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Gene Editing

CRISPR gene editing

 

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 transfusion-dependent beta-thalassaemia (TDT) received CTX001 in the first quarter of 2019 and data for this patient reflect nine months of safety and efficacy follow-up.
    • β0/IVS-I-110genotype and required 16.5 transfusions per year
    • At nine months after CTX001 infusion, the patient was transfusion independent and had total hemoglobin levels of 11.9 g/dL

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-Thal-111: 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 TDT. 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 six 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 TDT 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 treated with CTX001 in a Phase 1/2 clinical study of patients with TDT remains transfusion independent, greater than four months following engraftment.
  • 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 July 2019

No update available.

 

Update: 30 May 2019

  • The FDA has granted Fast Track Designation for CTX001 for the treatment of transfusion dependent beta thalassaemia.

Sources:

https://www.globenewswire.com/news-release/2019/04/16/1804601/0/en/CRISPR-Therapeutics-and-Vertex-Announce-FDA-Fast-Track-Designation-for-CTX001-for-the-Treatment-of-Beta-Thalassemia.html

 

Update: 29 March 2019

  • The Phase 1/2 Study in Beta Thalassaemia 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 transfusion-dependent thalassaemia (TDT), with non-β00genotype subtypes. Two patients will be initially treated sequentially and, pending data from these, the trial will open for broader enrolment.

The first patient has been treated already.

  • 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: 02 October 2018

CRISPR Therapeutics and Vertex Pharmaceuticals have become the first commercial sponsors of a human clinical trial for a CRISPR gene-editing system.

Clinical Trial Application for CTX001 was submitted in Europe to support initiation of Phase 1/2 clinical study in β-thalassemia in 2018

 The trial will enrol 30 β-thalassaemia patients at a single hospital in Regensburg, Germany.

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 thalassaemia produce altered and ineffective haemoglobin molecules.

Sources:

https://seekingalpha.com/article/4206056-crispr-therapeutics-tries-hand-thalassemia-vertex

http://ir.crisprtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-co-develop-and-co-commercialize

 

Update: 20 December 2018

  • 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-thalassaemia are enrolling in a Phase 1/2 trial in β-thalassaemia in Europe.

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

 

Editas gene editing (Thalassaemia)

 

Update: 31 January 2020

In vivo proof-of-concept data supporting the development of EDIT-301 as a potentially best-in-class, durable medicine to treat sickle cell disease and beta-thalassaemia were announced at the 61st Annual Meeting and Exposition of the American Society of Hematology (ASH).

EDIT-301 is the first experimental medicine in development using Cas12a (formerly known as Cpf1).

Sources: https://ir.editasmedicine.com/news-releases/news-release-details/editas-medicine-announces-vivo-proof-concept-data-edit-301

 

Update: 25 November 2019

No update available.

 

Update: 27 September 2019

No update available

 

Update: 30 July 2019

Results from a follow-up study to assess two different CRISPR genome editing strategies, one targeting the BCL11A erythroid enhancer (BC11Ae) and one targeting the beta-globin locus, for the treatment of sickle cell disease and beta-thalassemia were announced at the 24th Congress of the European Hematology Association in Amsterdam.

These demonstrated an increase of fetal haemoglobin.

Sources:

https://www.globenewswire.com/news-release/2019/06/15/1869292/0/en/Editas-Medicine-Presents-Pre-Clinical-Data-for-Treatment-of-Sickle-Cell-Disease-and-Beta-Thalassemia-at-the-24th-Congress-of-the-European-Hematology-Association.html

 

Bioverativ gene editing

 

Update : 31 January 2020

Preliminary results from the first three patients treated in the Phase 1/2 THALES study evaluating investigational ST-400 ex vivo gene-edited cell therapy in transfusion-dependent beta thalassaemia (TDT) were announced during the 61st Annual Meeting of the American Society of Hematology (ASH).

To date, ST-400 has been manufactured for five patients, three of whom had been treated at the time of the ASH data cut.

