Fenretinide for Dengue Fever

(PROTECT Trial)

Overseen By Mari Heghinian, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Island Pharmaceuticals

Must not be taking: Anticoagulants, NSAIDs, Corticosteroids, others

Disqualifiers: Pregnancy, HIV, Hepatitis, others

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 37

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized, placebo controlled single center study examines the extent to which 600 mg/m2/day of orally administered ISLA101 (fenretinide), given prophylactically or therapeutically, may reduce or eliminate signs and symptoms of dengue virus (DENV) infection over 29 days following subcutaneous challenge of healthy subjects with 'Dengue 1 Live Virus Human Challenge' (DENV-1-LVHC). Humoral and cellular immune responses, both innate and adaptive, circulating virus, and changes in clinical laboratory measures will also be examined.

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

The trial requires that you stop taking certain medications. Specifically, you cannot be on anti-coagulant medication, aspirin, NSAIDs, or drugs that inhibit or induce Cytochrome P450 3A4 enzymes within 30 days prior to the study and during participation.

Will I have to stop taking my current medications?

The trial requires that participants do not take certain medications, such as anti-coagulants, aspirin, NSAIDs, and drugs that affect specific liver enzymes, for at least 30 days before and during the study. If you are on these medications, you may need to stop taking them to participate.

What data supports the idea that Fenretinide for Dengue Fever is an effective treatment?

The available research shows that Fenretinide has promising antiviral activity against the dengue virus. In a study, it was found that effective concentrations of Fenretinide could be achieved in a mouse model of severe dengue infection. This suggests that Fenretinide could potentially be effective in treating dengue fever. However, the study also highlights challenges in its clinical use, such as solubility and metabolism issues, which need to be addressed to improve its effectiveness in humans. ^{1 2 3 4 5}

What data supports the effectiveness of the drug Fenretinide for treating Dengue Fever?

Research shows that Fenretinide has promising antiviral activity against flaviviruses, including the dengue virus, in both lab and animal studies. Effective plasma concentrations for anti-dengue activity can be achieved with current formulations, and new formulations may further enhance its effectiveness. ^{1 2 3 4 5}

What safety data is available for Fenretinide as a treatment?

Fenretinide (4-HPR) has an established safety record and has been evaluated in various studies for its antiviral and anticancer activities. It has been used in clinical trials for other indications, such as breast cancer prevention, where it showed accumulation in breast tissue. The compound has a favorable toxicity profile, but its low bioavailability has been a limitation. Studies have explored ways to increase its plasma levels, such as using lipid-based formulations and CYP3A4 inhibitors like ketoconazole. Overall, fenretinide is considered to have a good safety profile, but its clinical use is challenged by its low bioavailability. ^{1 2 4 6 7}

Is fenretinide generally safe for human use?

Fenretinide has been studied for various conditions and has shown a favorable safety profile in clinical trials, although its low bioavailability (how much of the drug is available in the body) has been a challenge. It has been used in cancer research with a good safety record, and normal liver cells were unaffected by it in studies, suggesting it is generally safe for human use. ^{1 2 4 6 7}

Is the drug Fenretinide a promising treatment for Dengue Fever?

Yes, Fenretinide shows promise as a treatment for Dengue Fever. It has been found to effectively reduce the virus in studies and has a good safety record. New formulations are being developed to improve its effectiveness in the body. ^{1 2 4 5 8}

How is the drug fenretinide unique in treating dengue fever?

Fenretinide is unique because it works by reducing the amount of viral RNA (genetic material) in the body, which helps to stop the virus from multiplying. This approach is different from other treatments that might not target the virus's genetic material directly. ^{1 2 4 5 8}

Research Team

Bert Slade, MD

Principal Investigator

CCRS

Eligibility Criteria

This trial is for healthy individuals who can participate in a study to test the effects of an oral drug, ISLA101, against dengue fever. Participants will be exposed to the dengue virus and monitored for 29 days.

Inclusion Criteria

I cannot become pregnant due to surgery or being post-menopausal.

I agree to use birth control or practice abstinence.

Ability and willingness to sign informed consent

Exclusion Criteria

Participation in other clinical trials, recent/scheduled receipt of vaccines, beliefs restricting blood product administration, chronic medical conditions, physician discretion

I have a blood clotting disorder.

