Rare lung diseases

Background

Healthy lungs are a pair of spongy, air-filled organs. Inhaled air travels into the lungs via the trachea and its tubular branches, the bronchi. These divide into smaller branches, the bronchioles, and eventually these bronchioles end in microscopic air sacs, the alveoli. Oxygen from the air is absorbed through the microscopically thin walls of the alveoli into the blood, and carbon dioxide travels from the blood into the alveoli, to be exhaled. The interstitium (the supporting framework of the lungs) is a thin layer of cells between the alveoli, which contains blood vessels and cells that support the alveoli.

Fibrotic lung disease

In patients with fibrotic lung disease, the lung tissue becomes thickened, stiff, and scarred. This results in less efficient absorption of oxygen, and breathing becomes increasingly difficult as the disease progresses, leading to dyspnoea. Severe, persistent dry cough is another particularly troubling symptom and correlates strongly with disease progression in conditions such as idiopathic pulmonary fibrosis (IPF). Other possible symptoms include fatigue, weight loss, aching muscles and joints, and widening and rounding of the fingertips.

https://vicorepharma.com/wp-content/uploads/2019/05/tabs-2-and-6-illustration-fibrotic-lung-disease.jpg Fibrotic lung disease.

Prognosis

Damage caused by fibrosis in the lung cannot be repaired, and patients have very limited therapeutic options. Quality of life is significantly impaired as the disease progresses and the prognosis is poor, with a life expectancy of 3-5 years after diagnosis in patients with IPF. The five-year survival rate for IPF is less than that for many cancers, including bladder, prostate, breast, thyroid, and colon cancer.

Increased pressure in the arteries of the lungs due to vascular compression by scar tissue and other pathological vascular changes can lead to pulmonary hypertension (PH) and subsequently to right heart failure. Pulmonary hypertension is a rare, often fatal, complication of lung diseases such as IPF.

The main immediate cause of death in patients with IPF is the disease itself (over 60% of patients), followed by coronary heart disease (around 15%). Women are less likely to die from the disease itself, and death from pneumonia is almost 10 times more common in men than in women. Another underlying cause of death is lung cancer, which is more likely to be the underlying cause of death in ex- and current smokers than in non-smokers.

The course of fibrotic lung disease.

Because of the debilitating symptoms and poor prognosis, patients face an uncertain future, and patients and their families or caregivers face daily challenges in terms of managing the disease and maintaining an acceptable quality of life.

At present, patients often have a tortuous path to a diagnosis of IPF, with little information about the disease when it is diagnosed, particularly if they are not treated at a specialist centre. Many patients do not immediately realize the gravity of their condition, and both patients and their families or caregivers can later be overwhelmed by the physical and psychological symptom burden, with relentlessly deteriorating quality of life and a continuous increase in distressing symptoms. For approximately 80% of patients, lung transplantation will not be possible because suitable donors are not available, and they currently have few other treatment options. The scientific literature supports the benefits of palliative care, but this is offered infrequently and usually late in the disease process.

Our sole focus at Vicore Pharma is to develop therapies for patients who are affected by fibrotic lung disease, a life-changing condition.

Fibrotic lung disease consists of several different disorders including:

  • Idiopathic pulmonary fibrosis
  • Systemic sclerosis  (lung manifestations)
  • Pulmonary sarcoidosis

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is the most common type of pulmonary fibrosis, and is a severe and devastating disease with no known cause. Debilitating symptoms of dyspnoea and severe, persistent dry cough typically appear between the ages of 50 and 70 years and, while the disease is more common in men, the number of cases in women is increasing.

The prevalence of pulmonary hypertension (PH) in people with IPF is difficult to ascertain, as estimates vary widely depending on the method used to identify PH. Right heart catheterization is the gold standard for the detection of PH.

Incidence and prevalence

The European Idiopathic Pulmonary Fibrosis and Related Disorders Foundation has estimated that between 80,000 and 111,000 people in the EU are currently living with IPF, with up to 35,000 new cases being diagnosed each year. In the USA, approximately 100,000 people are currently living with IPF according to the National Institutes of Health (NIH), with 30,000-40,000 new diagnoses per year. The NIH has estimated the overall prevalence worldwide to be 13-20/100,000 people.

