Benserazide for Beta Thalassemia

(PB04-001 Trial)

Enrolling by invitation at 4 trial locations

Overseen By Melissa Askin, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Phoenicia BioScience

Must not be taking: Erythropoiesis agents, MAO inhibitors

Disqualifiers: RBC transfusion, Pulmonary hypertension, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called Benserazide to aid individuals with beta thalassemia and sickle cell disease. These serious blood conditions result in insufficient healthy red blood cells, causing anemia and other issues. The trial aims to determine if this drug can increase levels of fetal globin, a type of hemoglobin that might improve blood health. Researchers are exploring different doses and schedules to identify the most effective one. The trial seeks participants with beta thalassemia intermedia or sickle cell disease who have not recently received a blood transfusion. As a Phase 1/Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are taking monoamine oxidase inhibitors or erythropoiesis stimulating agents within 90 days of the first dose. Also, you should not have received other investigational systemic therapy within 30 days prior to the first dose.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Benserazide has been safely used for over 50 years with other medications to treat Parkinson's disease. This long history suggests it is generally safe for long-term use. Currently, researchers are studying Benserazide for a new use in treating beta thalassemia, but specific studies for this are still ongoing.

Since this trial is in its early stages, the main goal is to assess the drug's safety in people. Early trials usually involve small groups to observe the drug's effects. The trial will test different doses to determine the safest and most effective amount. Although the drug has been safely used for another condition, researchers are exercising caution in these early trials to ensure its safety for this new use. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for beta thalassemia?

Benserazide is unique in treating beta thalassemia because it targets the condition differently than typical treatments like blood transfusions and iron chelation therapy. Most treatments for beta thalassemia focus on managing symptoms, but benserazide aims to address the underlying issue by potentially increasing the production of fetal hemoglobin. This new approach could reduce the need for frequent transfusions and iron overload, which are significant burdens for patients. Researchers are excited because, if successful, benserazide could offer a more direct and less burdensome way to manage beta thalassemia.

What evidence suggests that Benserazide could be an effective treatment for beta thalassemia?

Research has shown that benserazide can increase fetal hemoglobin (HbF) levels, which is important because higher HbF levels can reduce the symptoms of beta thalassemia, a blood disorder. In animal studies, benserazide increased HbF and its messenger RNA, aiding in the production of more red blood cells with HbF. The drug works by turning off certain genes that usually prevent the production of fetal hemoglobin. Although mainly studied in animals, benserazide has been safely used in humans for other purposes for many years. Early results are promising for its potential use in treating beta thalassemia. Participants in this trial will receive different doses of benserazide to evaluate its effectiveness and safety in increasing HbF levels. ^{1 2 6 7 8}

Who Is on the Research Team?

Hanny Al-Samkari, MD

Principal Investigator

Massachusetts General Hospital

Susan Perrine, MD

Principal Investigator

Phoenicia BioScience

Kevin Kuo, MD

Principal Investigator

University Health Network, Toronto General Hospital

Sylvia Singer, MD

Principal Investigator

UCSF Benioff Children's Hospital at Oakland

Sujit Sheth, MD MS

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

The trial is for adults with Beta thalassemia intermedia or Non-Transfusion Dependent Thalassemia who have a specific mutation, with hemoglobin levels between 6.0 and 10.0 g/dL. Participants must not be on oxygen therapy for pulmonary hypertension, have certain liver conditions, untreated HIV or hepatitis C, recent fever, other recent treatments or transfusions, or be pregnant/breastfeeding.

Inclusion Criteria

Able and willing to give consent and comply with all study procedures

My average hemoglobin levels have been between 6.0 and 10.0 g/dL in the last 6 months.

I am not pregnant and agree to use birth control during the study.

Exclusion Criteria

I haven't used any drugs to increase red blood cells in the last 90 days.

I have not had a fever over 38.5°C in the last week.

I am currently taking medication for depression or Parkinson's disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive the study drug by mouth once per day, every other day for 12 weeks. The first dose is taken in a clinical unit, and subsequent doses are taken at home.

12 weeks

6 visits (in-person) over 4 months

Dose Escalation

Sequential cohorts receive increasing doses of the study drug. Each new cohort begins after the prior cohort completes 2 weeks of treatment without serious adverse events.

2 weeks per cohort

Follow-up

Participants are monitored for safety and effectiveness after treatment, including laboratory tests and physical exams.

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Benserazide Only Product

Trial Overview

An oral drug known as Benserazide Only Product is being tested to increase fetal globin in red blood cells which could benefit those with beta thalassemia and related blood disorders. The study starts by testing three dose levels in nontransfused patients before moving to larger groups.

How Is the Trial Designed?

