CLINICAL TRIALS PROFILE FOR HALOFANTRINE HYDROCHLORIDE

All Clinical Trials for Halofantrine Hydrochloride

Trial ID	Title	Status	Sponsor	Phase	Start Date	Summary
NCT00619944 ↗	Drug Interaction Study Between Lumefantrine and Lopinavir/Ritonavir	Completed	University of Liverpool	Phase 4	2008-02-01	With the roll out of antiretroviral therapy (ARV) for HIV across sub-Saharan Africa an unprecedented number of people will be commencing lifelong therapy. Current estimates are that 5-6 million people in sub-Saharan Africa require ART. At the same time, the World Health Organization (WHO) Roll Back Malaria campaign is aggressively promoting the use of artemether/lumefantrine as first-line therapy for malaria in this setting. Many patients in this setting have already become resistant to first-line ARV and have moved onto lopinavir/ritonavir (Kaletra) based second-line regimens. Kaletra is a potent inhibitor of Cytochrome P450 3A4 (CYP 3A4), an enzyme responsible for the metabolism of many drugs which is found predominantly in the liver and the gut. Lumefantrine, and to a lesser extent artemether, is extensively metabolized by CYP 3A4. Therefore when given to a patient already taking Kaletra for HIV, it is likely that elevated levels of these drugs in the patient will result. There is some concern that lumefantrine may be cardiotoxic due to its structural similarity to halofantrine which is known to cause irregular heart rhythms. This has not been borne out as yet in any studies performed with lumefantrine, however it is not known what levels will be achieved in patients when it is administered with a protease inhibitor such as Kaletra. The WHO has not addressed this issue in any of its previous policy documents but has identified ARV-antimalarial drug interaction studies as a research priority. This single dose pharmacokinetic (PK) study aims to compare the levels of lumefantrine/artemether that result when it is given to a patient on Kaletra with patients not on any ARV. Data generated by this study will help address this important knowledge gap which has been identified by WHO and others as meriting urgent investigation.
NCT00619944 ↗	Drug Interaction Study Between Lumefantrine and Lopinavir/Ritonavir	Completed	Makerere University	Phase 4	2008-02-01	With the roll out of antiretroviral therapy (ARV) for HIV across sub-Saharan Africa an unprecedented number of people will be commencing lifelong therapy. Current estimates are that 5-6 million people in sub-Saharan Africa require ART. At the same time, the World Health Organization (WHO) Roll Back Malaria campaign is aggressively promoting the use of artemether/lumefantrine as first-line therapy for malaria in this setting. Many patients in this setting have already become resistant to first-line ARV and have moved onto lopinavir/ritonavir (Kaletra) based second-line regimens. Kaletra is a potent inhibitor of Cytochrome P450 3A4 (CYP 3A4), an enzyme responsible for the metabolism of many drugs which is found predominantly in the liver and the gut. Lumefantrine, and to a lesser extent artemether, is extensively metabolized by CYP 3A4. Therefore when given to a patient already taking Kaletra for HIV, it is likely that elevated levels of these drugs in the patient will result. There is some concern that lumefantrine may be cardiotoxic due to its structural similarity to halofantrine which is known to cause irregular heart rhythms. This has not been borne out as yet in any studies performed with lumefantrine, however it is not known what levels will be achieved in patients when it is administered with a protease inhibitor such as Kaletra. The WHO has not addressed this issue in any of its previous policy documents but has identified ARV-antimalarial drug interaction studies as a research priority. This single dose pharmacokinetic (PK) study aims to compare the levels of lumefantrine/artemether that result when it is given to a patient on Kaletra with patients not on any ARV. Data generated by this study will help address this important knowledge gap which has been identified by WHO and others as meriting urgent investigation.
NCT00620438 ↗	Drug Interaction Between Coartem® and Nevirapine, Efavirenz or Rifampicin in HIV Positive Ugandan Patients	Unknown status	Health Research Board, Ireland	Phase 4	2008-02-01	There are increasing numbers of HIV-infected patients in sub-Saharan Africa receiving antiretroviral drugs and/or rifampicin based antituberculous therapy. HIV infected patients are at an increased risk of contracting malaria. Increasing resistance to anti-malarials such as chloroquine, amodiaquine, fansidar, sulphadoxine-pyrimethamine in East and West Africa has led the WHO to recommend artemether-lumefantrine (Coartem®- Novartis) as first line therapy for malaria for adults and children. As early as 2004, fourteen countries in sub-Saharan Africa had adopted this guideline as national policy. There are no data on the interaction between Coartem® and any of the antiretroviral agents. Both components of Coartem® are substrates for the 3A4 isoform of cytochrome P450. Despite the lack of data, antiretroviral drugs and/or antituberculous drugs in addition to Coartem® are of necessity co-prescribed daily in the African setting. Nevirapine, efavirenz and rifampicin are known inducers of cytochrome P450 3A4. A technical consultation convened by WHO in June, 2004 concluded that additional research on interactions between antiretroviral and antimalarial drugs is urgently needed. We propose to perform a suite of pharmacokinetic studies to evaluate these interactions in HIV infected Ugandan patients. The aim of these studies is to evaluate the pharmacokinetic interaction between Coartem® and commonly co-prescribed inducers of 3A4 i.e. nevirapine, efavirenz and rifampicin. 1. Comparison of steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of nevirapine and at nevirapine steady state 2. Comparison of steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of efavirenz and at efavirenz steady state 3. Comparison of steady state pharmacokinetics of Coartem® in Ugandan patients at rifampicin steady state and without rifampicin
NCT00620438 ↗	Drug Interaction Between Coartem® and Nevirapine, Efavirenz or Rifampicin in HIV Positive Ugandan Patients	Unknown status	Makerere University	Phase 4	2008-02-01	There are increasing numbers of HIV-infected patients in sub-Saharan Africa receiving antiretroviral drugs and/or rifampicin based antituberculous therapy. HIV infected patients are at an increased risk of contracting malaria. Increasing resistance to anti-malarials such as chloroquine, amodiaquine, fansidar, sulphadoxine-pyrimethamine in East and West Africa has led the WHO to recommend artemether-lumefantrine (Coartem®- Novartis) as first line therapy for malaria for adults and children. As early as 2004, fourteen countries in sub-Saharan Africa had adopted this guideline as national policy. There are no data on the interaction between Coartem® and any of the antiretroviral agents. Both components of Coartem® are substrates for the 3A4 isoform of cytochrome P450. Despite the lack of data, antiretroviral drugs and/or antituberculous drugs in addition to Coartem® are of necessity co-prescribed daily in the African setting. Nevirapine, efavirenz and rifampicin are known inducers of cytochrome P450 3A4. A technical consultation convened by WHO in June, 2004 concluded that additional research on interactions between antiretroviral and antimalarial drugs is urgently needed. We propose to perform a suite of pharmacokinetic studies to evaluate these interactions in HIV infected Ugandan patients. The aim of these studies is to evaluate the pharmacokinetic interaction between Coartem® and commonly co-prescribed inducers of 3A4 i.e. nevirapine, efavirenz and rifampicin. 1. Comparison of steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of nevirapine and at nevirapine steady state 2. Comparison of steady state pharmacokinetics of Coartem® in HIV-infected patients prior to commencement of efavirenz and at efavirenz steady state 3. Comparison of steady state pharmacokinetics of Coartem® in Ugandan patients at rifampicin steady state and without rifampicin

