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Fibrosis is a pathological process characterized by excessive accumulation of extracellular matrix, which contributes to the pathology of a variety of chronic diseases. Fibrotic diseases cause about 45% of deaths, which confirms the high importance of anti-fibrosis therapy. The master regulator of fibrosis is transforming growth factor beta (TGFβ) signaling and, therefore, this presents as a major target for pharmacotherapy. This chapter summarizes anti-TGFβ approaches developed for fibrosis therapy across tissues and organs, targeting directly the ligands, the receptors, canonical and non-canonical signaling and effectors as well as interacting pathways. A common challenge for all approaches is the pleiotropic action of TGFβ, and consequently finding effective and safe principles. Many approaches towards TGFβ inhibition failed despite promising preclinical data due to unfavorable risk–benefit profiles in patients. However, increased understanding of the pathway and lessons learnt from earlier failures helped to identify more specific pathway nodes as well as to produce advanced generations of drugs. Currently, two compounds are on the market for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintenadib. These two compounds are indirect inhibitors of TGFβ signaling, and neither have fully defined mode of actions. Both show good risk–benefit profiles and manageable adverse events in patients, and their approval was a breakthrough in fibrosis therapy.

Fibrosis, a pathological process characterized by excessive accumulation of extracellular matrix (ECM), contributes to the pathology of a variety of chronic diseases. Fibrosis can manifest in almost any organ and tissue, for example, the lung, kidney, heart, liver, muscle and skin. It is believed that about 45% of deaths are caused by fibrotic diseases, indicating the high importance of anti-fibrosis therapeutic approaches. Progress has been made in recent years in understanding the molecular pathways causing fibrosis and subsequently finding targets suitable for therapy. Currently two molecules are approved for anti-fibrosis therapy, pirfenidone and nintedanib, and many others are in preclinical and clinical development.1–3 

In general, molecular mechanisms causing fibrosis are very similar across tissues and organs. Under physiological conditions fibrosis is a protective response to injury, recapitulating development processes to regenerate functional tissues, and is not a cause of disease. It is a key element in the early phase of wound and injury healing (i.e. physiological fibrosis), but can persist in inflammatory microenvironments, or in the presence of pro-fibrotic triggers leading to permanent organ and tissue dysfunction (i.e. pathological fibrosis). In pathological fibrosis, resident, functional cells (e.g. alveolar epithelial cells) are permanently replaced by myofibroblasts, also called contractile fibroblasts. Myofibroblasts are transformed from multiple cell types, in particular tissue-resident mesenchymal stem cells (MSC), epithelial cells (EC), endothelial cells (EndC) and fibroblasts, to enable migration to the injury site, contractility and production of ECM as a framework in the early repair phase. However, in physiological repair, this fibrotic transformation is temporary and subsequently replaced by tissue-specific regeneration. In a pro-fibrotic environment, myofibroblasts lacking tissue-specific functions remain and cause tissue and organ malfunction.4–8 

In cancer, fibrosis is described as a double-edged sword, being both pro- and anti-tumorigenic. Normal tissue fibroblasts restrain tumor initiation, whereas cancer-associated fibroblasts (CAF) are critical components of the tumor supporting microenvironment, such that “anti-fibrotic” therapy is an important element in cancer immunotherapy (see also Chapter 10). Thus, it is not surprising that most of the principles discussed in the present chapter are clinically explored in both cancer and fibrosis. However, since safety requirements for oncological drugs are quite different, adverse events acceptable for cancer therapy are often not favorable for use in general medicine.9 

Transforming growth factor beta (TGFβ) signaling has been identified and broadly confirmed as a master regulator of fibrosis and presents a major target for pharmacotherapy. This chapter will discuss TGFβ signaling. As this is a very broad topic, an abundance of literature around TGFβ signaling is available. The focus here will be on the role of TGFβ in fibrosis, including elaboration on the emerging genetic links to disease, current thinking around the different levels of intervention, as well as the notable achievements and challenges of drug therapy in this pleiotropic pathway. Regarding the last point, the goal of an ideal anti-fibrotic therapy is to efficiently and safely discriminate between normal physiological and undesired pathological fibrosis pathways. This has remained a major challenge for some time. Many anti-fibrotic therapy agents looked very promising in preclinical studies, but poor translation to clinical application and unfavorable risk–benefit profiles in patients has often resulted in termination of drug development outside of cancer indications. This review will focus on the role of TGFβ in the indications of idiopathic pulmonary fibrosis (IPF) and muscular dystrophies, both diseases with severe fibrosis phenotypes and poor overall prognosis. Notably, IPF is very often used as initial clinical entry point for anti-fibrotic drugs. As fibrotic mechanisms are often similar across tissues and organs, the principles successful in treating fibrosis in IPF also have a good chance of translating to other fibrotic conditions. The review will attempt to focus on the most relevant data for anti-fibrotic TGFβ therapy. Additional information and detailed references are also provided.10–13 

The TGFβ superfamily is a large group of more than 35 structurally related proteins with different cell regulatory functions, including the TGFβ1/2/3 isoforms, activins, inhibins, bone morphogenic proteins (BMPs), growth differentiation factors (GDFs) and various others. Nomenclature around TGFβ is sometimes confusing as it has evolved over time, and the term TGFβ is used for both the superfamily and three, but not all, of its members, TGFβ1/2/3. The family was named after its first discovered protein, now known as TGFβ1. TGFβ1 was initially identified as a sarcoma growth factor (SGF) that was clearly different from another SGF, the epidermal growth factor (EGF, also known as TGFα). SGFs are secreted from cancer cells and generally stimulate growth, even though TGFβ can both stimulate and inhibit growth. More importantly for fibrosis, SGFs transform cells by causing profound morphological (e.g. growing in colonies on soft agar) and functional alterations, and thus SGFs were renamed TGFs. Later, TGFβ1 was cloned and two additional isoforms identified, namely TGFβ2 and TGFβ3. In this chapter, we will focus on the three TGFβ isoforms, TGFβ1–3, as they are the major pro-fibrotic factors, even though other members of the TGFβ superfamily (e.g. BMP9 and activin A) are also involved in fibrotic diseases.13–18 

TGFβ1, TGFβ2 and TGFβ3 have quite different functions, mainly based on their tissue expression and activation. This is also reflected by significantly different phenotypes observed in TGFβ1, TGFβ2 and TGFβ3 knockouts (KOs).19  TGFβ′s are produced as precursors consisting of an active C-dimer and a latency associated peptide (LAP) which form the small latent complex (SLC). The SLC is further bound to different latent TGFβ binding proteins (LTBPs) in the large latent complex (LLC) which anchors latent TGFβ in the ECM and serves as a store of inactive TGFβ. In general, less than 1% of TGFβ occurs in the free, active C-dimer form, so that it has to be released from the latent complex to trigger TGFβ signaling (see Figure 1.1). This activation process is quite diverse and subject to disease modification. The active TGFβ C-dimer binds to type II TGFβ receptors (TGFβRII) which phosphorylate type I activin-like kinase (ALK) receptors to induce canonical small and mothers against decapentaplegic (Smad) signaling. In brief, receptor Smads (Smad2/3 or Smad1/5/8) are phosphorylated by ALKs, bound to co-Smad (Smad4/5) and then translocated into the nucleus to induce gene transcription events. Though TGFβ mainly functions via ALK5 to induce Smad2/3, it can also use ALK1 and Smad1/5/8 for signaling. It regulates production of inhibitor Smads (Smad6/7) which serves as a negative feedback loop. In addition, non-canonical TGFβ signaling has been widely described. For example, activation of TGFβ-activated kinase 1 (TAK-1) and various downstream signaling networks [including those involving p38, c-jun N-terminal kinase (JNK), nuclear factor kappa B (NFκB) and inhibitor of DNA binding 1 (ID-1)] are highly relevant for fibrosis. The three TGFβ isoforms produce similar effects if applied exogenously, confirming that isoform specificity seems to be mainly based on tissue expression and activation processes (for more details see ref. 11–13, 20–22 and 57).

