Tag Archives: disease progression

Blog: Why Spirometry is killing Pulmonary Fibrosis Patients and What We Can Do About It

 

By Dr. Jan De Backer, CEO FLUIDDA

In the wake of a very successful IPF summit in Boston, and with the European Respiratory Society Conference coming soon, I wanted to formulate some thoughts on a topic that is becoming increasingly relevant. I realize that the title of this article is somewhat provocative but I believe there is ground to support the statement that spirometry, and in particular the Forced Vital Capacity (FVC), indirectly leads to the observed high mortality [1] in Pulmonary Fibrosis patients.

FVC, one of the outcome parameters of spirometry, is considered the gold standard in assessing lung function, and often the primary endpoint in clinical trials for new drugs in pulmonary fibrosis. It is obtained by asking the patient to forcefully exhale into a spirometer, which records the total volume of air exhaled and is the dynamic difference between total lung capacity (TLC) and residual volume (RV).

(Idiopathic) Pulmonary Fibrosis (IPF) is characterized by scarring of the lung tissue, often without a known cause, resulting in a restrictive condition. For the same pleural pressures, the affected parts of the lung expand less. It is therefore assumed that a reduction in FVC indicates decreased lung volumes and hence be a good descriptor of the disease… and this is where things go wrong.

Even for normal FVC the disease has already significantly progressed

It is true that eventually the lungs and consequently FVC will become smaller but at the early stages of the disease the healthy areas of the lung compensate for progressing disease thereby maintaining lung function (i.e. normal FVC) despite declining lung health. In other words, spirometry tells us how functional the overall respiratory system still is while we actually want to know how diseased the lungs are. Two years ago, I wrote a small article entitled “when biological redundancy becomes dangerous” it seems that the same principles can be applied to IPF.

Figure 1. Lobe volumes decrease with progressing IPF disease as expressed by Forced Vital Capacity (FVC). Significant disease already present in lower lobes (60%p) for normal FVC values (100%p). Percent predicted is a function of age, gender, height.

At the IPF summit, I presented data from a recent drug trial in IPF performed by Fibrogen (San Francisco, USA) where FLUIDDA analyzed HRCT data obtained as part of that study. IPF patients received HRCT scans at baseline, 24 weeks and 48 weeks. FVC was measured at the same time points. Figure 1 shows the correlation between FVC [% predicted] and upper and lower lobe volumes [% predicted] derived from the HRCT scans as part of our quantitative Functional Respiratory Imaging (FRI) technology. A few observations can be made:

  1. Both upper and lower lobes decrease in volume with decreasing FVC (i.e. worsening IPF disease).
  2. Lower lobes seem to be consistently more affected by IPF than the upper lobes.

And:

  1. Up to 40% of the lower lobe volume has already been lost with no change in FVC (i.e. 100% predicted).

In other words, even though the conventional lung function test indicates that everything is normal, the disease has already significantly progressed. Late diagnosis of any disease is associated with poorer survival outcome. To make matters worse, therapies for IPF are often only reimbursed for patients with FVC <80%p, so many patients with early onset of IPF remain un(der)treated.

Therapies are more effective at the earlier stages of the disease

Pulmonary Fibrosis (PF) is a progressive disease with worsening stages of fibrosis formation. While the true mechanism of PF, and hence the best therapeutic pathway, remains the topic of ongoing research, there is consensus that stabilizing, let alone reversing, end-stage fibrosis is improbable. Thereby, the probability of success increases if one can intervene early on in the disease cascade. The inability of FVC to detect regional compensation limits identification of early stage disease progression. However, in HRCT scans, the progression from ground glass opacity to honeycombing can be visualized and quantified. The ability to identify PF at earlier stages could incite the development of targeted, novel therapeutics that move away from managing the disease to curing it.

