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Case Study

Translational Pharmacology Consulting Supports Combination Therapy for Treating Pulmonary Mycobacterium Avium Complex Disease

RedHill Biopharma Ltd., a specialty biopharmaceutical company, developed RHB-204, a treatment for MAC, and needed help streamlining the process of getting into Phase 3 clinical trials. RHB-204 combines three well-known antibiotics: clarithromycin (CLR), clofazimine (CFZ), and rifabutin (RFB). The effects of the three individual antibiotics as well as two-drug combinations have been described in several non-clinical models of NTM systemic and lung infection. However, there was no model available for the combination of the three antibiotics. tags so 3

Solutions

Late Clinical 

Background

Pulmonary non-tuberculous mycobacteria (NTM) is a debilitating disease that can lead to reduced lung function and decreased quality of life. The prevalence of NTM infections has been increasing in recent years, particularly in developed countries.1 It is caused by bacteria belonging to the genus Mycobacterium with approximately 80% of NTM infections caused by Mycobacterium avium complex (MAC).2

MAC is notoriously difficult to treat. Current treatment guidelines recommend that MAC infections be managed with a multidrug treatment plan consisting of at least three antimicrobials for no less than 12 months. Currently, no combination therapy has been approved by either the FDA or EMA as a first-line, standard-of-care combination therapy. In addition, many patients do not respond well to existing treatments, and some experience a recurrence of the disease or a new infection after finishing their treatment.

RedHill Biopharma Ltd., a specialty biopharmaceutical company, developed RHB-204, a treatment for MAC, and needed help streamlining the process of getting into Phase 3 clinical trials. RHB-204 combines three well-known antibiotics: clarithromycin (CLR), clofazimine (CFZ), and rifabutin (RFB). The effects of the three individual antibiotics as well as two-drug combinations have been described in several non-clinical models of NTM systemic and lung infection. However, there was no model available for the combination of the three antibiotics.3

Solution

RedHill collaborated with Certara scientists to facilitate moving into Phase 3 trials in the approval process. An integrative translational framework was applied that leveraged modeling and simulation to aid in translating effective drug concentrations from in vitro and in vivo non-clinical models to guide clinical trial dosing regimens. Mathematical and computational models used in translation of information from basic research into predictions about the efficacy and safety of potential new treatments for diseases can be used accelerate the drug development process while reducing the costs and risks associated with traditional methods.

  • In Vitro Hollow Fiber Study. In collaboration with Dr. Tawanda Gumbo from Praedicare Inc, Certara scientists supported the design and interpretation of an in vitro lung infection hollow fiber study (HFS) to evaluate the pharmacokinetics and behavior of a drug in a controlled and reproducible manner. This assay can be used to help optimize dosing regimens, reducing the number of animal and human trials required to evaluate a drug’s safety and efficacy.4

    The HFS-MAC was used to assess the contribution of each individual drug component of RHB-204 (CFZ, CLR, and RFB) when administered individually and as part of a two or three-drug combination. The study was also instrumental in determining anti-mycobacterial effects and understanding how the drugs react when used as part of a combination regimen

Figure 1. In vitro hollow fiber study.

  • Translational Model of NTM Disease. A translation model of NTM infection in mice was designed and analyzed in collaboration with Dr. Luiz Bermudez of Oregon State University. The model included pharmacokinetic (PK) analysis and histopathology to determine the reduction of bacterial counts in the lung and spleen. Pharmacokinetic modeling was then used to estimate the systemic drug exposure of each drug component alone and in combination which resulted in a reduction in bacterial counts and histopathologic improvement in lung tissue.
  • In Vitro Biofilm Model. Mycobacteria can form biofilms–a thin layer of microorganisms within the body– and can serve as a protective shield, allowing the bacteria to survive antibiotic treatment. Certara experts, in conjunction with Dr. Bermudez, designed and analyzed the complexities of mycobacterial biofilm formation using an in vitro model of biofilm. An in vitro model of biofilm recreates the physical and biological characteristics of biofilms in a controlled environment. The in vitro biofilm model of MAC infection showed that CFZ, CLR, and RFB, at physiologically relevant concentrations, have greater efficacy when given in combination as opposed to being given separately.5
  • Pharmacokinetic (PK) Modeling. PK modeling can provide important information about a drug’s absorption, distribution, metabolism, and elimination processes in the body. This information can be used to optimize a dosing regimen and demonstrate a drug’s safety and efficacy, which are crucial factors in obtaining regulatory approval and securing patent protection. Modeling of the drug components administered in combination to humans, followed by simulations, were performed to estimate the human dose and regimen which provided for comparable systemic exposure profiles of each drug component, to the effective concentrations in the HFS, mouse disease models of MAC infection, and biofilm experiments. Predicted human exposure supported the Phase 3 regimen of two divided doses three times per week, currently being studied in the CleaR-MAC trial (NCT04616924).
  • Integrated Analysis. Certara experts performed integrated analyses of all available human, non-clinical, and literature data to support dose rationale for the combination doses and frequency of administration. This analysis was then used to gain the FDA and other regulatory bodies’ acceptance of the protocol for the Phase 3 trial. The selection of doses for RHB-204, along with the dosing schedule, was made through combining pre-clinical evaluations, PK modeling, and clinical information. This was done to maximize efficacy against MAC while minimizing potential drug side effects.

Benefit

RHB-204 is currently undergoing a Phase 3 study in the U.S. as the first-line, stand-alone drug treatment for NTM disease caused by MAC infection.

RHB-204 has been granted U.S. FDA Fast Track, Orphan, and QIDP priority status, as well as EMA Orphan Drug designation under the Generating Antibiotic Incentives Now Act (GAIN Act), which makes it eligible for a 12-year exclusive market in the US. It has also been granted EU Orphan Designation, making it eligible for 10-year EU post-approval market exclusivity.

By leveraging Certara’s consulting expertise and cutting-edge technology, Redhill Biopharma reduced its development time needed to progress RHB-204 to the Phase 3 trial. Certara’s work was instrumental in getting a new patent granted for RHB-204 even though the component antibiotics were well-established drugs.

References
  1. Inderlied CB, Kemper CA, Bermudez LE. The Mycobacterium avium complex. Clin Microbiol Rev 1993;6(3):266-310. doi:10.1128/CMR.6.3.266. PMID: 8358707; PMCID: PMC358286. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC358286/.
  2. Akram SM, Attia FN. Mycobacterium Avium Intracellulare. [Updated 2022 Apr 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431110/.
  3. Fathi et al. Triple antibiotic fixed-dose combination products, dosing regimen, methods, and kits for treating pulmonary non-tuberculous mycobacterial infections. United States Patent Application Publication. Pub. No.: US 2021/0401865 A1. Pub. Date: 2021 December 30. [Internet]. [cited 2023 Feb 09].
  4. Nenortas E, Bakshi RP, Shapiro TA. Hollow-fiber methodology for pharmacokinetic/pharmacodynamic studies of antimalarial compounds. Curr Protoc Chem Biol. 2016 Mar 16;8(1):29-58. doi:10.1002/9780470559277.ch150194. PMID: 26995353; PMCID: PMC4811375. [Internet]. [cited 2023 Feb 09]. Available from: https://doi.org/10.1002/9780470559277.ch150194.
  5. Lebeaux D, Chauhan A, Rendueles O, Beloin C. From in vitro to in vivo models of bacterial biofilm-related infections. Pathogens. 2013 May 13;2(2):288-356. doi:10.3390/pathogens2020288. PMID: 25437038; PMCID: PMC4235718. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4235718/

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