Nebulized clofazimine trial in nontuberculous mycobacterial lung disease discontinued – Healio

Report on the ICoN-1 Clinical Trial Discontinuation and Relevance to Sustainable Development Goals

Executive Summary

• The multinational Phase 3 ICoN-1 trial for a nebulized clofazimine inhalation suspension (MNKD-101) has been discontinued due to futility.
• This development represents a challenge to achieving Sustainable Development Goal 3 (SDG 3), which focuses on ensuring good health and well-being, specifically in the area of treating communicable lung diseases.
• The sponsoring company, MannKind, has identified the drug’s delivery formulation, not the active molecule, as the likely cause of failure.
• In alignment with SDG 9 (Industry, Innovation, and Infrastructure), the company is pivoting its research and development efforts toward a more technologically advanced dry powder inhalation (DPI) formulation (MNKD-102).

1.0 Trial Background and Connection to SDG 3: Good Health and Well-being

1.1 Overview of the ICoN-1 Trial

The ICoN-1 study was a multinational, randomized, double-blind, placebo-controlled Phase 3 trial designed to assess a novel treatment for a serious health condition. Key characteristics included:

• Objective: To analyze the efficacy and safety of nebulized clofazimine inhalation suspension (MNKD-101).
• Target Population: Adults with refractory nontuberculous mycobacterial (NTM) lung disease.
• Methodology: The investigational drug was added to existing guideline-based therapy.

1.2 Contribution to Global Health Targets

Research into treatments for infectious diseases like NTM lung disease is fundamental to achieving global health objectives. This trial directly relates to the following SDG 3 targets:

1. Target 3.3: End the epidemics of communicable diseases. Developing effective therapies for persistent lung infections such as NTM is critical to reducing their burden.
2. Target 3.b: Support the research and development of medicines for communicable and non-communicable diseases. The ICoN-1 trial represented a significant investment in R&D aimed at addressing an unmet medical need.

2.0 Trial Discontinuation and Primary Findings

2.1 Basis for Discontinuation

The decision to halt the trial was made by the independent Data Safety Monitoring Board (DSMB) following an assessment of data from the first 46 adult participants. The primary reason cited was futility, as early results indicated the trial was unlikely to meet its primary goals. It is important to note that the DSMB observed no safety concerns during the study.

2.2 Analysis of Endpoints

The trial failed to meet its co-primary endpoints between baseline and the six-month mark.

• Sputum Culture Conversion: None of the participants achieved the primary efficacy endpoint, defined as three consecutive months of sputum cultures negative for NTM. While partial conversions were observed, no participant met the full criteria.
• Quality of Life: The second co-primary endpoint, change in quality of life, was also under evaluation.

3.0 Investigation of Failure and Alignment with SDG 9: Industry, Innovation, and Infrastructure

3.1 Hypothesis on Formulation-Related Failure

MannKind Corporation expressed confidence in the anti-mycobacterial properties of the clofazimine molecule itself. The company’s analysis points toward the drug delivery system as the source of the unexpected results.

• Formulation Complexity: The nebulized suspension required specific handling, including precise shaking duration (15 seconds) and nebulization time (18 minutes).
• Dosing Inconsistency: It is hypothesized that deviations from these preparation instructions may have led to inconsistent dosing, dramatically altering the amount of drug administered to patients.

3.2 The Role of Innovation and Iterative Development

The outcome of the ICoN-1 trial underscores the principles of scientific advancement and industrial innovation central to SDG 9.

• Enhancing Scientific Research (Target 9.5): The thorough analysis of the trial’s failure, including plasma pharmacokinetics and patient-reported outcomes, will contribute valuable knowledge to the scientific community. This process of learning from setbacks is crucial for upgrading technological capabilities in the pharmaceutical sector.
• Resilient Infrastructure: The ability to analyze failure and pivot to a new technological approach demonstrates the resilience and adaptability required for sustainable industrial development.

4.0 Future Strategy and Renewed Commitment to Health Innovation

4.1 Strategic Pivot to Dry Powder Inhalation (DPI) Technology

In response to the trial’s outcome, MannKind is shifting focus to an alternative formulation, MNKD-102, which utilizes Dry Powder Inhalation (DPI) technology. This strategic move aligns with the goal of leveraging superior technology to overcome previous challenges.

