NASH: Still Waiting

Sabina Heinz and Elizabeth Baynton look at how the continued absence of approved products affecting the management of NASH patients.

In 2016, Ipsos wrote about the race to treat NASH and which pipeline therapies held the greatest promise for treating patients with this condition. Nearly three years on, with the likes of Intercept’s Ocaliva (OCA) yet to be approved and Gilead’s selonsertib trials recently terminated, what does the future hold for NASH treatment and how do physicians continue to manage this condition?

What is NASH and how is it diagnosed?

Nonalcoholic steatohepatitis (NASH) is the buildup of fat in the liver and, in addition, liver inflammation and hepatocyte injury. It is the most severe form of nonalcoholic fatty liver disease (NAFLD).¹ Whilst global prevalence of NAFLD is estimated at 25.24% (95% CI: 22.10-28.65),² the need for a biopsy for a definite diagnosis of NASH means that the exact incidence and prevalence of NASH cannot be estimated accurately. There are suggestions that the prevalence could be between 1.5% and 6.45% in the global population.² Guidelines now suggest to screen for NAFLD in high risk patients, i.e. those with obesity, type 2 diabetes, dyslipidemia, metabolic syndrome or polycystic ovary syndrome. However, even if screening reveals NAFLD, differentiating between the more benign nonalcoholic fatty liver (NAFL) and NASH remains difficult, as NASH can only be confirmed using a liver biopsy. Since liver biopsies are costly, carry the risk of serious complications and are often refused by patients, not all patients get biopsied; it is hard to find published data on how many patients actually undergo a biopsy specifically for the diagnosis of NASH, but physician perceptual data from our syndicated NASH Therapy Monitor suggests that around 45% of our sampled physicians’ patient caseload in the EU and 52% in the US, for whom NASH was suspected, were confirmed with a biopsy.³ Both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) have published guidelines to help physicians manage their NASH patients. There are also practice guidelines in conjunction with the AASLD to put them into context of treatment.⁴ Guidance documents provide recommendations on how to differentiate between NAFL and NASH in the diagnosis process and how to manage them; as accurate diagnosis of the condition still proves difficult, the first question is how many physicians across the EU and US are aware of the guidelines?

We have drawn insights from Ipsos’ Syndicated NASH Therapy Monitor in the EU5 and US to shed light on this specific question and more.

Awareness of NASH treatment guidelines

When asked if they currently reference, or are aware of, any guidelines for treating NAFLD/NASH, the answer from 73% and 59% of our sampled EU5 and US physicians, respectively, was ‘Yes’.³ Whilst there is no statistically significant difference between the percentage of gastroenterologists and hepatologists vs endocrinologists who are aware of these guidelines across both regions, in the EU5 specifically there is a significantly lower percentage of Internists/PCPs who are aware compared to their specialist counterparts (57% vs 76%, respectively).  

Before delving into the specifics of NASH patient management, this suggests two levels of initial disengagement in this disease space to be aware of: 1) a proportion of the treating community in general are not aware of guidelines, highlighting a primary unmet need, and 2) there is a disparity between different specialties treating the same patient type that could be further bridged.

Diagnosis and Classification of NASH by physicians

Guidelines recommend to biopsy a patient when NASH and/or advanced fibrosis is suspected. NASH is distinguished from NAFL by the presence of lobular or portal inflammation and ballooning, which can only be seen histologically. Physicians should check whether a patient is likely to have NASH and fibrosis by a series of noninvasive tests, such as FIB-4, APRI, NAFLD fibrosis score (NFS), and only perform a biopsy when these tests confirm there is a high risk for NASH.

