Gene Therapy for Sickle Cell Disease

(Restore Trial)

Recruiting at 3 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

Trial Summary

What is the purpose of this trial?

This study is a first-in-human, single-arm, open-label Phase I/II study of nula-cel in approximately 15 participants, diagnosed with severe Sickle Cell Disease. The primary objective is to evaluate safety of the treatment in this patient population, as well as preliminary efficacy and pharmacodynamic data.

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.

What data supports the effectiveness of the treatment Nula-cel for sickle cell disease?

Research shows that gene therapy strategies, like those used in Nula-cel, can correct the genetic mutation causing sickle cell disease. Studies have demonstrated that modifying the genes in stem cells can lead to the production of healthy hemoglobin, reducing the symptoms of the disease. ^{1 2 3 4 5}

What makes the GPH101 drug unique for treating sickle cell disease?

The GPH101 drug, also known as Nula-cel, is a gene therapy specifically designed to treat sickle cell disease by addressing the genetic cause of the condition, which is different from traditional treatments that mainly focus on managing symptoms. ^{6 7 8 9 10}

Research Team

Mathew Porteus, MD, PhD

Principal Investigator

Kamau Therapeutics

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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 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 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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Dose-escalation study of ICA-17043 in patients with sickle cell disease. [2022]

2. United States 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. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Combination of lentiviral and genome editing technologies for the treatment of sickle cell disease. [2023]

5. England pubmed.ncbi.nlm.nih.gov

An α-chain modification rivals the effect of fetal hemoglobin in retarding the rate of sickle cell fiber formation. [2023]

6. England pubmed.ncbi.nlm.nih.gov

A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia. [2021]

7. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Haptenic agranulocytosis: treatment with hemopoietic growth factors]. [2011]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Identification of Low-Level Product-Related Variants in Filgrastim Products Presently Available in Highly Regulated Markets. [2017]

9. United States pubmed.ncbi.nlm.nih.gov

Enteral bioavailability of human granulocyte colony stimulating factor conjugated with poly(ethylene glycol). [2019]

10. England pubmed.ncbi.nlm.nih.gov

Characterisation of the site-specific monoPEGylated rhG-CSF analogue pegteograstim. [2022]