Clinical trial updates

Sickle Cell Disease

Imatinib

 

Update: 14 May 2020

  • A phase I clinical trial in the US aims to investigate whether imatinib (a SYK tyrosine kinase inhibitor) can reduce the expression of SCD symptoms (e.g. RBC deformability, adhesion / stickiness etc) and thus painful crises in patients with SCD.
  • The hypothesis focuses on the connection between the increased oxidative stress levels found in SCD and the subsequent increase of tyrosine phosphorylation of band 3 which in turn is responsible for some of the SCD symptoms. Inhibiting or blocking the increase of tyrosine phosphorylation band 3 with imatinib fewer complications in SCD patients may occur.
  • Still in early phase I, the study will enrol 48 paediatric patients who have not yet undergone transfusion

Sources:

https://www.hematologyadvisor.com/home/topics/anemia/sickle-cell-disease-treatment-using-tyrosine-kinase-inhibition/

https://clinicaltrials.gov/ct2/show/NCT03997903

FT-4202

 

Update: 14 May 2020

Granted Orphan Drug designation by FDA.

Sources:

https://www.hematologyadvisor.com/home/topics/anemia/novel-pyruvate-kinase-activator-gets-orphan-drug-status-for-sickle-cell-disease/

 

Update: 31 March 2020

  • FT-4202 is a small chemical molecule that is designed to bind to PKR in the RBCs and increases its activity. This increases the affinity of haemoglobin for oxygen in the sickled RBCs, and helps them deliver more oxygen to different tissues and organs in the body. When oxygen affinity increases, the sickling of the RBCs decreases. FT-4202 could, also alleviate other symptoms of SCD like vaso-occlusive crises.
  • A Phase 1 randomized, placebo-controlled, double-blind, single- and multiple-ascending dose study is assessing the safety, pharmacokinetics (movement in the body), and pharmacodynamics (effects on the body) of FT-4202 first in healthy volunteers and then in SCD patients.
  • With a favourable safety profile, the trial is currently recruiting SCD patients in the U.S. to conduct a planned second part; It is expected to finish by September 2020.
  • Given fast trackand rare paediatric disease designations by the U.S. Food and Drug Administration (FDA).

Sources:

https://sicklecellanemianews.com/2020/02/27/ft-4202-granted-fda-fast-track-rare-pediatric-disease-designation-scd/

https://sicklecellanemianews.com/ft-4202/

 

OTQ923 Gene Editing 

 

Update: 31 March 2020

The FDA has authorised the start of a Phase 1/2 clinical trial testing a genome editing-based therapy for adults with severe complications of sickle cell disease (SCD).

The clinical trial uses CRISPR/Cas9 genome-editing technology to edit the genome to increase the development of fetal haemoglobin, thus increasing the efficiency of oxygen transportation in the body.

Animal studies have suggested an increase of up to 30% of fetal haemoglobin in red blood cells.

Sources :

https://sicklecellanemianews.com/2020/04/02/phase-1-2-trial-of-crispr-gene-editing-scd-cleared-by-fda/?utm_source=Sickle+Cell+Anemia+News&utm_campaign=a9ec38e189-RSS_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_b01e3fbae8-a9ec38e189-73559237

 

ARU-1801 Gene Therapy (SCD)

 

Update: 31 March 2020

No update available.

 

Update: 31 January 2020

The U.S. Food and Drug Administration (FDA) granted rare pediatric disease designation to ARU-1801, an experimental gene therapy for the treatment of sickle cell disease (SCD) and beta-thalassaemia.

This designation means eligibility for a  priority review voucher once the FDA approves a biologics license application for ARU-1801.

Focus on delivering a modified version of the fetal haemoglobin gene, through a viral virus called lentivirus — optimized to enhance the protein’s natural oxygen carrying ability and anti-sickling properties.

Sources:

https://sicklecellanemianews.com/2020/01/09/aravant-sickle-cell-therapy-gets-fda-rare-pediatric-disease-designation/

 

CRISPR Gene Editing 

 

Update: 14 May 2020

  • Regenerative Medicine Advanced Therapy (RMAT) designation has been granted by the FDA.
  • RMAT seeks to fasten the development & review of new therapies, allowing for priority review and possibly faster approval by the FDA.
  • CTX001 uses CRISPR-Cas9 gene editing tool to produce higher levels of fetal haemoglobin in RBCs. Increased levels of fetal haemoglobin are expected to lower the frequency of vaso-occlusive crises (VOCs).
  • Preliminary datafrom the Phase 1/2 CLIMB-SCD-121 trial (NCT03745287), which is assessing the safety and effectiveness of a single dose of CTX001 in patients with severe SCD, has shown that the therapy safely increased the levels of fetal hemoglobin in the first patient dosed, effectively preventing the occurrence of VOCs.

