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Sickle Cell Disease

CRISPR gene editing (SCD)

 

Update: 25 November 2019

  • CRISPR Therapeutics and Vertex Pharmaceuticals announced positive, interim data from the first two patients with severe hemoglobinopathies 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 hemoglobin 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 thalassemia two patients will be initially treated sequentially and, pending data from these, the trial will open for broader enrolment.

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 Hemoglobin, 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-thalassemia 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-thalassemia in Europe.

Sources:

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

 

ZFN gene editing (SCD)

 

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/

Sevuparin

 

Update: 27 September 2019

No update available

 

Update: 30 May 2019

Phase II study of sevuparin did not show a meaningful benefit in the management of acute vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD),

Sources:

http://www.bioworld.com/content/modus-therapeutics-sickle-cell-disease-drug-sevuparin-fails-phase-ii-study

 

Update: 29 March 2019

The first of three cohorts has been successfully dosed in a phase I study to assess the safety of subcutaneous administration of sevuparin for the treatment of SCD.

This double-blind, placebo-controlled Phase I study, complements the currently ongoing Phase II study which is examining the safety of intravenous sevuparin infusion for the treatement of vaso-occlusive crisis (VOC). The Phase II study has completed enrolment and will report data in mid-2019.

The Phase I study will include approximately 24 Healthy Volunteers in three ascending single-dose cohorts in the USA, providing SCD patients a novel, non-opioid, therapy that can be dosed at home and could possibly pave the way for a therapy that could be used ‘on demand’ as a patient feels an oncoming painful VOC.

Sources:

http://www.modustx.com/first-cohort-dosed-in-us-phase-1-study-of-subcutaneously-administered-sevuparin/

 

Update: 01 February 2019

Sevuparin is a new compound based on the commonly used blood thinner, heparin. It is able to restore blood flow and prevent obstruction of small blood vessels due to its anti-adhesive and anti-inflammatory characteristics.

Received Orphan Drug Designation by FDA and EMA.

A multi-centre, phase II, randomized, double-blind, placebo-controlled study to explore efficacy and safety of sevuparin infusion (over 2 – 7 continuous days) for the management acute vaso-occlusive crisis (VOC) in adolescent and adult patients with SCD is currently ongoing.

  • Study locations include: Netherlands, Turkey, Lebanon, Bahrain, Oman, Saudi Arabia and Jamaica.
  • The study is expected to end in March 2019.

Sevuparin has received rare paediatric disease designation from the FDA (April 2018). This will provide the developing company a number of incentives and facilitations towards further study of the safety and efficacy of the drug and marketing authorisation and exclusivity.

In addition, phase 1 clinical study will be launched in the US to test the safety of subcutaneous administration of sevuparin for the treatment of SCD.  The FDA has accepted sevuparin’s investigational new drug application.

Sources:

https://clinicaltrials.gov/ct2/show/NCT02515838?term=sevuparin

http://www.modustx.com/research-development/clinical-trials/

http://www.modustx.com/sevuparin-receives-rare-pediatric-disease-designation-fda-treatment-children-sickle-cell-disease/

http://www.modustx.com/modus-therapeutics-announces-fda-acceptance-sevuparin-ind-treatment-sickle-cell-disease/

 

 

Imara (IMR-687)

 

Update: 25 November 2019

  • Early data from a Phase 2 trial show that once-a-day therapeutic oral inhibitor IMR-687is 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 testingIMR-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 hemoglobin and often increase before fetal hemoglobin 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 hemoglobin. 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/

 

 

Voxelotor (SCD)

 

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 hemoglobin polymerization, the root cause of SCD.
  • The accelerated approval of Oxbryta is based on clinically meaningful and statistically significant improvements in hemoglobin levels, accompanied by reductions in red blood cell destruction (hemolysis).
  • Results of the Phase 3 HOPE (Hemoglobin 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 hemoglobin 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 hemoglobin levels and reduced the incidence of acute anemic 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 hemolysis.
  • 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 hemolysis.
  • 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 hemoglobin, 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

 

 

Crizanlizumab (SUSTAIN study, part of SENTRY clinical trial program) (SCD)

 

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-thalassemia, HbS/beta+-thalassemia, 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

 

 

Ticagrelor (Brilinta)

 