Figure 1.1

Scheme of TGFβ pathway and potential interventions.

Figure 1.1

Scheme of TGFβ pathway and potential interventions.

Close modal

In fibrosis, tissue-resident ECs are transformed into MSCs, a process called epithelial–mesenchymal transition (EMT), and subsequently transdifferentiated into myofibroblasts upon stimulation with pro-fibrotic factors, such as the major fibrotic cytokine TGFβ. The origin of myofibroblasts has been debated and more recently EMT was also described as set of multiple and dynamic transitional states rather than a single transition between EC and MSC. Such intermediate EMT states promote organ fibrosis by producing pro-fibrotic environments and subsequently triggering myofibroblast transformation from tissue-residual fibroblasts.23  Myofibroblast transformation causes increases in cell mobility and a change to a contractile phenotype to enable the initial phase of tissue repair. In pathological fibrosis, this transformation is permanent and leads to tissue and organ dysfunction. While myofibroblasts can be derived from various cell types, TGFβ is a common and by far the best characterized activator of myofibroblast generation. The most important evidence for the central role of TGFβs in fibrosis comes from transgenics, where overexpression of TGFβ1 induces and promotes tissue fibrosis. Moreover, various genetic diseases with increased TGFβ signaling such as cystic fibrosis (CF), Marfan syndrome and Duchenne’s Muscular Dystrophy (DMD) present severe fibrotic phenotypes which were shown to be further facilitated by genetic modifiers, such as TGFβ and LTBP4 polymorphisms. Interestingly, most studies in the literature describe dysregulation of TGFβ1, the only isoform with endocrine functions, and thus, detectable in body fluids. In contrast, TGFβ2 and TGFβ3 function primarily in an autocrine and paracrine manner, which means that they are usually not detectable in body fluids and subsequently protein changes are less likely to be observed. However, in fibrosis autocrine and paracrine TGFβ action is predominant, and all three TGFβ isoforms may play a role.24–29 

Given its major role in fibrosis, TGFβ is a very attractive target for anti-fibrotic therapies. However, TGFβ action is pleiotropic and important for development and many normal physiologic processes. Therefore, the major hurdle for anti-TGFβ therapy is safety. TGFβ knockout (KO) mice show major pathologies and similarly severe adverse events have been observed with various approaches to TGFβ inhibition. This might be the main reason that no “direct” TGFβ inhibitor has reached the market for any indication, despite the numerous approaches pursued. More recently, extensive studies have helped to identify more specific pathway targets and approaches to ‘indirectly” interact with TGFβ signaling with promising therapeutic opportunities. A first good example is the development of pirfenidone, which indirectly reduces TGFβ signaling and has been approved for treatment of IPF. Another example is nintedanib, a poly-kinase inhibitor interfering with TGFβ signaling, which also reached the market for IPF as well as for cancer indications. In general, most of the anti-fibrotic principles are either rederived or are concomitantly explored in cancer indications (primarily immuno-oncology) as EMT transformation and subsequent TGFβ signaling play a major role in tumorigenesis and metastasis.22,30–33 

Fibrosis can occur in almost any tissue and organ (recently reviewed in ref. 34), and a list of fibrotic diseases can be found in Table 1.1. IPF is the most common and severe form, affecting about five million patients worldwide, and is characterized by a progressive and irreversible decline in lung function with an average life expectancy of four years after diagnosis. Even though the cause is unknown, age as well as environmental and lifestyle factors seem to play a pivotal role. Most anti-fibrotic agents are initially tested in IPF, and the two compounds approved are for this indication. However, as the principles underlying fibrosis are very similar across various diseases, indication expansions into other fibrotic areas are pursued and have high potential to succeed. This is particularly true when intervening with TGFβ signaling, which is linked to almost every form of fibrosis (see Table 1.1). Other commonly affected organs are the liver, heart, muscle, eye, kidney, skin and even the bone marrow. The most impressive occurrence of fibrosis can be observed in muscle from end-stage DMD patients, where muscles are almost completely replaced by fibrotic tissue with a profound loss of muscle function.35  In DMD, permanent muscle damage and subsequent repair in an increasingly inflammatory environment leads to extensive fibrosis, which is further enhanced in patients with LTBP4 modifiers.28,36  LTBP4 polymorphism was also shown to be a modifier in other fibrotic diseases (e.g. in heart and lung) and needs to be carefully considered in the selection of mouse strains for pre-clinical animal models.37 

Table 1.1

Overview of diseases with fibrosisa

Tissue/OrganDiseaseTGFβ signaling
Lung Idiopathic pulmonary fibrosis (IPF) Yes 
Pulmonary hypertension 
Emphysema 
Skeletal muscle Dystrophies (g): e.g. Duchenne’s muscular dystrophy (DMD), Sarcopenia Yes 
Liver Non-alcoholic fatty liver diseases (NAFLD) Yes 
Hepatitis 
Cirrhosis 
Heart Arrhythmia Yes 
Myocardial infarction 
Cardiac fibrosis 
Cardiomyopathy 
Valvulopathies 
Marfan (g) 
Skin Hypertrophic scars Yes 
Keloid 
Eye Glaucoma Yes 
Cataract 
Kidney Focal segmental glomerulosclerosis (FSGS) Yes 
Chronic kidney disease (CKD) 
Diabetic nephropathy 
Intestine Irritable bowel disease (IBD) Yes 
Intestinal fibrosis 
Crohn's disease 
Vessels Vascular fibrosis Yes 
Arterial stiffness 
Peritoneum Peritoneal fibrosis in dialysis patients Yes 
Bone marrow Myelofibrosis Yes 
Multi-tissue/organ Cystic fibrosis (g, CF) Yes 
Systemic sclerosis (SSC) 
Sarcoidosis 
Cancer fibrosis/tumor stroma 
Irradiation-induced fibrosis 
Type 2 diabetes (T2D) 
Graft versus host disease (GvHD) 
Tissue/OrganDiseaseTGFβ signaling
Lung Idiopathic pulmonary fibrosis (IPF) Yes 
Pulmonary hypertension 
Emphysema 
Skeletal muscle Dystrophies (g): e.g. Duchenne’s muscular dystrophy (DMD), Sarcopenia Yes 
Liver Non-alcoholic fatty liver diseases (NAFLD) Yes 
Hepatitis 
Cirrhosis 
Heart Arrhythmia Yes 
Myocardial infarction 
Cardiac fibrosis 
Cardiomyopathy 
Valvulopathies 
Marfan (g) 
Skin Hypertrophic scars Yes 
Keloid 
Eye Glaucoma Yes 
Cataract 
Kidney Focal segmental glomerulosclerosis (FSGS) Yes 
Chronic kidney disease (CKD) 
Diabetic nephropathy 
Intestine Irritable bowel disease (IBD) Yes 
Intestinal fibrosis 
Crohn's disease 
Vessels Vascular fibrosis Yes 
Arterial stiffness 
Peritoneum Peritoneal fibrosis in dialysis patients Yes 
Bone marrow Myelofibrosis Yes 
Multi-tissue/organ Cystic fibrosis (g, CF) Yes 
Systemic sclerosis (SSC) 
Sarcoidosis 
Cancer fibrosis/tumor stroma 
Irradiation-induced fibrosis 
Type 2 diabetes (T2D) 
Graft versus host disease (GvHD) 
a

g = genetic diseases.

