Crizanlizumab for Sickle Cell Disease

(CRIZ Trial)

Overseen By Andria Ford, MD

Age: Any Age

Sex: Any

Trial Phase: Academic

Sponsor: Andria Ford

Must not be taking: Investigational drugs, Monoclonal antibodies, Anticoagulants

Disqualifiers: Chronic transfusion, HIV, Hepatitis, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 30 months

31 Participants Needed

Trial Summary

What is the purpose of this trial?

In this prospective, single-arm, open-label, imaging and treatment study, the investigator will test the hypothesis that crizanlizumab will prevent the progression of silent cerebral infarcts in patients with sickle cell disease. Study participants will undergo brain MRI before initiation of crizanlizumab and at 6 and 30 months after starting crizanlizumab infusions. The crizanlizumab cohort will be compared to a matched, observational cohort of patients not receiving crizanlizumab.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on chronic transfusion therapy, have used other investigational drugs recently, or have taken certain medications like monoclonal antibodies or anticoagulants in the last 30 days.

What evidence supports the effectiveness of the drug crizanlizumab for sickle cell disease?

Crizanlizumab has been shown to reduce the frequency of painful episodes in sickle cell disease by 45.3% compared to a placebo in a clinical trial, making it an effective option for managing these crises. ^{1 2 3 4 5}

Is crizanlizumab safe for humans?

Crizanlizumab has been studied for safety in patients with sickle cell disease, showing similar rates of adverse events (unwanted effects) compared to a placebo. Common side effects include infusion-related reactions, joint pain, diarrhea, and nausea, but no serious treatment-related adverse events were reported. ^{1 2 3 4 6}

What makes the drug Crizanlizumab unique for treating Sickle Cell Disease?

Crizanlizumab is unique because it targets P-selectin, a protein that plays a key role in the inflammation and blockage of blood vessels in Sickle Cell Disease, helping to reduce pain crises. This mechanism is different from other treatments that primarily focus on managing symptoms or increasing fetal hemoglobin levels. ^{7 8 9 10 11}

Eligibility Criteria

This trial is for individuals with sickle cell disease at risk of silent cerebral infarcts. They should have had multiple pain crises in the past year and be over 16 years old. Participants must not be on chronic transfusion therapy, planning major treatments like stem cell transplants, or have used investigational drugs recently. Women who can bear children must use contraception and avoid pregnancy during and after the study.

Inclusion Criteria

Your doctor thinks you have a high chance of having silent strokes in your brain based on certain criteria.

I have sickle cell disease with a confirmed specific genotype.

I've had 2 to 10 pain crises due to sickle cell disease in the last year.

Exclusion Criteria

I cannot come back for follow-up visits.

I am currently on a long-term blood transfusion plan.

I currently have an acute infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive crizanlizumab infusions to prevent progression of silent cerebral infarcts

30 months

Regular infusions with MRI at baseline, 6 months, and 30 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Crizanlizumab

Trial Overview The study is testing Crizanlizumab's effectiveness in preventing silent brain injuries in sickle cell patients by comparing brain MRIs before treatment and at two intervals (6 and 30 months) after starting Crizanlizumab infusions against a group not receiving it.

Participant Groups

Group I: Single Arm: Crizanlizumab Experimental Treatment 1 Intervention

Single-arm: Patients with sickle cell disease and increased risk of silent cerebral infarcts

Crizanlizumab is already approved in United States for the following indications:

Approved in United States as Adakveo for:

• Prevention of recurrent vaso-occlusive crises in sickle cell disease patients aged 16 years and older

Who Is Running the Clinical Trial?

Andria Ford

Lead Sponsor

Trials

1

Recruited

30+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

Crizanlizumab is a monoclonal antibody that effectively reduces the frequency of vaso-occlusive crises (VOCs) in patients with sickle cell disease by blocking P-selectin, which is crucial for cell adhesion and inflammation.

Approved in the USA in November 2019 for adults and pediatric patients aged 16 and older, crizanlizumab is also under review in the EU and being studied for use in myelofibrosis, indicating its potential versatility in treating blood-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizanlizumab: First Approval. Blair, HA.[2020]

Crizanlizumab is the first monoclonal antibody approved for sickle cell disease, specifically designed to reduce the frequency of vaso-occlusive pain crises, based on data from a phase 2 clinical trial.

This medication is administered as a monthly intravenous infusion for patients aged 16 and older, showing efficacy in crisis prevention, although concerns about cost and long-term safety remain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizanlizumab for the Prevention of Vaso-Occlusive Pain Crises in Sickle Cell Disease. Stevens, DL., Hix, M., Gildon, BL.[2022]

Crizanlizumab may help reduce acute care visits for patients with sickle cell disease, especially among those who frequently use hospital services, with a significant decrease from an average of 40 visits to 16 after starting treatment.

Despite its potential benefits, the study found a high discontinuation rate, with only five out of fifteen patients remaining on crizanlizumab six months after starting, indicating a need for further research into the reasons for discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data of Crizanlizumab in Sickle Cell Disease: A Single-Center Analysis. Cheplowitz, H., Block, S., Groesbeck, J., et al.[2023]

Crizanlizumab, a monoclonal antibody targeting P-selectin, received conditional marketing authorization in the EU for preventing recurrent vaso-occlusive crises in sickle cell disease patients aged 16 and older, showing a 45.3% reduction in annual pain crises at a high dose compared to placebo.