Update: 30 May 2019

An antiplatelet agent for adults with coronary artery disease. The inhibition of platelet activation may decrease the frequency of vaso-occlusion crisis (VOC) in sickle cell disease (SCD). In a multicentre, randomised phase IIb study (HESTIA2 study), ticagrelor was well tolerated with a low bleeding risk, but no effect on diary-reported pain was detected. Potential effects on frequency of VOCs will need to be evaluated in a larger and longer study. It is produced by AstraZeneca and was approved for use in the European Union by the European Commission on December 3, 2010. The drug was approved by the US Food and Drug Administration on July 20, 2011 for coronary heart disease. A phase 3 trial in adults has now started. In a May 2019 report a new paediatric dispersible tablet formulation of ticagrelor for use across a wide age range of pediatric patients was found to have similar bioavailability compared with other oral ticagrelor formulations.

 

Sources:

Kanter J, Abboud MR, Kaya B, Nduba V, Amilon C, Gottfridsson C, Rensfeldt M, Leonsson-Zachrisson M; HESTIA2 study investigators. Ticagrelor does not impact patient-reported pain in young adults with sickle cell disease: a multicentre, randomised phase IIb study. Br J Haematol. 2019 Jan;184(2):269-278. doi: 10.1111/bjh.15646

Niazi M, Wissmar J, Berggren AR, Karlsson C, Johanson P. Development Strategy and Relative Bioavailability of a Pediatric Tablet Formulation of Ticagrelor. Clin Drug Investig. 2019  doi: 10.1007/s40261-019-00800-w.

The carrier state for sickle cell disease is not completely harmful: this is a study by Zhe Xu and Thein SL which identifies complications, such as renal and thromboembolism in HbS carriers. This is an alert to clinicians as well as to genetic counsellors.

Sources:

Xu JZ, Thein SL.The carrier state for sickle cell disease is not completely harmless. Haematologica. 2019 pii: haematol.2018.206060. doi: 10.3324/haematol.2018.206060

 

 

Gene Therapy

 

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 hemolysis, 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 hemoglobin (HbAT87Q) ranged from 4.5–8.8 g/dL and total unsupported hemoglobin (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 hematopoietic 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

 

 

N-acetyl-Cysteine

 

Update: 30 May 2019

An antioxidant which has been demonstrated to exert a broad range of beneficial effects in SCD, improving markers of oxidative stress and haemolysis, and possibly even the VOC rate. It is a safe, inexpensive drug that has been used for years for various indications, making it an accessible treatment for the majority of SCD patients in the developing world. In a recent placebo-controlled, double-blind trial, which aimed to evaluate the effect of NAC on the frequency of SCD-related pain in the daily life of patients (NCT01849016), the primary end point was the rate of SCD-related pain days per patient year. The conclusion, treatment with oral NAC was not of clinical benefit over placebo in this study. These findings are in contrast with previous studies with NAC, and trials evaluating other antioxidants.

Sources:

Sins JWR, Fijnvandraat K Rijneveld AW, Boom MB, Kerkhoffs JH, van Meurs AH, de Groot MR, Heijboer H, Dresse MF, Lê PQ, Hermans P, Vanderfaeillie A, Van Den Neste EW, Benghiat FS, Kesse-Adu R, Delannoy A, Efira A, Azerad MA, de Borgie CA, Biemond BJ. Effect of N-acetylcysteine on pain in daily life in patients with sickle cell disease: a randomised clinical trial. Br J Haematol. 2018 Aug;182(3):444-448. doi: 10.1111/bjh.14809.

 

L-arginine

 

Update: 30 May 2019

An amino-acid, which plays a role in regulating vascular tone by increasing the vaso-dilatory effect of nitric oxide (NO), and reducing the chronic vaso-constriction which is a consequence of haemolysis in sickle cell disease. Arginine supplementation, a low-cost approach, has shown promising results, which is particularly important considering most of the affected patients still live in unfavourable socioeconomic conditions. These findings should encourage further clinical trials, evaluating other outcomes and specific subpopulations. In a recently published double-blind clinical trial of arginine supplementation in the treatment of adult patients with sickle cell anaemia, the conclusions indicate a strong relationship between increased levels of NO metabolites and decreased pain frequency in patients with SCA, which supports the use of L-arginine supplementation as an adjuvant in the treatment of these patients. However, more studies are needed with a larger number of individuals and longer follow-up to evaluate the safety and efficacy of longterm supplementation with L-arginine.