 

Update: 31 March 2020

No update available.

 

Update: 31 January 2020

No update available

 

Update: 25 November 2019

  • CRISPR Therapeutics and Vertex Pharmaceuticals announced positive, interim data from the first two patients with severe haemoglobinopathies treated with the investigational CRISPR/Cas9 gene-editing therapy CTX001.
  • 1 patient with severe sickle cell disease (SCD) received CTX001 in mid-2019 and data for this patient reflect four months of safety and efficacy follow-up.
    • Experienced seven vaso-occlusive crises (VOCs) per year
    • At four months after CTX001 infusion, the patient was free of VOCs and had total haemoglobin levels of 11.3 g/dL
    • Three SAEs occurred, none of which the PI considered related to CTX001: sepsis in the presence of neutropenia, cholelithiasis, and abdominal pain, all of which resolved.

These studies are ongoing and patients will be followed for approximately two years following infusion. Several additional patients have been enrolled and have had drug product manufactured across the two studies.

CLIMB-SCD-121: An ongoing Phase 1/2 open-label trial, designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 18 to 35 with severe SCD. The study will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up study. Enrollment is ongoing at 12 clinical trial sites in the United States, Canada and Europe.

Sources:

http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-and-vertex-announce-positive-safety-and

 

Update: 27 September 2019

  • Enrollment in Phase 1/2 study of CTX001 in patients with severe SCD is ongoing. Based on the progression of the program, CRISPR Therapeutics expects to obtain preliminary safety and efficacy data in late 2019.
  • The first patient has been treated in a Phase 1/2 clinical study of CTX001 in severe SCD in the U.S.
  • There are plans to enrol at total of 45 patients in this study, with plans to review the safety of the therapy after the first 17 have been treated.

Sources:

http://www.globenewswire.com/news-release/2019/07/29/1893210/0/en/CRISPR-Therapeutics-Provides-Business-Update-and-Reports-Second-Quarter-2019-Financial-Results.html

https://time.com/5642755/crispr-gene-editing-humans/

 

Update: 30 May 2019

No update available.

 

Update: 29 March 2019

  • The Phase 1/2 Study in Sickle Cell Disease (SCD) is an open-label trial aiming to assess the safety and efficacy of a single dose of CTX001 in patients ages 18 to 35 with severe SCD. Similar to the trial in beta thalassaemia two patients will be initially treated sequentially and, pending data from these, the trial will open for broader enrollment.

The first patient has been enrolled in the U.S. and is expected to be infused with CTX001 in mid-2019.

Sources:

http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-and-vertex-announce-progress-clinical

 

Update: 01 February 2019

  • The FDA has granted Fast Track Designation for CTX001 for the treatment of sickle cell disease (SCD).
  • The Fast Track Program is designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.  A drug granted Fast Track Designation may be eligible for several benefits, including more frequent meetings and communications with the FDA and, if relevant criteria are met, the potential for Accelerated Approval, Priority Review or Rolling Review of a Biologics License Application (BLA).

Sources:

http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-and-vertex-announce-fda-fast-track

 

Update: 20 December 2018

This treatment will introduce a second genetic mutation into the patient’s genome that causes a naturally-occurring condition called Hereditary Persistence of Fetal Haemoglobin, or HPFH. HPFH is benign, asymptomatic, and requires no treatment. The only difference between those with HPFH and those without, is the type of haemoglobin they produce. HPFH patients produce fetal haemoglobin, while patients with SCD produce altered and ineffective haemoglobin molecules.

 

  • In October the FDA has lifted the hold (in place since May) for the initiation of human clinical trials for SCD patients.
  • The FDA approved trials for β-thalassaemia patients in August.
  • Approvals have already been obtained for initiation of trials multiple countries outside the U.S. for both β-thalassaemia and SCD.
  • The initiation of Phase 1/2 clinical study in SCD by the end of 2018 remains on track and currently patients with transfusion dependent β-thalassemia are enrolling in a Phase 1/2 trial in β-thalassaemia in Europe.

Sources:

http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-and-vertex-announce-fda-has-lifted-clinical

 

ZFN Gene Editing 

 

Update: 31 March 2020

No update available.

 

Update: 31 January 2020

Data presented at 61st Annual Meeting of the American Society of Hematology revealed that >90% of edited cells were biallelic, displaying on average 27-38% more HbF% despite variation in donor baseline levels.

Editing resulted in a 3-fold HbF increase.