Group I: Sickle Cell Disease Arm Experimental Treatment 1 Intervention

The most active dose given once per day on the most active regimen for up 24 weeks

Group II: Middle dose Experimental Treatment 1 Intervention

A middle dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 weeks

Group III: Low dose Experimental Treatment 1 Intervention

A low dose, by mouth, once per day, on Monday, Wednesday, and Friday for 12 weeks

Group IV: High dose 5 days per week Experimental Treatment 1 Intervention

The highest dose, by mouth once per day on 5 days per week for 24 weeks

Group V: High dose 3 days per week Experimental Treatment 1 Intervention

Highest dose, by mouth, once per day, on Monday, Wednesday, and Friday, for 12 to 24 weeks

Benserazide Only Product is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Benserazide for:

• Parkinson's disease

Approved in United States as Benserazide for:

• Not approved as a standalone product; used in combination products for Parkinson's disease

Approved in Canada as Benserazide for:

• Parkinson's disease

Who Is Running the Clinical Trial?

Phoenicia BioScience

Lead Sponsor

Trials

1

Recruited

40+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

In a study of 21 patients with epilepsy and complex medical conditions, levetiracetam was found to be effective, with 12 patients becoming seizure-free and 9 experiencing a significant reduction in seizure frequency after 12 months.

The treatment was well tolerated with no reported side effects, suggesting that levetiracetam is a safe option for patients who have had issues with other antiepileptic drugs due to interactions or toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of levetiracetam in treating epilepsy associated with other medical conditions. Di Bonaventura, C., Mari, F., Fattouch, J., et al.[2018]

In a study of 25 patients with brain tumor-related epilepsy (BTRE), adding Lacosamide (LCM) as an adjunctive therapy led to a significant reduction in seizure frequency, with 86.4% of patients showing a positive response, including 7 patients becoming seizure-free.

While LCM demonstrated comparable efficacy to Levetiracetam (LEV) in seizure control, there were no significant changes in quality of life measures, suggesting that LCM does not adversely affect patients' overall well-being despite some functional status decline.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life, mood and seizure control in patients with brain tumor related epilepsy treated with lacosamide as add-on therapy: A prospective explorative study with a historical control group. Maschio, M., Zarabla, A., Maialetti, A., et al.[2022]

In a review of five prospective audits involving 667 patients with uncontrolled partial-onset seizures, newer antiepileptic drugs (AEDs) like levetiracetam (LEV), lacosamide (LCM), and topiramate (TPM) showed higher rates of seizure freedom (around 20-23%) compared to zonisamide (ZNS) and pregabalin (PGB), which had lower rates (10-12%).

Despite the availability of these new AEDs, less than 25% of patients achieved seizure freedom, and tolerability was a significant factor in treatment continuation, with lacosamide being the best tolerated and pregabalin the least. Overall, the introduction of these modern AEDs has not significantly improved outcomes for patients with drug-resistant epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective audits with newer antiepileptic drugs in focal epilepsy: insights into population responses? Brodie, MJ., Kelly, K., Stephen, LJ.[2019]

In a phase I study involving 32 patients with relapsed/refractory neuroblastoma, the oral powderized lipid complex of fenretinide (4-HPR/LXS) demonstrated higher plasma levels and minimal toxicity compared to previous capsule formulations.

The study found evidence of anti-tumor activity, with four patients achieving complete responses and six showing stable disease, leading to a recommended phase II dosage of 1,500 mg/m²/day for further testing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium. Maurer, BJ., Kang, MH., Villablanca, JG., et al.[2022]

The synthetic retinoid Fenretinide (HPR) shows enhanced antitumor activity against neuroblastoma (NB) when delivered through GD2-targeted immunoliposomes, significantly reducing cell growth in vitro compared to other delivery methods.

In an in vivo model, treatment with anti-GD2-SIL-HPR completely inhibited the development of metastases in neuroblastoma, achieving 100% curability, which highlights its potential as an effective adjuvant therapy for this aggressive childhood cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo antitumor activity of liposomal Fenretinide targeted to human neuroblastoma. Raffaghello, L., Pagnan, G., Pastorino, F., et al.[2016]

Identifying individuals with the HLA-B*15:02 genetic variant and avoiding carbamazepine can significantly reduce the risk of severe cutaneous adverse reactions like Stevens-Johnson syndrome and toxic epidermal necrolysis.

The study suggests that antiepileptic drugs classified as BDDCS Class 2 are more likely to cause skin reactions, while Class 3 drugs have the lowest risk, indicating that Class 3 AEDs may be safer options for patients, especially those of Asian descent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to Help Predict the Occurrence of Idiosyncratic Cutaneous Adverse Drug Reactions Associated with Antiepileptic Drug Usage. Chan, R., Wei, CY., Chen, YT., et al.[2022]

In a study of 589 patients taking Levetiracetam (LEV), only 8 cases of cutaneous adverse drug reactions (cADRs) were identified, including severe reactions like Stevens Johnson syndrome (SJS) and drug reaction eosinophilia and systemic symptoms (DRESS), indicating that such reactions are quite rare.

