COPD and Chronic Bronchitis

COPD

PharmaLundensis AB develops Phal-501 into a new, effective and gentle treatment for the lung diseases COPD and chronic bronchitis.

Morbidity

Chronic obstructive pulmonary disease, COPD, and chronic bronchitis are common diseases affecting millions of people in the world. In the past, it was mostly smokers who were affected, but in recent years, more and more non-smokers have become ill. Today, 20-30% are non-smokers. It has therefore been concluded that it is not only tobacco smoke, but also general air pollution that can cause these diseases. Chronic bronchitis is characterized by a prolonged cough and mucus in the airways (the typical smoker’s cough). After a number of years, there is often also a deterioration in fitness and shortness of breath, at which point the disease develops into COPD. The deterioration of lung function eventually becomes more severe, and the patient may suffer from lung failure. COPD is the third leading cause of death, causing more than 3 million deaths annually worldwide.

Clinical study with IodoCarb

PharmaLundensis performed a double-blind, placebo-controlled clinical study in 40 COPD patients in which they were given either the experimental mercury-binding substance IodoCarb or placebo. The study showed that patients receiving IodoCarb had a significant improvement in lung function of 8.2% compared with the placebo group. No other new COPD drug in the world has shown such a large improvement of the lung function! However, IodoCarb was unsuitable as a drug due to certain side effects.

New drug candidate Phal-501

Through further research, PharmaLundensis has identified a new type of substance with promising properties, which we call Phal-501. This substance has very strong heavy metal binding properties, while side effects are expected to be very small, if any. The substance is new, as documented in a positive examination report from the European Patent Office (EPO). The fact that we can get patent protection is highly favorable as it means that other companies will now have difficulty entering the entire field of heavy metal-induced diseases and that PharmaLundensis will have great opportunities to reap its economic benefits. Recently, we managed to scale up the manufacturing method for Phal-501 so that we can now produce the substance on a kilo scale. The synthesis is complex and has required great chemical knowledge and experience. This is not only negative, but can constitute a “moat” against potential competitors, providing additional protection beyond that offered by patents.

Preparations for clinical studies

PharmaLundensis is now preparing for clinical studies with Phal-501. Stability tests both at room temperature and accelerated tests at 40 degrees Celsius are prepared, analyses to prove that the substance is stable and does not release anything inappropriate (degradation products, solvents, pollutants) in a simulated intestinal environment are planned, and animal tests to establish that the substance does not affect the mucosa of the gastrointestinal tract are to be carried out. Furthermore, the test substance must be manufactured according to GMP standards for the patients in the clinical studies. After that, the application to conduct a clinical study will be submitted to the Swedish Medical Products Agency and the Ethics Committee.

Clinical studies with Phal-501

The first clinical study with Phal-501 is planned to start in 2025, and will be a Phase 1a study in chronic bronchitis patients. The study will be conducted in 60 patients, of which 30 will receive active substance and 30 will receive placebo. After that, a clinical study in 60 patients with moderate-severe COPD is planned. Chronic bronchitis and COPD are closely related diseases; if the treatment works for one disease, it will likely work well for the other. Clinical studies are also planned in other diseases such as severe depression. We believe that there is a good chance that this disease will also respond well to Phal-501; see the “Depression” tab.

It is very difficult to develop new, effective drugs for COPD!

In fact, there has not been a single new type of effective COPD drug in the last 50 years! Different pharmaceutical companies have presented endless variants of old treatment principles and combinations of these. However, no one has been able to find a completely new mechanism that decisively affects the course of the disease. AstraZeneca’s COPD substance Fasenra (benralizumab) is a monoclonal antibody that recruits NK cells to induce depletion of airway eosinophils. However, a pivotal Phase 3 study failed to show any statistical improvement in lung function, cough or mucus in COPD patients. GlaxoSmithKline presented Phase 3 clinical results a while ago from their new COPD drug Nucala (mepolizumab), which is a monoclonal antibody that inhibits IL-5-mediated inflammation. The substance showed no statistical improvement in lung function and no reduction in cough mucus. Therefore, the U.S. Food and Drug Administration (FDA) did not approve the substance for treating COPD.

In contrast to these meager results, PharmaLundensis IodoCarb both improved lung function and reduced cough and mucus production in COPD patients. Thus, there is every reason to believe that PharmaLundensis is on the right track to develop a new, effective COPD drug!

New, unique mechanism

PharmaLundensis works on the unique hypothesis that it is the heavy metal content of smoke, mainly mercury, that damages the airways. Mercury is present in significant quantities in both tobacco smoke and emissions from fossil fuels (oil and coal). Volcanoes release large amounts of mercury into the atmosphere during eruptions. Fish and other marine products also contain significant amounts of organic mercury. The airborne mercury is drawn into the lungs when inhaled, penetrates the bronchial wall, and is stored in the lung tissue. When the mercury deposits become large enough, they begin to interfere with the normal regulatory mechanisms of the bronchi, probably by affecting the so-called NEE cells in the mucosa. For more detailed information, see below. The result is coughing, mucus and eventually bronchial obstruction (constricted airways). The more mercury that is stored, the worse the symptoms become. There is currently no treatment or method that can effectively reduce mercury levels in the airways.

Contraction regulation in small bronchi (advanced)

The mucous membrane of the airways contains a cell type called neuroepithelial endocrine (NEE) cells. The activity level of these cells is normally regulated by their content of the free oxygen radical, hydrogen peroxide (H₂O₂). The concentration of H₂O₂ is determined by an H₂O₂-producing NADPH oxidase, and this regulates the cells’ activity level through a closely associated H₂O₂-sensitive potassium channel. An increase in H₂O₂ production opens the potassium channels, which inactivates the NEE cells, while a decrease in H₂O₂ instead activates the cells. PharmaLundensis’ CEO Dr. Staffan Skogvall has shown in research that the NEE cells normally release a powerful relaxing factor (EpDRF) whose main function is to keep the airways open. When this mechanism is active, no substance, either neurotransmitter or inflammatory mediator, appears to be able to produce a prolonged, strong contraction. If it is turned off, the bronchi contract by 500 percent, which is why the airflow is greatly reduced. The relaxing factor from the NEE cells thus appears to have a key role in controlling the degree of contraction and, in doing so, the diameter of the small airways. We suspect the impaired lung function in COPD patients is mainly due to an NEE cell-induced contraction of the airway muscles rather than a structural breakdown of the lung tissue. This means that the disease can be treated with the right bronchodilator.

It is well known that heavy metals such as mercury increase the levels of free oxygen radicals (e.g., hydrogen peroxide, H₂O₂) in the body’s cells2+3. Prolonged inhalation of heavy metals in cigarette smoke leads to accumulation of the metals in the NEE cells of the lungs, among other places, which leads to increased H₂O₂ levels and, thus, reduced activity. This results in a decreased release of the critical relaxing factor, progressively greater contraction of the bronchi (windpipes), and, eventually, the development of COPD. By ingesting an effective mercury-binding substance (Phal-501), the mercury can be excreted, and normal lung function can be restored.

Asthma affects large and medium-sized airways, while COPD affects small airways. The small bronchi have been shown in studies led by Dr. Skogvall to have a much lower sensitivity to ß2-stimulants than large airways. The fact that there is varying sensitivity to regulatory factors in tissues at different levels is common in the body and is found, for example, in the vascular tree. The very low sensitivity to ß2-stimulants in small bronchi is likely to explain the weak effect of bronchodilating ß2-stimulants in COPD.