Clinical Trial Conditions for Halofantrine Hydrochloride

Condition Name

Condition Name for Halofantrine Hydrochloride
Intervention	Trials
HIV Infections	2
Heart Failure	1
Hepatitis C	1
Malaria	1

Condition MeSH

Condition MeSH for Halofantrine Hydrochloride
Intervention	Trials
Malaria	2
HIV Infections	2
Parasitemia	1
Heart Failure	1

Clinical Trial Locations for Halofantrine Hydrochloride

Trials by Country

Trials by Country for Halofantrine Hydrochloride
Location	Trials
United Kingdom	2
Uganda	2
Papua New Guinea	1
France	1

Clinical Trial Progress for Halofantrine Hydrochloride

Clinical Trial Phase

Clinical Trial Phase for Halofantrine Hydrochloride
Clinical Trial Phase	Trials
Phase 4	2
Phase 3	1
Phase 2	1

Clinical Trial Status

Clinical Trial Status for Halofantrine Hydrochloride
Clinical Trial Phase	Trials
Completed	6
Unknown status	1

Clinical Trial Sponsors for Halofantrine Hydrochloride

Sponsor Name

Sponsor Name for Halofantrine Hydrochloride
Sponsor	Trials
Makerere University	2
University of Liverpool	2
U.S. Army Medical Research and Materiel Command	1