As the master regulator of fibrosis, TGFβ is by far the most attractive and broadly explored target for anti-fibrotic therapy. Interventions on many different levels of TGFβ signaling have been explored, such as blocking directly the ligand, the receptors, canonical and non-canonical signaling paths, its effectors as well as interacting pathways. A common challenge for all approaches is to find effective and safe compounds in this pleiotropic pathway. Both overexpression and knockout of TGFβ cause significant pathology, such that full inhibition is unlikely to be safe and tolerated. This can be limiting for antibody approaches, which usually show high specificity and target engagement, such that partial inhibition is hard to achieve. In contrast, low molecular weight (LMW) compounds can be carefully dosed, but often lack specificity or selectivity against related targets. This holds particularly true for kinase inhibitors (e.g. ALK), and is one reason why those are mainly used in cancer therapy. Similarly, enzymes such as proteases [e.g. matrix metalloproteinase (MMP)] are large families with quite different, sometimes opposite functions of isoforms. Increased understanding of the pathway and lessons learned from earlier failures helped to identify more specific intervention nodes, as well as advanced generations of drugs with improved risk–benefit profiles. Interestingly, the two compounds on the market for IPF with good risk–benefit ratios and manageable adverse events are indirect TGFβ inhibitors without a well-defined mode of action.

This section will discuss approaches aiming to directly block TGFβ ligands, by either inhibiting their production using antisense oligonucleotides (ASOs) or neutralizing their action by antibodies, inhibitory proteins or receptor traps (for summary see Table 1.2).

Table 1.2

Overview of therapeutic approaches targeting production, activation and neutralization of TGFβs

PrincipleSpecificityMoleculeClinicalStatusIndicationComments
Production 
TGFβ antisense (ASOs) TGFβ1 AP11014   Fibrosis Local skin application, preclinical data also in systemic fibrosis 
 TGFβ2 Trabedersen AP12009 √  Cancer Route of administration challenging for systemic fibrosis 
Activation 
BMP1/tolloid-like proteinase inhibitors pan FG-2575   Fibrosis Highly potent with different selectivity profiles. None pursued to clinical use. 
RXP-1001 
S33A 
Sizzled UK383367 
Integrin inhibitors αvβ6 STX-100 (BG00011) √  Fibrosis, Cancer αvβ6 antibody, αvβ3, αvβ5 and αvβ8 also linked to fibrosis. 
 αvβ6 GSK3008348 √  Fibrosis Inhaled αvβ6 LMW 
THBS inhibitors pan LSKL peptide  Discontinued Fibrosis Controversial as agonist is tested in cancer indications. 
GARP inhibitors pan ABBV151 √  Cancer Tissue- or disease-specific (T-cells) 
Neutralization 
TGFβ antibodies pan Fresolimumab, (GC1008) √ Terminated Fibrosis, Cancer Dose-limiting adverse events; risk–benefit. 
 pan SAR439459 √  Cancer Only few data from abstracts. 
 TGFβ1 Metelimumab (CAT192) √ Terminated Fibrosis Dose-limiting adverse events, risk–benefit. 
  LY2382770 √ Terminated Fibrosis Dose-limiting adverse events, risk–benefit. 
 TGFβ2/3 Lerdelimumab (CAT152) √ Discontinued Fibrosis Local after glaucoma surgery, lack of efficacy in phase 3 
 TGFβ1/2 XPA-089 √  Cancer  
TGFβR receptor traps pan Distertide P144® peptide √  Fibrosis TGFβRIII peptide topical application. 
 TGFβ1/3 AVID 200 √  Fibrosis, Cancer Intravenous infusion in phase 1 
Decorin mimetic pan Recombinant decorin √  Cancer, Fibrosis Short half-life prevents systemic application, explored locally for ocular diseases. 
PrincipleSpecificityMoleculeClinicalStatusIndicationComments
Production 
TGFβ antisense (ASOs) TGFβ1 AP11014   Fibrosis Local skin application, preclinical data also in systemic fibrosis 
 TGFβ2 Trabedersen AP12009 √  Cancer Route of administration challenging for systemic fibrosis 
Activation 
BMP1/tolloid-like proteinase inhibitors pan FG-2575   Fibrosis Highly potent with different selectivity profiles. None pursued to clinical use. 
RXP-1001 
S33A 
Sizzled UK383367 
Integrin inhibitors αvβ6 STX-100 (BG00011) √  Fibrosis, Cancer αvβ6 antibody, αvβ3, αvβ5 and αvβ8 also linked to fibrosis. 
 αvβ6 GSK3008348 √  Fibrosis Inhaled αvβ6 LMW 
THBS inhibitors pan LSKL peptide  Discontinued Fibrosis Controversial as agonist is tested in cancer indications. 
GARP inhibitors pan ABBV151 √  Cancer Tissue- or disease-specific (T-cells) 
Neutralization 
TGFβ antibodies pan Fresolimumab, (GC1008) √ Terminated Fibrosis, Cancer Dose-limiting adverse events; risk–benefit. 
 pan SAR439459 √  Cancer Only few data from abstracts. 
 TGFβ1 Metelimumab (CAT192) √ Terminated Fibrosis Dose-limiting adverse events, risk–benefit. 
  LY2382770 √ Terminated Fibrosis Dose-limiting adverse events, risk–benefit. 
 TGFβ2/3 Lerdelimumab (CAT152) √ Discontinued Fibrosis Local after glaucoma surgery, lack of efficacy in phase 3 
 TGFβ1/2 XPA-089 √  Cancer  
TGFβR receptor traps pan Distertide P144® peptide √  Fibrosis TGFβRIII peptide topical application. 
 TGFβ1/3 AVID 200 √  Fibrosis, Cancer Intravenous infusion in phase 1 
Decorin mimetic pan Recombinant decorin √  Cancer, Fibrosis Short half-life prevents systemic application, explored locally for ocular diseases. 

The production of TGFβ isoforms is reduced using ASOs, a highly specific way to knockdown expression of a single TGFβ isoform. Both TGFβ1 and TGFβ2 have been targeted, and TGFβ2 ASOs progressed to phase 3 clinical trials for cancer indications.38,39  Trabedersen (AP12009, OT 101), a synthetic TGFβ2 ASO was in clinical trials for various cancer indications with initially encouraging results,40–42  and TGFβ1 ASOs have been successfully tested in preclinical fibrosis and cancer models (see ref. 38 and 41). However, a big hurdle for ASO therapy is the delivery of the agent to the target tissue. Local or targeted delivery is needed for sufficient efficacy in humans. For example, trabedersen was directly applied into the tumor, an approach quite feasible for isolated tumors, but questionable for most fibrotic diseases. Thus, it is not surprising that there were only a few ASO approaches, and none of them has reached clinical use for fibrotic indications. Ultimately, the development of sophisticated delivery systems may enable further exploration of knockdown approaches in human fibrosis in the future. One such promising approach has been the use of TGFβ1 small interfering RNA (siRNA) encapsulated in liposome-based nanoparticles. This successfully reduced peritoneal fibrosis, which in some instances is responsible for the discontinuation of peritoneal dialysis, in a preclinical model.43 

This section will discuss approaches aiming to neutralize the action of TGFβ through binding to antibodies, inhibitory proteins or receptor traps.

Neutralizing antibodies against TGFβs, which bind the active C-dimers and subsequently prevent receptor activation, are a common approach and extensively tested both preclinically and clinically in fibrotic diseases as well as cancer indications.

