Rare Community Profiles

Rare Community Profiles is a new Patient Worthy article series of long-form interviews featuring various stakeholders in the rare disease community, such as patients, their families, advocates, scientists, and more.

Understanding MAC Lung Disease, Bronchiectasis, and PAH: A Discussion with Dr. Martina Flammer

Research and advocacy play an important role in transforming the medical landscape. Through these means, we can work to not just understand underlying disease mechanisms, but work towards getting the right therapies to the right patients at the right times.

During the American Thoracic Society’s 2023 Annual Conference in May 2023, medical professionals in the fields of pulmonary disease, sleep disorders, and critical illnesses came together to discuss patient care, public health, and clinical studies.

Global biopharmaceutical company Insmed Incorporated (“Insmed”) shared eight presentations with the medical and scientific community during ATS 2023 which included clinical, pre-clinical, and real-world data on ARIKAYCE^® (amikacin liposome inhalation suspension) for refractory Mycobacterium avium complex (MAC) lung disease as well as its investigational treatment candidates, brensocatib, which is being investigated for non-cystic fibrosis bronchiectasis (NCFBE), and treprostinil palmitil inhalation powder (TPIP), which is being investigated for pulmonary hypertension associated with interstitial lung disease (PH-ILD) and for pulmonary arterial hypertension (PAH). ARIKAYCE was approved by the FDA in 2018 using the Limited Population pathway, which means the FDA approved it for a limited and specific patient population; comprehensive safety information can be found here.

Martina Flammer, MD, MBA, the Chief Medical Officer (CMO) at Insmed, recently provided more insight into the findings presented at ATS 2023. In our discussion, she also shared why improving healthcare accessibility and reducing diagnostic delays is a necessary step towards creating meaningful change for patients.

About Martina Flammer, MD, MBA

Dr. Flammer received her Master of Business Administration degree from New York University’s Stern School of Business, as well as a medical degree from the University of Vienna Medical School. She began her career by training as an internal and emergency medicine provider. Later, she joined Pfizer in Research & Development (R&D) capacities. It was here, Dr. Flammer says, where:

“I had the opportunity to work in areas from drug development to access. I learned what it actually takes to get a medicine not just approved, but covered. To me, getting people access means there has to be a reimbursement for it.”

Over the next twenty years of her career, Dr. Flammer worked in various therapeutic areas in respiratory and metabolic diseases, and in several different geographic areas, in her roles at Boehringer Ingelheim. She explains that the breadth of her experience has offered more nuance into the benefits and downsides of global healthcare systems:

“In the rare disease arena, how a patient flows through the healthcare system has to be part of the thought process. It isn’t just identifying or solving treatment issues but understanding how to bring a convincing argument from a health economic perspective. If that cannot be achieved, the goal has not been reached.”

Dr. Flammer joined Insmed in December 2019. While she appreciated her experience in big pharma, and came away with an important depth of knowledge, she explains:

“For me, it was important to get back to the roots of why I fell in love with medicine: to get closer to patients and do work where the patient is at the center. Many companies talk about patient-centricity. But where the rubber hits the road is—is this where you prioritize investments? At Insmed, that really is our north star.

Our focus is in serious and rare diseases, so we’re always looking at where there are truly unmet needs and gaps for patients. How do we solve that and what can we target? When we think about development efforts, we’re not just thinking about approval and regulatory endpoints, but what are the endpoints that are meaningful for patients? That is where additional focus is needed for rare diseases: knowing what is meaningful for patients and using that to drive drug development.”

Improving Diagnosis and Access

Dr. Flammer notes that this patient-centricity is grounding for Insmed. That the entirety of the drug development process maintains an acute awareness of the needs of the patients and the burdens they face when attempting to access care.

This means that Dr. Flammer is constantly working to check in with patients and advocacy organizations to understand their pain points and needs. The company offers multiple opportunities throughout the year for people living with these rare and serious conditions to visit Insmed and offer insight into their most detrimental symptoms, obstacles, or access issues. Says Dr. Flammer:

“If you look at how many medicines are approved, there is a big difference between what is approved and what patients have access to. We don’t just want to create helpful drugs, we want to get them into the hands of the people who need them. So throughout this entire development process, we are constantly asking: how do patients get access to this? How can we help them to overcome these hurdles? If this isn’t a central part of what we’re doing, we have not served our obligation to patients.”

A Quick Overview of Presentation Materials

When speaking about the presentations shared with healthcare professionals and researchers at ATS 2023, Dr. Flammer explains how the data supports the need for improved awareness, diagnostic tools, and care access. Before we dive into the presentations themselves, you can find the names (and links to the abstract) below:

• “A Qualitative Interview Study to Explore the Use of Adverse Event Mitigation Strategies Among Adults Receiving Amikacin Liposome Inhalation Suspension (ALIS) in Real World Settings”
• “Treprostinil Palmitil Hydrolysis Is Facilitated by Lung Esterases”
• “Long-term Hospitalization Burden Among Patients with Chronic Obstructive Pulmonary Disease with Possible Diagnostic Delays of Nontuberculous Mycobacterial Lung Disease”
• “Outcomes of Patients with Bronchiectasis by Disease Severity: Subgroup Analysis from the Brensocatib WILLOW Study”
• “The Dipeptidyl Peptidase-1 Inhibitor Brensocatib Reduces Airway Azurocidin-1 Levels in Bronchiectasis”
• “Treatment Patterns and Adverse Events (AEs) Among Patients with Bronchiectasis (BE) Chronically Receiving Macrolides Over a 1-Year Follow-up Period”
• “Association of Baseline and Subsequent Bronchiectasis Exacerbations in Patients from the US Bronchiectasis and NTM Research Registry (BRR)”
• “Longitudinal Changes in Forced Expiratory Volume 1 (FEV1) According to Exacerbation Frequency in Patients from the US Bronchiectasis and NTM Research Registry (BRR)”

