacement therapy.

While the results were positive, the relatively inefficient transduction of hematopoietic stem/progenitor cells required large quantities of vector. This resulted in relatively low vector copy numbers in myeloid cells in some patients, with delayed immune cell recovery and persistent clinical disease, especially in the last patient treated (patient 8). To address this, NIH developed a refined enhanced transduction procedure consisting of a single overnight transduction after 48 hours pre-stimulation in cytokines.

The presentation at ASH included data from six patients (referred to as Cohort B) treated by NIH, including re-treatment of patient eight. The patients, who were aged 12 to 36, had significant problems with donor T cell infiltration of liver, bone marrow, and kidneys, and were nearly absent of B and NK cells. The enhanced transduction procedure achieved much greater transduction efficiencies than were observed in Cohort A, with greater than 10-fold less vector, and resulted in faster immune reconstitution and more significant clinical benefit by 3 months.

 Forma Therapeutics Reports Clinical Data for SCD Therapy
Forma Therapeutics reported positive phase 1 results from the healthy volunteer arm of an ongoing study of FT-4202, a novel selective red blood cell pyruvate kinase-R activator in development as a potential disease-modifying therapy for sickle cell disease.

SCD is a progressive, debilitating genetic disease characterized by the sickling of RBCs.

FT-4202 is designed to impact the pathogenesis of SCD with a multimodal approach. First, FT-4202 works upstream by activating the RBCs’ natural PKR activity to decrease 2,3-DPG levels, which lead hemoglobin to hold onto oxygen molecules longer, potentially reducing RBC sickling. Second, the downstream activity of FT-4202 increases ATP levels to potentially improve RBC health and survival. Together, these effects are anticipated to increase hemoglobin levels and decrease the painful vaso-occlusive crises that patients often endure.

“The safety and tolerability profile observed in this study is exciting, as are the PK/PD data that confirm FT-4202 activates PKR with a simultaneous effect on hemoglobin oxygen affinity and ATP levels in healthy volunteers,” said Patrick Kelly, chief medical officer of Forma Therapeutics. “These data correlate with findings from in vitro studies of blood from patients with sickle cell disease, and we have now identified a well-tolerated dose range with PKR activity lasting up to three days following the last dose.”

FORMA is evaluating FT-4202 in an ongoing phase 1 study to characterize the safety, tolerability, and the pharmacokinetics/pharmacodynamics (PK/PD) of a single ascending dose and multiple ascending doses of FT-4202, first in the recently completed arm in healthy volunteers, and now in patients with sickle cell disease.


Achillion Reports Positive Data from Phase 2 Study of Danicopan in Combination with Eculizumab in PNH Patients
Achillion Pharmaceuticals reported top-line data from a dose-finding phase 2 trial assessing the safety and effectiveness of its oral small molecule factor D inhibitor danicopan (ACH-4471) in combination with intravenous eculizumab in paroxysmal nocturnal hemoglobinuria (PNH) patients who have an inadequate response to C5 monotherapy.

PNH is a rare, acquired blood disease caused by a somatic mutation resulting in the absence of key receptors, CD55 and CD59, on the surface of red blood cells (RBCs). The complement system recognizes these unprotected red blood cells as foreign and destroys them in the circulatory system (intravascular hemolysis [IVH]) and in the liver or spleen (extravascular hemolysis [EVH]). The current standard of care for PNH targets IVH by inhibiting C5 complement protein (C5), leaving some patients with persistent EVH from early phases of complement activation (alternative pathway [AP] activity) which C5 inhibition cannot address. This may leave patients with partial control of their PNH symptoms.

Up to 75 percent of PNH patients treated with C5 inhibitors remain anemic during treatment, with up to one-third of those patients reporting the need for blood transfusions within the last year. Factor D is the critical, rate-limiting protein within the AP. By targeting Factor D, proximal AP inhibition may disable both downstream terminal complement activation (IVH) and upstream C3 fragment opsonization (EVH). Achillion is developing a potentially more complete approach to PNH with factor D inhibition to selectively block alternative pathway activity and protect against both destructive processes of RBCs in PNH with convenient oral therapies.

The primary endpoint of the trial was an increase in hemoglobin from baseline. A mean increase of 2.4 g/dL at 24 weeks of treatment was achieved in this proof-of-concept trial. Danicopan, in combination with eculizumab, resulted in a significant reduction in blood transfusions with 10 patients receiving 34 transfusions (58 units) in the 6 months prior to screening to 1 patient receiving 1 transfusion (2 units) during the 24-week trial.   

“C5 inhibition, the current standard of care, is an effective treatment approach for patients with PNH. While this treatment approach shows control of intravascular hemolysis and improved overall survival, many patients remain anemic and some may continue to be transfusion dependent due to persistent extravascular hemolysis,” said Austin Kulaskeraraj, lead author of the phase 2 poster presentation at ASH and consultant hematologist at Kings College Hospital in London. “In this clinical trial, the addition of danicopan, a factor D inhibitor that addresses the extravascular hemolysis caused by PNH, to C5 inhibitor therapy resulted in a greater than 2-gram increase in hemoglobin, and significant reduction of transfusions.”

In addition to improvements in hemoglobin and transfusions, there were also meaningful improvements in markers of hemolysis including bilirubin, reticulocytes, and PNH red blood clone size.

Danicopan was generally well tolerated. All treatment emergent adverse events were considered mild to moderate in severity except for grade 3 severe adverse events that occurred in two patients. Both patients had resolution of their events, remained on danicopan, and completed the study.  

Achillion was granted Breakthrough Therapy designation by the FDA and PRIME designation by the European Medicines Agency for danicopan for the treatment of PNH in combination with a C5 monoclonal antibody for patients who are suboptimal responders to a C5 inhibitor therapy alone.

Dova Presents Burden-of-Disease Survey Results for ITP
Dova Pharmaceuticals, a wholly owned subsidiary of Swedish Orphan Biovitrum AB, presented results from an online survey highlighting disease burden and impact for patients with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disorder causing reduced platelet counts with potential bleeding consequences and reduced quality of life. Treatment is generally reserved for adults with platelet counts <30,000/µL.

ITP patients from the Platelet Disorder Support Association were recruited to complete a one-time cross-sectional survey online. Eligible adults from the United States self-reported that they had been diagnosed with ITP and received at least one treatment. Patients completed a 30-45-minute online survey about demographics, diagnosis experience, symptoms, disease management and treatment.

The survey found two-thirds of respondents had been diagnosed at least ten years previously. A total of 58 percent of patients reported that ITP-related fatigue interfered with their work, family, or social life. Prior to being treated, 35 percent reported fatigue daily and 13 percent reported it twice a week. Despite treatment, a similar proportion reported fatigue daily (39 percent) or twice a week (16 percent).

Overall, the results of the survey did not suggest that bleeding was a concern for most patients: 59 percent reported that bleeding does not interfere with their work, family, or social life.

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