RESPIRATORY DISEASES

Hans Schambye: Fibrotic disease is a very broad topic, because you can essentially develop fibrosis in any organ, and it’s always detrimental to the function of the organ. There are some claims in literature that up to 45% of all people eventually die of fibrosis-related complications. 1

A particularly clear unmet medical need within this field is that there are no good treatments, and no good prophylaxis, for fibrosis. This is the short answer. If we dive into it more specifically, the only disease where there is some treatment is lung fibrosis. But the treatments available are not very safe, have got very significant side effects, and are not very effective. There is a big need for more efficacious and safe medicines, even in pulmonary or lung fibrosis, where there is treatment available. Beyond that, within cardiac fibrosis for example, there are no treatments; or kidney fibrosis, there are no treatments; or liver fibrosis, there are no treatments. There is clearly a massive need to develop treatments, which could help patients with all of these different diseases within fibrosis.

There’s really been a dramatic change in our understanding of fibrotic disease. Ten or fifteen years ago, most experts would say that there’s nothing you can do within these diseases, because all treatment attempts had failed. Some of the logical treatment attempts have even proven to be dangerous for patients, like steroids, with the belief that the disease probably has something to do with inflammation, and that’s what causes their fibrosis, or the belief that if we deal with the inflammation, it will be effective. But it turned out that this treatment path instead increased mortality for patients.

What we have learned in the last 15 years is that fibrosis is much more dynamic, and that you can actually change the disease with very targeted therapy – but we’ve also learned that this is very difficult. This is the reason there have been so few medicines developed, alongside the fact that the clinical trials needed in order to demonstrate efficacy in a targeted therapy are very long, complicated, and therefore very expensive.

There have not been nearly as many attempts at solving this as necessary. But this lack of attempts in the field just reflects the nature of the disease.

We’re developing an inhaled therapy that we believe will slow down the disease, and it looks to be very well tolerated. It makes a lot of sense when you have a lung disease to give medication in an inhaled form, so you get the drug to go where the disease is, and not everywhere else. This can potentially lead to fewer side effects, too.

Currently, with many IPF medications in development or on the market, you either have to take an IV infusion, for which you have to go into the hospital every two or three weeks, or you have to take the medication several times a day. A medication which is very convenient, in terms of remembering to take your medication or having it administered, is definitely needed in this area. Inhaled technologies, where patients take one or two puffs once a day, present a much better proposition, and could really impact the lives of patients. The medications that are out there today, are often required several times a day, sometimes in the form of many pills a day.

The main quality of life impact is, of course, their gradual loss of lung function. The best thing you can do for these patients is to develop medications that slow down the progression, or even reverse, the disease. Equally, you want to achieve this without too many side effects, because today, the patients are faced with a choice between losing their lung function fast, or losing it slower but suffering very significant side effects alongside that slower disease progression. A treatment is needed that is both very safe, well tolerated, and also good at slowing down the negative effects in the lungs.

Arguably, that is the approval of the two first drugs (pirfenidone and nintedanib), because the approvals showed that it was possible. It took away the basic doubts around the concept, of “Can you even do this right?”. Now we know that you can, with drugs, impact how this disease develops. This was a major breakthrough. Of course, part of that is agreeing with the regulatory authorities, such as the FDA and the EMA, what it is that needs to be demonstrated in order to get a drug approved.

Originally, because there’s a high mortality in this disease, the assumption from the authorities was that you need to show that you can reduce the mortality. But it is very, very difficult to run clinical trials while you reduce mortality. One reason is that those patients who are going into a clinical trial are taken much better care of than those patients who are not, so they actually live longer, just by being part of a clinical trial. This is sad, because it shows that if we just treated all patients the way we treat patients who are in clinical trials, we could actually keep them alive longer. However, this just showed it was really too high a bar to assess mortality – it would become infinitely costly, and therefore prohibited. By then agreeing and saying no, we are measuring lung function, and if we can show a difference in how the lung function develops over time, then it is good enough to assume that this is actually good for the patients.

I envision that there are going to be developments in combination therapies, just like what we see for cancer. IPF looks like a cancer disease: you have growth in your lung of tissue that really shouldn’t be there, and that growth ultimately destroys the lungs. Additionally, in terms of how these patients fare, they have a mortality and morbidity that is as high as with many cancers. Ten years ago, they were not treated, only managed, and it’s taken a massive effort to now have most patients actually on treatment. In the future, I expect much more aggressive treatment because we will have better tools, and we’ll be able to show that by combining these tools, we can actually extend the life, and improve the quality of life, of these patients.