Within our data, we see significant differences in both awareness of, and testing rate for, all four tests suggested by Rinella and Sanyal.⁵ 59% of our sampled physicians in EU5 and US state that they are aware of FIB-4, but only 14% say they are using it regularly for diagnosis. Whilst NFS has higher awareness than FIB-4 (79%), only 39% state they regularly use it to diagnose NASH. When focusing on the testing rates within the reported patient cohort specifically, 44% of patients of guideline-aware physicians across EU5 and US had undergone Fibroscan, vs 23% of those from physicians who were unaware. Similarly, a significantly higher proportion of patients treated by physicians not aware of the guidelines reported no NFS (53% in EU5/61% in US) compared to those treated by a physician aware of the guidelines (38% in EU5 and 32% in US). Interestingly, when comparing patients with these test results, we see almost identical proportions falling into intermediate risk (i.e. a NFS of -1.455-0.675) and high risk (i.e. a NFS above 0.675) categories, showing that there is no difference in the disease severity of patients treated by guideline-aware and guideline-unaware physicians.

Given the difference in the range of tests conducted which would help clarify the need for a biopsy, we then looked at the biopsy rates between the two samples. Amongst patients reported by our sampled US physicians, there was a significantly higher proportion of patients biopsied by physicians aware of the guidelines (61% vs 44%); the same disparity was not significantly prominent amongst our EU sample, potentially because of a lower propensity to perform biopsies in this region in general.

As confirmation of a NASH diagnosis is likely to be a prerequisite for payer approval – and this confirmation currently still hinges on a biopsy – there should be an understanding of which patients to biopsy to ensure that those who need urgent treatment for their NASH will be able to receive it promptly and those with lower risk do not undergo an unnecessary invasive procedure.

Current treatment of NASH

The guidance document from Chalasani et al.⁴ mentions several drug classes, with some degree of clinical information on the benefit (or lack thereof) of using these to treat NASH patients:  metformin, pioglitazones, GLP1 analogues, vitamin E and bariatric surgery.

Comparing treatment approaches between guideline-aware and guideline-unaware physicians and the treatments used in our data we do see some differences, but these are not always what one may expect. Metformin (although at some point recommended) is now no longer endorsed as it does not significantly improve liver health. However, amongst our US patient sample, a significantly higher proportion are more likely to be treated with this drug if they derive from physicians who are aware of guidelines vs. those who are unaware (45% vs 29% respectively). In EU5, 48% of patients receive it, regardless of physician guideline awareness. Pioglitazones, on the other hand, have shown benefits in improving liver values and fibrosis, although these are not without risk. Amongst our sampled patient data they are prescribed rarely, but significantly more frequently by guideline-aware physicians vs. the unaware cohort (6% vs 2% in EU5, and 10% vs 6% in the US, respectively).

Vitamin E has also shown liver benefits in some NASH patients, and again, here we see differences. A greater number of patients receive Vitamin E if they are treated by a guideline-aware physician (22% vs 14% in EU5 and 46% vs 33% in the US).

Bariatric surgery is rare but has shown benefits in the outcomes of NASH for some patients. Within our US dataset, it is interesting to note there are more patients considered for bariatric surgery (35%) who are managed by guideline-aware physicians vs. those unaware (30%).

It is difficult to draw sound conclusions regarding the use of GLP1 inhibitors in NASH patients in our data; whilst we see usage of them they are focused within the diabetic cohort, so any differences cannot be attributed to the treatment intent for NASH specifically. However, these therapies are in clinical trials for NASH and awareness of them amongst our sampled physicians is notable; 60% in the EU5 and 54% in the US were aware of liraglutide. That brings us to our final thoughts: what does the future hold for the treatment of NASH?

What the future holds

Despite there being an active therapy pipeline in NASH, the marketplace is yet to see approval of a product specifically to treat this condition. Intercept’s hotly tipped Ocaliva (OCA) is currently in phase III trials, with a primary completion date not expected until July 2020,⁶ whilst Gilead recently discontinued its STELLAR-4 trials for the ASK-1 inhibitor selonsertib.⁷ Other phase III hopefuls include Genfit’s elafibranor and Allergan’s cenicriviroc, with Madrigal planning to initiate their first-in-class, thyroid hormone receptor (THR) beta-selective agonist, MGL-3196, into phase III trials following favorable phase II data.⁸ As different trials have different endpoints, whether it is fibrosis improvement, resolution of NASH, or both, it will be interesting to monitor how this difference could shape the future of defined treatment of these patients.⁹

