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With the NASH pipeline filling up fast, Mariel Metcalfe looks at what pharma companies need to do to ensure their products do not end up as also-rans in this dynamic new market segment.
A serious disease that is often invisible, poorly understood and inconsistently diagnosed, non-alcoholic steatohepatitis (NASH) presents significant challenges for patients and healthcare systems. It also creates multiple opportunities for the pharmaceutical industry, as evidenced by the rich development pipeline for the disease. Getting these compounds successfully to market, though, will require close understanding of patient experiences, characteristics and needs in the NASH space.
NASH is an advanced form of non-alcoholic fatty liver disease (NAFLD), in which accumulation of fat in the liver, for reasons most commonly associated with obesity, insulin resistance, metabolic syndrome and/or genetic polymorphisms, is aggravated by inflammation and fibrosis. It’s a progressive disease, with an estimated 10% of patients developing decompensated liver disease (where liver scarring is so severe that the organ starts to fail) over a 13-year period, and 25% progressing to cirrhosis over nine years. Once decompensation occurs, median survival is estimated at around two years. NASH is also associated with increased risk of complications such as liver cancer and cardiovascular disease. The disease was first identified in the 1980s. Since then, its prevalence has grown rapidly in line with that of NAFLD[MM1] , now one of the most common liver diseases worldwide. These trends reflect a growing epidemic of type 2 diabetes and obesity worldwide. One recent meta-analysis found the global prevalence of NAFLD to be around 25%, while the global prevalence of NASH is estimated at 3-5%.
In a country such as the US, where over two in three adults are considered overweight or obese, and 9.4% of the population has diabetes, the risk of developing NASH rises significantly. According to one estimate, around 20% of the US population has NAFLD and 3.5-5% of those patients have progressed to NASH.
In the absence of any licensed pharmacological options, physicians generally recommend weight loss through dietary and lifestyle changes as the first line of treatment for NASH. Once the condition progresses to end-stage disease, the only real option is a liver transplant.
A wide range of compounds targeting different stages and components of NASH (e.g., metabolic, fibrotic, inflammatory), as well as different disease pathways and receptors, are vying for a piece of what could eventually be a $20 billion to $35 billion market worldwide.
Four of these drug candidates are already in Phase III clinical trials and over 20 are in Phase II clinical trial development. Dr. Jean-François Dufour, the head of hepatology and director of the University Clinic for Visceral Surgery and Medicine at the University of Bern (Switzerland) said at the International Liver Congress in May that there is such a range of options which target different pathways, from fatty acid and bile acid synthesis to the early and late stages of fibrosis, that it is very likely these drugs will be used in combination.
Judging by the investment flow into NASH-related R&D, it could turn out to be a crowded marketplace. Therefore, clearly defined, patient-centric value propositions may be crucial determinants of commercial success for NASH therapies.
A study recently conducted by Research Partnership amongst 108 patients in the US reveals some interesting findings about the characteristics, unmet needs and management approaches of people living with NASH. Respondents in the study included both NAFLD and NASH-confirmed patients with varying levels of liver fibrosis from F0 through to F4 with the majority F2-F3, providing a snapshot of all potential patients on the path to NASH. Patients are generally young to middle-aged (average age at diagnosis: 46 years), with longstanding comorbidities – in particular, excess weight or obesity; high blood pressure; high cholesterol: and type-2 diabetes. Patients typically have three comorbidities on average, and 30% are unable to work due to health problems.
Despite this heavy burden of disease, half of all patients are asymptomatic. If NASH-associated symptoms are present, such as fatigue or weakness, they overlap with co-morbidities. Only a minority of patients, generally those with more advanced fibrosis and cirrhosis, have explicitly NASH-related symptoms.
As a result, in most cases the diagnosis of NASH is unexpected. Half of the patients are seeing their doctor about another condition when the issue arises. Coupled with the speed of diagnosis (usually within one month), the way it is handled (sometimes insensitively), and the lack of information on NASH, leave patients feeling worried, overwhelmed and confused.
There is also a residue of guilt over failure to address the diet and lifestyle problems associated with NASH, exacerbated by concern that the condition will be attributed to alcoholism or drug abuse. The focus at diagnosis tends to be on excess weight as a cause: 26% of patients were told initially that their weight was to blame for NASH.