Reducing Exacerbations in Respiratory Illnesses

As you can see, the presentations centered around three illnesses in particular:

Bronchiectasis and Brensocatib

There are two main forms of bronchiectasis: cystic fibrosis (CF) bronchiectasis and non-CF bronchiectasis. Bronchiectasis causes the permanent dilation or widening of bronchial tubes within the lungs. In more severe cases, multiple parts of the lungs may be affected. Symptoms can include a chronic cough that produces blood or mucus, chest pain, shortness of breath, fatigue, and frequent respiratory infections.

Currently, the standards-of-care for bronchiectasis include antibiotics, vaccinations, and respiratory support. However, people taking these therapies may still experience potentially debilitating flares and disease exacerbations. Thus, identifying new interventions could significantly benefit these patients.

That is what Insmed is hoping to do with its investigational treatment candidate brensocatib, a small molecule dipeptidyl peptidase 1 (DPP1) inhibitor. DPP1 is an enzyme which activates neutrophil serine proteases (NSPs) in neutrophils (a type of white blood cell that plays a role in inflammatory mediation). Neutrophils can build up in the airways in chronic neutrophil-driven respiratory diseases, causing unchecked inflammation.

Dr. Flammer explains that the Phase 2 WILLOW study evaluated 10mg and 25mg brensocatib, compared to a placebo, in 256 individuals living with bronchiectasis. She further shares:

“In particular, we wanted to look at patients across the spectrum of disease severity. At ATS we shared a subanalysis based on severity index and found that brensocatib reduced the risk of exacerbations across the patient groups, regardless of whether they had mild, moderate or severe bronchiectasis.”

A separate sub-analysis presented at ATS identified a potential anti-inflammatory effect of this treatment beyond NSPs. A Phase 3 study on brensocatib in NCFBE is ongoing. More than 1,700 patients have been enrolled. Today, there are no approved therapies specifically targeting bronchiectasis in the U.S.

Outside of the Phase 3 study, Dr. Flammer shares that brensocatib is also being explored for a variety of other neutrophil-associated conditions such as chronic rhinosinusitis without nasal polyps.

MAC Lung Disease

Mycobacterium avium and Mycobacterium intracellulare are two different forms of bacteria that are part of Mycobacterium avium complex (MAC) infection in the lungs. These bacteria are often found in soil, water, and household dust. Many people who are exposed to mycobacteria don’t get sick. But it can happen, especially in those who are older in age, have other illnesses or who have a compromised immune system.

These mycobacteria cause a chronic lung infection characterized by symptoms such as chronic cough that may produce mucus or blood, fatigue, shortness of breath, low-grade fever, drenching night sweats, extreme fatigue, and weight loss.

At ATS, Insmed shared a real-world cohort study that used a predictive model based on U.S. Medicare claims to understand the connection between diagnostic delay in NTM lung disease (the broader disease category that encompasses MAC lung infection) and hospitalization among patients with chronic obstructive pulmonary disease (COPD). The study showed that there were fewer hospitalizations among patients with COPD who received an early diagnosis of NTM lung disease versus patients in the late diagnosis group. Says Dr. Flammer:

“In rare diseases, diagnosis is a major hurdle. Educating and raising awareness with physicians is a good first step. If physicians don’t hear about it, they won’t think about it. So part of our focus is on raising awareness of the urgency to diagnose, especially with available treatment and clinical guidelines. If you delay diagnosis and treatments, it leads to higher rates of hospitalization, with the burden highest in the late diagnostic group.”

PAH and TPIP

Finally, one presentation explored the underlying mechanisms of treprostinil palmitil inhalation powder (TPIP), which us being explored in people living with pulmonary arterial hypertension, a chronic and progressive form of high blood pressure in the lungs, and in pulmonary hypertension associated with interstitial lung disease (PH-ILD).

Most often caused by BMPR2 mutations, PAH results from the narrowing or blockage of tiny arteries in the lungs. This means that the heart has to work harder to pump blood and receive oxygen, causing damage. PAH is twice as common in women than men. Symptoms include shortness of breath that worsens during exercise, fatigue, chest pain, fainting or dizziness, and swelling of the ankles and legs.

Treprostinil is currently used as a treatment for PAH. However, shares Dr. Flammer:

“The problem that we found is that as patients progress, they require higher doses of treatment to stabilize their condition. With treprostinil, patients do respond with a reduction in pulmonary arterial resistance. But treprostinil stays in the body for about 45 minutes before breaking down. So many people end up on IV therapy or take medicine multiple times per day. In developing TPIP, we wanted to see if we could allow treatment to reside longer in the body.”

This investigational treatment is a dry powder formulation of treprostinil palmitil. It is administered in a capsule-based inhalation device. Prior to administration, TPIP is a prodrug (meaning it isn’t active) but it is converted to the active drug following inhalation. Dr. Flammer explains:

“We’re looking at this in the Phase 2 program to see whether it would allow for once-daily administration while still maintaining the level needed to reduce pulmonary arterial pressure. It’s still early in the Phase 2 program, but we hope this will show real potential for patients. And in the end, that’s what we want to achieve: better health and options for those with rare conditions.”