Novel fibrosis therapeutics: walking down the TGF-beta pathway

Recent weeks brought startling news of clinical trial successes in the treatment of Idiopathic Pulmonary Fibrosis (IPF). The clinical and commercial consequences have been heavily reviewed elsewhere (eg. GLPG and FGEN).

This short commentary will focus on the underpinning science, with particular reference to the TGF-beta (TGFb) pathway and the role of that pathway in fibrotic disease.

First a quick primer on the recent advances in IPF drug development. Fibrogen pulled off a successful and surprising 48 week Phase 2 trial of pamrevlumab, an old antibody targeting CTGF, while Galapogos followed with very compelling early Phase 2a data of GLPG1690, an autotaxin inhibitor, including the apparent reversal in decline of lung function that is the hallmark of IPF (nb. small sample size, short analysis period (12 weeks). These two new drugs are poised to contribute to the next wave of IPF therapeutics, joining pirfenidone (Esbriettm, Roche) and nintedanib (Ofevtm, Boehringer Ingelheim), approved for the treatment of IPF in 2014. Of note, pirfenidone and nintedanib are considered moderately efficacious, slowing but not reversing the rate of decline in lung function, and only modestly improving life expectancy, if at all. Therefore, if pamrevlumab or GLPG1690 can differentiate by either reversing lung damage or increasing life expectancy, they would be expected to overtake the earlier drugs.

What’s interesting is that the mechanism of each of these drugs intersects with the activity of TGFb, a dominant cytokine that normally controls wound healing and other tissue repair activities. When dysregulated, TGFb becomes pathogenic, supporting disease processes spanning oncology and fibrosis. We can visualize the initiation and progression of fibrosis as a series of steps controlled, at least in part, by the continuous activity of TGFb signaling through the TGFb-receptors. Indeed, pirfenidone’s mechanism of action includes inhibition of TGFb-receptor signaling, among other activities (both pirfenidone and nintedanib are tyrosine kinase receptor inhibitors, and neither is particularly selective, hitting multiple receptors simultaneously).

Here is a cartoon with different stages of fibrosis induction and progression, simplified:

 cascade 1

Without dwelling overly on the various pathologies at work, we can point to several critical steps underpinning the cascade:

1) influx of inflammatory cells upon injury

2) increase in autotaxin and therefore LPA (autotaxin cleaves the abundant lipid moiety LPC, to release LPA)

3) triggering of the LPA receptors, that, among other activities, are responsible for the activation of beta integrins, leading to the release of TGFb from sequestration

4) activation of TGFb receptors, that, among other activities, induce the secretion of growth factors including CTGF

5) induced production of TGFb by the action of CTGF

6) myofibroblast activation and ECM deposition leading to fibrosis

Now we can overlay some of the therapeutics developed for IPF on the cascade (simplified even further here):

 cascade 2

Note that Fibrogen’s anti-CTGF antibody pamrevlumab sits along side the approved drugs pirfenidone and nintedanib, a bit downstream of the initiation of the fibrotic cascade. The clinical data to date suggest that pamrevlumab has activity similar to pirfenidone and nintedanib. It is critical to stress here that CTGF secretion is tightly controlled by, among other things, TGFb. Further, in the fibrotic setting, TGFb appears to be a master regulator of CTGF expression, and, as noted above, the regulation is feed forward, since CTGF signaling through it’s receptor induces expression of more TGFb. It makes sense then that an anti-CTGF antibody could derail this chronic signaling loop, and thereby provide therapeutic benefit by reducing TGFb levels as well as tempering the pathologic activity of CTGF.

Further downstream is the anti-LOXL2 antibody, simtuzumab, formally under development at Gilead for IPF and NASH (a form of liver fibrosis). LOXL2 enzyme is responsible for crosslinking collagen, thus contributing to ECM deposition. Perhaps being too far down the fibrotic cascade is ineffective, as simtuzumab was dropped based on poor efficacy in Phase 2 trials.

Turning upstream we find autotaxin inhibition, integrin inhibition and LPA inhibition. The mechanism of action of all three targets is related, since, as noted above, autotaxin cleaves LPC to yield LPA; LPA in turns binds the LPA receptors. LPA receptors are G-protein coupled receptors with diverse functions, prominent among them being the activation of integrin beta strands. Among the integrins then, integrin avb6 has been tied directly to TGFb release in the setting of lung fibrosis. This complex system is tightly regulated, with the relationship of autotaxin/LPA/LPA receptor/integrin/TGFb preserved in different organ systems. The relative contribution of the different LPA receptors and different integrins does vary however.

The three upstream therapeutics illustrated have presented a mixed clinical picture. The anti-LPA antibody Lpathomab was a clinical flop, and the company developing it, Lpath Inc., reversed merged into oblivion several years ago. Anti-LPA might have worked if the antibody were optimal, however the suspicion at the time was that the antibody bound to only some of the myriad isoforms of LPA, and was therefore ineffective. Biogen’s anti-alpha-v beta-6 antibody STX-100 has finished a Phase 2 trial in IPF but has not reported data. This may be due to issues of efficacy and/or safety or may be due to Biogen’s frank disinterest in fibrosis (or anything outside of neurology). However, we simply don’t know. And finally, we have the new data on the Galapogos autotaxin inhibitor, GLPG1690.

The results obtained in the small Phase 2 trial of GLPG1690 in IPF were very good, and if they hold up the drug could certainly be best-in-class for IPF. Further, as a therapeutic sitting at the top of the fibrotic cascade, there is every reason to believe that this drug will show promising efficacy in other fibrotic conditions.

We expect updates from these programs and others at the fall academic meetings, starting with the European Respiratory Society Congress on 9-13 September. Importantly, Fibrogen will report data from combination studies of pamrevlumab plus pirfenidone or nintedanib in IPF.

 stay tuned.