• Technological Advantage: A DPI formulation is expected to provide a more predictable and accurately delivered dose.
• Reduced Human Error: This delivery method requires less complex human intervention compared to the nebulized suspension, mitigating risks associated with preparation and administration.

4.2 Projected Timeline and Next Steps

The company has outlined a clear path forward for its clofazimine program.

1. Apply key learnings from the ICoN-1 data to the ongoing development of MNKD-102.
2. Advance MNKD-102 from preclinical development toward a Phase 1 clinical trial.
3. Prepare the GMP (Good Manufacturing Practice) batch required for the clinical trial.
4. Provide further updates on the DPI program in the second quarter of the upcoming year.

This continued investment in R&D, despite a significant setback, reaffirms the organization’s commitment to addressing NTM lung disease and contributing to the broader objectives of SDG 3 and SDG 9.

Analysis of Sustainable Development Goals in the Article

1. Which SDGs are addressed or connected to the issues highlighted in the article?

1. SDG 3: Good Health and Well-being

   • The article’s central theme is the development of a treatment for refractory nontuberculous mycobacterial (NTM) lung disease. This directly aligns with SDG 3, which aims to ensure healthy lives and promote well-being for all at all ages. The research described, including the ICoN-1 trial, is an effort to address a specific, challenging health problem and improve the lives of patients suffering from this communicable disease.

2. SDG 9: Industry, Innovation, and Infrastructure

   • The article details the research and development (R&D) activities of a pharmaceutical company, MannKind. The discussion of the phase 3 clinical trial, the analysis of the formulation’s failure, and the subsequent development of a new dry powder inhalation (DPI) formulation (MNKD-102) are prime examples of industrial innovation and scientific research. This connects directly to SDG 9’s goal of building resilient infrastructure, promoting inclusive and sustainable industrialization, and fostering innovation.

2. What specific targets under those SDGs can be identified based on the article’s content?

1. Target 3.3: End epidemics of communicable diseases

   • This target aims to “end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases.” Nontuberculous mycobacterial (NTM) lung disease is a communicable disease. The ICoN-1 trial, designed to test a new treatment (nebulized clofazimine), represents a direct effort to combat such a disease, particularly in its “refractory” form, which is resistant to existing therapies.

2. Target 3.b: Support research and development of medicines

   • This target calls for supporting “the research and development of vaccines and medicines for the communicable and non-communicable diseases.” The entire article is a case study of this process. It describes a multinational phase 3 clinical trial, which is a critical stage in the R&D of new medicines. The company’s commitment to continue development with a new formulation, despite the initial trial’s failure, underscores the ongoing investment in medical R&D.

3. Target 9.5: Enhance scientific research and encourage innovation

   • This target aims to “enhance scientific research, upgrade the technological capabilities of industrial sectors in all countries…including…encouraging innovation and substantially increasing…public and private research and development spending.” The article highlights a private company’s R&D efforts. The decision to discontinue one formulation due to inefficacy and pivot to a more advanced dry powder inhalation (DPI) technology is a clear example of applying scientific learnings to upgrade technological capabilities and foster innovation within the pharmaceutical industry.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

1. Clinical Efficacy and Patient Well-being Indicators

   • The article explicitly mentions two co-primary endpoints for the clinical trial, which serve as direct indicators for measuring the success of a new medical intervention (Target 3.3 and 3.b):
   • Sputum culture conversion: Defined as “negative for nontuberculous mycobacteria (NTM) for 3 consecutive months,” this is a specific, measurable clinical indicator of whether the treatment successfully eradicates the bacteria causing the disease.
   • Change in quality of life: This patient-reported outcome is a direct indicator of well-being, measuring the treatment’s impact on the patient’s daily life beyond just clinical results.

2. Research and Development Process Indicators

   • The article implies several indicators related to the R&D process itself (Target 3.b and 9.5):
   • Safety Profile: The article notes that “no safety concerns were observed by the DSMB.” Monitoring and reporting on safety is a critical indicator in the development of any new medicine.
   • Pharmacokinetics: The plan to analyze “plasma pharmacokinetics vs. phase 1 results” is an indicator used in R&D to understand how a drug is absorbed, distributed, metabolized, and excreted by the body, which is essential for developing an effective product.
   • Technological Innovation: The development of the “MannKind 102 dry powder formulation of clofazimine” is an indicator of ongoing innovation and investment in new drug delivery technologies.

4. Summary Table of SDGs, Targets, and Indicators

Source: healio.com