Sources: https://ashpublications.org/blood/article/134/Supplement_1/974/427026/Zinc-Finger-Nuclease-Mediated-Disruption-of-the?searchresult=1

 

Update: 25 November 2019

  • The results of ex vivo gene-edited cell therapy data will be featured in poster presentations at the 61st Annual Meeting of the American Society of Hematology, under the title “Zinc Finger Nuclease-Mediated Disruption of the BCL11A Erythroid Enhancer Results in Enriched Biallelic Editing, Increased Fetal Hemoglobin, and Reduced Sickling in Erythroid Cells Derived from Sickle Cell Disease Patients”
  • Data showed increased HbF (between 27 – 38%), and reduced sickling in erythroid cells.
  • Phase 1/2 trial evaluating the safety, tolerability and efficacy of a BIVV003, a gene editing therapy using the ZFN technology in adults with severe SCD. This trial, taking place at four U.S. sites, is currently recruiting eligible patients.

Sources:

https://investor.sangamo.com/news-releases/news-release-details/sangamo-announces-gene-therapy-and-ex-vivo-gene-edited-cell

https://sicklecellanemianews.com/2019/11/12/gene-editing-technology-in-bivv003-trial-severe-scd-supported-early-study/

 

Imara (IMR-687)

 

Update: 31 March 2020

Based on the interim Phase 2a data, the initiation of two Phase 2b studies in the first half of 2020 are expected. One in in sickle cell disease and the other in beta thalassaemia. Preliminary data from both studies are expected in the first half of 2021.

Sources:

https://www.fool.com/investing/2020/03/05/hematology-focused-biotech-imara-to-ipo-soon.aspx

https://xconomy.com/boston/2020/03/12/imara-dives-into-coronavirus-churned-financial-waters-with-a-75m-ipo/

 

Update: 31 January 2020

No update available

 

Update: 25 November 2019

  • Early data from a Phase 2 trial show that once-a-day therapeutic oral inhibitor IMR-687 is well-tolerated, and shows signs of potential for lowering blood biomarkers of SCD, targeting both red cell and white cell aspects of the disease.
  • The Phase 2 trial still recruiting participants at several trial centers in the U.S. and the U.K., is testing  IMR-687’s safety and tolerability.
  • Results from analysing the interim data of 19 participants (receiving 50 mg or 100mg IMR-687 only – without hydroxyurea. IMR-687 is doubled at week 13 and continues for another 24 weeks).
  • After five weeks patients treated with high doses of IMR-687 had a trend for lower levels of disease biomarkers in their blood (i.e. soluble P selectin (sPsel), soluble vascular cell adhesion molecule-1 (sVCAM), and myeloperoxidase (MPO)).
  • At week 13, this same group experienced an increase of 110% in F-cells — red blood cells that have fetal haemoglobin and often increase before fetal haemoglobin rises. At this time point, researchers detected a decrease in the number of reticulocytes (immature red blood cells), and a trend toward lessening of pain.

Sources:

https://sicklecellanemianews.com/2019/06/25/imara-investigational-imr-687-shows-promising-results-in-ongoing-phase-2-clinical-trial/

 

Update: 27 September 2019

No update available

 

Update: 30 May 2019

  • The FDA has granted the IMR-687 Fast Track designation.

Sources:

https://www.businesswire.com/news/home/20190529005463/en/

 

Update: 29 March 2019

Developed for sickle cell disease, IMR-687 is a highly potent, selective inhibitor of phosphodiesterase-9 (PDE9i) in blood cells. It targets the same biochemical pathway as hydroxyurea, a chemotherapeutic agent, but without its safety issues.

IMR-687 has been shown in cell and animal models to increase fetal globin, which prevents the polymerization of the sickled haemoglobin. This reduces red blood cell sickling, reduces red blood cell death and reduces occlusion of blood vessels. PDE9 inhibition also reduces white blood cell “stickiness” which further reduces the blockage of blood vessels.

The drug is currently being tested in a mid-stage study, which is expected to be concluded by June. Initial data is expected by the second half of this year, and the full readout in the first quarter of 2020.

Sources:

https://endpts.com/months-away-from-completing-a-key-sickle-cell-trial-upstart-imara-scores-63m-in-round-co-led-by-arix-orbimed/

 

 

Oxbryta (ex-Voxelotor) 

 

Update: 31 March 2020

No update available.

 

Update: 31 January 2020

In a draft report, the Institute for Clinical and Economic Review (a cost watchdog) concluded that the newly authorised sickle cell disease drugs in the US (from GBT, Novartis and Emmaus Medical) are too expensive to meet traditional cost-effectiveness measures. To fall within one measure of cost-effectiveness—below $150,000 per quality-adjusted life year—the companies would have to dramatically cut their prices.

