Isis antisense drug lowers triglycerides; Phase III ongoing
This article was originally published in Scrip
Isis Pharmaceuticals has one Phase III clinical trial under way with a second late-stage trial expected to start before the end of 2015 for its antisense drug volanesorsen (ISIS-APOCIIIRx), which was able to significantly lower patients' triglyceride levels in a Phase II study.
Results of the 85-patient clinical trial were published in the New England Journal of Medicine (NEJM) on 29 July, showing that volanesorsen lowered apolipoprotein C-III (ApoC-III) by as much as 79.6%, which led to triglyceride reductions of as much as 70.9% in patients with hypertriglyceridemia – a condition that can lead to pancreatitis and may increase cardiovascular risk.
If volanesorsen is successful in Phase III studies, Isis will seek US FDA approval in two rare conditions characterized by high triglyceride levels, but the company will pursue approval in general hypertriglyceridemia with a more potent version of the drug, which will enter the clinic later this year.
Volanesorsen was administered in the Phase II study published in the NEJM as a once-weekly injection at 100mg, 200mg or 300mg. One cohort had 57 patients who received one of the three doses or placebo. All 28 patients in the second cohort were treated with fibrates plus 200mg or 300mg of volanesorsen or placebo.
The study's primary outcome measure was reduction at 13 weeks in ApoC-III, a regulator of lipoprotein metabolism that is involved in regulating plasma triglyceride levels.
| Mean baseline ApoC-III | Mean 13-week APOC-III | ApoC-III Percent change | Mean baseline triglycerides | Mean 13-week triglycerides | Triglyceride % change |
100mg plecanatide n=11 | 22.4 mg/dl | 12 mg/dl | -40% | 590.6 mg/dl | 311.6 mg/dl | -31.3% |
200mg n=13 | 23.1 | 7.6 | -63.8% | 641.5 | 234.7 | -57.7% |
300mg n=11 | 22.6 | 4.4 | -79.6% (p<> | 559.1 | 139.5 | -70.9% (p<> |
Placebo n=16 | 22.2 | 21.9 | -1.4% | 522.7 | 547.1 | +20.1% |
200mg + fibrate n=8 | 15.5 | 6.1 | -60.2% | 281.8 | 141.1 | -51% |
300mg + fibrate n=10 | 18.3 | 5.1 | -70.9% (p<> | 393.7
| 134 | -64% |
Fibrate only n=8 | 19 | 17.7 | -2.2% | 457 | 371.1 | -7.7% |
Isis CEO Stanley Crooke said ApoC-III is the right target for a drug that's meant to reduce triglycerides, because it plays a central role in management of triglycerides.
"Other targets don't lower triglycerides as much," Dr Crooke told Scrip.
He also noted that antisense is "the right technology, because ApoC-III has been very difficult to target with small molecules and monoclonal antibodies, and we don't target ApoC-III, we target the RNA that makes it."
Cholesterol effects
In addition to volanesorsen's effects on ApoC-III and triglycerides, the antisense drug affected various measures of cholesterol.
Mean baseline HDL – often referred to as "good" cholesterol – ranged from 31.1mg/dl in the 100mg volanesorsen group to 36.9mg/dl in the 200mg/dl volanesorsen plus fibrate group. At 13 weeks HDL levels were stable at 33.2mg/dl in the placebo group and 36.3mg/dl in patients who were given a placebo and a fibrate, but HDL increased to as much as 52.4mg/dl in the 200mg plus fibrate group.
LDL, or "bad" cholesterol, increased from 79.5mg/dl to 127.8mg/dl in patients who received volanesorsen monotherapy, but total non-HDL levels were relatively unchanged and similar to placebo.
The Phase II study investigators noted in the NEJM paper that LDL increases may be due to 1) conversion of VLDL to LDL due to greater lipoprotein lipase activity, because of the ApoC-III decrease, 2) remodeling of lipoprotein content by cholesterol ester transfer protein (CETP), or 3) changes in secretion and catabolism of LDL. The effect of volanesorsen on LDL cholesterol could be treated with statins or fibrates, the investigators said.
Sagient Research principal scientific analyst Peter Chang said in a 29 July BioMedTracker report that the LDL increase may not be a big concern for patients with severely high triglyceride levels, such as individuals with familial chylomicronemia syndrome (FCS) – the indication in which volanesorsen is being evaluated in an ongoing Phase III study. The second Phase III clinical trial will enroll patients with familial partial lipodystrophy (FPL).
"In the more general patients with triglycerides over 500mg/dl (where the FDA allows drugs to be approved without a [cardiovascular (CV)] outcomes trial, since such drugs may also lower the risk for pancreatitis), there could be some questions," Dr Chang wrote. "Since there was not much of a reduction in non-HDL-c, [volanesorsen] may not generally lower CV risk much, as had been hoped, without the use of additional LDL-c lowering therapies. The lack of an increase in non-HDL-c could be reassuring for lack of harm, but we are not certain that would be enough for the FDA."
Dr Crooke said the LDL increase for volanesorsen-treated patients is not a significant concern, because total non-HDL matters more and that was essentially unchanged. While LDL was elevated in the volanesorsen treatment groups, the mean at 13 weeks of 127.8mg/dl (+44.9mg/dl) was still within the range of healthy LDL levels, which peak at 190mg/dl.
"We have great confidence that we will reduce cardiovascular events," Dr Crooke said.
The second Phase III study in FPL patients is slated to start before end of 2015, but data are expected from both Phase III clinical trials by the end of 2016 or early in 2017.
Isis plans to hold on to development and commercialization rights for volanesorsen and its follow-up ISIS-APOCIII-LRx, which is 10 times more potent. ISIS-APOCIII-LRx can be administered at a lower-dose that's more appropriate for the larger population of people with severely high triglycerides.
Isis created a wholly-owned subsidiary called Akcea to develop and market both drugs, but may consider a partnership in larger indications, Dr Crooke said.
Related stories
ISIS-APOCIIIRx data positive in latest Phase II analysis
Isis slips then recovers on Phase II triglyceride drug event
Isis rises 29% on PII triglyceride-lowering data
Phase III safety key to Isis antisense CV potential