Recent travel to specified areas, positive urine screen for specified substances

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Prophylactic Treatment

Participants receive ISLA101 or placebo prior to inoculation and for 21 days thereafter

3 weeks

Daily visits for 18 days

Therapeutic Treatment

Participants receive ISLA101 or placebo starting on Day 8 post-inoculation and continue for 14 days

2 weeks

Daily visits for 18 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Fenretinide

Trial Overview The study tests if taking 600 mg/m2/day of ISLA101 orally can prevent or treat symptoms of dengue after being challenged with a live virus. It's randomized and placebo-controlled; some people get the real drug, others get a dummy pill.

Participant Groups

Group I: Cohort C Experimental Treatment 2 Interventions

The second cohort (Cohort C) is planned to enroll in two groups of five subjects each, using 4:1 randomization (active:control). All subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL) on Day 1. After the inoculation, subjects will be evaluated in the clinic daily through day 18 (eighteen consecutive daily clinic visits). Dosing with ISLA101 will commence on the morning of Day 8 and continue with a total of 28 doses taken twice daily through Day 21.

Group II: Cohort A Experimental Treatment 2 Interventions

The first cohort (Cohort A) allows examination of prophylaxis as well as treatment, as ISLA101 will be taken prior to inoculation and for 21 days thereafter. Subjects will be randomized 3:1 (active:control), enrolling in a single group three days prior to inoculation. Following the morning dose on the 4th day of dosing, all subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL).

Group III: Cohort D Placebo Group 2 Interventions

The second cohort (Cohort D) is planned to enroll in two groups of five subjects each, using 4:1 randomization (active:control). All subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL) on Day 1. After the inoculation, subjects will be evaluated in the clinic daily through day 18 (eighteen consecutive daily clinic visits). Dosing with placebo will commence on the morning of Day 8 and continue with a total of 28 doses taken twice daily through Day 21.

Group IV: Cohort B Placebo Group 2 Interventions

The first cohort (Cohort B) allows examination of prophylaxis as well as treatment, as placebo will be taken prior to inoculation and for 21 days thereafter. Subjects will be randomized 3:1 (active:control), enrolling in a single group three days prior to inoculation. Following the morning dose on the 4th day of dosing, all subjects will be administered 0.5 mL DENV-1-LVHC (6.5 x 103 PFU/mL).

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

Approved in United States as Fenretinide for:

• Orphan drug designation for the treatment of B-cell lymphoma

Who Is Running the Clinical Trial?

Island Pharmaceuticals

Lead Sponsor

Trials

2

Recruited

40+

Findings from Research

In a study involving 14 women with suspected breast cancer, the synthetic retinoid 4-HPR was shown to accumulate significantly in breast tissue compared to plasma, especially at a dose of 200 mg/day, which is relevant for its potential use in breast cancer prevention.

The concentrations of 4-HPR in breast tissue at this dose were similar to levels that inhibit breast cancer cell growth in laboratory settings, suggesting that 4-HPR could be an effective preventive treatment, particularly for premenopausal women at risk for estrogen receptor-negative breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Breast tissue accumulation of retinamides in a randomized short-term study of fenretinide. Sabichi, AL., Modiano, MR., Lee, JJ., et al.[2016]

N-(4-hydroxyphenyl) retinamide (4-HPR) shows promising antiviral activity against flaviviruses like dengue, and its safety profile is well-established, but its clinical use faces challenges due to limited exposure.

New lipid-based formulations of 4-HPR can significantly enhance its plasma concentration, achieving over a 3-fold improvement compared to existing formulations, suggesting that these new approaches could optimize its effectiveness in treating dengue virus infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased In Vivo Exposure of N-(4-Hydroxyphenyl) Retinamide (4-HPR) to Achieve Plasma Concentrations Effective against Dengue Virus. Martin, AJ., Shackleford, DM., Charman, SA., et al.[2023]

Fenretinide (4-HPR) and its metabolite (4-MPR) effectively suppress tumor formation in a mouse skin cancer model, with their effects lasting even after treatment stops, unlike all-trans retinoic acid (ATRA).

