Gene Therapy for Sickle Cell Disease

(Restore Trial)

Recruiting at 4 trial locations

Overseen By Restore Clinical Study Support

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Kamau Therapeutics

Disqualifiers: Malignancy, Immunodeficiency, Infection, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy for individuals with severe Sickle Cell Disease. The main goal is to assess the treatment's safety and gather early data on its effectiveness. Participants will receive a treatment called nula-cel (also known as GPH101 Drug Product), which uses a gene-editing technique to correct the sickle cell mutation. This trial may suit those who have experienced multiple severe pain crises or lung problems related to Sickle Cell Disease, despite standard care. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I have to stop taking my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that nula-cel, also known as GPH101, is a promising treatment for sickle cell disease. In studies, the first patient treated with nula-cel showed good results after one year, suggesting the treatment is well-tolerated over time. Researchers used a gene-editing tool called CRISPR-Cas9 to correct the sickle cell mutation in the patient's stem cells.

While this treatment remains under investigation, CRISPR-Cas9 has proven effective in similar therapies. It is important to note that this study is in the early stages, so researchers are closely monitoring nula-cel to ensure its safety. Overall, early findings appear positive for safety, but more information is needed as the study progresses. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for sickle cell disease, which often include blood transfusions and hydroxyurea, the GPH101 Drug Product uses a groundbreaking approach with CRISPR-Cas9 gene-editing technology. This treatment involves correcting the sickle cell mutation in the patient's own hematopoietic stem and progenitor cells (HSPCs), potentially addressing the root cause of the disease rather than just alleviating symptoms. Researchers are excited about this because it represents a shift towards a more targeted and potentially curative therapy, offering hope for long-term relief and significantly improved quality of life for patients.

What evidence suggests that nula-cel might be an effective treatment for Sickle Cell Disease?

Research has shown that nula-cel, a type of gene therapy under study in this trial, might cure sickle cell disease. This treatment uses CRISPR-Cas9 to repair the faulty gene causing sickle cell disease in a person's own cells. Early results from the first patient treated with nula-cel are promising, showing less sickle hemoglobin and more normal hemoglobin, which could help reduce symptoms. Studies also suggest that nula-cel might address all related complications. Although still in early stages, these findings offer hope for a long-term solution to sickle cell disease. ^{2 3 4 6 7}

Who Is on the Research Team?

Mathew Porteus, MD, PhD

Principal Investigator

Kamau Therapeutics

Are You a Good Fit for This Trial?

This trial is for people aged 12-40 with severe Sickle Cell Disease who've had multiple acute chest syndrome episodes or recurrent severe pain crises, despite treatment. They must be generally well-functioning (good performance status). Those with prior gene therapy, a perfect sibling donor match, active infections, pregnancy/breastfeeding, or certain genetic risks are excluded.

Inclusion Criteria

I have had 4 or more severe pain crises in the last 2 years despite treatment.

I have had 2 or more acute chest syndrome episodes in the last 2 years.

I can carry out most of my everyday activities without help.

Exclusion Criteria

I have had a stem cell transplant or gene therapy.

I have or had another cancer, blood disorder, clotting issue, or immune system disorder.

I have a genetic change that could lead to blood cancer, as my doctor has determined.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo myeloablative conditioning prior to receiving nula-cel infusion

1-2 weeks

Treatment

Participants receive nula-cel via IV infusion

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• GPH101 Drug Product

Trial Overview The study tests nula-cel Drug Product in about 15 participants to see if it's safe and effective for treating severe Sickle Cell Disease. It's an early-phase trial where all enrolled patients receive the experimental treatment and are monitored for results.

How Is the Trial Designed?

Group I: nula-cel Drug Product Experimental Treatment 1 Intervention

nula-cel Drug Product is a human autologous CRISPR-Cas9 edited and sickle mutation-corrected HSPC product.

Who Is Running the Clinical Trial?

Kamau Therapeutics

Lead Sponsor

Trials

1

Recruited

20+

Graphite Bio, Inc.

Lead Sponsor

Trials

1

Recruited

20+

Published Research Related to This Trial

A CRISPR-Cas9 gene correction strategy demonstrated up to 60% correction of the sickle cell disease-causing mutation in patient-derived hematopoietic stem cells, showing promising efficacy for potential treatment.

Preclinical studies in mice showed that the corrected cells engrafted successfully without signs of abnormal blood cell formation or tumor development, indicating a favorable safety profile for this gene therapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease. Lattanzi, A., Camarena, J., Lahiri, P., et al.[2022]

A patient with drug-induced agranulocytosis was successfully treated with filgrastim (Neupogen), which is a recombinant human granulocyte colony-stimulating factor.

This case highlights the efficacy of filgrastim in promoting the recovery of white blood cells in patients experiencing severe neutropenia due to medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Haptenic agranulocytosis: treatment with hemopoietic growth factors]. Pivnik, AV., Tonkoglaz, VN., Boĭko, DV.[2011]

Pegteograstim, a novel monoPEGylated recombinant human granulocyte colony-stimulating factor, shows high purity and stability, making it a promising treatment for chemotherapy-induced neutropenia.

In pharmacokinetic studies on male Sprague-Dawley rats, pegteograstim demonstrated favorable properties compared to filgrastim, indicating its potential for long-lasting therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterisation of the site-specific monoPEGylated rhG-CSF analogue pegteograstim. Hong, J., Lee, B., Kang, K., et al.[2022]

A pharmacokinetic model was successfully developed for filgrastim and pegfilgrastim in mice, showing that both drugs can be explained by the same model but have different parameters affecting their distribution and clearance.