For GBT’s Oxbryta, the cut would have to be almost 90% – a cost of $9,218 per year would be more appropriate —down from an estimated list price of $84,000 per year. And for Novartis’ Adakveo, ICER’s calculations suggested an annual cost of $25,410, less than one-third of its existing cost of $88,000 per year, as estimated by ICER.

Sources:

https://www.fiercepharma.com/pharma/new-sickle-cell-disease-drugs-from-novartis-global-blood-therapeutics-need-big-discounts

 

Update: 25 November 2019

  • The U.S. Food and Drug Administration (FDA) has granted accelerated approval for Oxbryta™ (Voxelotor) tablets for the treatment of sickle cell disease (SCD) in adults and children 12 years of age and older.
  • Oxbryta, an oral therapy taken once daily, is the first approved treatment that directly inhibits sickle haemoglobin polymerization, the root cause of SCD.
  • The accelerated approval of Oxbryta is based on clinically meaningful and statistically significant improvements in haemoglobin levels, accompanied by reductions in red blood cell destruction (haemolysis).
  • Results of the Phase 3 HOPE (Haemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization) Study of 274 patients 12 years of age and older with SCD showed that, after 24 weeks of treatment, 51.1% of patients receiving Oxbryta achieved a greater than 1 g/dL increase in haemoglobin compared with 6.5% receiving placebo (p<0.001).
  • Most common adverse reactions headache, diarrhea, abdominal pain, nausea, fatigue, rash and fever.
  • Information suggests a list price of $10,417 per month.

Sources:

https://www.globenewswire.com/news-release/2019/11/25/1952236/0/en/FDA-Approves-Oxbryta-Voxelotor-the-First-Medicine-Specifically-Targeting-the-Root-Cause-of-Sickle-Cell-Disease.html

https://www.fiercepharma.com/pharma/global-blood-therapeutics-scores-fda-nod-for-oxbryta-and-execs-expect-a-paradigm-shift

 

Update: 27 September 2019

The FDA has accepted for filing the application seeking accelerated approval for Voxelotor supported by the data of the multi-national Phase 3 HOPE Study of Voxelotor in patients ages 12 and older with SCD who enrolled in the study from 60 institutions across 12 countries.

FDA granted Priority Review for Voxelotor, which provides for a six-month review, and assigned a Prescription Drug User Fee Act (PDUFA) target action date of February 26, 2020. Under PDUFA, a Priority Review targets a review time of six months compared to a standard review time of 10 months.

Sources:

https://www.globenewswire.com/news-release/2019/09/05/1911462/0/en/GBT-Announces-U-S-Food-and-Drug-Administration-Acceptance-of-New-Drug-Application-and-Priority-Review-for-Voxelotor-for-the-Treatment-of-Sickle-Cell-Disease.html

 

Update: 30 July 2019

The results of the phase 3 HOPE trial were announced at the 24th Annual Congress of the European Hematology Association. The trial had a total of 274 participants, ranging from 12 to 65 years old, from 60 institutions across 12 countries.

Trial participants were randomized to receive  a daily dose of 1500mg/day, 900mg/day and placebo.

Results showed that:

1.The primary end point was a rise in total Hb by 1g/dl achieved by 59.5% of the 1500mg/day group, 38% of the 900mg/day group and 9.2% of the placebo group at 24 weeks.

2. A reduction of indirect bilirubin. 29.1% reduction in the 1500mg/day group

20.3% reduction in the 900mg/day group and 3.2% in the placebo group.

3. Reduced reticulocyte count. 19.9% reduction in the 1500mg/day group

1.3% reduction in the 900mg/day group and 4.5% increase in the placebo group

Hence,

  • The inhibitor significantly increased haemoglobin levels and reduced the incidence of acute anaemic episodes,
  • significant improvement in the health of red cells within two weeks of therapy, as indicated by decreases in bilirubin, reticulocyte counts, and other markers of haemolysis.
  • Fewer vaso-occlusive crises in the treatment group
  • No significant differences in the treatment related adverse events between the groups
  • 3 cases had MRI for cerebral blood flow – all showed reduction indicating a possible effect in reducing stroke by the use of Volexotor.