The treatment was found to have a similar safety profile to placebo, with common side effects including infusion-related reactions and arthralgia, indicating that crizanlizumab is both effective and relatively safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Crizanlizumab for the Prevention of Recurrent Vaso-Occlusive Crises in Patients With Sickle Cell Disease. Delgado, J., Voltz, C., Stain, M., et al.[2021]

Crizanlizumab, a new treatment for sickle cell disease (SCD), has shown promise in reducing the annual rates of vaso-occlusive crises (VOC) with a favorable safety profile, marking a significant advancement in therapy options beyond hydroxyurea.

While hydroxyurea has been effective in decreasing VOC and hospitalizations, adherence to this treatment can be challenging due to side effects; crizanlizumab offers a new approach that may improve patient compliance and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of crizanlizumab and its potential in the prevention of pain crises in sickle cell disease: evidence to date. Riley, TR., Riley, TT.[2020]

Crizanlizumab effectively reduces the frequency of vaso-occlusive crises (VOCs) in patients with sickle cell disease, showing a significant reduction in the annualized rate of VOCs after more than 12 months of treatment, with a median reduction of -0.88 and -0.93 for the 5.0 mg/kg and 7.5 mg/kg doses, respectively.

The treatment demonstrated a favorable safety profile, with only one treatment-related adverse event reported and no serious treatment-related adverse events, indicating that crizanlizumab can be safely administered over long periods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease. Kanter, J., Brown, RC., Norris, C., et al.[2023]

Imatinib, the first tyrosine-kinase inhibitor (TKI) for chronic myeloid leukemia (CML), has significantly improved patient outcomes since its introduction 10 years ago.

Second generation TKIs like dasatinib and nilotinib are more effective and better tolerated than imatinib, suggesting they may soon become the standard first-line treatment for CML, with a future goal of achieving curative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current therapy of chronic myeloid leukemia]. Koskela, H., Koskenvesa, P., Mustjoki, S., et al.[2022]

Imatinib, a first-line treatment for chronic myeloid leukemia (CML), often leads to intolerance in patients, prompting the need for second- and third-generation tyrosine kinase inhibitors (TKIs) like ponatinib, which is effective against all BCR-ABL1 mutants, including those resistant to other TKIs.

There is a lack of consistent definitions of intolerance across clinical trials, which complicates the assessment of adverse events and their impact on patient quality of life, highlighting the need for better evaluation methods and consideration of ponatinib for patients who cannot tolerate other TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib. Breccia, M., Efficace, F., Iurlo, A., et al.[2019]

Imatinib (Gleevec) has significantly improved survival rates for patients with chronic myeloid leukemia in chronic phase (CML-CP), transforming a previously poor prognosis into one comparable to that of healthy individuals of similar age.

While newer TKIs like nilotinib (Tasigna) and dasatinib (Sprycel) offer faster responses and are effective for patients who cannot tolerate or are resistant to imatinib, they have not demonstrated a survival advantage over long-term imatinib treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is imatinib still an acceptable first-line treatment for CML in chronic phase? Goldman, JM., Marin, D.[2017]

A patient with chronic myeloid leukemia (CML) carrying the T315I mutation, which is resistant to other treatments, showed a complete response to ponatinib therapy, with the mutation burden dropping to undetectable levels.

Before treatment with ponatinib, the patient had a high level of BCR-ABL1 transcripts (18%), but after therapy, this level significantly decreased to just 0.011%, indicating the drug's efficacy in overcoming resistance to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation. Ferri, CA., Bianchini, M., Bengió, RM., et al.[2015]

Dasatinib has been approved by the FDA as a treatment for pediatric chronic myeloid leukemia, providing a new therapeutic option for young patients.

As the second tyrosine kinase inhibitor approved for this condition, dasatinib can be used in both first- and second-line treatment, expanding the choices available for managing this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib Approved for Pediatric CML. [2019]

References

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

Crizanlizumab: First Approval. [2020]

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

Crizanlizumab for the Prevention of Vaso-Occlusive Pain Crises in Sickle Cell Disease. [2022]

3. Canada pubmed.ncbi.nlm.nih.gov

Real-World Data of Crizanlizumab in Sickle Cell Disease: A Single-Center Analysis. [2023]

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

The European Medicines Agency Review of Crizanlizumab for the Prevention of Recurrent Vaso-Occlusive Crises in Patients With Sickle Cell Disease. [2021]

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

Profile of crizanlizumab and its potential in the prevention of pain crises in sickle cell disease: evidence to date. [2020]

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

Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease. [2023]

7. Finland pubmed.ncbi.nlm.nih.gov

[Current therapy of chronic myeloid leukemia]. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib. [2019]

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

Is imatinib still an acceptable first-line treatment for CML in chronic phase? [2017]

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

Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation. [2015]

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

Dasatinib Approved for Pediatric CML. [2019]