Date: 2014-12-03
Type of
information: Publication of results in a medical journal
phase: 2a
Announcement: publication of results in The New English Journal of Medicine
Company: Ionis Pharmaceuticals (USA - CA)
Product: volanesorsen (ISIS-APOCIIIRx)
Action
mechanism:
- antisense oligonucleotide. ISIS-APOCIIIRx is an antisense drug intended to treat patients with severely high triglycerides either as a single agent or in combination with other triglyceride-lowering agents. ISIS-APOCIIIRx targets apoC-III, a protein produced in the liver that plays a central role in the regulation of serum triglycerides. Humans who do not produce apoC-III have lower levels of triglycerides and lower instances of cardiovascular disease. Humans with elevated levels of apoC-III have high triglycerides associated with multiple metabolic abnormalities, such as insulin resistance and/or metabolic syndrome. In addition, the prevalence of type 2 diabetes is increased in patients with elevated triglycerides.
Disease: familial chylomicronemia syndrome
Therapeutic
area: Rare diseases - Genetic diseases - Metabolic diseases
Country: Canada
Trial
details:
- The Phase 2 open-label cohort was designed to assess the safety and activity of ISIS-APOCIIIRx in patients with extremely high triglyceride levels and a genetic confirmation of FCS.
Latest
news:
- • On December 3, 2014, Ionis Pharmaceuticals announced that data from a Phase 2 study of ISIS-APOCIIIRx in patients with familial chylomicronemia syndrome (FCS) were published in The New England Journal of Medicine. The paper, titled "Targeting ApoC-III in the Familial Chylomicronemia Syndrome" (Gaudet et al, N Engl J Med 2014: 371:23: 2200-2206), show that patients with FCS treated with ISIS-APOCIIIRx achieved substantial reductions in apoC-III, triglycerides, chylomicrons and apoC-III-associated very low density lipoprotein-cholesterol (VLDL-C) particles. The three FCS patients in this open-label study had baseline triglyceride levels ranging from 1,406 mg/dL to 2,083 mg/dL and all three patients achieved triglyceride levels below 500 mg/dL during the study. FCS is a rare genetic disorder characterized by severe elevated levels of triglycerides. Current treatment options do not adequately reduce triglycerides and, as a result, patients with FCS have increased risk of recurrent and potentially fatal pancreatitis and other complications.
- Table 1: Substantial Reductions of Triglycerides and ApoC-III as a Single Agent Observed in a Phase 2 Study in ISIS-APOCIIIRx- treated Patients with FCS.
- Patient 1 Patient 2 Patient 3
|
B |
PE |
* %
Change |
B |
PE |
* %
Change |
B |
PE |
* %
Change |
Mean
% Change |
| Triglycerides |
1406 |
616.5 |
-56 |
2083 |
287.5 |
-86 |
2043 |
734.5 |
-64.0 |
-69 |
| ApoC-III |
18.9 |
5.5 |
-71 |
35.1 |
3.4 |
-90 |
19.8 |
3.5 |
-83 |
-81 |
| VLDL-ApoC-III |
12.2 |
4.5 |
-63 |
32.6 |
2.5 |
-92 |
16.8 |
2.3 |
-86 |
-80 |
| HDL-C |
16 |
24 |
+50 |
8 |
21 |
+163 |
14 |
17 |
+21 |
+78 |
| Non-HDL-C |
214 |
114.5 |
-46 |
327 |
84 |
-74 |
244 |
111 |
-55 |
-58 |
- Baseline (B) and Primary Endpoint (PE) in mg/dL
- Patient 1: 485 mg/dL lowest triglyceride level achieved during study
- Patient 2: 251 mg/dL lowest triglyceride level achieved during study
- Patient 3: 234 mg/dL lowest triglyceride level achieved during study
- *Percent changes from baseline at primary endpoint (an average measurement of day 85 and 92)
- The FCS patients in this study were treated with 300 mg of ISIS-APOCIIIRx as part of a Phase 2 open-label study that was designed to assess the safety and activity of ISIS-APOCIIIRx in patients with severely high triglycerides. All three FCS patients had a genetic confirmation of FCS, no detectable LPL activity and baseline triglyceride levels greater than 1,400 mg/dL.
- The safety and tolerability of ISIS-APOCIIIRx in patients with FCS to date supports continued development. The most common adverse event was injection site reactions, which were predominantly mild and typically resolved rapidly. There were no flu-like symptoms, no treatment-related elevations of liver enzymes greater than three times upper limit of normal, no abnormalities in renal function, no clinically meaningful changes in other laboratory values and no treatment-related serious adverse events.
- • On May 2, 2014, Isis Pharmaceuticals has announced the final data from its Phase 2 study of ISIS-APOCIIIRx as a monotherapy in patients with familial chylomicronemia syndrome, or FCS. In this open-label study, three patients with FCS treated with ISIS-APOCIIIRx achieved substantial reductions in triglycerides with all three patients achieving a triglyceride level below 500 mg/dL, which substantially reduces the risk of an acute pancreatitis event. In addition, significant reductions in chylomicrons were observed that correlated with reductions in triglyceride levels. These data were presented by Dr. Daniel Gaudet at the National Lipid Association clinical lipid update meeting in Orlando, Florida.The data reported are the final data from three FCS patients who all had baseline triglyceride levels greater than 1,400 mg/dL and completed 13 weeks of treatment with 300 mg of ISIS-APOCIIIRx. Isis reported an interim analysis of these data in September 2013. In this study, all three patients treated with ISIS-APOCIIIRx achieved substantial reductions in total triglyceride levels with a mean reduction of 69 percent that correlated with a comparable reduction of 69 percent in chylomicron-triglycerides. In addition, these patients experienced positive effects on other lipid parameters, including a mean reduction of 81 percent in apoC-III, a mean reduction of 81 percent in apoC-III-associated VLDL-C, and a mean increase of 78 percent in HDL-C.
- ISIS-APOCIIIRx was well tolerated in the study. The most common adverse event was injection site reactions, which were predominantly mild and typically resolved rapidly. There were no flu-like symptoms, no treatment-related elevations of liver enzymes greater than three times upper limit of normal, no abnormalities in renal function, no clinically meaningful changes in other laboratory values and no treatment-related serious adverse events. In the study reported, all three patients were homozygotes for null LPL gene mutations resulting in undetectable LPL activity.
Is
general: Yes
