NASH is a complex disorder, characterized by multiple distinct patient phenotypes that have different outcomes and time lines of progression. This heterogeneity poses a challenge to clinical development as the natural history of the disorder is not completely understood. Longitudinal studies demonstrate that only 10% to 20% of NASH patients end up with major liver complications such as cirrhosis or liver-related death. Dr. Raza Malik, assistant professor of medicine at Harvard Medical School and director of the Liver Failure Program at Beth Israel Deaconess Medical Center in Boston, explains that figuring out how to identify the patients at risk is important not just for drug development but ultimately for clinical practice. “We need to know who is at risk for dire consequences to decide who to treat,” he notes.
Currently, researchers and physicians are unsure what differentiates the minority of NASH patients who go on to develop serious liver complications from those who do not. Existing evidence suggests that the fibrosis stage is the strongest predictor of liver transplantation and liver-related mortality. Severity of liver fibrosis (stage) in NASH is measured on a scale ranging from F0 to F4, where F0 denotes no fibrosis and F4 is the most severe stage known as cirrhosis. In the absence of alternative markers for risk-stratification, this known correlation between fibrosis severity and long-term outcomes has focused clinical development on NASH patients with fibrosis rather than with earlier disease. But the interpatient variability does not stop here; even fibrotic patients follow a heterogeneous course. Recent studies have highlighted that patients tend to fall into roughly three equal groups – progressors, regressors, and those with stable disease (see Exhibit 3). Rates of fibrosis progression also vary considerably – while on average it takes seven to 10 years for fibrosis to worsen by one stage, a fraction of patients progress much more rapidly, stepping from no fibrosis to cirrhosis in as little as five years, as noted in the 2015 paper "Fibrosis Progression in Nonalcoholic Fatty Liver versus Nonalcoholic Steatohepatitis: A Systematic Review and Meta-analysis of Paired-Biopsy Studies."
Nash Patients Experience Variable Disease Progression
Heterogeneity in the underlying etiology of NASH is likely one of the key factors behind this diversity in prognosis and rate of progression. The current hypothesis is that NASH develops due to the interplay of distinct influences, including genetic predisposition and risk factors such as obesity, metabolic syndrome (a cluster of abnormalities, such as hypertension, high blood sugar, and excess fat around the waist, leading to predisposition to cardiovascular disease and type 2 diabetes), and diabetes. Variability arises from the fact that in some patients, NASH may be triggered primarily by genetic predisposition, while in others by, say, insulin resistance. Dr. Rosana Kapeller, former Chief Scientific Officer of Nimbus Therapeutics, explains: “We now talk about NASH as one disorder but probably in the next 20 years we will find out that there are at least 10 different types of NASH and they are going to be treated in different ways and the outcomes are going to be different.”
Unfortunately, until there is a better way to reliably predict which patients will progress and at what rate, the variation in patient progression will continue to pose a challenge to clinical development. Enrolling patients with heterogeneous disease course can affect clinical trial readouts – spontaneous fibrosis regression in the placebo arm of a study could obscure therapeutic efficacy due to high placebo effects.
To fill the knowledge gaps around the natural history of NASH more expeditiously, drug developers can partner with academic institutions to conduct longitudinal observational studies. A real-world example from a therapeutic area where this approach has made an impact is the Framingham Heart study – a multigenerational, observational study to understand cardiovascular disease. The study started in 1945, sparked by the death of US President Franklin D. Roosevelt due to a heart condition. At the time, little was known about the causes of heart disease, so, in order to further understand the condition, President Harry Truman signed the National Heart Act allocating half a million dollars for research in the area. Interestingly, what was meant to be a 20-year epidemiological heart study continues to this day and has been critical in advancing understanding of the disease and continues to guide clinical development.
Developers are currently making efforts to study NASH natural history in pivotal trials by, for example, enrolling a small number of patients with milder disease purely for exploratory purposes. Pooling data from all of the ongoing clinical trials will undoubtedly advance the understanding of how NASH develops and progresses. These learnings can be supplemented by sponsoring academic studies to study the real-world heterogeneity of the disease, outside of the controlled environment of clinical trials.
The Case For Combination Treatment
NASH is not only heterogeneous in terms of its root causes but also in terms of the biological mechanisms driving progression – a complexity that must be accounted for when selecting a therapeutic approach. The progression of NASH is affected by a multitude of biological pathways that could be pursued as potential therapeutic targets. “Our understanding of the underlying pathophysiology is still evolving,” says Dr. Malik, “we know which pathways are involved but we don’t know the hierarchy of the pathways and their relative contributions.” It is this biological complexity, and the unanswered questions surrounding it, that likely explains the development of a large volume of pipeline agents with remarkably diverse targets.