Conclusion

The NASH treatment market currently features an array of disconnects: gaps in awareness of management guidelines, inconsistent methods of identifying NASH patients, a lack of noninvasive tests that could provide a definitive diagnosis of NASH and an ongoing wait for dedicated and effective treatments. As NASH is a relatively ‘new’ disease, it may be understandable that not all physicians are aware of relevant patient management guidelines yet. However, the benefit of this knowledge is clear when we look at the differences in management approach by physicians aware vs those not aware. Before even considering which drug would be most beneficial to bring to market, this highlights a pertinent opportunity for supportive bridges to be built with the treating community in order to facilitate informed evaluation procedures to both identify and treat NASH patients. Once arriving at the treatment stage, given the number of comorbidities the average NASH patient has (and with this a high pill burden), a successful drug also needs to be well tolerated and without drug-drug interactions.

In our last paper we concluded that the winner in the NASH race would not necessarily be the first drug to market, but the first that can demonstrate the best outcome. Three years on, it is clear that there is more to consider and that meaningful NASH outcomes on their own are not enough. Supporting the physician community with a more streamlined, informed and consistent patient diagnosis and management process, as well as adopting a more patient-centric approach, may all contribute to crossing the finish line first.

About the Research

Patient treatment management patterns were investigated using EU5 and US data from the Ipsos Global NASH Therapy Monitors^©, which is a proprietary syndicated patient record database. Specifically, physicians reported on their most recent NASH patients (regardless of biopsy) seen in consultation during the study period. Physicians who participated in the Therapy Monitors were required to treat a minimum number of NASH patients in a typical month and be the treatment decision maker for these patients. Dates and sample sizes are given below, and all research was conducted online. All results cited were tested for significance using Pearson’s chi-squared test; all results were significant at a threshold level of p<0.05. Data are copyright Ipsos 2019, all rights reserved. 

Dr. Sabina Heinz is Research Director at Ipsos Healthcare. Elizabeth Baynton is Associate Director at Ipsos Autoimmune Therapy Monitors.

References

• Nonalcoholic Steatohepatitis (NASH) | Stanford Health Care. 2019. Nonalcoholic Steatohepatitis (NASH) | Stanford Health Care. [ONLINE] Available at: https://stanfordhealthcare.org/medical-conditions/liver-kidneys-and-urinary-system/nonalcoholic-steatohepatitis-nash.html. [Accessed 4^th April 2019].

• Younossi, Z. et al., 2016. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology, 64/1, 73-84.

• Ipsos NASH Therapy Monitor (478 sampled gastros/heps/endos/PCPs reporting on a predefined quota of NASH patients across the EU5 and US in Q3 2017)

• Chalasani, N. et al., 2018. The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases. Hepatology, 67/1, 328-357.

• Rinella ME, Sanyal AJ., 2016. Management of NAFLD: a stage-based approach. Nature Reviews Gastroenterology & Hepatology, 13, 196-205.

• Study Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis - Full Text View - ClinicalTrials.gov. 2019. Study Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects With Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis - Full Text View - ClinicalTrials.gov. [ONLINE] Available at: https://clinicaltrials.gov/ct2/show/NCT03439254?term=OCA&cond=NASH+-+Nonalcoholic+Steatohepatitis&rank=1. [Accessed 4^th April 2019]

• FierceBiotech. 2019. Gilead rocked by phase 3 failure of selonsertib in NASH | FierceBiotech. [ONLINE] Available at: https://www.fiercebiotech.com/biotech/gilead-rocked-by-phase-3-failure-selonsertib-nash. [Accessed 4^th April 2019].

• Madrigal Pharmaceuticals. 2019. Madrigal Pharmaceuticals. [ONLINE] Available at: https://www.madrigalpharma.com/ourapproach/mgl3196/. [Accessed 4^th April 2019].

• BioPharma Dive. 2019. At JPM, the NASH flood gates start to crack | BioPharma Dive . [ONLINE] Available at: https://www.biopharmadive.com/news/nash-2019-jpm-readouts-deals-market-competition/545772/. [Accessed 4^th April 2019].