7:27 PM
Nov 02, 2018
 |  BioCentury  |  Product Development

New partners for NASH

New NASH targets and combinations will be in the spotlight at this year’s AASLD

Pharmas are loading up their NASH portfolios expecting that addressing the full disease spectrum will require combinations, though the field lacks the tools to sort the different mechanisms on offer strategically.

Meanwhile, at least three companies presenting at this year’s American Association for the Study of Liver Diseases (AASLD) meeting will have proof-of-concept data from new targets that could add to the clinical armamentarium and list of potential combination partners.

Combos have become a major component of pharmas’ strategies for non-alcoholic steatohepatitis (NASH), because the consensus view is that no single therapy can control the multifactorial processes driving most patients’ disease (see “Combo Deals”).

Dealmaking has become a core strategy, as pharmas build toolboxes that enable them to take a modular approach to tackling the disease.

The most recent example is the Oct. 29 deal in which Novartis AG will pair its farnesoid X receptor (FXR) agonist tropifexor with the three different mechanisms of action in Pfizer Inc.’s clinical NASH pipeline.

Zobair Younossi, chairman of the department of medicine at Inova Fairfax Hospital, compared NASH treatment to the diabetes landscape, where different therapies are added together to control individual patients’ disease processes.

“A regimen with a single drug is unlikely to be the answer for treating NASH in the long run. You probably have to target multiple different pathways at the same time,” he said.

However, finding the right combinations is challenging because many of the compounds’ mechanisms affect more than one of the metabolic, inflammatory or fibrotic aspects of NASH, and it’s not known which set of mechanisms will make the most difference for a given patient at a given time.

In addition, NASH lacks clear biomarkers, like HbA1c level in diabetes, to guide drug development and use, said Younossi.

Some clarity may come as soon as next year among readouts from four candidates in Phase III NASH monotherapy studies. These will give a better indication of which disease processes each affects, and to what extent.

Earlier stage programs are filling out the picture in NASH. At AASLD, companies will present data showing a handful of up-and-coming NASH targets can alter liver fat, plasma lipids and inflammation.

The abstracts include data from Phase II proof-of-concept trials of two thyroid hormone receptor β (THRB) agonists showing activation of the pathway can lower both liver fat content and serum LDL-c; one of the abstracts contained data that hadn’t been presented before (see “Table: NASH at AASLD”).

Table: NASH at AASLD

The table shows selected abstracts with new clinical or preclinical data to be presented at this year’s American Association for the Study of Liver Diseases (AASLD) annual meeting on Nov. 9-13 in San Francisco. MRI-PDFF = magnetic resonance imaging-estimated proton density fat fraction, a non-invasive measurement of liver fat. Sources: AASLD, BCIQ: BioCentury Online Intelligence

CompanyProductMechanism of ActionPhaseResultNumber
Farnesoid X receptor (FXR; NR1H4) agonists
Gilead Sciences Inc. (NASDAQ:GILD) GS‐9674FXR agonistPh II (n=140)In patients with baseline MRI-PDFF ≥8%, MRI-PDFF was reduced by ≥30% in 39% of patients receiving 100 mg GS-9674 (p=0.011), in 14% of patients receiving 30 mg GS‐9674 (p=0.87) and in 12.5% of patients receiving placebo736
Novartis AG (NYSE:NVS; SIX:NOVN)Tropifexor (LJN452)FXR agonistPh IIbWill present interim data from parts A-B...

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