Dr. Kapeller explains that “current investigational approaches target three key axes – fat, inflammation and fibrosis.” Some drugs aim to resolve metabolic issues, such as excess fat or insulin resistance, others target inflammation, and still others aim to chew up fibrotic scars. As NASH is complex and multifactorial, Dr. Kapeller anticipates that a single therapeutic target will not be able to effectively manage NASH in all patients but she is hopeful that the ultimate solution to the disorder lies in combination approaches. According to Dr. Kapeller, “Targeting fibrosis is not enough; I think you definitely need to target all three underlying mechanisms – fat, inflammation and fibrosis. We don’t know yet which approach is going to be the most effective but I think you might have to hit all three axes equally.”
Indeed, the monotherapies in development are not effective in all patients. In trials, 10% to 20% of patients on placebo are responders compared to 30% to 50% of patients on investigational compounds – in other words, the drugs benefit only about a third of participants. Scientists have not been surprised by these modest results and have interpreted them as evidence that several underlying processes contribute in varying amounts to the overall disease progression. The hope is that combining compounds targeting multiple pathways in the progression of NASH will offer improved efficacy to more patients.
Prime Time For Combos?
Combination approaches were a central topic at the 2nd annual NASH Summit held in Boston, MA, in April 2018. While many are united behind the vision of combination treatment as the ultimate solution to NASH, there are mixed views on whether it is timely to take investigational combos into the clinic. Those in favor of immediate pursuit cite the modest efficacy observed in ongoing trials as key motivation. More cautious developers believe the understanding of NASH biology is currently insufficient to support rational design of combinations, and warn that repeat trial failures may jeopardize the ability to justify future trials for the entire field. With the exception of ongoing activity in oncology, it is generally unusual to be exploring combination approaches before either asset has demonstrated efficacy as a monotherapy. Advancing combinations of investigational agents is inherently more exploratory than combining approved drugs. Complexity arises from having to predict drug-drug interactions, including resultant toxicity and synergistic therapeutic effects, from limited safety and efficacy data.
However, skepticism may be quelled as soon as the first Phase II combination trials read out in a year or so. Compelling evidence that combinations outperform monotherapy in preclinical studies is emerging from multiple developers. Furthermore, the first-in-human test of a combo approach completed earlier this year; Gilead Sciences Inc. reported a positive efficacy signal from a proof-of-concept study of several combination treatments in NASH and intends to develop them further.
Premature or not, pursuit of combination therapies is likely here to stay. In addition to Gilead, Pfizer Inc. is planning to test combinations independently, while Novartis AG and Allergan PLC just kicked-off the first cross-company collaboration trial. It may be timely for other developers to reflect on how to best navigate a space that is already shifting focus to combinations. Dedicating resources to cracking the NASH riddle is an important consideration for accelerating development. Focus could range from in vitro organ systems with human tissue to help generate more precise rationale for how to combine treatments to precision medicine approaches for identification of the right treatment for the right patient. On the strategic front, exploring suitable cross-company partnerships to combine compounds with complementary mechanisms of actions that best address the underlying complexity of the disorder is of significant importance.
Considerations For Clinical Trial Design
Testing in the right patient population is critical to success. Numerous clinical trials are currently underway despite the challenges outlined above. Dr. Kapeller advises that “selecting the right patient population is key to successful clinical development,” given the significant heterogeneity of clinical outcomes and therapeutic needs across patient segments. From a strategic perspective, biopharma would ideally pursue the opportunity that combines the highest clinical unmet need with the lowest developmental hurdles.
Some practicing hepatologists propose that the ideal approach to NASH would be to intervene relatively early, in patients with F1 or F2 fibrosis, to prevent progression to more advanced disease. The concern is that “if you try to intervene in F3 or F4, you may have missed the boat on these patients,” says Dr. Malik. In fact, “for a long time, companies were focusing on F1 and F2,” explains Dr. Kapeller, but as NASH is a slow-progressing disorder “it was taking too long to show therapeutic effect.” As a result, the FDA and the European Medicines Agency (EMA) started advising developers to focus on F2 and above, given the higher likelihood of these patients progressing to serious liver events sooner. “You can’t do clinical trials for 20 years,” says Kapeller. Targeting advanced disease allows for the demonstration of efficacy in more practical time-frames providing some much-needed cost relief.
Currently, developers can pursue two distinct pathways to FDA or EMA approval (see Exhibit 4). One approach is accelerated/conditional approval, based on reasonably accepted surrogate endpoints in moderate-severe disease (NASH F2-F3). This approach requires post-approval studies to demonstrate that the surrogates translate to clinically meaningful benefit. The other option is a standard approval, based on hard clinical outcomes in compensated cirrhosis. Both options have their own unique considerations and deciding which path to pursue should be primarily guided by the mechanism of action of the drug that is being assessed. While potentially a shorter path to market, accelerated approval based on novel surrogate biomarkers leaves room for payers to place significant restrictions on product utilization until definite approval is obtained. Pursuing standard approval in compensated cirrhosis is equally risky as the patient population is much sicker and harder to manage. Furthermore, demonstrating efficacy in cirrhosis likely requires a therapeutic approach with strong anti-fibrotic effect.