Sources:

Benites BD, Olalla-Saad ST. An update on arginine in sickle cell disease. Expert Rev Hematol. 2019;12(4):235-244. doi: 10.1080/17474086.2019.1591948

Eleutério RMN, Nascimento FO, Araújo TG, Castro MF, Filho TPA, Filho PAM, Eleutério J Jr, Elias DBD, Lemes RPG. Double-Blind Clinical Trial of Arginine Supplementation in the Treatment of Adult Patients with Sickle Cell Anaemia. Adv Hematol. 2019 Feb 3;2019:4397150. doi: 10.1155/2019/4397150. eCollection 2019.

 

Bosentan

 

Update: 30 May 2019

An agent that modulates vascular tone and is mainly suggested to treat SCD associated pulmonary hypertension. Doppler-defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months.  Even mild PH may be clinically significant in SCD. In a recent trial it was demonstrated that 16 weeks of bosentan in SCD patients with confirmed PH (by right heart catheterization) was well tolerated. Despite small sample sizes, the correlations between exercise capacity and hemodynamics were consistent with previous reports in other PAH patients. Further investigation is warranted.

Sources:

Barst RJ(1), Mubarak KK, Machado RF, Ataga KI, Benza RL, Castro O, Naeije R, Sood N, Swerdlow PS, Hildesheim M, Gladwin MT; ASSET study group*. Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies. Br J Haematol. 2010;149(3):426-35. doi: 10.1111/j.1365-2141.2010.08097

 

Omega 3

 

Update: 30 May 2019

Dietary supplementation  may protect against vasculopathy in SCD. SC411 is a novel DHA ethyl ester formulation that enhances DHA bioavailability since blood cell membranes in sickle cell disease (SCD) have low docosahexaenoic acid (DHA). DHA treatment reduces sickle cell crisis (SCC) rate and ameliorates the inflammation, oxidative stress, and hypercoagulable state of SCD [9]. In a double-blind, randomized, multicenter phase 2 study of SC411 in children with sickle cell disease (SCOT trial), it was demonstrated that there was a significant increase in hemoglobin against placebo in subjects receiving 20 mg DHA/kg per day (P = .039). SC411 significantly reduced analgesic use at home, and days absent from school because of sickle cell pain. All tested doses were safe and well tolerated.

Sources:

Kalish BT, Matte A, Andolfo I, Iolascon A, Weinberg O, Ghigo A, Cimino J, Siciliano A, Hirsch E, Federti E, Puder M, Brugnara C, De Franceschi L. Dietary ω-3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease. Haematologica. 2015 Jul;100(7):870-80. doi: 10.3324/haematol.2015.124586

 

 

L-glutamine (marketed as Endari)

 

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.

 

 

Rivipansel (developed by Pfizer)

 

Update: 30 May 2019

Another selectin blocker, which has reached phase 3 clinical trials and which had received orphan drug status and fast-track designation from the U.S. Food and Drug Administration (FDA), in order to speed its approval process if it is shown to be effective. Phase 3 study is complete and an open label extension study in subjects with Sickle Cell Disease (SCD) who have completed the double blind Phase 3 study (B5201002), is ongoing. In addition a clinical study evaluating the efficacy and safety of rivipansel in treating subjects with sickle cell disease (SCD) who are 6 years of age or older experiencing a pain crisis necessitating hospitalization, is also ongoing.

 

Non-invasive prenatal test (SCD)

 

Update: 27 September 2019

Researchers analyzed samples from 24 pregnant SCD carriers. Using unique molecular identifiers, a kind of molecular barcode, they were able to reduce errors, and by only analyzing smaller fragments they were able to enhance the fetal contribution to the samples. This led to successful diagnosis of the sickle cell status for 21 of the 24 pregnancies, in samples from as early as eight weeks gestation, with three samples giving inconclusive results. Further development and validation of the findings is ongoing.

 

Sources:

https://medicalxpress.com/news/2019-06-noninvasive-prenatal-diagnosis-fetal-sickle.html

 

Xromi (SCD)

 

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