The study highlights the importance of considering both granulocytotic and granulocytopaenic conditions together to accurately model the effects of G-CSF derivatives, which is crucial for optimizing treatment schedules during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia. Scholz, M., Ackermann, M., Engel, C., et al.[2021]

A modification to the α chain of hemoglobin (αPro114Arg) can effectively reduce fiber formation in sickle cell disease, similar to the protective effects of fetal hemoglobin (HbF).

This new approach can be combined with existing therapies, potentially improving treatment outcomes for adults with sickle cell disease by enhancing the effectiveness of current interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An α-chain modification rivals the effect of fetal hemoglobin in retarding the rate of sickle cell fiber formation. Worth, EH., Fugate, MK., Grasty, KC., et al.[2023]

A new therapeutic approach combining lentiviral gene addition and CRISPR-Cas9 strategies shows promise for treating sickle cell disease (SCD) by allowing for effective gene editing and expression of anti-sickling hemoglobins with lower vector copy numbers.

This method not only enhances the levels of beneficial hemoglobins but also reduces the risk of genotoxicity associated with high vector amounts, making it a safer option for patients with SCD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease. Ramadier, S., Chalumeau, A., Felix, T., et al.[2023]

A Phase I study involving 28 patients with sickle cell disease found that ICA-17043 was well tolerated with no dose-limiting adverse events, indicating a good safety profile for this medication.

The pharmacokinetics showed that the total systemic exposure to ICA-17043 increased with higher doses, and the drug has a long half-life of 12.8 days, suggesting that once-daily dosing could effectively maintain therapeutic levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-escalation study of ICA-17043 in patients with sickle cell disease. Ataga, KI., Orringer, EP., Styles, L., et al.[2022]

The BCH-BB694 lentiviral vector effectively reactivates fetal hemoglobin production while reducing harmful adult sickle hemoglobin in sickle cell disease, showing a 3- to 5-fold increase in fetal hemoglobin levels in transduced cells.

Preclinical studies indicate that BCH-BB694 is non-toxic and can be produced at a clinically relevant scale, supporting its potential for safe and effective use in human trials for treating sickle cell disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. Brendel, C., Negre, O., Rothe, M., et al.[2020]

Pegylation of recombinant human granulocyte colony stimulating factor (PEG-G-CSF) enhances its stability and bioactivity when administered through the enteral route, making it a promising candidate for oral delivery.

In an in vivo model, PEG-G-CSF demonstrated a bioavailability of 1.8 to 3.5% via constant infusion, while the unmodified G-CSF did not show a measurable response, indicating that the pegylated version is more effective for therapeutic use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enteral bioavailability of human granulocyte colony stimulating factor conjugated with poly(ethylene glycol). Jensen-Pippo, KE., Whitcomb, KL., DePrince, RB., et al.[2019]

This study identified and quantified low-level product-related variants in filgrastim products, including newly discovered variants, using advanced mass spectrometry techniques.

Despite the presence of these variants in some filgrastim products, they are mostly found at levels below 1% and are not expected to have any significant clinical impact on their efficacy or safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of Low-Level Product-Related Variants in Filgrastim Products Presently Available in Highly Regulated Markets. Hausberger, A., Lamanna, WC., Hartinger, M., et al.[2017]

Citations

1. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/5000/501743/One-Year-Follow-up-on-the-First-Patient-Treated

One Year Follow-up on the First Patient Treated with Nula-Cel One year follow-up on the first patient treated with Nula-Cel: An autologous CRISPR/Cas9 gene corrected CD34+ cell product to treat sickle cell disease.

2. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123116016

An Autologous CRISPR/Cas9 Gene Corrected CD34+ Cell ... We describe the clinical results of the first patient treated with an autologous cell product (nula-cel) in which the pathologic variant was directly corrected.

3. crisprmedicinenews.com crisprmedicinenews.com/news/clinical-update-graphite-bio-doses-first-patient-with-potential-crispr-cure-for-sickle-cell-disease/

Clinical Update: Graphite Bio Doses First Patient With ... Pre-clinical data supports curative potential of GPH101. In November 2021, the company presented pre-clinical data for GPH101 at the 49th Annual Sickle Cell ...

4. clinicaltrialsarena.com clinicaltrialsarena.com/news/graphite-bio-sickle-cell-disease/

Graphite Bio doses first subject in Phase I/II sickle cell ... This aids in lowering the production of sickle haemoglobin (HbS) and restoring the expression of adult haemoglobin (HbA) to potentially cure SCD ...

5. ir.lenz-tx.com ir.lenz-tx.com/sec-filings/content/0000950170-22-016657/grph-ex99_1.htm

August 11, 2022 - EX-99.1 - 8-K: Current report filing “We believe nula-cel could be a definitive cure for sickle cell disease, with the potential to address all complications associated with this ...

6. cgtlive.com cgtlive.com/view/graphite-bio-drops-lead-sickle-cell-gene-edited-cell-therapy

Graphite Bio Drops Lead Sickle Cell Gene-Edited ... Graphite Bio doses first patient with investigational gene editing therapy GPH101 for sickle cell disease. News release. Graphite Bio, Inc ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0268960X24000183

Gene Editing's breakthrough against sickle cell disease This review delves into the growing field of gene editing, particularly the extensive research focused on curing haemoglobinopathies like SCD.