JK,

Unfortunately I don't have access to the full 2015 Nicholls article. However, it appears that the Genentech/Roche authors were mainly focusing on observations in the shorter 12-week ASSERT trial in which patients were dosed with 50mg, 100mg, or 150mg twice per day. Perhaps Nicholls made a comment in the 2015 paper that was similar to the one in the ASSERT study. However, in several news releases, annual information forms, or corporate update/webcasts, we have been told more about the behavior of ALT in the 6 month SUSTAIN/ASSURE studies (100mg twice per day) that have alleviated any concern.

Here is the statement from the ASSERT paper: "These increases were transient and reversible, characterized by rapid increases in levels, typically between weeks 4 and 8, with rapid return to baseline levels upon discontinuation of the study drug," which sounds quite similar to what the Genentech/Roche authors wrote: "The liver enzyme elevations were observed between 4 and 8 weeks of treatment and resolved when drug administration was discontinued."

8/28/2012 News release: "The SUSTAIN trial also showed that increases in alanine aminotransferase (ALT) reported in previous trials were infrequent and transient with no new increases observed beyond week 12 of the 24-week trial."

9/3/2013 News release: "Furthermore, the safety component of both trials [referring to combined SUSTAIN/ASSURE analysis] again illustrated that the rare RVX-208 induced rise in the ALT was benign and manageable, i.e.) short in duration and appearing prior to week 12 of dosing."

From the 2015 Resverlogix Annual Information Form: "The SUSTAIN trial also showed that increases in alanine aminotransferase (“ALT”) liver signals similar to those which were reported in previous trials were infrequent and, when allowed according to the trial’s protocol, returned to normal either as a result of continued dosing or short-term interruption, with no new increases observed beyond week 12 of the 24-week trial."

9/29/2015 Corporate Update: "Obviously, we have some adverse events. Every product has adverse events. The overall adverse events are approximately similar between active and placebo. The main adverse event that we see that is different is an increase in hepatic enzymes. Seven to eight percent of patients have a rise of ALT greater than three times the upper limit of normal. Of these patients, if you stop the drug, they revert back in a matter of days. Usually for five times the upper limit of normal, it’s about 15 days for them to revert back. There’s no inflammatory component. For the lesser elevations, if you re-start, or if you continue, the drug is well tolerated, and these ALTs reverse with continued therapy. We did not see a Hy’s law. That’s something that the FDA worries about. If you see an increase in bilirubin at the same time as increasing enzymes, that’s indicative of serious liver damage. We have not seen a case of Hy’s law. We actually do not see a raise in bilirubin in these studies. They tend to occur early. They tend to occur within four to six weeks. We’ve only ever seen one case after twelve weeks, and that was a patient who had coincidental acute cholecystitis. And a lot of the patients with ALT elevations were seropositive for Hepatitis A or were taking drugs known to increase the ALT."