Sources:

https://www.ucsf.edu/news/2019/06/414701/patients-sickle-cell-increase-healthy-blood-cells-new-drug-trial

https://ir.gbt.com/news-releases/news-release-details/gbt-announces-updated-24-week-efficacy-data-all-patients

 

Update: 30 May 2019

Results of the phase IIa trial for the safety and efficacy of Voxelotor in SCD will be presented at the upcoming EHA Congress in June. These will include:

  • 38 participants were treated with Voxelotor 500 mg, 700 mg, or 1000 mg per day or placebo for 28 days
  • 16 participants were treated with Voxelotor 700 mg or 900 mg per day or placebo for 90 days, 4 patients of these participants were then enrolled in a separate extension study and treated with Voxelotor 900 mg per day for 6 months.
    Within 2 weeks of treatment, all doses of Voxelotor resulted in an increase of Hb level and/or a reduction in markers of haemolysis.
  • For patients treated long term with 900 mg, these improvements were sustained throughout the 6 months of treatment, with a median increase in Hb of approximately 1 g/dL. Nearly half of these patients (46%) achieved an increase in Hb of >1 g/dL from baseline.
    All treatment doses also resulted in reductions in the proportion of sickled red cells.
  • Adverse events that were reported in 10% or more patients were typically grade 1 or 2 and included headache, diarrhea, and rash.

Sources:

https://www.ajmc.com/newsroom/ascending-dose-study-demonstrates-safety-efficacy-of-voxelotor-in-sickle-cell-disease

 

Update: 29 March 2019

No update available.

 

Update: 01 February 2019

The preliminary results from phase IIa HOPE trials for the safety and efficacy of Voxelotor in SCD were presented at the 2018 ASH Annual Meeting. Results reflected the findings of two randomized, multi-centred trials with 154 patients participating – one with adults and adolescents over 12 years of age, and one with children and adolescents between the ages of 6 – 17.

Voxelotor is once-daily therapy for patients with SCD, is designed to work by helping haemoglobin, hold onto more oxygen as the red blood cells travel through the body. This keeps red blood cells in their normal shape and helps stop sickling. Thus leading to fewer VOCs.

Results:

  • Increases haemoglobin in a dose-dependent manner
  • 55% of patients experienced an Hb increase >1 g/dL after 16 weeks of treatment with Voxelotor 900 mg
  • Rapid, robust, and sustained improvement in haemoglobin and haemolysis
  • Safe and well tolerated
  • Fewer VOC with substantial increase in haemoglobin

The results also are potentially confounded by the concomitant administration of hydroxyurea.

However, the results support a potential for Voxelotor to reduce stroke risk in children – thus needing further investigation.

The FDA has granted Voxelotor Fast Track, Orphan Drug and Rare Pediatric Disease status. The EMA has designated Voxelotor as an Orphan Medicinal Product and included it in its Priority Medicines (PRIME) program.

Sources:

https://www.gbt.com/file.cfm/22/docs/Results_from_Part_A_HOPE_final_presentation.pdf

https://www.ashclinicalnews.org/on-location/voxelotor-offers-new-hope-sickle-cell-disease/ https://www.gbt.com/file.cfm/22/docs/Interim-Results_Phase-2a-Study_Adolescents_final-presentation.pdf

 

 

Adakveo (ex-Crizanlizumab) / SUSTAIN study (part of SENTRY clinical trial program) 

 

Update: 31 March 2020

No update available.

 

Update: 31 January 2020

In a draft report, the Institute for Clinical and Economic Review (a cost watchdog) concluded that the newly authorised sickle cell disease drugs in the US (from GBT, Novartis and Emmaus Medical) are too expensive to meet traditional cost-effectiveness measures. To fall within one measure of cost-effectiveness—below $150,000 per quality-adjusted life year—the companies would have to dramatically cut their prices.

 

For GBT’s Oxbryta, the cut would have to be almost 90% – a cost of $9,218 per year would be more appropriate —down from an estimated list price of $84,000 per year. And for Novartis’ Adakveo, ICER’s calculations suggested an annual cost of $25,410, less than one-third of its existing cost of $88,000 per year, as estimated by ICER.

Sources:

https://www.fiercepharma.com/pharma/new-sickle-cell-disease-drugs-from-novartis-global-blood-therapeutics-need-big-discounts

 

Update: 25 November 2019

  • US Food and Drug Administration (FDA) approved Adakveo® (Crizanlizumab), previously known as SEG101, a targeted biologic, to reduce the frequency of vaso-occlusive crises (VOCs), or pain crises, in adult and pediatric patients aged 16 years and older with sickle cell disease.
  • 45% reduction in VOCs regardless of SCD genotype and/or hydroxyurea use.
  • Fewer hospitalisation days per year (4 vs 6.87)
  • SUSTAIN is a randomized, multicenter, placebo-controlled, double-blind study. A total of 198 patients with any genotype of sickle cell disease (HbSS, HbSC, HbS/beta0-thalassaemia, HbS/beta+-thalassaemia, and others) and a history of 2-10 VOCs in the previous 12 months were eligible for inclusion.

