Issue: January 2021
Disclosures: Harrison reports being scientific advisor or consultant for Akero, Alentis, Altimmune, Arrowhead, Axcella, Canfite, Cirius, CiVi Biopharma, Cymabay, Echosens, Fibronostics, Forest Labs, Galectin, Genfit, Gilead, Hepion, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Liminal, Ridgeline, Sagiment, Terns, Viking, 89 Bio; has stock options in Akero, Cirius, Galectin, Genfit, Hepion, HistoIndex, PathAI, Metacrine, NGM Bio, Northse and receives grant/research support from Akero, Axcella, BMS, Cirius, CiVi Biopharma, Conatus, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Sagimet and Viking.
January 15, 2021
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NASH: A pandemic with an unmet need for pharmacotherapies

Issue: January 2021
Disclosures: Harrison reports being scientific advisor or consultant for Akero, Alentis, Altimmune, Arrowhead, Axcella, Canfite, Cirius, CiVi Biopharma, Cymabay, Echosens, Fibronostics, Forest Labs, Galectin, Genfit, Gilead, Hepion, HistoIndex, Intercept, Madrigal, Medpace, Metacrine, NGM Bio, Northsea, Novartis, Novo Nordisk, PathAI, Poxel, Liminal, Ridgeline, Sagiment, Terns, Viking, 89 Bio; has stock options in Akero, Cirius, Galectin, Genfit, Hepion, HistoIndex, PathAI, Metacrine, NGM Bio, Northse and receives grant/research support from Akero, Axcella, BMS, Cirius, CiVi Biopharma, Conatus, Cymabay, Enyo, Galectin, Genentech, Genfit, Gilead, Hepion, Hightide, Intercept, Madrigal, Metacrine, NGM Bio, Novartis, Novo Nordisk, Northsea, Pfizer, Sagimet and Viking.
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There is a significant medical need to find effective pharmacotherapies to manage NASH, the liver disease that is really a pandemic.

Stephen A. Harrison
Stephen A. Harrison

The COVID pandemic firmly highlights the fact that liver disease is a big problem in our world, not just the U.S., as noted by the fact that patients with fatty liver disease do worse when infected with COVID-19. It’s interesting how that’s brought some light to fatty liver disease in the setting of this pandemic that we’re dealing with. But when we talk about treatments for NASH, there are three main target areas: the metabolic aspect, the inflammatory component and the fibrotic component. Understanding from a metabolic perspective how you get fat in the liver is important because at that point we can begin to build therapies that prevent that from occurring.

Farnesoid X Receptors

The FXR class was the first drug studied in NASH. Intercept Therapeutics led the way with obeticholic acid. The company completed its phase 3 trial and is still following patients in that trial toward the final endpoint, which is how well patients do; did researchers prevent the progression to cirrhosis, decompensation, death and liver transplant.

But to get FDA approval or conditional approval to use the drug, there needs to be improvements in fibrosis by at least 1 stage without worsening of NASH or NASH resolution without worsening fibrosis. Obeticholic acid met its primary endpoint on fibrosis improvement without worsening of NASH, however, the FDA did not approve the drug. The FDA noted concern with the risk–benefit ratio. They did leave the door open to further dialogue pending further information.

Peroxisome Proliferator-activated Receptor Gamma Agonist

PPAR gamma agonists do a very good job of reducing peripheral insulin resistance and have shown positive impact on liver pathology. However, PPAR gamma has developed a bad reputation because it leads to water weight gain and potential unmasking of heart failure. It seems to have been relegated to the back seat in many ways, but there are newer agents that led researchers to look at this in a slightly different way. One of those agents, PXL065 (Poxel), is in phase 2 development now. There is also lanifibranor (Inventiva), a pan-PPAR agonist. It has activity against alpha, delta and gamma and it showed very positive impacts on histopathology at 24 weeks of treatment. However, there was some weight gain associated with the highest dose of 1,200 mg but it didn’t tend to be linked necessarily to water weight gain, and we know that people who improve insulin resistance also tend to gain a little weight. The trial is moving into phase 3 and we’re hopeful that it will maintain its positive impact without the additional negative impact of weight gain.

Fibroblast Growth Factor 21

FGF21 drugs modulate liver fat content, in part by impacting lipolysis. Now there are multiple drugs that modulate or agonize the hormone FGF21; in fact, there are at least five of them currently in development. They’re not all created equal. So, these drugs work by modulating FGF1, 2 and 3 and they do it with different degrees of potency.

There’s another drug that modulates FGF19, it’s an FGF19 analogue. It showed positive results on liver fat content, serum aminotransferases and histopathology and we expect in 2021 a read-out using additional doses of that drug, one lower dose, one higher dose in non-cirrhotic NASH patients treated for 24 weeks.

GLP-1 Agonists

Researchers of semaglutide (Ozempic, Novo Nordisk) shared data from a very large phase 2b trial in 320 patients treated for 18 months at the recent AASLD meeting, showing positive results on NASH resolution. However, it didn’t hit the endpoint of fibrosis improvement. Further analysis is underway to better understand this result.

Additional Metabolic Targets

There are thyroid hormone receptor beta class drugs that may improve mitochondrial health and beta-oxidation of fatty acids and early studies show positive impacts on both non-invasive tests and histopathology. Researchers are also studying drugs that modulate de novo lipogenesis. At the recent AASLD meeting, we saw early data from a fatty acid synthase inhibitor (FASN inhibitor). It was a noninvasive short-term trial: there were no biopsy data included, but it did have very positive results on some of the noninvasive tests to include liver fat content and liver enzymes.

Drugs That Modulate Inflammatory Pathways

There are also drugs in development that work predominantly on inflammatory pathways that are upregulated in NASH. Investigators are currently enrolling participants into a large phase 2b trial designed to assess the safety and efficacy of a JNK inhibitor.

Drugs That Modulate Fibrosis

CRV431 is a pan-cyclophilin inhibitor that is an oral agent given once a day and in preclinical data showed positive impacts on fibrosis regression. Researchers are in the middle of an early phase human trial right now, what we call a phase 1b study, and we’re anxious in 2021 to see the results on some of the noninvasive tests of fibrosis in patients with NASH and fibrosis.

Another compound in later stage development is Belapectin, an inhibitor of galectin-3. This is given by intravenous infusion every two weeks and in a phase 2b study it showed it may prevent the development of esophageal varices in patients with late stage NASH. Investigators of the drug are now enrolling well compensated NASH cirrhotic participants in an adaptive phase 2b/3 study.

Combination Therapy

We’re going to end up going with combination therapy and we’re anxious to see what different combinations of NASH drugs would do. Because of the nature of this disease, there are multiple pathways that can led to dysregulated energy metabolism within the hepatocyte that results in the histopathologic findings that we call NASH and fibrosis. Subsequently, it is thought that the optimal therapy will be one that combines different mechanisms of action. By doing so, we can accentuate the histopathologic response on both NASH resolution as well as on fibrosis.

What’s to Come in 2021

Intercept is planning on refiling their new drug application although they receive a CRL from the FDA on obeticholic acid. There is an opportunity in 2021 to get a treatment for NASH with an obeticholic acid, but it’s not a guarantee. If this agent is not approved, I would look to 2023 for the first opportunity for the next drug to receive conditional approval.