Fear of disease progression is a particular source of anxiety, especially among patients without any liver fibrosis, and fear of liver cancer is a stress inducer for over half of non-fibrotic and cirrhotic patients alike. Patients with some fibrosis are much more worried about having a liver transplant than non-fibrotic or cirrhotic patients with NASH.
NASH patients are typically diagnosed with blood tests ultrasound and liver biopsies. Biopsy diagnosis is markedly higher for fibrotic and cirrhotic than for non-fibrotic patients. Cost is also a significant factor (over three times the number of insured patients is given biopsies than those who are uninsured). Of those patients who do not have a liver biopsy, the vast majority are not offered one.
Patients experience anxiety and confusion at diagnosis mainly due to the lack of information provided about NASH, and the worry that the condition could worsen and lead to cirrhosis or liver cancer. Most patients expect to be informed about possible treatments, but with no pharmacological options available, recommended management approaches centre mainly on lifestyle adjustments, such as a healthier diet, losing weight, exercise or reducing alcohol intake.
Many patients want to know more about their condition and how to deal with it. Almost three quarters of patients would like more information at diagnosis, particularly on the causes of NASH, lifestyle guidance and treatment options. Treatment options only come up in a third of consultations, with more detail given to patients who are partially fibrotic or cirrhotic. In contrast to most chronic illnesses, more patients are seeking information about NASH online than from their doctor or family/friends. Knowledge of the disease is patchy, though. Only a third of interviewees refer to their condition as NASH, while the remainder talk about NAFLD/fatty liver. Even among patients with fibrosis, the terms NAFLD or fatty liver are used more frequently than NASH and the same applies to cirrhotic patients.
These findings offer a number of pointers for pharmaceutical companies with NASH therapies in the pipeline.
One is that patients are looking for treatment options, particularly as an already heavy disease burden and reluctance to make lifestyle changes may complicate efforts to manage NASH through dietary or lifestyle changes alone. When asked about how NASH management should be improved, 41% of survey participants want to see better treatments and 31% want new treatments tackling the root causes of the disease. Earlier diagnosis and non-surgical/better screening tools for NASH are also important to patients.
New diagnostic tests (particularly non-invasive ones) under development for NASH could help physicians pick up the disease at an earlier stage. This would also give companies opportunities to explore drug-diagnostic combinations as a lever for treatment selection. Companies should also bear in mind that the disease is being managed by a range of physician types – hepatologists and gastroenterologists will likely confirm the diagnosis; endocrinologists and diabetologists will see the diabetic patients who may go on to develop NASH; PCPs often manage long-term patients with less fibrosis (FO/F1) in order to observe progression. Consequently, pharma companies will need to manage and understand the needs of a range of different HCPs and the patients under their individual care.
Information, communication and awareness, especially at and prior to diagnosis, will remain critical in shaping the emerging NASH market. More patients want a better understanding of the condition’s impact on their life and health than any other potential improvements to NASH management. In terms of potential support from companies, patients are looking for educational materials to better understand the treatment options for NASH and for materials that will help them understand the condition more. ‘Beyond the pill’, patient-centric support, such as websites, patient forums or mobile apps to encourage engagement in diet and exercise would go a long way to helping the growing groups of patients in this emerging category.
Better/earlier diagnosis, coupled with improved education and awareness, should help to identify patients at different stages of NASH and understand how their needs differ – not just in terms of alternative disease pathways but in addressing the whole treatment paradigm.
These considerations will help to build compelling platforms for patient segmentation and product differentiation, either in monotherapy or in combination. With the NASH pipeline filling up fast, companies need to ensure their products do not end up as also-rans in a dynamic new market segment for the industry.
Mariel Metcalfe is Head of Living With at Research Partnership.
 Living with NASH is a syndicated report based on quantitative market research with 108 Non-alcoholic steatohepatitis and Non-alcoholic fatty liver disease (NAFLD) patients based in the USA. 41 patients were non-cirrhotic, no scarring; 53 patients were non-cirrhotic, some scarring; 14 patients were cirrhotic. The interviews were conducted May-July 2017.