3. Safety profile does matter in the long-term and Genfit's drug is much safer
On top of efficacy, safety is a real matter of concern in a therapy that is deemed to become a chronic treatment: Intercept's Phase 3 design will run for at least several years to deliver complete results while the final length of the trial remains uncertain as it is tied to progression to a pre-determined number of adverse events.
When discussing potential adverse effects of NASH therapies from a molecular biology perspective, the mechanism of action of both compounds looks quite different.
Genfit's drug, elafibranor, is a dual peroxisome proliferator-activated receptor (PPAR) agonist: it works by activating PPARalpha and PPARdelta, which are nuclear receptors that have a totally natural effect on lipid storage and metabolism regulation in the liver. In fact, that is the very natural mechanism you would expect to activate when increasing intakes of polyunsaturated fatty acids such as omega-3, and precisely why high-calorie diets full of saturated fat are so damageable for your liver - that is actually one of the root causes of NASH.
Besides, PPARalpha and delta have been shown to regulate glucose metabolism, lipoprotein cholesterol metabolism, liver inflammation, and amino acid metabolism (Contreras et al., 2013; Reilly et al., 2007). In brief, due to its mechanism of action, elifibranor works by improving about every possible cardio-metabolic parameter you can think of (see Figure 2), and ultimately, it does reverse NASH even in the more severely ill patients. Indeed, in Genfit's study, beneficial cardio-metabolic effects of elafibranor (GFT505) were confirmed (statistically significant) including:
- decrease in "bad" lipids (including LDL-C), increase in cardioprotective lipids (HDL-C)
- improvement in glycemic parameters, particularly in diabetic patients
- improvement in cardio-vascular risk (PROCAM score)
(source: Genfit's data)
Figure 2: Therapeutic targets of PPAR agonists in the metabolic syndrome
(click to enlarge)
Figure 2 - Therapeutic targets of PPAR agonists in the metabolic syndrome
(Source: EASL postgraduate course on metabolic liver disease)
On the other hand, Intercept's drug, OCA, is an agonist of the farnesoid X receptor, or FXR. FXR plays a role in regulating lipid and glucose metabolism, but in particular it affects how cholesterol is converted into bile acid (Claudel et al., 2005) - that is the primary function of OCA, which was first developed by Intercept as a treatment for primary biliary cirrhosis, or PBC. Unfortunately, FXR activation leads to undesired side effects on cholesterol, which were confirmed by the results of the FLINT study: OCA naturally increases "bad" cholesterol (LDL-C) levels. Besides, as FXR activation also modulates the clearance of triglycerides in the blood, this incidentally decreases "good" cholesterol (HDL-C) levels as well. This is already bad in general, but it is even far worse for the kind of patients that Intercept intends to treat with OCA.
Regarding LDL-C levels, Intercept has already suggested that taking statins could help manage the adverse effects induced by OCA. However, an increasing number of recent studies seem to demonstrate that statins themselves have severe adverse effects, including a very stronger risk (+250%) of developing type 2 diabetes (Cederberg et al., 2015), damages to peripheral nerves (Otruba et al., 2011) and an increased risk of developing rheumatoid arthritis (de Jong et al., 2012).
Besides, in addition to abnormalities in cholesterol levels, the FLINT study's complete results also showed that pruritus (itchy skin) was confirmed in 23% of patients receiving OCA (vs. 6% in the placebo arm), and that five severe or life-threatening adverse events in the patients receiving OCA were judged to be possibly related to the treatment (3 severe pruritus, 1 hyperglycaemia and 1 dysarthria and dizziness possibly due to cerebral ischaemia). Genfit's study, on the contrary, showed that no severe adverse event were associated with elafibranor and demonstrated a very favorable safety profile.
In brief, when comparing elafibranor and OCA, what comes out is that the very rationale behind both drugs is substantially different. Elafibranor is a global, cardioprotective drug with nearly nothing but beneficial effects; OCA has some inherent adverse side effects that might prove worse in the long-term than its beneficial effect on NASH patients - in fact, NASH patients are far more likely to die from cardiovascular disease than from NASH itself (Misra et al., 2009).
So, even though a CVOT study was not required by the FDA along with Intercept's Phase 3 trial, I believe that this is a significant risk associated with Intercept's NASH drug in the long run, that has been considerably overlooked by the market at this point.