Sources: https://ml-eu.globenewswire.com/Resource/Download/72d8bac9-2ce7-44de-ba9e-578e5a11b8e2

 

Update: 27 September 2019

No update available

 

Update: 30 July 2019

The FDA has accepted the BLA Application and granted Priority Review within six months (instead of 10 months).

Sources:

https://www.novartis.com/news/media-releases/fda-accepts-file-and-accelerates-review-novartis-sickle-cell-disease-medicine-crizanlizumab-seg101

 

Update: 30 May 2019

No update available.

 

Update: 29 March 2019

No update available.

 

Update: 01 February 2019

  • FDA has granted Crizanlizumab Breakthrough Therapy designation for the prevention of VOCs in patients of all genotypes with SCD.

Sources:

http://hugin.info/134323/R/2230725/876675.pdf

 

Update: 20 December 2018

New data from a post hoc analysis of the Phase II SUSTAIN study of Crizanlizumab for the treatment of sickle cell disease (SCD) presented at the 60th Annual Meeting of the American Society of Hematology (ASH) in San Diego, held on 01 – 04 December 2018.

The once-a-month, humanized anti-P-selectin monoclonal antibody infusion being investigated shows greater reductions of vaso-occlusive crises (VOCs) in patients who were adherent to the treatment protocol.

The trial enrolled 132 patients under treatment for 52 weeks.

Results:

  • Reduced the frequency of painful crises (37.5% vs 12.2% taking the placebo).
  • Decreased the annual rate of VOCs (1.04 vs 2.18).
  • Adverse events occurred in 10% or more of the patients in active-treatment, and at a frequency that was at least twice as high as that in the non-active treatment group. These included joint pain, diarrhea, severe itching, vomiting, and chest pain. There were no apparent increases in infections with Crizanlizumab treatment.

SENTRY clinical trial program including seven active or planned clinical studies designed to generate an array of additional data on the role Crizanlizumab plays in the management of sickle cell disease. More studies may be added as plans are finalized.

Major active trials in the SENTRY program include:

  • SOLACE-adults (A2202) Phase II study investigating the pharmacological properties and safety of Crizanlizumab in patients with sickle cell disease aged 16 and above
  • SOLACE-kids (B2201) Phase II study investigating the safety and efficacy of Crizanlizumab in pediatric patients with sickle cell disease
  • STAND (A2301) Phase III study investigating the efficacy and safety of Crizanlizumab in sickle cell disease patients aged 12 and above
  • SUCCESSOR retrospective cohort study among adult sickle cell disease patients in the US

Sources:

https://www.novartis.com/news/media-releases/novartis-announces-new-crizanlizumab-seg101-data-analysis-sickle-cell-disease-and-investment-sentry-clinical-program

https://www.raredr.com/news/crizanlizumab-reduces-pain-in-sickle-cell-disease

 

Gene Therapy (SCD)

 

Update: 31 March 2020

A new Phase 3 study of LentiGlobin for sickle cell disease (HGB-211) has been announced. This study is expected to begin enrolling patients in 2020, with a target of approximately 18 patients, ages 2-14 years with SCD and elevated stroke risk.

The primary endpoint of the study will be transcranial doppler response without transfusion.

HGB-211 is in addition to the company’s previously announced Phase 3 study (HGB-210)

Together with the phase 3 study HGB-210, HGB-211 is intended to support potential approval of LentiGlobin for SCD in pediatric patients at elevated stroke risk.

 

  • COVID-19 EFFECTS – The company expects that the COVID-19 pandemic will shift the timing of enrollment and completion of clinical studies by at least three months and expects timing shifts to vary by clinical trial and by program.

Sources:

http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-fourth-quarter-and-full-year-2019-financial

http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-provides-assessment-impact-covid-19-update-business

 

Update : 31 January 2020

New data from the ongoing Phase 1/2 HGB-206 study of investigational LentiGlobin™ gene therapy for sickle cell disease (SCD), including additional patients treated in the study and updated data for those previously reported were presented at the 61stAmerican Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida.

Phase 1/2: HGB-206 results:

HGB-206 is an ongoing, Phase 1/2 open-label study designed to evaluate the efficacy and safety of LentiGlobin gene therapy for SCD that includes three treatment cohorts: Groups A, B and C.

