Panobinostat for Sickle Cell Disease

(LBH589 Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Abdullah Kutlar

Must not be taking: Hydroxyurea, Butyrates, Decitabine, others

Disqualifiers: Recent vaso-occlusive crisis, Cardiac diseases, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 12 weeks

18 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to find out about the safety and effects of a drug called panobinostat when given to adults with sickle cell disease. Panobinostat is a pan histone deacetylase (HDAC) inhibitor. HDAC inhibitors have been shown to significantly increase hemoglobin F induction, which is well documented to improve outcomes in sickle cell disease. HDAC inhibitors are also known to potently inhibit cell-specific inflammation, which is a primary contributor to the debilitating effects of sickle cell disease. Given the relevance of these mechanisms of action in SCD, panobinostat may prove to contribute significantly to the management of SCD patients, a population in critical need of further effective treatment options.

Do I need to stop my current medications to join the trial?

The trial requires that you stop using certain medications that can induce Hb F, such as hydroxyurea, at least 60 days before starting the study. If you are on any prohibited medications, you must either discontinue them or switch to a different medication before enrolling.

How does the drug Panobinostat differ from other treatments for sickle cell disease?

Panobinostat is unique because it is a histone deacetylase inhibitor, which means it can modify gene expression by affecting the structure of chromatin in cells. This mechanism is different from traditional sickle cell treatments, which often focus on managing symptoms or increasing fetal hemoglobin levels. ^{1 2 3 4 5}

Research Team

Abdullah Kutlar, MD

Principal Investigator

Augusta University

Eligibility Criteria

Adults over 18 with sickle cell disease who haven't responded well to or can't take hydroxyurea. They should have had at least two hospitalizations or three pain crises in the past year, or a history of other severe complications related to sickle cell disease. People with certain blood counts, organ dysfunctions, heart conditions, active infections like HIV/Hepatitis B/C, recent surgeries, and women who are pregnant/breastfeeding or not using contraception are excluded.

Inclusion Criteria

I am 18 years old or older.

I have been diagnosed with SS or S-β0 Thalassemia.

I have needed treatment for a prolonged erection in the last two years.

Exclusion Criteria

I have a condition that affects my heart's rhythm.

I cannot stop or change my current medication for the study.

- Albumin <3.0 g/dl

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

1 visit (in-person)

Treatment

Participants receive escalating doses of panobinostat to determine safety and tolerability over a 12-week period

12 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Panobinostat

Trial Overview The trial is testing panobinostat's safety and effectiveness for adults with sickle cell disease. Panobinostat is an HDAC inhibitor that may increase hemoglobin F levels and reduce inflammation—both potentially beneficial for managing this condition.

Participant Groups

Group I: Panobinostat Experimental Treatment 1 Intervention

All patients will receive Panobinostat at specified dose levels and dosing schedules.

Panobinostat is already approved in United States, European Union for the following indications:

Approved in United States as Farydak for:

• Multiple myeloma

Approved in European Union as Farydak for:

• Multiple myeloma

Who Is Running the Clinical Trial?

Abdullah Kutlar

Lead Sponsor

Trials

1

Recruited

20+

Secura Bio, Inc.

Industry Sponsor

Trials

9

Recruited

200+

Findings from Research

Panobinostat, a histone deacetylase inhibitor for treating relapsed multiple myeloma, primarily undergoes metabolism through the CYP3A4 enzyme, which is crucial for understanding its drug interactions and dosing.

Physiologically based pharmacokinetic (PBPK) modeling predicted that the presence of rifampin, a strong CYP3A4 inducer, could significantly reduce panobinostat exposure by 65%, while its absorption is not affected by changes in stomach pH, leading to important dosing recommendations for clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiologically Based Pharmacokinetic Model Predictions of Panobinostat (LBH589) as a Victim and Perpetrator of Drug-Drug Interactions. Einolf, HJ., Lin, W., Won, CS., et al.[2018]

In a study involving 36 patients with advanced cancer, food intake was found to have a minor effect on the oral bioavailability of panobinostat, a novel anti-cancer drug, with systemic exposure reduced by 14-16% after meals.

Panobinostat was well tolerated among patients, showing common side effects like thrombocytopenia and fatigue, and demonstrated antitumor activity, with one patient achieving a partial response and six maintaining stable disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of food on the bioavailability of panobinostat, an orally active pan-histone deacetylase inhibitor, in patients with advanced cancer. Shapiro, GI., Frank, R., Dandamudi, UB., et al.[2021]

Panobinostat is a potent pan-histone deacetylase (HDAC) inhibitor that promotes the expression of repressed genes, leading to reduced cancer cell growth and increased cell death (apoptosis).

It has shown strong preclinical efficacy at nanomolar concentrations and is being tested in both intravenous and oral forms for various tumor types, indicating its potential as a novel cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of panobinostat and its potential for treatment in solid tumors: an update. Anne, M., Sammartino, D., Barginear, MF., et al.[2023]

Panobinostat, an oral pan-deacetylase inhibitor, was found to increase the exposure of the CYP2D6 substrate dextromethorphan (DM) by 64% when co-administered, indicating a weak inhibition of CYP2D6 activity in patients with advanced cancer.

Due to this interaction, it is recommended to closely monitor the safety of other medications that are CYP2D6 substrates, especially those with a narrow therapeutic index, when used alongside panobinostat.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer. Feld, R., Woo, MM., Leighl, N., et al.[2018]

Panobinostat (Farydak(®)) is an HDAC inhibitor that has been approved in the US for use in combination with bortezomib and dexamethasone to treat recurrent multiple myeloma in patients who have undergone at least two prior treatments.

The drug is currently being explored in clinical trials for various hematological and solid tumors, indicating its potential as a versatile cancer treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Panobinostat: first global approval. Garnock-Jones, KP.[2018]

References

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

Physiologically Based Pharmacokinetic Model Predictions of Panobinostat (LBH589) as a Victim and Perpetrator of Drug-Drug Interactions. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

The effect of food on the bioavailability of panobinostat, an orally active pan-histone deacetylase inhibitor, in patients with advanced cancer. [2021]

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

Profile of panobinostat and its potential for treatment in solid tumors: an update. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

A clinical investigation of inhibitory effect of panobinostat on CYP2D6 substrate in patients with advanced cancer. [2018]

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

Panobinostat: first global approval. [2018]