NEWS & VIEWS NASH
could be given. The phase I trial data dem‑ onstrated that blood TNF levels decreased as expected (on the basis of the known role of PDE4 in reducing inflammation).4 TNF levels reached a nadir in healthy individuals 1–2 h after dosing, with a rebound back to baseline by 4 h after the 50 mg or 100 mg doses. Higher doses resulted in more sustained reductions but unfortunately these doses were not tol‑ erated because of gastrointestinal adverse effects. Although the doses used were con‑ sidered adequate on the basis of preclinical animal experiments, such extrapolations are challenging at best. Furthermore, the finding that TNF levels dropped in healthy individuals treated with this drug raises the possibility that the primary effect of this drug in humans is on adipose tissue TNF produc‑ tion, as this tissue might be the primary source of basal TNF. This factor is not irrel‑ evant given that proinflammatory signal ling between the liver and adipose tissue might have an important role in NASH. This consideration highlights the importance of choosing appropriate animal models for preclinical testing.
The tribulations of conducting NASH trials Brent A. Neuschwander-Tetri
Designing clinical trials for the treatment of NASH is challenging. The pathogenesis of this disease is poorly understood and is probably multifactorial. A trial of a phosphodiesterase‑4 inhibitor produced negative results, despite promising preclinical data. Examining why this trial failed might help us design better trials of treatments for NASH in the future. Neuschwander-Tetri, B. A. Nat. Rev. Gastroenterol. Hepatol. advance online publication 8 April 2014; doi:10.10.38/nrgastro.2014.51
Finding effective preventive and therapeutic strategies for NASH is the next major thera‑ peutic challenge in eliminating the burden of liver disease worldwide. The past two decades have brought us remarkable progress in treat‑ ing viral hepatitis and other liver diseases, but during this same period we have witnessed a steady increase in the prevalence of cir‑ rhosis and hepatocellular carcinoma caused by NASH.1,2 Lifestyle modification with a focus on healthy eating habits and increased physical activity remains the cornerstone of NASH treatment. However, these modi‑ fications are difficult to achieve for many patients, and pharmacological therapies are needed to prevent a new epidemic of cirrho‑ sis and liver cancer. Unfortunately, designing and conducting trials of drugs to treat NASH is difficult.3 A clinical trial of a promising therapeu‑ tic agent for NASH demonstrates some of the challenges in finding effective drugs for this major liver disease. Ratziu et al.4 tested the phosphodiesterase‑4 (PDE4) inhibitor ASP9831 in a phase I trial and then in patients with NASH in a placebocontrolled randomized controlled phase II trial. These trials were undertaken because of the anti-inflammatory effects of PDE4 inhibitors5 and promising results in pre‑ clinical animal and cell culture studies. Unfortunately, no benefits of ASP9831 on ALT (alanine aminotransferase) levels and other markers of NASH and inflammation were found after completing 12 weeks of treatment when compared with placebo. Given that well-designed clinical trials such as this one require a substantial investment
of time, energy and resources by inves‑ tigators, sponsors and patients, negative studies deserve careful retrospective analy‑ sis to determine how similar experiences might be avoided in the future;6 some issues might have been specific to this trial, but broader issues regarding NASH trials are also worth considering. For this particular drug, one might ques‑ tion if the appropriate dose was given or Fatty acid metabolism
Bile acids
Steatosis
Inflammation
Hepatic insulin resistance
Gut microbiome
? Hepatocyte ballooning
Lipotoxicity
Adipose inflammation
Dietary components
Cholesterol
Adipose insulin resistance
Figure 1 | Developing therapeutic agents for NASH is challenging because of uncertainty about which abnormalities are the best targets. A recent trial of a phosphodiesterase‑4 inhibitor that targets inflammation was negative. Whether this result was due to using an inadequate dose of the drug or mis-targeting inflammation as an essential mechanism of the disease is uncertain. Negative trials such as this can be important for our understanding of the disease and designing future trials.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
ADVANCE ONLINE PUBLICATION | 1