Group C:

  • 17 patients were treated with LentiGlobin for SCD, with the longest follow-up at 21 months; none required regular RBC transfusions post-treatment. There were no reports of ACS or serious VOC.
  • 12 patients had a follow up of six or more months with median levels of gene therapy-derived anti-sickling haemoglobin, HbAT87Q, at least 40% of total haemoglobin. Total haemoglobin and HbAT87Qlevels ranged from 9.3 – 15.2 g/dL and 2.7 – 9.0 g/dL, respectively, at last visit.
  • Treatment with LentiGlobin for SCD reduced key markers of haemolysis, including reticulocyte counts, lactate dehydrogenase (LDH) levels and total bilirubin concentration, which suggests that treatment is improving biological markers of the disease.
  • 9/12 who had four or more VOC or ACS events in the two years prior to treatment, saw a 99% reduction in annualized rate of VOC and ACS.
  • Key difference with Groups A & B: A refined manufacturing process that increases vector copy number (VCN) and improves engraftment potential of gene-modified stem cells was used for Group C. Group C patients also received LentiGlobin for SCD made from HSCs collected from peripheral blood after mobilization with plerixafor, rather than via bone marrow harvest, which was used in Group A and Group B.

Groups A and B:

  • 7/9 total patients in Groups A and B (5/7 in Group A and 2/2 in Group B) did not require regular RBC transfusions post-treatment.
  • All seven patients in Group A had reached at least three years of post-treatment follow-up. Levels of HbAT87Qand total haemoglobin remained durable in all seven patients. At last evaluable visit, median HbAT87Q levels were 0.9 g/dL and total haemoglobin was 9.0 g/dL.
  • Of the two patients in Group B, levels of HbAT87Qand total haemoglobin remained durable at two years of post-treatment follow-up. At last visit, HbAT87Q levels were 3.6 g/dL and 7.1 g/dL, and total haemoglobin was 11.3 g/dL and 13.0 g/dL.
  • Overall, patients in Groups A and B experienced a reduction, but not complete elimination of VOC and ACS events at two years post-treatment, suggesting that the levels of gene therapy-derived haemoglobin may have been sufficient to reduce but not eliminate continued sickle-related disease manifestations.

Sources: http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-presents-new-data-ongoing-phase-12-hgb-206-study

 

Update: 25 November 2019

  • A phase III study of LentiGlobin in sickle cell disease will be open and enrolling patients by the end of 2019.

Sources:

https://medcitynews.com/2019/11/bluebird-bio-eyes-clinical-updates-on-blood-cancer-blood-disorder-programs-by-year-end/

 

Update: 27 September 2019

No update available

 

Update: 30 July 2019

HGB-206 is an ongoing, Phase 1/2 open-label study designed to evaluate the efficacy and safety of LentiGlobin gene therapy for SCD that includes three treatment cohorts: Groups A, B and C. As of March 7, 2019, 25 patients were enrolled and a total of 13 patients had been treated with LentiGlobin in Group C, with a median post-treatment follow-up of nine months (1.0 – 15.2 months).

Group C of the Phase 1/2 HGB-206 study of LentiGlobin now includes multiple patients with at least one year of follow-up, many with a history of vaso-occlusive crises.

New data from patients in Group C of the ongoing Phase 1/2 HGB-206 study for LentiGlobin® gene therapy for sickle cell disease (SCD) were presented at the 24th European Hematology Association (EHA) Congress.

 

Phase 1/2: HGB-206 results:

  • No incidents of acute chest syndrome or serious vaso-occlusive crises reported at up to 15 months post-treatment with LentiGlobin. In an exploratory analysis, key markers of haemolysis, including reticulocyte counts, lactate dehydrogenase (LDH) and total bilirubin concentration, trended toward normal levels.
  • Eight of the 13 treated patients in Group C had at least six months of follow-up at the time of the data cutoff.
  • In these patients, production of gene therapy-derived haemoglobin (HbAT87Q) ranged from 4.5–8.8 g/dL and total unsupported haemoglobin (Hb) levels ranged from 10.2–15.0 g/dL at the last study visit.
  • The median concentration of HbAT87Q continued to increase, accounting for ≥50 percent of total Hb in patients with at least 12 months of follow up (n=4).

Sources:

http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-presents-new-data-lentiglobinr-gene-therapy-sickle

 

Update: 30 May 2019

The first patient treated with lentiviral vector–mediated addition of an antisickling β-globin gene into autologous haematopoietic stem cell, was reported in 1017 by the Bluebird Bio group at the Necker Children’s Hospital in Paris. The National Institutes of Health (NIH)  recently presented preliminary findings of an ongoing multicenter, nationwide (US) clinical trial of gene replacement therapy involving people with severe sickle cell disease.