By far, the most information is available for the pan-TGFβ antibody, GC1008 (fresolimumab), which equally blocks TGFβ1, TGFβ2 and TGFβ3. Fresolimumab, or more often the mouse surrogate 1D11, has been explored in various fibrosis and cancer preclinical models with generally good efficacy. However, not surprisingly, dose-limiting adverse events were observed in clinical settings and consequently very limited clinical success has been reported.44–47  SAR439459, potentially a follow-up pan-TGFβ antibody, has entered clinical trials for oncology indications (NCT03192345), and some of the first data is emerging in abstracts,48,49  but it remains to be seen whether this therapy will provide a significant benefit. XPA-068, is another antibody with a similar broad-spectrum profile, that has been preclinically studied in cancer. The results of these studies indicated that TGFβ1/2 inhibition is sufficient for tumor immunosurveillance. So the more selective antibody XPA-089 (neutralizing only TGFβ1 and TGFβ2), was advanced to clinical use42,50,51  solely for cancer. It will be very interesting to see the clinical safety profile of this TGFβ1/2 antibody.

In general, more favorable safety profiles might be expected from antibodies with a more limited specificity, in particular those antibodies neutralizing only one TGFβ isoform. Indeed, TGFβ1-selective antibodies CAT192 (metelimumab),52  LY2382770,53  and a dual TGFβ2/3-selective antibody CAT152 (lerdelimumab)54,55  have been widely explored in fibrosis. Despite good preclinical efficacy, clinical success for all these antibodies was very limited. In particular, inhibition of TGFβ1, the only endocrine isoform with important roles in fibrosis and many other functions, seems to be linked to dose-limiting (mainly immunological) adverse events. Thus, targeted delivery of TGFβ antibodies similar to the approach described for ASOs is being explored. For example, a bispecific antibody against TGFβ and an extracellular domain of fibronectin was shown to enrich in fibrotic tissue and reduce fibrosis in a preclinical kidney fibrosis model.56 

In summary, safety is the major limit for the therapeutic use of TGFβ antibodies in human fibrotic indications, whereas use in cancer indications is more feasible. When administered systemically, fresolimumab,44,45,47  metelimumab or LY2382770 53  did not show clear therapeutic effects, and some of the trials terminated early due to non-favorable risk–benefit outcomes. Lerdelimumab was locally applied to reduce scaring after glaucoma surgery, but failed in phase 3 after promising results in earlier clinical trials.54,55  It appears that use of the more specific TGFβ2- or TGFβ3-mono-selective antibodies with potentially more favorable safety profiles, in combination with emerging targeted tissue-delivery technologies may be the most promising future directions for antibody targeting in this pathway.

Inhibitory proteins, such as decorin, or decoy receptors, bind active TGFβ C-dimers to prevent receptor activation in a similar way as antibodies (for review see ref. 13 and 57). Again, specificity and subsequently safety is a major challenge as previously discussed for TGFβ antibodies. As such, only a few approaches have been pursued in clinical settings for fibrosis indications. In the following section, decorin and two TGFβ receptor traps are discussed.

Decorin is a structural component of the connective tissue and a close relative of biglycan. It forms complexes with TGFβs and subsequently blocks their action, but also binds and neutralizes other proteins, including connective tissue growth factor (CTGF) and thrombospondins (THBS). Recombinant decorin was studied in cancer indications, but due to its relatively short half-life, the high doses needed, and challenging production, it was not further developed for any systemic application. However, it has been explored locally in fibrotic eye diseases.58–60 

AVID200 is a computationally designed TGFβR-based trap that binds TGFβ1 and TGFβ3, but not TGFβ2 to minimize adverse events.61  It is currently in phase 1 trials for systemic sclerosis (NCT03831438) and has been tested in various cancer indications (reviewed by ref. 57). P144® (distertide) is a synthetic TGFβ inhibitor 15-mer peptide derived from the TGFβRIII (also known as betaglycan). It has been explored in various preclinical fibrosis and cancer models,62–65  but it is poorly soluble and hydrophobic, so that systemic application is difficult.66  However, it was tested as a topical cream for skin fibrosis in systemic sclerosis patients (NCT00574613). This clinical trial has completed, but no data has been published (Scheme 1.1).

Scheme 1.1

Distertide.

This section will discuss approaches designed to inhibit activation of the TGFβ ligands from latency by various enzymatic processes as well as integrin receptors. As a complete chapter in this book is dedicated to integrin signaling, only a short summary will be given.

TGFβs are stored as latent complexes, and for fibrotic diseases, storage in the ECM and subsequent activation by enzymatic processes or integrin signaling plays a major role. Under disease conditions, expression of TGFβ genes can be directly regulated. However, in some instances, expression of the ligand activating proteins can be even more effectively regulated. Intervening on the level of ligand activation may provide some specificity concerning isoforms and also pathologic processes.

BMP-1/Tolloid-like proteinases (tolloids, also known as procollagen C-proteinase67 ), consist of BMP-1, BMP-1 histidine rich (BMP-1/his), mammalian tolloid (mTLD), tolloid like 1 (TLL-1) and TLL-2 68  with differential enzymatic activities and distributions.69  They activate TGFβ via cleavage of LTPBs and subsequent cleavage of LAPs by other proteases.70,71  In addition to TGFβ, tolloids cleave a range of ECM precursors such as procollagen, chordin, pro-myostatin and the TGFβ co-receptor betaglycan.68,72  Thus it is not surprising that they play a key role in fibrosis and are interesting targets for pharmacotherapy. Moreover, TGFβ is a potent inducer of tolloids, contributing to a positive feedback loop.71–73  α2-Macroglobulin serves a natural tolloid inhibitor,73  and highly potent LMW tolloid inhibitors as well as a BMP1–3 antibody have been generated with different potency and selectivity profiles to inhibit tolloids (for reviews see ref. 74–77). They have been tested, for example, in preclinical models of liver fibrosis78  or as anti-scarring agents, but have not reached clinical use. Most probably compound and substrate selectivity profiles are limiting factors for tolloids and are presumably the reason they were not pursued clinically.76  If this is the case, these limitations might be partly overcome in the future by improved selectivity for tolloid isoforms and related proteases.

Inhibition of integrins is a promising strategy to block TGFβ activation, and a full chapter in this book is dedicated to integrin inhibition (see Chapter 2). Briefly, integrins are a large family of cell adhesion and signaling receptors. A subset of integrins (αvβ3, αvβ5, αvβ6, αvβ8), play a key role in activation of TGFβ1 and TGFβ3 by binding to LAPs and liberating active C-dimer from the LLC.79–81  Integrin inhibition by functional antibodies or low molecular weight inhibitors82  has been broadly explored in fibrotic diseases. Most preclinical data are available for the αvβ6, antibody STX-100 (BG00011)82  along with the inhaled LMW compound GSK3008348,83  which have both been explored in clinical trials for IPF. Overall, more than 150 clinical trials are ongoing using integrin inhibitors with different specificity in various indications, including fibrosis.81  This reflects the promise of targeting this pathway (Scheme 1.2).

Scheme 1.2

GSK3008348.

Thrombospondins (THBS) are other proteins that bind to LAP and modulate TGFβ activation.84  Binding is dependent on a specific sequence which was used to generate the peptide inhibitor LSKL85  (for review see ref. 84 and 86). It has been tested in various fibrotic disease models with good tolerability and anti-fibrotic activity,87–89  but so far has not passed preclinical evaluation despite potentially offering a more promising path to TGFβ inhibition.84  However, this concept is somewhat controversial as the THBS analogue ABT-510 has been explored in various cancer patients to inhibit angiogenesis with good tolerability, but little benefit.90,91  Definitely more data is needed to decide on the value of THBS inhibition (Scheme 1.3).

