Identifying Best Disease Indications for Anti-Fibrotic Drugs

By Peter G. Traber, MD

Executive Summary

Anti-fibrotic drugs have the potential to broadly impact the course of multiple chronic diseases, but the choice of initial and follow-on disease indications must be carefully considered early in strategic planning. This short review briefly outlines important clinical development issues that should be thoroughly evaluated in staging the most successful strategic approach including disease etiology, drug mechanism of action, medical care considerations, availability of drug target engagement and fibrosis biomarkers, clinical trial design, and regulatory issues.  Emphasis is placed on close coordination between pre-clinical research and clinical development groups in devising an optimum disease selection strategy.

While I have focused on clinical and drug development issues in this review, another important aspect of disease indication analysis is assessment of the market and comparison with other drugs on the market and in development for individual indications. This is beyond the scope of this discussion but is often a key element in decision making and should be systematically evaluated.


Anti-fibrotic drug candidates, prior to entering clinical development, often have a mechanism of action that may be beneficial for treatment of multiple diseases. Early strategic issues in advancement of such drugs include identification of disease indications with the best likelihood of success in proof of concept (POC) and registration clinical trials and predicting the economic impact on the company for various development pathways.

All tissues and organs contain connective tissue, including various types of collagen, elastin, and others, that provides architectural support for parenchymal cells. The amount of connective tissue is normally finely tuned so that a steady-state is balanced between production and degradation. In response to various inflammatory or toxic insults production of collagen increases more than degradation leading to accumulation of fibrotic tissue. This is a normal wound healing response to acute insults.  However, when the insult is chronic, fibrogenesis may lead to pathologic accumulation of fibrotic tissue (scarring) which may result in organ dysfunction and failure.

Fibrosis is the final common pathway for most pathophysiological processes in multiple organs and is the primary reason for organ transplants. In fact, it has been estimated that nearly 50% of deaths in the developed world is due to fibrosis of key organs including heart, liver, kidney, lung, and others. Therefore, pharmaceutical and biotech companies are keenly focused on developing drugs that can prevent, mitigate or reverse the fibrotic process.

Disease Etiology Considerations

Because virtually all chronic human diseases can result in organ fibrosis, the underlying etiology or cause of the chronic inflammation or tissue damage is an important consideration in choosing disease targets. In liver for example, the three major chronic diseases that result in liver fibrosis include viral hepatitis B and C, alcohol abuse, and non-alcoholic steatohepatitis (NASH). Less prevalent, but important diseases, include primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Choice of a target liver disease for anti-fibrotic drugs must take into consideration many aspects of the underlying cause. For example, viral hepatitis C would have been considered a leading indication prior to the emergence of highly effective anti-viral drugs. While an antifibrotic may still be desirable in some patients with established fibrosis or cirrhosis from hepatitis C, this indication has become less desirable with the advent of curative anti-viral therapy. Alcoholic liver disease is a less desirable initial disease target because of the profound effect that abstinence, recidivism, and drinking patterns have on disease outcomes.

For these reasons, diseases with incompletely understood underlying mechanisms have been targeted for anti-fibrotic therapy. NASH, which has a complex metabolic pathophysiology, is one of the prime indications currently being targeted for anti-fibrotic therapy in liver. Likewise, PBC and PSC, which have a poorly defined immunologic underlying etiology, are two other prime disease targets.

In other organs, there may be different factors to consider in the choice of disease target. For example, in diabetic kidney disease, it is established that glucose control is the key factor in disease progression. However, glomerulopathy and renal interstitial fibrosis may progress despite optimal implementation of currently available approaches for serum glucose control. Therefore, in this disease an antifibrotic drug that arrests or reverses glomerulopathy or interstitial fibrosis would be highly desirable even through the underlying etiology is well defined.

Drug Mechanism of Action (MOA) Considerations

Anti-fibrotic drugs often have many potential indications because they target molecules and pathways involved in fibrosis of multiple organs. Additionally, some targets may affect several pathologic pathways in addition to purely anti-fibrotic mechanisms including, immune cell modulation, intermediary metabolism, cytokine expression, and cell death. Consideration of potential indications is greatly aided by deep understanding of the disease pathophysiology and how the drug may affect multiple pathways. This is also important for potential disease biomarkers, discussed below. Close interaction between scientific and development teams is critical during the early stages of selecting therapeutic indications.

One of the important considerations in pre-clinical pharmacology experiments is whether the drug inhibits the development or progression of fibrosis or whether it reverses existing fibrotic tissue, or ideally both. While the design of pre-clinical experiments to ascertain this may be challenging, such an effort will be rewarded in designing the most effective development program.

Medical Considerations

Patient care issues may be overlooked or given short attention in the early stages of selecting a target disease. In my view, it is important to carefully consider the patient experience and the interaction of the patient with the health care system as an element in choosing indications to pursue and in designing the most effective development program.

In addition to the typical assessment of epidemiology, market, and potential disease/commercial impact, one should also assess how patients come to medical attention, detail on the clinical course of the disease, how the disease is diagnosed and monitored in clinical practice, how the disease and potential therapy may affect patient lifestyle, and where in the disease process intervention may be best targeted based on standards of clinical care. Such an assessment for each potential disease indication will inform the decision-making process for selecting disease indications and aid in designing the clinical development program.

Target Engagement and Disease Biomarker Considerations

Biomarkers to assess target engagement are important for all clinical development programs to assess dosing in humans and to make assumptions on efficacy effects in translation from pre-clinical species. Target engagement biomarkers are uniquely important in fibrotic disease for several reasons. Fibrotic diseases are chronic, often progress slowly over long periods of time, and are usually asymptomatic until relatively advanced. Therefore, it is risky to advance drugs into development for fibrotic diseases without having robust tools for assessing whether the drug adequately engages with the intended target at clinically relevant and safe doses in humans.