This trial was among several testing experimental sickle cell gene therapies for which preliminary findings were reported at the 60th annual American Society of Hematology meeting in San Diego. Twelve clinical trials studying gene therapy to treat sickle cell anaemia are now ongoing. 

Sources:

Ribeil A, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, Caccavelli L,  Neven B, Bourget P,El Nemer W, Bartolucci P, Weber L.  Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med 2017; 376:848-855, doi: 10.1056/NEJMoa1609677

Rubin R. Gene Therapy for Sickle Cell Disease Shows Promise. JAMA. 2019;321(4):334. doi:10.1001/jama.2018.21119

  

L-glutamine (US marketed as  »Endari »)

 

Update: 31 March 2020

No update available.

 

Update: 31 January 2020

In a draft report, the Institute for Clinical and Economic Review (a cost watchdog) concluded that the newly authorised sickle cell disease drugs in the US (from GBT, Novartis and Emmaus Medical) are too expensive to meet traditional cost-effectiveness measures. To fall within one measure of cost-effectiveness—below $150,000 per quality-adjusted life year—the companies would have to dramatically cut their prices.

For GBT’s Oxbryta, the cut would have to be almost 90% – a cost of $9,218 per year would be more appropriate —down from an estimated list price of $84,000 per year. And for Novartis’ Adakveo, ICER’s calculations suggested an annual cost of $25,410, less than one-third of its existing cost of $88,000 per year, as estimated by ICER.

Sources:

https://www.fiercepharma.com/pharma/new-sickle-cell-disease-drugs-from-novartis-global-blood-therapeutics-need-big-discounts

 

Update: 27 September 2019

In the face of a negative opinion from the European Medicines Agency (EMA) over efficacy doubts, Emmaus Life Sciences has withdrawn its marketing application.

The drug continues to be licensed for use in the USA by the FDA.

The EMA’s main objection focused on the fact that Xyndari did not show it was effective at reducing the number of sickle cell crises or hospital visits, due to the higher number of dropouts in the trial.

 

Sources:

https://seekingalpha.com/news/3500602-emmaus-withdraws-european-application-scd-med-xyndari

https://endpts.com/emmaus-rescinds-eu-marketing-application-following-negative-review/

 

Update: 30 July 2019

Emmaus Medical Europe Limited has requested a re-examination of the CHMP’s opinion. After receiving the relevant documentation, the CHMP will re-examine its opinion and issue a final recommendation.

Sources:

https://www.ema.europa.eu/en/medicines/human/summaries-opinion/xyndari

 

Update: 30 May 2019

The first substance licenced by FDA for use in SCD in the last 20 years. It has completed phase 3 trials in 2017. It reduces oxidative stress and so reduces vaso-occlusive episodes. It is given orally at a dose of 0.3g/kg twice daily and may be given concomitantly with hydroxyurea. Low grade side effects such as nausea, musculoskeletal pains and fatigue may be experienced Approved for patients over the age of 5 years. 

Sources:

Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, Gordeuk VR, Viswanathan K(1), Sarnaik S(1), Osunkwo I(1), Guillaume E(1), Sadanandan S, Sieger L, Lasky JL, Panosyan EH, Blake OA, New TN, Bellevue R, Tran LT, Razon RL, Stark CW, Neumayr LD, Vichinsky EP; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med. 2018. 19;379(3):226-235. doi: 10.1056/NEJMoa1715971.

 

Xromi 

 

Update: 31 March 2020

No update available.

 

Update: 31 January 2020

No update available

 

Update: 25 November 2019

  • The Phase 3 RESET trial testing the effectiveness and safety of Rivipansel(GMI-1070),  to treat vaso-occlusive crisis (VOC) in hospitalized patients with sickle cell disease (SCD), failed to reach both its primary and secondary goals, top-line study results show.

Sources:

https://sicklecellanemianews.com/2019/08/06/rivipansel-for-vaso-occlusive-crisis-in-scd-fails-to-meet-goal-in-phase-3-trial/

 

Update: 27 September 2019

Granted marketing authorisation in the EU.

Xromi is a hybrid medicine of Hydrea which has been authorised in the EU since 29 May 1986. Xromi contains the same active substance as Hydrea but is authorised for a different indication. Hydrea is authorised for the treatment of certain cancers.

With new supportive data, Xromi is intended for the prevention of vaso-occlusive complications of sickle cell disease in patients over 2 years of age, to be available as a 100 mg/ml oral solution.

The active substance of Xromi is hydroxycarbamide.

Sources:

https://www.ema.europa.eu/en/medicines/human/EPAR/xromi

https://www.ema.europa.eu/en/medicines/human/summaries-opinion/xromi

 

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