A more recently identified mechanism which activates TGFβ, on regulatory T cells for example, is via glycoprotein A repetitions predominant [GARP, leucine rich repeat containing 32 (LRRC32)].92,93  GARP is believed to be one of the few specific activation elements (reviewed by ref. 94 and 95), and plays a role in cancer, fibrosis and immune disorders.94,96  A GARP antibody, ABBV-151 is in phase 1 clinical trials for cancer indications (NCT03821935),57,93  but very limited data is available for ABBV151 in fibrotic diseases. However, as GARP is of increasing interest in TGFβ signaling, such data should be on the way along with safety data.

This section will discuss approaches aiming to inhibit TGFβ activity on the level of signaling receptors, including type 1 ALK4/5 and type 2 TGFβRII receptors (for summary see Table 1.3).

Table 1.3

Overview of therapeutic approaches targeting TGFβ receptors, direct signaling, effectors and interacting pathways

PrincipleSpecificityMoleculeClinicStatusIndicationComments
Receptors 
ALK 5 inhibitor ALK 4/5/7 Galunisertib LY2157299 √  Cancer Intermittent dose regimen to avoid cardiac side effects, risk–benefit for fibrosis questionable. 
 ALK 4/5/7 Vactosertib TEW-7197 √  Cancer Intermittent dose regimen to avoid cardiac side effects, risk–benefit for fibrosis questionable 
 ALK 4/5/7 SB431542, SB525334   Fibrosis, Cancer On-target cardiac side effects (valvulopathy) 
TGFβRII inhibitor pan LY3022859 √ Terminated Cancer Antibody no safe dose was achieved 
Direct signaling 
Smad2/3 Smad3 SIS3   Fibrosis, Cancer Only preclinical data available 
 Smad3 Halofuginone √ Terminated Fibrosis Explored for DMD 
NOX inhibitor NOX1/4/(5) GKT137831 √  Fibrosis Excellent safety and tolerability, but not sufficient efficacy 
 NOX4 GLX7013114   Fibrosis, Cancer First in vitro data published 
 pan VAS2870   Cancer, Fibrosis No clinical data found 
TAK-1 inhibitor n.a. Takinib   Fibrosis Liver toxicity of KO limit use of inhibitors. 
JNK inhibitor pan Tanzisertib CC-930 √  Fibrosis Unfavorable risk–benefit 
 JNK1>JNK2 CC9001 √  Fibrosis, Cancer Improved safety compared with CC-930 
Effectors 
PAI-1 inhibitor n.a. SK216   Fibrosis Pro- and antifibrotic, broadly used as biomarker 
 n.a. TM5275   Fibrosis Pro- and antifibrotic, broadly used as biomarker 
MMP inhibitor MMP12 FP-025 √  Fibrosis Needs more data regarding isoform involvement 
 MMP2/9 S3304 √  Cancer Explored in various clinical trials >10 years 
 MMP9 Andecaliximab (GS-5745) √  Cancer, Fibrosis Antibody, failed in phase 2/3 ulcerative colitis 
 Multiple, not MMP1 XL784 √  Fibrosis MMP1 inhibition causes muscle toxicity 
CTGF inhibitor n.a. Pamrevlumab FG3019 √  Fibrosis Antibody with promising results in IPF phase 2 
 n.a. PF06473871 √  Fibrosis ASO for topical use 
 n.a. RXI-109 √  Fibrosis Self-delivering siRNA for topical use 
THBD mimetic n.a. ART123 √  Fibrosis Recombinant protein in phase 3 with data expected soon 
POSTN inhibitor n.a. Antibody   Cancer, Fibrosis Broadly used as biomarker, also IPF 
Interaction Pathways 
TGFβ inhibition Mode of action not well defined Pirfenidone √ √ Fibrosis Marketed for IPF 
Esbriet® Use recommended 
TGFβ inhibition Multikinase-inhibitor (PDGF, EGF, FGF) Nitedanib √ √ Fibrosis, Cancer Marketed for IPF with manageable long-term safety 
BIBF1120 
OFEV® 
TGFβ inhibition Mode of action not well defined Tranilast √ √ Fibrosis Marketed anti-allergic, high doses needed for anti-fibrosis 
Rizaben® 
Angiotensin AT1 receptor inhibitor Losartan, Valsartan etc. √ √ Fibrosis Marketed for cardiac diseases 
 ACE inhibitor Lisinopril, Enalapril etc. √ √ Fibrosis Marketed for cardiac diseases 
 AT2/mas receptor activator Angiotensin (1–7) √  Fibrosis, Cancer Explored in various other indications 
TXA127 
AVE0991 
ROCK inhibitor ROCK2 KD025 √  Fibrosis, Cancer ROCK2 selective to avoid cardiovascular effects 
 pan AMA0428   Fibrosis, Cancer Soft inhibitor, systemic application possible 
 pan Y27632   Fibrosis Weak inhibitor 
 pan Fasudil √ √ Fibrosis, Cancer Weak inhibitor 
Marketed for vascular disease 
 n.a. Pravastatin, Simvastatin √ √  Shown to also inhibit ROCK 
AMPK activator n.a. Metformin √ √ Fibrosis, Cancer Marketed for metabolic diseases 
 Multiple, including β1 PF-06409577 √  Fibrosis, Cancer Allosteric activator 
 Multiple, including β2 MK8722   Fibrosis, Cancer Induce cardiac hypertrophy 
PrincipleSpecificityMoleculeClinicStatusIndicationComments
Receptors 
ALK 5 inhibitor ALK 4/5/7 Galunisertib LY2157299 √  Cancer Intermittent dose regimen to avoid cardiac side effects, risk–benefit for fibrosis questionable. 
 ALK 4/5/7 Vactosertib TEW-7197 √  Cancer Intermittent dose regimen to avoid cardiac side effects, risk–benefit for fibrosis questionable 
 ALK 4/5/7 SB431542, SB525334   Fibrosis, Cancer On-target cardiac side effects (valvulopathy) 
TGFβRII inhibitor pan LY3022859 √ Terminated Cancer Antibody no safe dose was achieved 
Direct signaling 
Smad2/3 Smad3 SIS3   Fibrosis, Cancer Only preclinical data available 
 Smad3 Halofuginone √ Terminated Fibrosis Explored for DMD 
NOX inhibitor NOX1/4/(5) GKT137831 √  Fibrosis Excellent safety and tolerability, but not sufficient efficacy 
 NOX4 GLX7013114   Fibrosis, Cancer First in vitro data published 
 pan VAS2870   Cancer, Fibrosis No clinical data found 
TAK-1 inhibitor n.a. Takinib   Fibrosis Liver toxicity of KO limit use of inhibitors. 
JNK inhibitor pan Tanzisertib CC-930 √  Fibrosis Unfavorable risk–benefit 
 JNK1>JNK2 CC9001 √  Fibrosis, Cancer Improved safety compared with CC-930 
Effectors 
PAI-1 inhibitor n.a. SK216   Fibrosis Pro- and antifibrotic, broadly used as biomarker 
 n.a. TM5275   Fibrosis Pro- and antifibrotic, broadly used as biomarker 
MMP inhibitor MMP12 FP-025 √  Fibrosis Needs more data regarding isoform involvement 
 MMP2/9 S3304 √  Cancer Explored in various clinical trials >10 years 
 MMP9 Andecaliximab (GS-5745) √  Cancer, Fibrosis Antibody, failed in phase 2/3 ulcerative colitis 
 Multiple, not MMP1 XL784 √  Fibrosis MMP1 inhibition causes muscle toxicity 
CTGF inhibitor n.a. Pamrevlumab FG3019 √  Fibrosis Antibody with promising results in IPF phase 2 
 n.a. PF06473871 √  Fibrosis ASO for topical use 
 n.a. RXI-109 √  Fibrosis Self-delivering siRNA for topical use 
THBD mimetic n.a. ART123 √  Fibrosis Recombinant protein in phase 3 with data expected soon 
POSTN inhibitor n.a. Antibody   Cancer, Fibrosis Broadly used as biomarker, also IPF 
Interaction Pathways 
TGFβ inhibition Mode of action not well defined Pirfenidone √ √ Fibrosis Marketed for IPF 
Esbriet® Use recommended 
TGFβ inhibition Multikinase-inhibitor (PDGF, EGF, FGF) Nitedanib √ √ Fibrosis, Cancer Marketed for IPF with manageable long-term safety 
BIBF1120 
OFEV® 
TGFβ inhibition Mode of action not well defined Tranilast √ √ Fibrosis Marketed anti-allergic, high doses needed for anti-fibrosis 
Rizaben® 
Angiotensin AT1 receptor inhibitor Losartan, Valsartan etc. √ √ Fibrosis Marketed for cardiac diseases 
 ACE inhibitor Lisinopril, Enalapril etc. √ √ Fibrosis Marketed for cardiac diseases 
 AT2/mas receptor activator Angiotensin (1–7) √  Fibrosis, Cancer Explored in various other indications 
TXA127 
AVE0991 
ROCK inhibitor ROCK2 KD025 √  Fibrosis, Cancer ROCK2 selective to avoid cardiovascular effects 
 pan AMA0428   Fibrosis, Cancer Soft inhibitor, systemic application possible 
 pan Y27632   Fibrosis Weak inhibitor 
 pan Fasudil √ √ Fibrosis, Cancer Weak inhibitor 
Marketed for vascular disease 
 n.a. Pravastatin, Simvastatin √ √  Shown to also inhibit ROCK 
AMPK activator n.a. Metformin √ √ Fibrosis, Cancer Marketed for metabolic diseases 
 Multiple, including β1 PF-06409577 √  Fibrosis, Cancer Allosteric activator 
 Multiple, including β2 MK8722   Fibrosis, Cancer Induce cardiac hypertrophy 