Studies of new drugs on top of standard of care (Pirfenidone and Nintedanib) will require very large and long studies with FVC as primary endpoint

With two approved drugs on the market (Pirfenidone and Nintedanib) it will be increasingly difficult to perform placebo controlled studies with natural disease progression (i.e. no treatment in the placebo group). This means that for new drugs, the study sample size and duration will become larger than before. This also means that the time to bring novel drugs to the market will increase unless the new drugs have very high efficacy which is, considering the former, rather unlikely. Incremental innovation, which is often the pathway to disease stabilization and potential cure, is therefore difficult in IPF with FVC as primary endpoint.

What can we do to improve matters?

Perhaps we should look at how other therapeutic areas dealt with the need for earlier diagnosis. In the cardiovascular field the dangers of atherosclerotic plaque formation are well known. Rather than wait until the patient experience symptoms or function decline a more prophylactic approach is preferred. Consequently, the cardiologist will use a range of imaging tools to assess the extent of the proliferation and to determine the efficacy of interventions. An example closer to the respiratory field are lung tumors. Again, luckily, today doctors don’t need to wait until the tumor causes symptoms or function declines, but rather relies on imaging for the detection of lung nodules and to assess how well chemo- or immunotherapy works.

I would argue that the same approach will work in IPF. Quantitative CT Imaging, including our FRI technology, has the ability to yield quantitative, regional information about lung structure and function in a non-invasive way. As such it has the ability to detect disease presence in an early stage without being concealed by compensatory behavior of the lung. Ideally, changes observed in HRCT images correlate with the pathophysiology of the disease. It seems that in IPF such image-based parameters exist. FRI technology can not only provide quantifiable measures of lobe volumes as depicted in Figure 1, it can also quantify airway volumes (radii). Interestingly, it appears that the airway volumes (radii) increase with progressive disease as can be seen in Figure 2.

Figure 2. Specific airway radii increase with progressing IPF disease as expressed by Forced Vital Capacity

A potential driver for the increase in specific airway radii is the redistribution of intrapulmonary pressure measured from the HRCT scan taken at total lung capacity during breath-hold as explained in Figure 2.

Figure 3. Link between observed changes in imaging and IPF disease severity.

If follows then that by using FRI imaging in IPF clinical trials we could have a better indication of the true disease stage and progression and would be able to detect significant differences between treatment and placebo sooner than FVC and in smaller number of patients.

Functional Respiratory Imaging (FRI) as endpoint to study novel drug GLPG1690

In a recent study with a novel autotaxin compound GLPG1690 (Galapagos, Belgium), FRI in combination with FVC was used to assess the efficacy of the drug. In 22 patients (17 treated with GLPG1690, 5 treated with placebo) and after 12 weeks of treatment two FRI parameters, specific airway volume and specific airway resistance, were significantly (p < 0.05) different between the treatment and placebo arm. FVC showed a signal but was not significant as the study was not powered for FVC.

Figure 4. Both specific airway volume and specific airway resistance demonstrated significant difference between treatment and placebo at 12 weeks, thereby confirmed signal observed in FVC.

 

Figure 5. example of improvement in airway and lobe volumes for a patient treated with GLPG1690 versus a worsening in a patient treated with placebo.

This clinical trial demonstrates the potential of imaging to enhance drug development in Pulmonary Fibrosis  by providing direct measurements of regional lung structure and function allowing for smaller sample sizes.

At FLUIDDA we are hopeful that the further development and utilization of Functional Respiratory Imaging (FRI) as a drug development and diagnostic tool will lead to better treatments for Pulmonary Fibrosis patients in the near future.

Key Words: Idiopathic Pulmonary Fibrosis, IPF, Functional Respiratory Imaging, FRI, FVC, clinical trials, disease progression

[1] Raghu G, Collard HR, Egan JJ, et al. (2011). “An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management”. Am. J. Respir. Crit. Care Med183 (6): 788–824.

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Belgium

BE 0877 160 706

Tel: +32/(0)3 450 87 20

Fax: +32/(0)3 450 87 29

info@fluidda.com

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FLUIDDA, Inc

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United States

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Medical Imaging pvt ltd
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India

FLUIDDA India

Medical Imaging pvt ltd
A-95/96, DGP Nagar -2, Ambad
Nashik 422010
India

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