Disentangling fibrosis: finding ways to fix ‘repair gone wrong’

Millions of patients around the world are suffering from the dramatic effects of fibrotic diseases; their lives forever changed by the damage fibrosis inflicted to their organs. As a researcher, I am inspired by their stories. Now, more than ever, I am convinced that we can change their disease trajectory, reverse or halt the worsening of fibrosis, and by doing so save or improve their lives.

Whether the damage occurs in the liver, as in non-alcoholic steatohepatitis (NASH); in the lung, as in idiopathic pulmonary fibrosis (IPF); in the kidney, as in chronic kidney disease (CKD); in the skin, as in scleroderma; or in the gut, as in inflammatory bowel disease (IBD); the consequences of fibrosis are devastating to patients’ health, and may ultimately necessitate drastic measures such as organ transplant, or tragically, cause an untimely death.

The associated health care costs are substantial, reflecting the toll of fibrotic diseases on patients and society. Notably, a US Medicare study of beneficiaries aged 65 and older estimated annual total costs of IPF to the US healthcare system to be $2 billion, excluding medication costs.¹ Similarly, lifetime costs associated with NASH are estimated to have reached $222 billion in 2017 in the USA, and incidence of new cases are predicted to continue to grow resulting in an estimated $359 billion lifetime costs by 2060.²

Currently, many patients have limited or no treatment options. However, hope is on the horizon as we gain new scientific insights into the underlying mechanisms of fibrosis, a pathogenesis with fundamental similarities across many different tissues and diseases. We have the potential to discover a new generation of breakthrough medicines. We, at Boehringer Ingelheim, are compelled to act and are determined to make a difference for these patients.

Understanding what goes wrong

Fibrosis has been, for some time, a key focus of drug discovery. There have been numerous attempts over the years to develop robust anti-fibrotic medicines, but the complexity of this pathogenesis has led to several clinical failures. Consequently, to date, there are only two approved anti-fibrotic medicines available to patients.

Over the past years, we have come to understand that fibrosis is essentially ‘repair gone wrong’. In healthy tissue, an insult or injury triggers a complex cascade of cellular and molecular responses that ultimately repair the damage or heal the wound. In contrast, in the disease state, a chronic insult leads to a disruption of the homeostatic balance between injury and repair. The repair mechanism goes into overdrive resulting in excessive connective tissue deposition, often accompanied with chronic inflammation, and ultimately leading to a remodeling of the organ and loss of its functionality. Our challenge in fibrosis research is to restore the lost homeostatic balance by blocking excessive matrix accumulation while allowing healthy repair to take place.

Building on success with nintedanib

We made a significant advance in the treatment of lung fibrosis with the discovery and development of OFEV^® (nintedanib), the first treatment approved by the FDA for IPF (2014), subsequently approved to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (2019), and in March of this year for the treatment of chronic interstitial lung diseases with a progressive phenotype. Discovering nintedanib has enabled us to gain insights into the pathways critical in lung fibrosis and gauge the translatability of our preclinical models in a new way. Further, by comparing its effects across fibrotic organs, we are able to assess the importance of specific fibrotic pathways in different diseases. Nintedanib gives us a unique opportunity to learn from clinical translational research and apply these findings to the discovery of novel anti-fibrotics.

Taking a dual approach to boost progress

Using this expertise and experience, we are exploring shared pathways across multiple fibrotic diseases. In the long term, this will enable us to advance the most effective anti-fibrotic medicines and provide them to patients with a range of fibrotic diseases such as NASH, IPF, IBD, and scleroderma. However, we are cognizant that each of these diseases has tissue and disease-specific aspects beyond fibrosis. Our comprehensive research programs in these areas allow us to design and test specific combinations that will give the greatest benefit for patients. For example, in the case of NASH, a combination of an anti-fibrotic with an anti-steatotic, may not only reverse the fibrosis, but also block the insult leading to the injury.

Image courtesy of Enleofen Bio Pte Ltd

Honing in on the IL-11 pathway

In our quest for transformative therapies, we are exploring innovative mechanisms, differentiated from previously explored anti-fibrotic approaches. In particular, the interleukin-11 (IL-11) pathway is emerging as a promising therapeutic target for treating fibrotic diseases. The IL-11 cytokine acts on key cell types involved in fibrosis; it drives fibroblast activation required for the synthesis of fibrogenic proteins and injures the epithelium leading to further organ damage. One of the key advantages of targeting the IL-11 pathway is its propensity to cause fibrosis in multiple organs including the lung, liver, skin, gut, kidney and heart.^3,4 Laboratory studies have also shown that anti-IL-11 treatment has the potential to stop - and even reverse fibrosis - in different fibrotic diseases.^5,6

We recently announced a partnership with Enleofen, adding the biotech company’s world- leading preclinical anti-IL11 platform to our existing expertise and pipeline portfolio. This expands our broad panel of research collaborations in these areas, including projects to explore novel pathways and molecular targets for the treatment of IPF and NASH with the Harvard Fibrosis Network. Working with our partners, we are unraveling the molecular underpinning of fibrosis and are advancing a growing pipeline of diverse and innovative mechanisms with the potential to transform the treatment of fibrotic diseases.

Working together to beat fibrosis

In addition to tapping into the knowledge and skills of our partners, we recognize the need to leverage expertise across R&D and other areas such as translational clinical medicine, by facilitating cross-functional and global working. Our large community of scientists with diverse expertise and disease knowledge – we call them our ‘fibrosis cluster’ – work together to identify shared mechanisms and pathways which could point to the most effective anti-fibrotic medicines and to the fastest approach for demonstrating their action in the clinic. We are convinced that this multi-disciplinary approach is the key to unlocking the biology that will lead to transformative treatments for patients.

Improving patients’ lives

As a drug discoverer, I aspire to improve the lives of patients; patients with IPF who struggle to breath, patients with liver cirrhosis with no option but liver transplant, patients with scleroderma suffering from painful and fragile skin, and patients with many other devastating conditions. Effective anti-fibrotic therapies can truly transform their lives, and together with my colleagues at Boehringer Ingelheim, I am committed to the discovery of these breakthrough medicines.

References

1. Collard H et al. Ann Am Thorac Soc 2015;12(7):981–987
2. Younossi Z et al. Hepatology 2019; 69(2):564-572
3. Schafer S et al. Nature 2017 December 07; 552(7683)
4. Cook S and Schafer S. Annu. Rev. Med. 2020;71:263–76
5. Ng et al., Sci. Transl. Med. 11, eaaw1237 (2019)
6. Widjaja A et al. Gastroenterology 2019;157:777–792