Two Potential Regulatory Pathways Exist For Investigational Therapies
Keeping tabs on co-morbid conditions. While a regulatory pathway for approval of NASH treatments has been established, clinical success remains uncertain. Beyond ensuring that trials enroll patients in the right stage of disease progression, developers must also be mindful of the fact that NASH frequently co-exists with co-morbid conditions such as obesity, type 2 diabetes and cardiovascular disease. Each of these conditions is associated with its own set of clinical complications, which may affect outcomes in clinical trials. In some cases, the co-morbid condition may actually be a stronger driver of risk and mortality than NASH. “The endpoints have to reflect the patient population that you are assessing your drug on,” advises Dr. Malik. He explains that “in patients with obesity and mild NASH, morbidity and mortality will be primarily from diabetes, CVD, and stroke, and assessing liver-related mortality in those patients is inappropriate.”
While the field has shifted focus onto patients with advanced disease who are at the highest risk of liver-related mortality, early trial readouts are starting to show that even patients with increased risk of liver events have elevated cardiovascular risk with their obesity, which could still taint trial outcomes. “Trials need to be very carefully developed to make sure you are selecting the right patient population to demonstrate a liver outcome,” concludes Dr. Malik.
The high frequency of co-morbid conditions in NASH patients also impacts the safety profile required for approval of a potential NASH therapy. For example, as more than a third of NASH patients succumb to cardiovascular events, regulators require that NASH drugs are at least neutral in terms of cardiovascular risk. Pivotal trials are expected to demonstrate no sign of elevated CVD risk, which has to be confirmed by large post-approval safety studies.
Non-Invasive Biomarkers Needed
The lack of non-invasive biomarkers for diagnosis, risk stratification and treatment monitoring of NASH is one of the key hurdles facing the field. Currently, liver biopsy is the only accepted approach for diagnosis and assessment of response in trials. However, biopsy is invasive, carries risk of hospitalization and mortality, and is prone to sampling error and high inter-observer variability. Various alternative approaches are in development but none are ready for prime time yet. Reliable methods for quantification of fat and fibrosis are starting to emerge but detecting inflammation remains an unsolved challenge. “We need tools that allow us to distinguish steatosis (simple fat) from steatohepatitis (fat with inflammation),” says Dr. Malik.
Ongoing innovation in the diagnostics space has the potential to accelerate drug development and ultimately reshape how patients are managed. However, adopting new biomarkers in clinical trials requires substantial efforts and investment to validate the reliability of these biomarkers as surrogate endpoints. In an effort to address one of the biggest challenges in the field, developers are currently integrating exploratory markers as secondary endpoints in Phase II and Phase III studies. The field has also seen the formation of two multi-stakeholder consortia, LITMUS and NIMBLE, aimed at accelerating validation of non-invasive markers by sharing resources and patient samples. A collaboration between European biopharma and academic entities, LITMUS is overseen by the Brussels-based Innovative Medicines Initiative. NIMBIL is the North American counterpart, supported by the National Institutes of Health.
A biopharma company can further its position in the field by investing in developing and validating innovative diagnostic techniques to improve on current limitations of biopsy and facilitate easier trial recruitment. At the very least, it is strategically important to surveil development in non-invasive markers and endpoints to adopt the latest innovations in trial design.
The Rest Is Unwritten
It is clear that the story of NASH is just starting to be written and that the ultimate NASH therapeutic is still some years in the making. Dr. Malik explains, “This is a young condition, the pathophysiology is evolving, drug development is evolving; we have to be patient and we will identify the answer hopefully in the next decade or two.” While current patients are not adequately managed by diet and lifestyle modifications, typically due to issues with compliance, the evidence that these interventions can alter the course of the disease is perceived as encouraging proof that the condition is reversible.
The continued efforts of academic, clinical, biotech and biopharma communities will drive the field forward and bring it closer to a solution. However, building a complex therapeutic area from the ground up requires substantial investment, time and cross-collaboration between all relevant stakeholders to accelerate development.
Amama Sadiq, MD, MPH, is a Medical Director and Engagement Manager at Clarion, a life sciences strategy consultancy located in Boston, MA. She can be reached at firstname.lastname@example.org. Iliyana P. Atanasova, PhD, and Katherine J. Franklin are Consultants at Clarion.
[Editor's note: In February 2018, Clarion partnered with MassBio to co-host a panel on NASH. The event brought together a diverse group of esteemed NASH thought-leaders, blending medical, commercial, and health economics viewpoints. The content of this article reports on some of the issues discussed by the panel. Clarion thanks MassBio for this collaboration and the panelists Raza Malik, MD, Rosana Kapeller, MD, PhD, and Jagpreet Chhatwal, PhD, for their perspectives, as well as Thomas J. Murtagh, a Founder and Managing Director at Clarion, for his support and many contributions.]