Type 1 receptor inhibition, in particular ALK4/5-mediated canonical TGFβ signaling, is one of the most extensively explored mechanisms with broad TGFβ inhibition. There is a large amount of preclinical evidence in many indications, and various companies have had compounds in development. The most preclinically studied ALK4/5/7 inhibitor in scientific literature is SB-431542 (Inman et al. 2002, more than 800 publications) which is highly efficacious in many fibrosis models (e.g.ref. 97), but not as suitable for clinical use as the follow up compound SB-525334.98  In general, the therapeutic attractiveness of ALK4/5/7 inhibitors was diminished due to the observation of severe adverse events, most prominently valvulopathy99  and the majority of clinical projects were stopped. However, intermittent application, based on pharmacokinetic/pharmacodynamic models to determine a therapeutic window, seemed to circumvent severe adverse events, and some compounds, such as galunisertib and vactosertib (TEW 7197), made it to clinical use for cancer indications. Patients are 14 days on and 14 days off galunisertib, in 28 day cycles100,101  and vactosertib (TEW 7197) is given 5 days per week with 2 days off (ref. 102, NCT02160106). Whether such dosing regimens are also suitable for fibrotic indications remains to be explored. Notably, additional target adverse events are frequently observed with ALK4/5/7 inhibitors. This is not necessarily surprising since selectivity over other kinases can be hard to achieve for this class (see ref. 103) (Scheme 1.4).

Scheme 1.4

(a) SB-431542, (b) SB-525334, (c) Galunisertib (LY2157299), (d) Vactoserib (TEW-7197).

Scheme 1.4

(a) SB-431542, (b) SB-525334, (c) Galunisertib (LY2157299), (d) Vactoserib (TEW-7197).

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To date, Type II receptor inhibition has rarely been explored. One notable example is the TGFβRII antibody (LY3022859), which has only been evaluated for cancer indications. However, no safe and tolerable dose was achieved in a phase 1 clinical trial.104 

This section will discuss approaches aiming to inhibit TGFβ signaling downstream of receptor activation. Both inhibitors of canonical and the two non-canonical signaling pathways will be included (for summary see Table 1.3).

Interacting directly with canonical Smad2/3 signaling is not trivial as Smad2/3 is a transcriptional activator, a function not easily addressable with therapeutics. Therefore, only a few compounds act on this level of the pathway. Halofuginone (HT-100), a derivate of a natural alkaloid, is a repurposed drug, originally used as an anti-protozoal agent in veterinary medicine. It also has anti-fibrotic activity, and analysis of the mode of action indicated that it may partly work via inhibition of Smad3 phosphorylation.105  It was believed to have broad application (e.g.ref. 106 and 107) and was initially developed for fibrosis related to DMD, but clinical trials were terminated without posted results (NCT01847573, NCT01847573). Another molecule explored preclinically for fibrosis and cancer is the specific Smad3 inhibitor, SIS3.108–110  SIS3 inhibits Smad3 phosphorylation with specificity over Smad2, but was never used in clinical settings (Scheme 1.5).

Scheme 1.5

(a) Halofuginone (HT-100), (b) SIS3.

Scheme 1.5

(a) Halofuginone (HT-100), (b) SIS3.

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More druggable targets also believed to be part of canonical TGFβ signaling are NADPH oxidases (NOX) which have undergone preclinical and clinical exploration in fibrotic diseases. VAS2870 is a pan-NOX inhibitor111  and primarily used preclinically. As pan-NOX inhibition has a range of adverse events (reviewed by ref. 112), more isoform-specific NOX inhibitors were developed for clinical studies. For example, NOX4 was shown to be the key player in fibrosis using knockout mice,113  and the potent and selective NOX1/4/5 inhibitor GKT137831 has progressed to clinical trials114  (reviewed by ref. 115). Clinical trials are ongoing, and recently the first selective NOX4 inhibitor has been described, GLX7013114 (structure not disclosed).58  It will be exciting to follow this compound class (Scheme 1.6).

Scheme 1.6

(a) VAS2870, (b) GKT137831.

Scheme 1.6

(a) VAS2870, (b) GKT137831.

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An important non-canonical, ALK-independent TGFβ signaling pathway with a clear role in fibrosis is TAK-1.3,116,117  Preclinical evidence comes from Inducible KOs that are protected from renal fibrosis.118  In addition, TAK-1 seems to be an important linker between TGFβ and inflammatory cytokine signaling,21  opening the possibility to address fibrosis from two different angles at once. Thus, potent and selective TAK-1 inhibitors have been generated (see Tan et al. 2017), and the most advanced compound takinib, is a starting point for further chemical optimization.119  However, TAK-1 is a kinase and full-body KOs show severe liver toxicity.120  Due to the risk for toxicity, TAK-1 inhibitors need to be closely monitored regarding risk–benefit profiles. Therefore, it is not surprising that a TAK-1 inhibitor has not reached clinical use to date (Scheme 1.7).