NEWS & VIEWS Animal models of disease will never be perfect for understanding disease patho genesis. For example, diseases such as NASH develop and progress over decades but by practical necessity, every effort is usually made to compress the time course of animal experiments into weeks or months. The best animal models of NASH reproduce the pri mary histological features of NASH in the setting of obesity, insulin resistance and other features of the metabolic syndrome.7–9 For the preclinical testing of the PDE4 inhibitor used in this trial, three models of liver injury were used. Perhaps an important lesson from this negative trial was that the three models— D-galactosamine + lipopolysaccharide, con canavalin A and the methionine–choline deficient diet—can produce liver injury with or without steatosis, but not with the appro‑ priate pathophysiologic milieu of the meta‑ bolic syndrome with obesity and adipose tissue insulin resistance. Inflammation might have a more dominant role in liver injury in these models than might be true in human NASH and thus might have given false hopes for agents targeting i nflammation, such as the PDE4 inhibitor. Selecting the best end points for NASH trials remains challenging.3 Improvement in ALT elevations over 12–24 weeks of treat‑ ment is considered an adequate surrogate for phase II studies such as this trial, but liver histology remains the best predictor of pro‑ gression to cirrhosis, death and liver trans‑ plant over time. No treatment trial has yet shown improvement in histology without improvement in ALT levels compared with baseline and thus the observation that ALT levels did not improve after 12 weeks of drug treatment can be interpreted to mean
that the liver histology was also not going to improve. Finally, we need a better understanding of the pathogenesis of NASH to rationally design and appropriately interpret clinical trials.10 NASH is currently diagnosed by a histological phenotype in the appropriate clinical setting (lack of alcohol abuse) and might be the outcome of multiple patho‑ physiological processes and genetic pre dispositions present to varying degrees in different individuals but resulting in a common histological phenotype. Perhaps someday the term NASH will be abandoned as specific underlying causes are identified and subsets are named accordingly, just as the term chronic active hepatitis was abandoned as we understood more about hepatitis C, autoimmune hepatitis and the other entities that comprised that prior phenotypic diagno‑ sis based on liver histology. The multifactorial pathogenesis of NASH has major implica‑ tions for the rational design of treatments that target specific environmental, metabolic and genetic abnormalities (Figure 1). Until we identify and understand these factors, we must continue in the search for treatments while being cognizant of these shortcomings. An unfortunate consequence of this reality is that an agent such as the PDE4 inhibitor could be the perfect drug for a small minority of patients with NASH, but this finding might be lost in the data analysis of an entire group. Until we have enough knowledge to stratify patients according to pathophysiological mechanisms, we cannot change this reality. In the field of liver disease we now face a remarkably challenging adversary in the form of NASH, which is proving to be a major cause of progressive liver disease in
2 | ADVANCE ONLINE PUBLICATION
children and adults. We must push forward with clinical trials despite our lack of a com‑ plete understanding of its causes. Hopefully through good trial design and careful retro‑ spective analysis of our successes and failures, these trials will continue to contribute to our understanding of NASH. Saint Louis University, 3635 Vista Ave, Saint Louis, MO 63105, USA. [email protected] Competing interests B.A.N.-T. acts as an advisor for Boehringer-Ingelheim, Genentech/Roche and Nimbus, and was an advisor for Astellas when trials of ASP9831 were being considered in 2010–2011. 1.
Welsh, J. A., Karpen, S. & Vos, M. B. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988–1994 to 2007–2010. J. Pediatr. 162, 496–500.e491 (2013). 2. Loomba, R. & Sanyal, A. J. The global NAFLD epidemic. Nat. Rev. Gastroenterol. Hepatol. 10, 686–690 (2013). 3. Sanyal, A. J. et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 54, 344–353 (2011). 4. Ratziu, V. et al. Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. http://dx.doi.org/ 10.1016/j.cgh.2014.01.040. 5. Spina, D. PDE4 inhibitors: current status. Br. J. Pharmacol. 155, 308–315 (2008). 6. Hayes, A. & Hunter, J. Why is publication of negative clinical trial data important? Br. J. Pharmacol. 167, 1395–1397, (2012). 7. Hebbard, L. & George, J. Animal models of nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 8, 35–44 (2011). 8. Maher, J. J. New insights from rodent models of fatty liver disease. Antioxid. Redox. Signal. 15, 535–550 (2011). 9. Stärkel, P. & Leclercq, I. A. Animal models for the study of hepatic fibrosis. Baillieres Best Pract. Res. Clin. Gastroenterol. 25, 319–333 (2011). 10. Michelotti, G. A., Machado, M. V. & Diehl, A. M. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656–665 (2013).