Diagnosis and disease progression

Diagnosis is often delayed because the symptoms of IPF are similar to those of other lung diseases:

  • Lung function testing, including spirometry, provides information on the amount of air that the lungs can hold and how forcefully air can be exhaled, which will indicate the severity of the disease
  • A high-resolution CT scan can confirm the extent of lung scarring

Although IPF is progressive, the rate of scar tissue formation in the lungs varies among patients. The prognosis for patients diagnosed with IPF is usually poor, with patients surviving for only 3-5 years after diagnosis.

Treatment options

Currently, there is no cure for IPF, and treatment options are limited:

  • Two medicines have been approved for use in IPF: pirfenidone and nintedanib. Both have been shown to slow the progression of the disease; however, associated side-effects have limited their use
  • Although the antifibrotic drugs for IPF have a positive effect on disease progression, their effect on symptom control (e.g. cough) or quality of life is limited and not fully explored
  • Supportive treatments include oxygen therapy, and immunization against pneumonia and influenza to avoid infections

Patients are advised to keep as active as possible and to follow a healthy diet with plenty of rest. Clearly, new treatments are urgently needed to reduce the significant burden of this disease.

Systemic sclerosis/scleroderma

Diffuse systemic sclerosis (SSc) is characterized by dysregulation of innate and adaptive immunity, vasculopathy, and fibrosis which may affect several organ systems, e.g. the oesophagus, lower gastrointestinal tract, lungs, heart, and kidneys.

The peak onset for SSc is in the fourth decade for females and usually later for males. It is more common among women than men, and is most common in women aged 60-70 years.

Although most of the long-term consequences of SSc arise from fibrosis, vascular changes in themselves are a key driver of the disease and can exacerbate the progression of fibrosis. As the disease progresses, patients can commonly develop Raynaud’s disease (painful vascular spasms in the fingers and/or toes), digital ulcers, and fibrosis in a number of internal organs.

Interstitial lung disease develops in 50% of SSc patients after approximately five years and is due to damage to both the alveoli and pulmonary blood vessels. The main cause of death in systemic sclerosis is interstitial lung disease, followed by pulmonary hypertension (PH).

Diagnosis and disease progression

Usually, the diagnosis is clinical. Although dyspnoea is not always apparent, worsening of lung function may be evident with lung function tests. The earliest signs of PH may appear as decreased transfer of gas from the air in the lung to the blood. As with other fibrotic diseases, PH can progress to right heart failure and death.

Treatment options

While there is no cure for patients with SSc, there are different treatment options that target the different organ manifestations of the disease. As with other fibrotic diseases, there is a pressing need for new and improved medicines for patients with SSc.

Pulmonary sarcoidosis

The course is unpredictable: some patients may have no obvious symptoms although their organs are affected; in others, onset may be sudden and/or severe but subsides after a short period of time. In other patients onset may be slow and subtle but long-lasting.

Incidence and prevalence

There are significant racial and gender differences in the incidence and prevalence of PS, with higher rates apparent in women than men. The American Thoracic Society (ATS) has reported that the incidence and prevalence are highest in African Americans and Nordic countries.

The ATS has estimated that the number of cases/year is 36/100,000 in African Americans, compared with 11/100,000 in Caucasian Americans.

Geographical location has been identified as an important factor. For example, the incidence per 100,000/year in Sweden and France is 12 and 5, respectively, while the prevalence per 100,000 in these two countries is 160 and 30, respectively.

Diagnosis and disease progression

A diagnosis of PS is often delayed because the symptoms are similar to those of other lung diseases, and sometimes it is discovered by chance in patients without symptoms. The main diagnostic tools are lung function tests, chest X-rays, high-resolution CT scans, breathing tests, and bronchoscopy to extract lung tissue samples for examination. While there is no cure for PS, the disease resolves on its own over time in 50% of cases.

Steroids are the first choice of treatment for symptomatic PS. However, these drugs are associated with long-term side-effects. Pulmonary fibrosis can be devastating in terms of morbidity and mortality: as the disease progresses, patients can develop PH and lung transplantation may offer the only chance for long-term survival in patients with advanced sarcoidosis-induced pulmonary fibrosis.