Expectations for nonalcoholic steatohepatitis (NASH) are still sky-high—some see tens of billions for any drug that gets it right at peak—but the reality of clinical trials assessing fatty liver assets has been a lot murkier.
Nearly everyone in biopharma, it seems, is going after this disorder: essentially a buildup of fat in the liver caused, predominately, by obesity (i.e., not from alcohol misuse) that can cause scarring (fibrosis) over time and, in a minority of cases, increases risk of liver cirrhosis, failure and cancer.
At the extreme end, liver transplantation is needed if the organ is beyond repair, and NASH is slated to be the biggest cause of this in the coming decades, replacing alcoholic liver disease and hepatitis C as the biggest risk factor.
Currently, the best thing to fight against a buildup of fat in the liver is to lose weight via diet and exercise, but biopharma is looking to drug the problem out, especially for those who are already seeing scarring and further damage.
Given the potentially hundreds of millions of people with NASH, some analysts have seen a $35 billion a year at peak sales opportunity for this market, but nearly everyone over the past few years, either early or late-stage, has seen setbacks and issues arise out of their clinical trials to dampen down enthusiasm.
Today, NGM Biopharmaceuticals posted a peek at a small phase 2 test that has been somewhat positive, but, as ever with NASH, there are caveats, and the pros were seen as pretty underwhelming for investors. Its shares were initially up around 3% this morning on the news in early trading, then dropped into the red by more than 20%.
Here are the numbers: The fourth cohort from a midstage test was looking at its engineered variant of the human hormone FGF19 aldafermin (formerly known as NGM282) across 78 patients with biopsy-confirmed NASH with F2-F3 liver fibrosis. (These are the latter stages of scarring, but one stage before cirrhosis, which is F4.)
The primary endpoint was its drug's effect on absolute changes in absolute liver fat content (LFC), which was measured by magnetic resonance imaging-estimated proton density fat fraction, or MRI-PDFF, and compared to a dummy treatment over half a year.
Secondary and exploratory endpoints included relative changes in LFC, biomarkers of liver function and effect on liver histology. The interim analysis of noninvasive measures of efficacy, including LFC, liver transaminases and exploratory fibrosis biomarkers, was conducted when 38 patients completed 24 weeks of treatment.
The results: A once-a-day shot with 1 mg of aldafermin for 24 weeks in patients with liver fibrosis resulted in a statistically significant change in the absolute LFC of -7.9% (measured by MRI-PDFF), as compared to -2.0% in the placebo arm, and a statistically significant change in relative LFC of -39.6%, as compared to -5.9% in the placebo arm. (The company is not yet sharing its p-values for these.)
It also said that 72% of patients treated with aldafermin achieved a ≥5% absolute reduction in LFC versus 17% for placebo. Similarly, 72% of patients treated with aldafermin achieved a ≥30% relative reduction in LFC versus 17% for placebo.
Of the patients treated with aldafermin, 28% achieved a normal LFC after 24 weeks, defined as ≤5% absolute LFC, versus none in the placebo arm.
In addition, in assessing biomarkers of liver inflammation and injury, treatment with aldafermin resulted in clinically meaningful (but not, it would seem, statistically significant) reductions in alanine aminotransferase and aspartate aminotransferase, which are measurements of liver function and indicators of when the organ is struggling. Treatment with aldafermin also resulted in a statistically significant reduction in PRO-C3, an exploratory biomarker of liver fibrogenesis, as compared to placebo.
But treatment increased cholesterol levels, something the biotech already knew, and said this was controlled by those who needed it with statins. (This may still be a concern for some patients, given the heightened CV risk for obesity.)
Overall safety appeared good, however, as there were no study withdrawals and “no serious adverse events in the aldafermin arm of the Cohort 4 interim analysis,” the biotech said, as compared to one withdrawal due to an adverse event and two serious adverse events in the placebo arm.
The most common adverse events in the aldafermin arm, which were generally mild to moderate, were diarrhea, headache, nausea and arthralgia (joint pain).
The midstage test is being spread out across four cohorts, with more detailed results from this final cohort of the phase 2 trial coming in 2020, which will also help “inform planning activities for our phase 3 study,” the company said.
Back in April 2017, NGM posted data from its higher dose cohort 1 trial, which met its primary endpoint of reducing liver fat, as evidenced by the use of MRI-PDFF, with the higher 3-mg and 6-mg dose groups lowering absolute LFC by 9.7% and 11.9%, respectively, against a dummy treatment over 12 weeks.
Of the small batch of 53 patients (across both doses) treated with NGM282, 34% reached a normal LFC, with the greatest effect seen in those with the highest baseline LFC and most active disease. In all, 79% of patients in the study met the primary endpoint of a reduction of at least 5% in liver fat.
NGM designed the molecule to maintain the biological activity of FGF19, which modulates two receptors: FGFR4, a primary regulator of bile acid synthesis in the liver, and FGFR1c, a signaling receptor in metabolic processes in adipose tissue (peripheral fat) that regulates de novo lipogenesis, glucose homeostasis and body weight.
The biotech hopes NGM282’s activity on those receptors will make it a powerful and direct modulator of multiple pathways that are key to the development and progression of NASH.
Other companies are taking a different approach: Intercept’s obeticholic acid (OCA) is an agonist of the farnesoid X receptor (FXR), which is a nuclear receptor. FXRs like OCA (there are many in development in the industry, including at Gilead, Novartis and Allergan) turn on as many as 100 different genes.
Genfit’s elafibranor, meanwhile, is a dual PPAR receptor agonist that aims to modulate targets that play a role in various aspects of metabolic syndrome.
Analysts at Jefferies said in a note to clients: “Consistent with 12-week results presented at AASLD 2018, where 1mg of Aldafermin was assessed in a uncontrolled study, administration of Aldafermin over a 24 week period led to improvement in MRI-PDFF, ALT and other measures of NASH.
“While on a numerical basis the results today appear slightly worse. We believe that could be readily attributable to cross trial variability. We think more notable is that the addition of 12 weeks did not lead to marked improvement in MRI-PDFF or other measures. It will be interesting to see whether the extended period on drug will translate to improved biopsy data in Q1:20 and remains an important key question.
“Regardless, NGM's Aldafermin remains one of the more interesting drugs for NASH, demonstrating both resolution in NASH and improvement/reversal of fibrosis. However, we think commercially, a daily injectable will more likely be a niche product based on our doctor checks and more focus will be on orals like ICPT's OCA, which is under FDA review and is set to launch next year.”