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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called fenretinide to determine if it can reduce or eliminate symptoms of dengue fever, a virus spread by mosquitoes. Researchers will administer either fenretinide or a placebo to participants to compare the effects. The trial aims to understand how fenretinide affects the immune system's response to the virus. Participants should be healthy adults who have never had dengue, have not been vaccinated against it, and have not recently traveled to areas where dengue is common. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

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.

Is there any evidence suggesting that fenretinide is likely to be safe for humans?

Research shows that fenretinide is generally safe. It has been used for many years in cancer treatments without safety concerns. Studies have found that fenretinide, when taken as an oral powder, is safe and well-tolerated.

In earlier studies, this treatment effectively reduced the dengue virus in test models and was well-received by patients. Although these studies did not report specific side effects, its past use in cancer suggests general safety.

The current trial is in a phase that typically assesses a treatment's safety for people, meaning any serious issues would likely have been identified in earlier tests. Fenretinide's use in other conditions also suggests it is safe for humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for dengue fever?

Most treatments for dengue fever focus on supportive care, such as hydration and pain relief, since there are no specific antiviral drugs approved for this condition yet. However, fenretinide is unique because it targets the virus itself, potentially inhibiting its replication. This makes it different from standard care options, which don't directly address the virus. Researchers are excited about fenretinide because it offers a proactive approach by possibly preventing the virus from spreading within the body, which could lead to quicker recovery times and less severe symptoms.

What evidence suggests that fenretinide might be an effective treatment for dengue fever?

Research has shown that fenretinide, also known as 4-HPR, might help fight the dengue virus. Studies have found that it can reduce the virus's ability to multiply in the lab. In animal studies, fenretinide lowered the amount of virus in the blood. It has also been effective against all four types of dengue virus in lab tests. This trial will evaluate fenretinide's potential to manage dengue infection by reducing virus levels in the body. Participants will receive fenretinide in different cohorts to assess its effectiveness and safety. ^{1 2 4 6 7}

Who Is on the Research Team?

Bert Slade, MD

Principal Investigator

CCRS

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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) 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 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10384639/

Increased In Vivo Exposure of N-(4-Hydroxyphenyl) ... This study evaluated the in vivo exposure profile of a 4-HPR dosage regime previously shown to be effective in a mouse model of severe dengue virus (DENV) ...

2. academic.oup.com academic.oup.com/jid/article/210/11/1780/2908496

Nuclear Transport Inhibitor That Modulates the Unfolded ... N-(4-hydroxyphenyl) retinamide (4-HPR) effectively reduces dengue virus serotype 2 (DENV-2) RNA replication when added 12 hours after infection. A–C, Huh-7 ...

3. journals.asm.org journals.asm.org/doi/10.1128/aac.04177-14

The Bioactive Lipid 4-Hydroxyphenyl Retinamide Inhibits ... 4-HPR inhibits the steady-state accumulation of viral genomic RNA and reduces viremia when orally administered in a murine model of DENV infection. The ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06528457

Study to Examine the Effects of Oral Fenretinide This Phase 2 study is to evaluate the effectiveness of fenretinide in an encapsulated oral formulation (ISLA101) against challenge with Dengue 1 Live Virus ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0166354216301346

Novel dengue virus inhibitor 4-HPR activates ATF4 ... We recently identified N-(4-hydroxyphenyl) retinamide (4-HPR), an anti-DENV agent effective against all 4 serotypes of DENV in cell culture, and in a lethal ...

6. withpower.com withpower.com/trial/phase-2-dengue-9-2024-27d76

Fenretinide for Dengue Fever · Info for Participants 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 ...

7. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/60/NCT06181760/Prot_000.pdf

53 ph 1 protocol Fenretinide has been used to treat cancer patients for decades with a favorable safety profile. To strategically support the development of ...