The investigation into the association between specific HLA alleles and LEV-related cADRs in a North Indian population did not yield statistically significant results, suggesting that genetic predisposition may not play a strong role in these reactions for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spectrum of Cutaneous Adverse Reactions to Levetiracetam and Human Leukocyte Antigen Typing in North-Indian Patients. Ramanujam, B., Ihtisham, K., Kaur, G., et al.[2020]

HLA-A*31:01 is a significant genetic risk factor for both serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI) caused by carbamazepine, with odds ratios indicating a strong association in European populations.

The study identified that the hypersensitivity syndrome is particularly linked to HLA-A*31:01, while a different genetic marker, HLA-B*57:01, is associated with more severe cases like Stevens-Johnson syndrome, highlighting the importance of genetic testing in predicting adverse reactions to carbamazepine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions. Nicoletti, P., Barrett, S., McEvoy, L., et al.[2021]

In a 12-week study involving 93 patients with partial-onset seizures, BGG492 at 150 mg showed a 37.32% greater reduction in seizure frequency compared to placebo, although no significant dose-response trend was observed between the 100 mg and 150 mg doses.

The safety profile of BGG492 was consistent with previous findings, with common side effects including dizziness, somnolence, and fatigue, particularly in the 150 mg group, but no new safety risks were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BGG492 as an adjunctive treatment in patients with partial-onset seizures: A 12-week, randomized, double-blind, placebo-controlled, phase II dose-titration study with an open-label extension. Elger, CE., Hong, SB., Brandt, C., et al.[2018]

In a study of 93 patients with brain tumor-related epilepsy, adding lacosamide to existing antiepileptic drugs resulted in 76.7% of patients experiencing a 50% reduction in seizure frequency after 6 months, indicating its effectiveness as a treatment option.

Lacosamide was generally well tolerated, with an 86% retention rate over 6 months and only 16.1% of patients reporting adverse drug reactions, suggesting it is a safe addition to epilepsy management in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and tolerability of lacosamide as add-on therapy in patients with brain tumor-related epilepsy: Results from a prospective, noninterventional study in European clinical practice (VIBES). Rudà, R., Houillier, C., Maschio, M., et al.[2020]

Topiramate is effective in reducing seizure frequency by 35-47% at a dose of 400 mg/day for patients with partial-onset seizures, and it can also be used alone for this type of seizure.

While topiramate has a good safety profile with no serious toxicity reported, common side effects include psychomotor slowing, which often resolves with time or dosage adjustments; 11-28% of patients may stop taking it due to side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical studies of topiramate. Faught, E.[2019]

The combination of fenretinide (4-HPR) and venetoclax (ABT-199) showed strong synergistic effects against high BCL-2-expressing neuroblastoma in preclinical models, significantly improving event-free survival in mice with patient-derived xenografts.

BCL-2 expression at diagnosis may serve as a biomarker to identify neuroblastoma patients who are likely to respond to this treatment combination, suggesting a targeted approach for therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenretinide via NOXA Induction, Enhanced Activity of the BCL-2 Inhibitor Venetoclax in High BCL-2-Expressing Neuroblastoma Preclinical Models. Nguyen, TH., Koneru, B., Wei, SJ., et al.[2022]

The combination of the pan-HDAC inhibitor vorinostat and the synthetic retinoid fenretinide showed strong cytotoxic synergy against T-cell lymphoid malignancies (TCLMs) in nine different cancer cell lines, while sparing non-malignant cells, indicating a targeted therapeutic approach.

In vivo studies demonstrated that this combination, along with ketoconazole to enhance fenretinide exposure, resulted in greater anti-tumor activity in TCLM xenograft models, supporting the potential for clinical trials in patients with relapsed and refractory TCLMs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vorinostat and fenretinide synergize in preclinical models of T-cell lymphoid malignancies. Makena, MR., Nguyen, TH., Koneru, B., et al.[2021]

Treatment with retinoids, specifically etretinate and acitretin, led to significant improvement in skin conditions for patients with ichthyosis bullosa of Siemens (IBS) and bullous ichthyosiform erythroderma of Brocq (BIE).

The effective maintenance doses were found to be 10-25 mg per day for IBS patients and 40-60 mg per day for the BIE patient, indicating a tailored approach to dosage based on the specific condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ichthyosis bullosa of Siemens responds well to low-dosage oral retinoids. Steijlen, PM., van Dooren-Greebe, RJ., Happle, R., et al.[2019]

In a study of 28 breast cancer patients, those treated with CDK4/6 inhibitors (CDKiA) showed a higher prevalence of vertex involvement in alopecia compared to those on endocrine monotherapy, indicating a distinct pattern of hair loss associated with this treatment.

After 4-6 months of minoxidil treatment, 80% of patients with CDKiA experienced moderate to significant improvement in alopecia, although this was less effective than in patients with endocrine-induced alopecia (EIA), suggesting that alternative treatments may be needed for better outcomes in CDKiA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective cohort study of CDK4/6-inhibitor-induced alopecia in breast cancer patients. Minta, A., Rose, L., Park, C., et al.[2023]

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