First approval of an inhaled antibiotic for treatment of NTM caused lung disease

Non-tuberculous mycobacteria (NTM) can cause chronic lung infection, especially in patients with additional immunodeficiency or chronic lung disease. The therapy is very time-consuming, is always carried out in combination with at least three tablet antibiotics for at least 12-18 months and is, therefore, often only moderately to poorly tolerated. An inhaled antimicrobial therapy has not been available until now. The results of the CONVERT study, in which BREATH scientist Dr. Felix Ringshausen has been involved, now led to the approval of the first inhaled antibiotic to treat lung disease caused by NTM (NTM lung disease).

Mycobacteria are primarily associated with Mycobacterium tuberculosis, the causative agent of tuberculosis. However, there are a number of other types, the so-called non-tuberculous mycobacteria (NTM). These bacteria, which are found everywhere in the environment, are rarely pathogenic. In the presence of immunodeficiency or an existing pre-injury from e.g. COPD, bronchiectasis, or cystic fibrosis (CF) NTM can cause chronic and difficult-to-treat lung infections. In Europe, Mycobacterium avium Complex (MAC) occurs most frequently as the causative agent of the disease. The NTM lung disease is diagnosed  only relatively rarely in Germany, with currently between 2000-3000 cases per year. However, it is thought that the disease is severely underdiagnosed due to the lack of specific symptoms. The treatment of NTM lung disease is often much more complex than the treatment of uncomplicated pulmonary tuberculosis.

The antibiotic amikacin, which is well effective against mycobacteria, is usually administered intravenously in standard therapy in severe cases, but can cause severe side effects, in particular disorders of the kidney function as well as damage to the hearing and the organ of balance.

A novel way to administer amikacin is to pack the antibiotic into liposomes. In this way, amikacin can be inhaled safely and act directly against the usually intracellular pathogens at the disease site. This treatment form was used in the clinical phase III CONVERT study, at which the Clinic for Pulmonology of the Hannover Medical School under the leadership of BREATH scientist Dr. Felix Ringshausen was involved. Based on this study, the liposome-packaged amikacin for inhalation (LAI) was recently approved in America as the first specific treatment for NTM-induced bronchiectasis. The drug can now be used for the therapy of refractory MAC bronchiectasis, when mycobacteria are still culturally detectable after 6 months of standard guideline-based therapy. Dr. Ringshausen explains: "Inhaled therapy of NTM lung disease by MAC has not been available so far. Despite existing guidelines, patients are often treated with a variety of different treatment approaches, especially if severe side effects occur or patients do not respond to standard therapy." The BREATH scientist is also the head of the bronchiectasis, NTM and cystic fibrosis outpatient clinic at the MHH and oversees a large number of patients with NTM lung disease.

For the CONVERT study, patients were recruited, in which, despite guideline-compliant standard therapy for NTM lung disease by MAC for 6 months, MAC bacteria could still be detected. Of the approximately 300 patients enrolled in the study, approximately 100 continued to receive standard care, while the remaining 200 patients received additional LAI once daily. Patients were treated until the time of negative MAC detection and for an additional 12 months.

The authors of the study recently reported their 6-month results in the American Journal of Respiratory and Critical Care Medicine. After this time, the patients showed an improvement in bacterial load with additional treatment with LAI. In 29% of this group compared to only 9% of patients in the control group, no MAC bacteria were repeatedly detected after 4 months of therapy. Although no difference was observed between the two therapy groups during the 6-minute walk test, patients who no longer had any bacteria, regardless of the therapy, scored significantly better, underlining the clinical relevance of the so-called sputum conversion. Although respiratory adverse events were more common with LAI compared to standard therapy, they were often short-lived. Serious side effects were equally common.

Liposomal amikacin for inhalation in addition to standard therapy, thus, proved to be effective in the treatment of NTM lung disease by MAC. Based on their findings, the authors also recommend testing LAI for patients with other NTM infections and in first-line therapy. LAI approval in Germany is expected in 2020.

 

The Link to the original publication.

 

Text: BREATH / CD

Photo: MHH /Tom Figiel

Dr. Felix Ringshausen, head of the bronchiectasis, NTM and cystic fibrosis outpatient clinic at MHH.