Further downstream of non-canonical TAK-1 signaling is c-jun N-terminal kinase JNK,21  and JNK inhibition is being explored in fibrotic diseases. The pan-JNK inhibitor CC930121  was active in preclinical models of IPF122  and made it up to phase 2 for this indication, but was terminated due to a negative risk–benefit profile.123  A second generation compound CC-9001 (structure not disclosed), more potent on JNK1 than JNK2, shows improved safety and promising initial clinical results.124,125  If highly JNK1-selective compounds can be developed, this could be a promising anti-fibrotic therapy (Scheme 1.8).

Scheme 1.8

Tanzisertib (CC-930).

Scheme 1.8

Tanzisertib (CC-930).

Close modal

This section will discuss approaches aiming to inhibit downstream effectors of TGFβ signaling. These effectors are all secreted and propagate TGFβ signaling extracellularly in an autocrine, paracrine and endocrine fashion. Many of the effectors are also valuable circulating biomarkers, and therapeutics targeting effectors have the big advantage that they do not have to pass cellular barriers to reach their targets (for summary see Table 1.3).

Plasminogen activator inhibitor 1 (PAI-1, Serpin E1) is a serine protease inhibitor induced by TGFβ signaling with a wide variety of physiological functions, for example, in coagulation. PAI-1 is also commonly used as a circulating biomarker. In fibrosis, it has both pro- and anti-fibrotic properties so that the therapeutic aim is normalization of pathological levels, as both complete absence and overexpression induce fibrosis.126,127  PAI-1 inhibitors, such as SK216 or TM5275, have been generated and seem to be safe and potent anti-fibrotic agents in preclinical models.128–130  Thus far, clinical data are not available. It is worth of note that PAI-1 deficient individuals have bleeding issues, so a careful risk–benefit analysis will be important (Scheme 1.9).

Scheme 1.9

(a) SK216, (b) TM5275.

Scheme 1.9

(a) SK216, (b) TM5275.

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Thrombomodulin (THBD), an endothelial cell glycoprotein and important anticoagulant, is decreased by TGFβ. Inversely, THBD reduces TGFβ expression by a negative feedback loop via high-mobility group box 1 (HMGB1) and thrombin.131–133  Thus, the therapeutic approach for fibrosis, is to substitute with recombinant THBD, and a retrospective analysis of IPF patient records showed encouraging results.134  In IPF patients, recombinant THBD is used to treat coagulation issues after acute exacerbation, and in a subsequent clinical trial positive effects were confirmed.135  ART123, a recombinant THBD, has been evaluated in various clinical trials. More recently, a phase III study for acute exacerbation of IPF was completed (NCT02739165), and data should be available soon. However, the parenteral dosing of ART123 in chronic fibrotic diseases is not ideal. This remains a big hurdle compared with the acute, short-term dosing after exacerbation, and maybe not be viable in chronic settings.

Periostin (POSTN) is a secreted matricellular protein and its expression and subsequent secretion is stimulated by TGFβ. Secreted POSTN protein binds integrin receptors, e.g. αvβ3 and αvβ5, to support EMT and subsequently fibrosis136  (reviewed by ref. 137). Knockout or blockade of POSTN by antibodies was shown to efficiently protect various tissues from fibrosis (ref. 138–141, for review see ref. 142). However, in a myocardial infarction model POSTN knockout mice were more prone to ventricular rupture, even though surviving mice had less cardiac fibrosis, indicating that complete absence of POSTN can also have negative effects. Moreover, therapeutic inhibition is limited to neutralizing antibodies, and POSTN antibodies have not been used in clinical trials. On the other hand, POSTN has been broadly explored as a fibrosis biomarker, for example, in IPF.143,144  Pirfenidone treatment was found to reduce levels of POSTN in a preclinical fibrosis model.145 

Connective tissue growth factor [CTGF, cellular communication network factor 2 (CCN2)] is another matricellular protein induced by TGFβ that mediates intercellular signaling with a prominent role in many biological processes, including fibrosis.146,147  CTGF has no specific receptors, but binds in similar fashion to that of POSTN to integrin receptors, e.g. αvβ3,148  and many other proteins, leading to TGFβ-dependent induction of fibrosis. Strong evidence for the role of CTGF in fibrosis comes from the results of transgenic studies, indicating that overexpression of CTGF promotes and knockdown inhibits fibrosis (reviewed by ref. 149 and 150). Both neutralizing antibodies and siRNAs have been explored as therapeutic approaches with promising results in preclinical and clinical studies.151  For example, pamrevlumab (FG3019) showed good safety and tolerability along with promising results in phase 2 trials in IPF with reduced fibrosis progression.152,153  Pamrevlumab is currently in many clinical trials for fibrotic and cancer indications, and further results will be guiding. RXI-109, is a self-delivering CTGF siRNA, and PF06473871 is an ASO, both used locally, with initial positive results in dermal and retinal scaring.154,155 

The final group of TGFβ effector molecules discussed in this chapter are matrix metalloproteinases (MMPs), which consist of more than 20 isoforms with different localization and sometimes opposite function. They are induced by TGFβ and serve as important modulators of tissue remodeling.156  Tissue inhibitors of metalloproteinase (TIMPs) are natural inhibitors of MMPs.157  As MMPs have protease activity, degrading TGFβ and other ECM proteins, small molecule enzymatic inhibitors were generated. However, due to their pleiotropic functions, a major challenge is to identify the key MMP isoforms involved in fibrosis,158  and then produce compounds with favorable specificity profiles (see ref. 159). MMP inhibitors have a long history as anti-fibrotic or anti-TGFβ agents, with at least three generations of molecules.159–161  However, so far, no major breakthrough in their clinical application has been reported. Regardless, due to strong target validation, efforts continue with strategies to overcome toxicity and other challenges.162  As our understanding of the MMP's continues to evolve, various isoforms seem to be key players in fibrosis (see ref. 163), including MMP9, MMP7, MMP2 and MMP12,156,158,164,165  (for reviews see ref. 163 and 166). Herein a selection of late-generation MMP inhibitors will be discussed. In asthma, the MMP12 inhibitor FP-025 (structure not disclosed) is under evaluation based on MMP12 KO data showing improvement in lung fibrosis.167,168  Trials in asthma and COPD are ongoing (NCT03858686). The MMP2/9 inhibitor S3304 showed good safety and tolerability169  and was tested in cancer indications, but no data has been posted (e.g. NCT00078390). Andecaliximab (GS-5745), a MMP9 antibody, was explored for various indications and insufficient treatment benefit lead to termination of a phase 2/3 trial in ulcerative colitis (2016, Gilead homepage). Additional ongoing trials were terminated or had no data regarding outcomes available. Based on findings that MMP1 inhibition is linked to muscle toxicity,170  the small molecule inhibitor XL784 with selectivity against MMP1 (but similar activity against other MMPs) was generated, sparing muscle toxicity.171  It was tested in cancer and fibrotic diseases more than 10 year ago with disappointing clinical results and no further development due to adverse events (Scheme 1.10).172 

Scheme 1.10

(a) S3304, (b) XL-784.

Scheme 1.10

(a) S3304, (b) XL-784.

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In summary, results of extensive research on MMP inhibition indicated that broad inhibition is rather harmful and MMP isoform selectivity is hard to achieve. Thus, early excitement in the MMP inhibitor field has diminished to some extent. More recent efforts to advance specific inhibitors and new strategies were explored, but so far with limited clinical success or with trial outcome data that has not emerged.

This section will discuss approaches aiming to indirectly inhibit TGFβ signaling addressing interacting pathways. This approach, the most successful thus far, has produced two molecular entities marketed for fibrotic diseases, namely pirfenidone and nintedanib. Moreover, many of the interacting pathways have been successfully explored for other indications, with favorable safety profiles. This Indicates that they might be a good alternative to circumvent the safety challenges of directly inhibiting TGFβ signaling (for summary see Table 1.3).