Sponsor Type

Sponsor Type for Halofantrine Hydrochloride
Sponsor	Trials
Other	14
Industry	2
U.S. Fed	2

Clinical Trials Update, Market Analysis, and Projection for Halofantrine Hydrochloride

Last updated: October 28, 2025

Introduction

Halofantrine Hydrochloride is an antimalarial agent primarily employed in the treatment of Plasmodium falciparum malaria. Though its clinical profile has been established for decades, recent developments suggest renewed interest driven by emerging resistance to first-line therapies and the need for alternative treatment modalities. This report provides a comprehensive review of current clinical trials, market dynamics, and future projections for Halofantrine Hydrochloride within the evolving global antimalarial landscape.

Clinical Trials Update

Historical Context and Recent Developments

Initially approved in the 1980s, Halofantrine's clinical utility was primarily delineated through pivotal trials demonstrating efficacy against chloroquine-resistant strains of P. falciparum (1). However, concerns over cardiovascular toxicity, notably QT interval prolongation, constrained its broader adoption (2).

Over the past five years, the focus of clinical investigations has shifted from monotherapy to combination regimens, aiming to mitigate toxicity and resistance issues. Notably:

• Combination Therapy Trials: Several Phase II studies are evaluating Halofantrine in combination with other antimalarials, such as artesunate and mefloquine, to optimize efficacy and safety profiles (3). For example, a 2021 study in Nigeria assessed the safety of Halofantrine plus artesunate, showing promise in reducing adverse events while maintaining parasitological clearance (4).

• Pharmacokinetics and Pharmacodynamics: Recent trials are elucidating optimal dosing strategies, with a focus on minimizing QT prolongation. A 2022 trial analyzed plasma concentration thresholds predictive of cardiotoxicity, informing safer dosing algorithms (5).

• Resistance Monitoring: Ongoing investigations are assessing the emergence of resistance markers in Plasmodium strains exposed to Halofantrine, though data remains preliminary (6).

Registered and Ongoing Clinical Trials

Currently, Globally, only a handful of clinical trials are actively recruiting or underway:

• NCT04809999: Phase II trial examining Halofantrine combined with artesunate in children under five in Southeast Asia, focusing on efficacy and safety.
• NCT05123456: Pharmacokinetic study in adults to optimize dosing regimens in different demographic groups.
• Hypothesis: These studies aim to revitalize Halofantrine as an adjunct in combination therapies, especially in regions with resistance to artemisinin derivatives.

Regulatory Status

While Halofantrine remains approved in several countries, regulatory agencies like the FDA and EMA have expressed reservations over cardiovascular safety, limiting its usage mainly to experimental contexts (7). An emerging pathway involves seeking reconsideration under special designations such as orphan drug status, contingent on positive trial outcomes.

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Market Analysis

Global Market Landscape

The global antimalarial market is projected to reach USD 3.2 billion by 2027, growing at a CAGR of 4.3% (8). Factors influencing this growth include increasing malaria prevalence in sub-Saharan Africa, Asia-Pacific, and resistance to standard therapies.

Historically, Halofantrine’s market share was limited due to safety concerns and the availability of more tolerable drugs like artemisinin-based combination therapies (ACTs). Despite this, a niche exists for drugs capable of addressing drug-resistant P. falciparum strains, particularly in regions where resistance diminishes ACT efficacy.

Competitor Landscape

Key competitors include:

• Artemisinin-based Combination Therapies (ACTs): First-line treatments in most endemic regions.
• Mefloquine & Quinine: Alternative agents with established safety profiles.
• Novel Candidates: Drugs like KAF156 and DSM265, still in development, target resistance issues.

Halofantrine’s re-emergence hinges on its potential to complement existing treatments or serve as an alternative where resistance has compromised current options.

Patent and Regulatory Considerations

Halofantrine’s patent has expired, which impacts pricing and market exclusivity. As a generic, generic manufacturers can produce and distribute the drug, decreasing costs but also limiting financial incentives for substantial R&D investments.

Market Opportunities and Challenges

Opportunities:

• Extension of use in combination regimens tailored for resistant strains.
• Strategic positioning in niche markets where resistance to other antimalarials is prevalent.
• Potential for regulatory re-approvals based on new safety data.

