Bacteriophage Therapy for Mycobacterium Abscessus Pulmonary Infection

Hypothesis

Hypothesis: Mycobacteriophage therapy, using identified in-vitro effective Mycobacteriophage Muddy\_HRMN0052, along with combination conventional antimycobacterial therapy for their NTM pulmonary disease with MABS will reduce infection burden and improve pulmonary disease.

Objectives:

1. Efficacy - Assess MABS pulmonary disease response mycobacteriophage therapy 2. Safety - Determine tolerability and off target effects of IV and inhaled mycobacteriophage therapy

Specific End Points (during and post treatment up to last clinical follow-up (\>24month):

1. Microbiologic: Time to sputum smear and culture conversion; durability of sputum culture conversion during and post treatment; change in sputum microbiology on and post treatment; change in MABS drug and mycobacteriophage susceptibility on and post treatment; mycobacteriophage neutralizing antibody development. 2. Clinical: Pulmonary and systemic symptom report; sputum production volume (patient report); chest imaging response (CT scan); Spirometry and full PFT; quality of life 3. Other: Adverse clinical and laboratory events

Information on the Investigational Product (Mycobacteriophage Muddy\_HRMN0052):

1. Mechanism of action Bacteriophage therapy (phage therapy) involves the use of live, lytic bacteriophages to treat bacterial infections via bacterial cell lysis. Lytic bacteriophages mediate their antimicrobial effect by way of specific attachment to bacterial cell wall receptors, injection of bacteriophage DNA into the bacterium, recruitment of bacterial host cell machinery for bacteriophage protein production, and subsequent lysis of the bacterial cell with release of bacteriophage progeny. 2. Dose, frequency, route of administration for the product

Initial IV dosing of Mycobacteriophage Muddy\_HRMN0052 for treatment of Mycobacterium abscessus should be 1mL containing 1 x 10\^9 PFU/mL to be given IV twice daily.

Inhalation:

Initial inhaled (by nebulization or aerosolization) dosing of Mycobacteriophage Muddy\_HRMN0052 for treatment of Mycobacterium abscessus should be 1mL containing 1 x 10\^9 PFU/mL to be given inhaled twice daily. For inhaled use, Mycobacteriophage Muddy\_HRMN0052 is supplied in the lyophilized form that enhances the stability during nebulization.

The treatment duration for both routes of administration is expected to be between 16 to 24 weeks at minimum with a possible extension up to 24 months if necessary, based upon clinical response.

Treatment Regimen and Duration:

Initial IV dosing for treatment of Mycobacterium abscessus with Mycobacteriophage Muddy\_HRMN0052 should be 1mL containing 1 x 10\^9 PFU/mL to be given IV twice daily.

Initial inhaled dosing for treatment of Mycobacterium abscessus with Mycobacteriophage Muddy\_HRMN0052 should be 1mL containing 1 x 10\^9 PFU/mL to be given inhaled twice daily.

The duration of treatment to be determined based on clinical response, but the recommended initial course of treatment is expected to be at least 16-24 weeks and used together with antimicrobial therapy targeted at the infecting organism recovered from the patient. The duration and start timing of IV and inhaled formulation will be guided by tolerance and clinical response with potential transition to single route as treatment progresses.

If the inhaled route of administration is not tolerated by the patient, as determined by a drop in FEV1 percent predicted (FEV1pp) of greater than 20% from baseline with the first dosage, and/or intolerable symptoms of cough or shortness of breath that are not relieved with bronchodilator (salbutamol) with the first dose, or if respiratory symptoms develop with later dosing that are deemed intolerable by the patient, then the treatment will revert to IV administration.

Concurrent with MUDDY phage treatment the following antibiotics will be use. Use of phage plus antibiotics is similar to prior reported human treatment of NTM disease with mycobacteriophages and in line with Antibacterial Resistance Leadership Group (ARLG) Phage Taskforce (U.S.) guidance. To balance effectiveness and toxicity risk two antibiotics that Mycobacterium abscessus has been demonstrated susceptible to will be used. Selection of drugs is also informed by tolerance during prior treatment. Alternate medications will be used if toxicity from first choice antibiotics encountered. Antibiotics/rationale are as follows, all doses are standard weight-based dosing:

Initial Regimen:

1. Amikacin 1000mg IV 3x/wk - prior good tolerance, evidence based preferred agent for treatment of NTM disease 2. Clofazimine 100mg PO OD - prior good tolerance; general low toxicity profile, M. abscessus demonstrated to have favorable low MIC.

Alternate agents (use if toxicity/intolerance to initial regimen agents to ensure on 2 antibiotics throughout):

1. Bedaquiline 400mg PO OD x 2 weeks then 200mg PO 3x/wk - prior good tolerance; general low toxicity profile, M. abscessus demonstrated to have favorable low MIC. 2. Linezolid 600mg PO OD (dose reduce to 600mg PO 3x/wk if adverse effects) - unclear if contributed to prior anorexia while on multidrug regimen, risk of toxicity with extended use 3. Sulfamethoxazole/Trimethoprim 800/160mg PO BID - less evidence available supporting use for M. abscessus disease, prior issues with associated hyperkalemia

AMENDMENT May 30, 2026:

Additional antibiotics to be used guided by follow-up drug susceptibilty testing (stopping medications that may show acquired resistance) and allowing up to 6 potentially effective antibiotic agents may include:

1. Imipenem 1g IV Q12 2. Ceftaroline 600mg IV Q12H 3. Omadacycline 300mg PO BID

• Microbiologic: Resistance development [Срок оценки: 2 years]
• Microbiologic: Neutralizing antibody status. [Срок оценки: 2 years]
• Clinical: Symptoms [Срок оценки: 2 year]
• Clinical: Sputum [Срок оценки: 2 year]
• Clinical: Radiographic [Срок оценки: 2 year]
• Clinical: Pulmonary Function [Срок оценки: 2 year]
• Clinical: Adverse effects [Срок оценки: 2 year]
• Clinical: Symptoms [Срок оценки: 2 year]