Both 4-HPR and 4-MPR appear to work through mechanisms that do not involve the classic retinoid receptors, suggesting they may offer a different approach to cancer prevention compared to traditional retinoids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemoprevention of skin carcinogenesis by phenylretinamides: retinoid receptor-independent tumor suppression. Xu, H., Cheepala, S., McCauley, E., et al.[2014]

Fenretinide (4-HPR) and its derivatives, particularly those with charged groups, can inhibit cell growth and induce differentiation in cancer cells, suggesting their potential as chemopreventive agents.

The study found that while some phenylretinamides act through retinoid receptors to promote differentiation, 4-MPR, a metabolite of 4-HPR, inhibits cell growth independently of these receptors, highlighting its importance in the therapeutic effects of 4-HPR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retinoid receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites. Sabichi, AL., Xu, H., Fischer, S., et al.[2023]

The compound 4-HPR demonstrated significant cytotoxic effects, killing over 99.9% of cancer cells in nine out of fifteen tested cell lines, indicating its strong potential as an anti-cancer treatment.

Both 4-HPR and its metabolite oxoHPR showed comparable effectiveness in increasing reactive oxygen species and inducing apoptosis, while the other metabolites, cis-HPR and MPR, were less effective, suggesting that maximizing exposure to 4-HPR is crucial for its therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxicity and molecular activity of fenretinide and metabolites in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines in physiological hypoxia. Song, MM., Makena, MR., Hindle, A., et al.[2020]

The study identified six metabolites of fenretinide (4-HPR) in both human and mouse plasma, with 4-HPR being oxidized to 4-oxo-4-HPR primarily through the CYP3A4 enzyme.

Co-administration of ketoconazole, a CYP3A4 inhibitor, significantly increased plasma levels of 4-HPR in mice by more than twofold, suggesting that this combination could enhance the bioavailability of 4-HPR in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure. Cooper, JP., Hwang, K., Singh, H., et al.[2021]

The new compound 5-hydroxyphenyl butanoate retinamide (5-HPBR) showed 2- to 6-fold greater cytotoxicity against various cancer cell lines compared to its parent compound, fenretinide (4-HPR), indicating enhanced antitumor potential.

5-HPBR was found to induce apoptosis in cancer cells while showing no harmful effects on normal liver cells, suggesting a favorable safety profile alongside its increased efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potent effect of 5-HPBR, a butanoate derivative of 4-HPR, on cell growth and apoptosis in cancer cells. Han, HS., Kwon, YJ., Park, SH., et al.[2016]

N-(4-hydroxyphenyl) retinamide (4-HPR) has been identified as a potent antiviral compound that effectively inhibits Zika virus (ZIKV) in cell cultures and reduces viral levels in infected mice, suggesting its potential as a treatment option.

The mechanism of 4-HPR's antiviral action involves significantly decreasing the synthesis of viral RNA, which is crucial for ZIKV replication, while also demonstrating a favorable safety profile from previous clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiviral activity of N-(4-hydroxyphenyl) retinamide (4-HPR) against Zika virus. Pitts, JD., Li, PC., de Wispelaere, M., et al.[2018]

References

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

Breast tissue accumulation of retinamides in a randomized short-term study of fenretinide. [2016]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Increased In Vivo Exposure of N-(4-Hydroxyphenyl) Retinamide (4-HPR) to Achieve Plasma Concentrations Effective against Dengue Virus. [2023]

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

Chemoprevention of skin carcinogenesis by phenylretinamides: retinoid receptor-independent tumor suppression. [2014]

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

Retinoid receptor-dependent and independent biological activities of novel fenretinide analogues and metabolites. [2023]

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

Cytotoxicity and molecular activity of fenretinide and metabolites in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines in physiological hypoxia. [2020]

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

Fenretinide metabolism in humans and mice: utilizing pharmacological modulation of its metabolic pathway to increase systemic exposure. [2021]

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

Potent effect of 5-HPBR, a butanoate derivative of 4-HPR, on cell growth and apoptosis in cancer cells. [2016]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Antiviral activity of N-(4-hydroxyphenyl) retinamide (4-HPR) against Zika virus. [2018]