A critical issue in assessing the suitability of target engagement biomarkers for fibrotic disease is tissue penetration of the drug. Target cells are often embedded in thick layers of fibrotic tissue and drug action is in the tissue often governed by cell-cell, cell-matrix and paracrine effects between different cell types. Biomarkers, or ex-vivo assays, that assess target engagement in blood may not be relevant to the levels or effects in tissues.

In the development of drugs that target fibrosis, there have been prominent development failures that may be related to tissue penetration. For example, pre-clinical studies showed an anti-fibrotic effect of an anti-LOXL2 antibody and early clinical trials showed serum inhibition of the LOXL2 enzyme. However, multiple large phase 2 clinical trials in NASH fibrosis and cirrhosis, lung fibrosis, and myelofibrosis failed to demonstrate an effect. It has been hypothesized that failure of the monoclonal antibody to penetrate fibrotic tissue may be a component of the clinical trial failures. The impact of tissue penetration may be more important for large drug molecules such as proteins or antibodies rather than small molecule drugs.

Prior to initiating clinical trials with anti-fibrotic drugs, it is crucial to spend special effort on identifying and validating both serum, and if possible tissue, target engagement biomarkers. This effort should be part of every pre-clinical pharmacology program and informed by clinical development goals for the intended indication. If such biomarkers are available during clinical development, they will provide confidence on dosing and clinical trial design, as well as confidence in the market with investors.

In addition to developing target engagement biomarkers, it is desirable to define a set of validated biomarkers for disease activity to provide early reads of drug effect in clinical trials. This area of research in multiple fibrotic diseases is in evolution, so it is important to evaluate potential biomarkers in animal models to correlate with clinical findings. Additionally, it is advisable to include multiple biomarkers that may correlate to both fibrotic tissue synthesis as well as degradation, including some biomarkers that are in early development since they may become better validated during the course of clinical trials. Finally, it is important to collect undesignated samples from clinical trial patients, including DNA, that may be evaluated for biomarkers/gene profiles that may become important for further integration of clinical trial results. Post hoc analysis of these samples for newly identified biomarkers may provide important support for findings in clinical trials and analysis of patient subsets.

Clinical Development and Regulatory Considerations

The full development plan for a disease indication should be broadly assessed prior to settling on the disease target. Ideally, there should a clear pathway to POC as well as the subsequent studies necessary for approval, which may include provisional approval based on an endpoint that is a surrogate for clinical outcomes. However, in many situations the existing endpoints are not viewed by regulatory agencies as validated surrogates nor sufficient clinical endpoints for approval of the indication. Whatever the planned clinical endpoints, preclinical experiments should attempt to evaluate these endpoints when feasible to provide some confidence of the success of POC clinical trials.

Assessment of endpoints that regulatory agencies consider validated or potential surrogates and approvable endpoints is essential. Such an assessment may be straightforward in the situation where there are already approved drugs for the indication. For example, in idiopathic pulmonary fibrosis (IPF), there are two marketed drugs (pirfenidone and nintedanib), one of which is an anti-fibrotic agent (pirfenidone) that inhibits TGF-β induced collagen deposition. In this case, approvable endpoints are well-defined, although the sequencing of endpoints in clinical trials for POC and evaluation of additional potential surrogates may need additional thought depending on the drug MOA.

A common situation with anti-fibrotic drugs is there are no approved drugs for the indication and a lack of clarity from regulatory agencies on appropriate endpoints.  One pitfall companies may encounter is that regulatory agencies are not prepared to commit to trial endpoints even after clinical trials are well underway. The early years in fibrosis drug development for specific indications is a process of data analysis and discussion between industry, regulatory agencies, and academia before appropriate endpoints are agreed. This can be a trying process for companies in the early years, but those that enter later benefit from the previous activity even if there are no approved therapies.

A brief discussion of clinical trial endpoints in NASH studies is illustrative of this point. When the first major positive phase 2 clinical trial was reported in NASH (FLINT trial of obeticoholic acid), the primary endpoint was a two-point reduction in the NAFLD activity score, an endpoint validated by the NASH Clinical Research Network sponsored by the NIH, but not agreed by the FDA for drug registration. At that time, and since, there were multiple other trials that used the same primary endpoint. Following discussion with agencies, the eventual agreed phase 3 endpoints in pre-cirrhotic NASH were not NAFLD activity score, but rather at least a one-point reduction in fibrosis score with no change in NASH activity, the reversal of NASH using a newly agreed definition of reversal of hepatocyte ballooning and an inflammation score of 0-1, or the lack of progression to cirrhosis. During the period of gaining this clarity, there was confusion in the field.

It should be noted that one of the key elements in facilitating agreement on pre-cirrhotic NASH endpoints was structured discussion between the regulatory agencies, industry, and academic experts. The Forum for Collaborative Research at the University of California Berkeley coordinated the Liver Form which has been instrumental in facilitating discussions, as they did previously for HIV and hepatitis C. When considering anti-fibrotic disease indications, it is important to explore similar programs and other organizations, such as non-profit disease and patient advocacy groups and academic consensus panels, for the intended indication and vigorously participate.

The final regulatory issue I will mention is whether there is a possibility for orphan drug designation which can facilitate development and provides multiple advantages once the drug is approved.


Companies with interesting anti-fibrotic drugs should broadly evaluate the full spectrum of potential indications before settling on disease indication(s). Focusing too early on a single indication may lead to development challenges as the program progresses and other opportunities may be missed in the process. Additionally, evaluation of multiple disease indications facilitates the sequencing of programs if more than on disease indication is chosen to pursue. Moreover, the full analysis of clinical development pathways will provide investors with additional confidence at various stages during the program execution.


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