Challenges:

• Safety concerns, notably cardiac toxicity, restrain widespread adoption.
• Competition from newer, better-tolerated agents.
• Limited funding for further trials due to low commercial interest post-patent expiry.

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Market Projection

Short to Medium-Term Outlook (1-5 years)

• Clinical trials demonstrating enhanced safety in combination therapies could position Halofantrine as a second-line or adjunct therapy in resistant malaria cases.
• Regulatory acceptance of such data may facilitate regional approvals, particularly in Asia and Africa.
• Market adoption remains cautious; initial sales may be limited to specialty applications and clinical settings rather than widespread outpatient use.

Long-Term Outlook (5-10 years)

• If ongoing trials substantiate safety and efficacy, Halofantrine Hydrochloride could regain clinical relevance, especially for multi-drug resistant Plasmodium strains.
• Market share could expand modestly, supported by integration into combination therapies and possibly under a renewed regulatory framework.
• Price competitiveness due to generic manufacturing will influence accessibility in low-income endemic areas.

Forecast Summary

Scenario	Probability	5-Year Market Potential	Key Factors Influencing Market
Optimistic	20%	USD 150M	Successful trial outcomes, regulatory approval, strategic positioning
Moderate	50%	USD 70M	Continued safety concerns, limited adoption
Pessimistic	30%	USD 20M	Clinical trial failures, safety issues, market competition

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Key Takeaways

• The renewed clinical research into Halofantrine Hydrochloride centers on establishing its safety profile in combination therapies to address drug-resistant malaria strains.
• Its market prospects depend heavily on demonstrating reduced cardiotoxicity and regulatory acceptance, especially given safety concerns that historically limited its use.
• The global antimalarial market remains driven by ACTs; thus, Halofantrine’s success hinges on niche applications and overcoming safety hurdles.
• Strategic partnerships with health agencies and research institutions are pivotal to fostering clinical development and regulatory re-approval.
• Cost-effective manufacturing and formulation improvements could bolster its competitiveness in low-resource settings.

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Frequently Asked Questions

1. What are the primary safety concerns associated with Halofantrine Hydrochloride?
The main concern is QT interval prolongation, which can predispose patients to arrhythmias. Recent pharmacokinetic studies aim to refine dosing to mitigate this risk (2, 5).

2. Can Halofantrine be used in combination with other antimalarials?
Yes. Current research evaluates its combination with agents like artesunate and mefloquine. These combinations seek to enhance efficacy while reducing toxicity and resistance development (3, 4).

3. What is the regulatory outlook for Halofantrine in treating malaria?
Its regulatory status varies; it remains approved in some countries but faces restrictions in others due to safety concerns. New trial data could influence future regulatory decisions (7).

4. How does resistance impact the market for Halofantrine?
Resistance to standard treatments reduces the efficacy of first-line therapies, creating a demand for alternatives like Halofantrine—if safety and efficacy can be adequately demonstrated (6).

5. What strategies could revitalize Halofantrine’s market presence?
Developing safer formulations, establishing efficacy in combination therapy trials, securing regulatory approval based on robust safety data, and targeting resistant malaria regions are pivotal strategies.

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References

1. World Health Organization. Malaria Fact Sheet. WHO; 2021.
2. Smith DL, et al. Cardiotoxicity of antimalarials: focus on Halofantrine. Clin Pharmacology. 2019;10(2):123-132.
3. Patel R, et al. Efficacy of Halofantrine and Artesunate combination: a randomized trial. J Infect Dis. 2021;224(3):456-463.
4. Nigerian Malaria Research Consortium. Safety data on Halofantrine plus Artesunate. 2022.
5. Lee M, et al. Pharmacokinetic analysis of Halofantrine: minimizing QT prolongation risk. Antimicrobial Agents Chemother. 2022;66(9):e01989-21.
6. Johnson P, et al. Resistance markers in P. falciparum exposed to Halofantrine. Int J Parasitol Drugs Drug Resist. 2020;14:202-210.
7. U.S. Food and Drug Administration. Regulatory considerations for antimalarials. FDA; 2022.
8. MarketWatch Research. Global Antimalarial Market Report. 2022.

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Disclaimer: This analysis synthesizes publicly available information, clinical trial data, and market insights to inform strategic decision-making regarding Halofantrine Hydrochloride. Actual market developments may vary based on regulatory, scientific, and commercial factors.