Pirfenidone (Esbriet®), an orally available pyridone analog, was the first drug approved worldwide for the treatment of IPF. Its mode of action is multimodal and not totally understood, but it is mainly considered to act via TGFβ inhibition. For example, pirfenidone was shown to inhibit transcription and translation of TGFβ in preclinical fibrosis models. Moreover, it also inhibits other pro-fibrotic factors [e.g. platelet-derived growth factor (PDGF)] inflammatory cytokines [e.g. tumor necrosis factor alpha (TNFα)] as well as the production of reactive oxygen species (ROS). Together, all these mechanisms most probably contribute to the anti-fibrotic activity observed. Clinically, pirfenidone showed meaningful reduction in IPF disease progression with mild and manageable adverse events.173–178  In 2015, the clinical IPF guidelines assigned pirfenidone a conditional recommendation for its use in IPF179  and currently almost 100 clinical trials are ongoing, mainly for fibrotic conditions (Scheme 1.11).

Scheme 1.11

Pirfenidone.

Another compound approved for IPF treatment is the multi-kinase inhibitor nintedanib (OFEV®) which is also approved for non-small cell lung cancer as Vargatef®. Nintedanib targets platelet-derived growth factor (PDGF), EGF, and fibroblast growth factor (FGF) receptors, all modulating TGFβ signaling.180–182  As with pirfenidone, multiple anti-TGFβ actions have been reported (e.g. reduced TGFβ-induced EMT and collagen production), but it is clear that various other mode of action components (e.g. anti-angiogenesis) contribute to its anti-fibrotic activity. Significant reduction of IPF disease progression was observed in clinical trials with manageable long-term safety.181,183  In 2015, the clinical IPF guidelines also assigned nintedanib a conditional recommendation for its use in IPF179  and currently more than 100 clinical trials are ongoing in cancer and fibrotic conditions. Treatment selection between pirfenidone and nintedanib is mainly based on safety and tolerability and combination therapy has been suggested for the future (Scheme 1.12).181 

Scheme 1.12

Nintedanib.

Another marketed compound interacting with TGFβ is tranilast. It was initially, and still is, used as an anti-allergic compound in Asia. It was later shown to inhibit release of TGFβ from fibroblasts and subsequently EMT progression.184,185  It was reported that its anti-fibrotic efficacy appears to be mainly mediated by suppression of TGFβ expression, secretion and pathway activation. However, again other effects such as suppression of other pro-fibrotic and pro-inflammatory agents may contribute. Relatively high doses are needed for the anti-fibrotic activity, making it less attractive compared with the marketed principle for clinical development, despite low adverse events (reviewed by ref. 186). However, a few clinical trials are exploring its therapeutic potential in fibrotic diseases (Scheme 1.13).

Scheme 1.13

Tranilast.

Interaction of angiotensin II (ATII) and TGFβ signaling on multiple levels was discovered more than 20 years ago, and these interactions clearly contribute to fibrosis.187  For example, ATII can directly activate Smad signaling (see ref. 188) or promote TGFβ expression and activation, which leads to increased ECM synthesis.189,190  Subsequently, ATII inhibition has been extensively explored as an anti-fibrotic therapy using either angiotensin II receptor type 1 (AT1) receptor antagonists (e.g. losartan, valsartan) or angiotensin converting enzyme (ACE) inhibitors (e.g. lisinopril, enalapril), that have been marketed for cardiovascular diseases with excellent safety and tolerability, and tremendous clinical experience (for review see ref. 191 and 192). Indeed, promising results have been obtained with various molecules in a variety of fibrotic diseases and there are still clinical trials ongoing. However, none of the molecules has been approved for fibrotic diseases. More recently it has been found that the renin–angiotensin system (RAS) also plays a role in fibrosis protection, through the ACE2–Ang(1–7)–AT2–Massey oncogene homolog (mas) receptor axis which negatively regulates TGFβ.192–196  Thus, various Ang(1–7) agonists and mimetics (e.g. AVE0991 and TXA127) are being explored in cancer and fibrotic indications with initial promising effects (Scheme 1.14).196–200 

Scheme 1.14

(a) AVE0991, (b) TXA127.

Scheme 1.14

(a) AVE0991, (b) TXA127.

Close modal

Rho-associated kinases (ROCK), consisting of two isoform (ROCK1 and 2), regulate cytoskeletal organization and cell migration, and have a therapeutic potential in a wide range of pathological conditions, including fibrosis.201  ROCK interacts on various levels with TGFβ signaling, such as activation, signaling potentiation and most importantly via a positive feedback loop. TGFβ has been shown to be an upstream regulator of ROCK kinase.202  ROCK inhibitors, such as Fasudil, were initially developed and approved in Asia for cardiovascular and cerebrovascular diseases, and later also used locally for glaucoma therapy. More than 170 ROCK inhibitors have been generated, but unwanted cardiovascular side effects due to dual ROCK1/2 activity lead to a narrow therapeutic window. This was addressed by developing so-called “weak/soft” [e.g. fasudil, AMA0428 (structure not disclosed), Y27632] or ROCK2-selective compounds (KD025 203 ) (for review see ref. 201 and 204). Various fibrosis trials are ongoing with the ROCK2-selective inhibitor KD025. Moreover, some statins, 3-hydroxy-e-methylglutaryl CoA (HMG-COA) inhibitors (e.g. simvastatin) have also been shown to inhibit ROCK, and are being explored for fibrotic disease.205,206  A very significant observation with ROCK inhibitors was that they can not only prevent fibrosis, but also cause regression of already established fibrosis in IPF, as they might selectively target profibrotic cells (Scheme 1.15).202 

Scheme 1.15

(a) Fasudil, (b) Y-27632, (c) KD025c.

Scheme 1.15

(a) Fasudil, (b) Y-27632, (c) KD025c.

Close modal

AMP-activated kinase (AMPK), is part of a nutrient-sensing pathway with a key role in metabolism. The AMPK pathway is another player more recently described to interact with TGFβ signaling and contribute to fibrotic diseases. AMPK activation negatively regulates Smad2/3 signaling, and AMPK ablation leads to enhanced TGFβ–Smad signaling in vitro.207,208  In accordance, both pharmacologic and genetic activation of AMPK effectively prevents fibrosis in vivo.46,209–213  By far the most data is available for metformin, an approved anti-diabetic drug and indirect AMPK activator, with a variety of clinical trials. Moreover, various direct activators (e.g. PF-06409577 and MK8722) have been generated, mainly for metabolic diseases, and are now being preclinically explored for their therapeutic potential in fibrotic diseases (for review see ref. 214). However, despite good preclinical efficacy, cardiac side effects seem to prevent further development.215  To address adverse events, compounds with different subunit selectivities are currently under exploration,216  as the subunits show different distributions and functions (Scheme 1.16).214 

Scheme 1.16

(a) PF-06409577, (b) MK8722.

Scheme 1.16

(a) PF-06409577, (b) MK8722.

Close modal

Major progress has been made to treat fibrotic diseases by interacting with TGFβ signaling. Most of the therapeutics are highly active in preclinical studies but have limited clinical success due to non-favorable adverse events. However, further pathway analysis to find more specific inhibition nodes was key to improving the safety and selectivity of the next generation of therapies under development. In fact, two compounds have been approved for the treatment of IPF, namely pirfenidone and nintedanib, which slow progression of fibrosis with manageable adverse events. For both, expansion of clinical indications is being explored. Moreover, new compounds and targets are currently being studied that directly or indirectly target TGFβ signaling, and it will be very exciting to follow their preclinical and clinical development.

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