  • Patient 1, age 36, has a β00genotype, the most severe form of TDT, and had 27 annualized packed red blood cell (PRBC) events prior to enrollment into the study. The patient underwent a second cycle of mobilization and apheresis due to the low cell dose and potency achieved in the first cycle. In both ST-400 lots, editing efficiency was approximately 25%, which was lower than the other patients enrolled in the study. Following ST-400 infusion, fetal haemoglobin levels increased to approximately 2.7 g/dL at Day 56 and remained elevated compared to baseline at 0.9 g/dL at week 39, the most recent measurement at the time of the ASH data cut. After an initial transfusion-free duration of 6 weeks, the patient resumed intermittent packed RBCs transfusions, with an overall 33% reduction in annualized packed RBC units transfused since engraftment.
  • Patient 2, age 30, is homozygous for the severe β+ IVS-I-5 (G>C) mutation and had 18 annualized packed RBCs events prior to enrollment into the study. Following ST-400 infusion, fetal haemoglobin levels increased as compared with baseline, but have been <1 g/dL through to 26 weeks, the lowest induction level observed in the three patients treated to date. The patient is currently receiving intermittent packed RBC transfusions.
  • Patient 3, age 23, has a β0/β+ genotype that includes the severe IVS-II-654 (C>T) mutation and had 15 annualized packed RBCs events prior to enrollment into the study. Following ST-400 infusion, fetal haemoglobin levels have increased as compared to baseline and were continuing to rise as of the latest measurement of 2.8 g/dL at Day 90. Following an initial transfusion-free period of 7 weeks, the patient has received two packed RBC transfusions commencing at 62 days post-infusion.
  • Patient 4, age 18 with a βWT(αα)/βº (αααα) genotype, and Patient 5, age 35 with a βº/β+ (severe IVS-I-110 G>A) genotype, were dosed after the time of the ASH data cut. A sixth and final patient is expected to be enrolled in the study in the coming months.
  • Results from additional patients and longer-term follow-up data are expected in the second half of 2020.

Sanofi is running a parallel clinical trial with BIVV003, which uses a similar approach in sickle cell disease.

Sources:

https://www.biospace.com/article/releases/sangamo-announces-preliminary-results-from-the-first-three-patients-in-a-phase-1-2-study-evaluating-st-400-ex-vivo-gene-edited-cell-therapy-in-beta-thalassemia/

 

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 “Preliminary Results of a Phase 1/2 Clinical Study of Zinc Finger Nuclease-Mediated Editing of BCL11A in Autologous Haematopoietic Stem Cells for Transfusion-Dependent Beta Thalassaemia”

  • Data from the first three patients enrolled in the Phase 1/2 THALESstudy, all with severe beta thalassaemia genotypes: β00, homozygous for the severe β+ IVS-I-5 (G>C) mutation, and β0+ genotype including the severe IVS-II-654 (C>T) mutation, respectively will be shared.
  • Patient 1 after being free from packed red blood cell (PRBC) transfusions for 6 weeks, subsequently required intermittent transfusions. Patient 2 had rising HbF levels observed through 90 days post-infusion. For both patients on-target insertions and deletions (indels) were present in circulating white blood cells indicating that the successful ex vivo editing of the BCL11A gene.

Sources:

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

 

Update: 27 September 2019

No update available

 

Update: 30 July 2019

No update available.

 

Update: 30 May 2019

No update available.

 

Update: 29 March 2019

The results received from the first patient treated with ST-400 in the Phase 1/2 THALES study have shown:

  • Stable haemoglobin levels at 7 weeks post ST-400 infusion (~9 g/dL)
  • Continuous increase in levels of fetal haemoglobin (from 1% of total hemoglobin at the time of infusion to 31% as of the most recent measurement)
  • Presence of indels (genome edits) around white blood cells, indicating that the successful ex vivo editing of the BCL11A gene

It is noted that the patient has the most severe form of transfusion-dependent beta thalassemia (β00), and for the two years prior to treatment in the study, received packed red blood cell (PRBC) transfusions every other week.

The patient received several PRBC transfusions for approximately two weeks after the ST-400 infusion. During the subsequent five weeks no further PRBC transfusions have been required.

During the ST-400 infusion, the patient experienced a serious adverse event, a transient allergic reaction considered related to the cryoprotectant present in the product. Thereafter, the post-transplant clinical course was routine.

More date is expected to be presented in late 2019.

Sources:

https://investor.sangamo.com/news-releases/news-release-details/sangamo-provides-clinical-development-update-including-early

 

Update: 02 October 2018

Sangamo Therapeutics and Bioverativ Therapeutics have begun a Phase 1/2 study of gene editing in patients with transfusion-dependent β-thalassemia in the United States.

This trial will investigate whether increasing the production of fetal haemoglobin can reduce or eliminate the need for blood transfusions.

Participating patients will have their CD34+ blood stem cells removed and genetically edited so as to boost their production of fetal haemoglobin. These edited stem cells will then be infused back into patients. The trial will enrol 6 patients between the ages of 18 and 40 with transfusion-dependent β-thalassemia. The first trial site has just opened in Oakland and additional trial sites are expected to open soon.

Source:http://www.thalassemia.org/sangamo-therapeutics-bioverativ-therapeutics-begin-new-clinical-trial-transfusion-dependent-beta-thalassemia/

 

Update: 20 December 2018

No update available.