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
could be given. The phase I trial data dem‑ onstrated that blood TNF levels decreased as expected (on the basis of the known role of PDE4 in reducing inflammation).4 TNF levels reached a nadir in healthy individuals 1–2 h after dosing, with a rebound back to baseline by 4 h after the 50 mg or 100 mg doses. Higher doses resulted in more sustained reductions but unfortunately these doses were not tol‑ erated because of gastrointestinal adverse effects. Although the doses used were con‑ sidered adequate on the basis of preclinical animal experiments, such extrapolations are challenging at best. Furthermore, the finding that TNF levels dropped in healthy individuals treated with this drug raises the possibility that the primary effect of this drug in humans is on adipose tissue TNF produc‑ tion, as this tissue might be the primary source of basal TNF. This factor is not irrel‑ evant given that proinflammatory signal ling between the liver and adipose tissue might have an important role in NASH. This consideration highlights the importance of choosing appropriate animal models for preclinical testing.
The tribulations of conducting NASH trials Brent A. Neuschwander-Tetri
Designing clinical trials for the treatment of NASH is challenging. The pathogenesis of this disease is poorly understood and is probably multifactorial. A trial of a phosphodiesterase‑4 inhibitor produced negative results, despite promising preclinical data. Examining why this trial failed might help us design better trials of treatments for NASH in the future. Neuschwander-Tetri, B. A. Nat. Rev. Gastroenterol. Hepatol. advance online publication 8 April 2014; doi:10.10.38/nrgastro.2014.51
Finding effective preventive and therapeutic strategies for NASH is the next major thera‑ peutic challenge in eliminating the burden of liver disease worldwide. The past two decades have brought us remarkable progress in treat‑ ing viral hepatitis and other liver diseases, but during this same period we have witnessed a steady increase in the prevalence of cir‑ rhosis and hepatocellular carcinoma caused by NASH.1,2 Lifestyle modification with a focus on healthy eating habits and increased physical activity remains the cornerstone of NASH treatment. However, these modi‑ fications are difficult to achieve for many patients, and pharmacological therapies are needed to prevent a new epidemic of cirrho‑ sis and liver cancer. Unfortunately, designing and conducting trials of drugs to treat NASH is difficult.3 A clinical trial of a promising therapeu‑ tic agent for NASH demonstrates some of the challenges in finding effective drugs for this major liver disease. Ratziu et al.4 tested the phosphodiesterase‑4 (PDE4) inhibitor ASP9831 in a phase I trial and then in patients with NASH in a placebocontrolled randomized controlled phase II trial. These trials were undertaken because of the anti-inflammatory effects of PDE4 inhibitors5 and promising results in pre‑ clinical animal and cell culture studies. Unfortunately, no benefits of ASP9831 on ALT (alanine aminotransferase) levels and other markers of NASH and inflammation were found after completing 12 weeks of treatment when compared with placebo. Given that well-designed clinical trials such as this one require a substantial investment
of time, energy and resources by inves‑ tigators, sponsors and patients, negative studies deserve careful retrospective analy‑ sis to determine how similar experiences might be avoided in the future;6 some issues might have been specific to this trial, but broader issues regarding NASH trials are also worth considering. For this particular drug, one might ques‑ tion if the appropriate dose was given or Fatty acid metabolism
Bile acids
Steatosis
Inflammation
Hepatic insulin resistance
Gut microbiome
? Hepatocyte ballooning
Lipotoxicity
Adipose inflammation
Dietary components
Cholesterol
Adipose insulin resistance
Figure 1 | Developing therapeutic agents for NASH is challenging because of uncertainty about which abnormalities are the best targets. A recent trial of a phosphodiesterase‑4 inhibitor that targets inflammation was negative. Whether this result was due to using an inadequate dose of the drug or mis-targeting inflammation as an essential mechanism of the disease is uncertain. Negative trials such as this can be important for our understanding of the disease and designing future trials.
NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY © 2014 Macmillan Publishers Limited. All rights reserved
ADVANCE ONLINE PUBLICATION | 1
NEWS & VIEWS Animal models of disease will never be perfect for understanding disease patho genesis. For example, diseases such as NASH develop and progress over decades but by practical necessity, every effort is usually made to compress the time course of animal experiments into weeks or months. The best animal models of NASH reproduce the pri mary histological features of NASH in the setting of obesity, insulin resistance and other features of the metabolic syndrome.7–9 For the preclinical testing of the PDE4 inhibitor used in this trial, three models of liver injury were used. Perhaps an important lesson from this negative trial was that the three models— D-galactosamine + lipopolysaccharide, con canavalin A and the methionine–choline deficient diet—can produce liver injury with or without steatosis, but not with the appro‑ priate pathophysiologic milieu of the meta‑ bolic syndrome with obesity and adipose tissue insulin resistance. Inflammation might have a more dominant role in liver injury in these models than might be true in human NASH and thus might have given false hopes for agents targeting i nflammation, such as the PDE4 inhibitor. Selecting the best end points for NASH trials remains challenging.3 Improvement in ALT elevations over 12–24 weeks of treat‑ ment is considered an adequate surrogate for phase II studies such as this trial, but liver histology remains the best predictor of pro‑ gression to cirrhosis, death and liver trans‑ plant over time. No treatment trial has yet shown improvement in histology without improvement in ALT levels compared with baseline and thus the observation that ALT levels did not improve after 12 weeks of drug treatment can be interpreted to mean
that the liver histology was also not going to improve. Finally, we need a better understanding of the pathogenesis of NASH to rationally design and appropriately interpret clinical trials.10 NASH is currently diagnosed by a histological phenotype in the appropriate clinical setting (lack of alcohol abuse) and might be the outcome of multiple patho‑ physiological processes and genetic pre dispositions present to varying degrees in different individuals but resulting in a common histological phenotype. Perhaps someday the term NASH will be abandoned as specific underlying causes are identified and subsets are named accordingly, just as the term chronic active hepatitis was abandoned as we understood more about hepatitis C, autoimmune hepatitis and the other entities that comprised that prior phenotypic diagno‑ sis based on liver histology. The multifactorial pathogenesis of NASH has major implica‑ tions for the rational design of treatments that target specific environmental, metabolic and genetic abnormalities (Figure 1). Until we identify and understand these factors, we must continue in the search for treatments while being cognizant of these shortcomings. An unfortunate consequence of this reality is that an agent such as the PDE4 inhibitor could be the perfect drug for a small minority of patients with NASH, but this finding might be lost in the data analysis of an entire group. Until we have enough knowledge to stratify patients according to pathophysiological mechanisms, we cannot change this reality. In the field of liver disease we now face a remarkably challenging adversary in the form of NASH, which is proving to be a major cause of progressive liver disease in
2 | ADVANCE ONLINE PUBLICATION
children and adults. We must push forward with clinical trials despite our lack of a com‑ plete understanding of its causes. Hopefully through good trial design and careful retro‑ spective analysis of our successes and failures, these trials will continue to contribute to our understanding of NASH. Saint Louis University, 3635 Vista Ave, Saint Louis, MO 63105, USA. [email protected] Competing interests B.A.N.-T. acts as an advisor for Boehringer-Ingelheim, Genentech/Roche and Nimbus, and was an advisor for Astellas when trials of ASP9831 were being considered in 2010–2011. 1.
Welsh, J. A., Karpen, S. & Vos, M. B. Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988–1994 to 2007–2010. J. Pediatr. 162, 496–500.e491 (2013). 2. Loomba, R. & Sanyal, A. J. The global NAFLD epidemic. Nat. Rev. Gastroenterol. Hepatol. 10, 686–690 (2013). 3. Sanyal, A. J. et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 54, 344–353 (2011). 4. Ratziu, V. et al. Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. http://dx.doi.org/ 10.1016/j.cgh.2014.01.040. 5. Spina, D. PDE4 inhibitors: current status. Br. J. Pharmacol. 155, 308–315 (2008). 6. Hayes, A. & Hunter, J. Why is publication of negative clinical trial data important? Br. J. Pharmacol. 167, 1395–1397, (2012). 7. Hebbard, L. & George, J. Animal models of nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 8, 35–44 (2011). 8. Maher, J. J. New insights from rodent models of fatty liver disease. Antioxid. Redox. Signal. 15, 535–550 (2011). 9. Stärkel, P. & Leclercq, I. A. Animal models for the study of hepatic fibrosis. Baillieres Best Pract. Res. Clin. Gastroenterol. 25, 319–333 (2011). 10. Michelotti, G. A., Machado, M. V. & Diehl, A. M. NAFLD, NASH and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 10, 656–665 (2013).
www.nature.com/nrgastro © 2014 Macmillan Publishers Limited. All rights reserved
