dm+d

37648411000001106

New Medicines

WaylivraType 1 hyperlipoproteinaemia (familial chylomicronemia syndrome)

Information

Waylivra
New molecular entity
Akcea Therapeutics
Ionis Pharmaceuticals

Development and Regulatory status

Launched
Launched
Not approved
October 2020
Yes
Yes
Oct 20NICE recommends use of Waylivra as an option for treating familial chylomicronaemia syndrome in adults with genetically confirmed familial chylomicronaemia syndrome who are at high risk of pancreatitis, and when response to diet and triglyceride-lowering therapy has been inadequate. It is recommended only if the company provides volanesorsen according to the commercial arrangement. Waylivra becomes the first treatment for FCS to become available on the NHS in England [26-28].
Nov 19Akcea waiting for NICE guidance to be published (guidance due June 2020) before releasing the launch date [25].
Sep 19UK launch date is yet to be confirmed; product is not currently available to order [24].
May 19Akcea and Ionis plan to launch Waylivra in Germany this year followed by additional European countries in 2020 [21].
May 19Granted conditional marketing authorisation in EU [20].
Feb 19Recommended for EU approval by CHMP - the full indication is "an adjunct to diet in adult patients with genetically confirmed familial chylomicronaemia syndrome (FCS) and at high risk for pancreatitis, in whom response to diet and triglyceride lowering therapy has been inadequate.” It is proposed that treatment should be initiated by and remain under the supervision of a physician experienced in the treatment of patients with FCS [19].
Aug 18Not approved in US. The companies said they have received a complete response letter from the FDA, but did not reveal the reasons for the rejection [18].
May 18Recommended for approval in US [18]
Mar 18Granted EAMS status in the UK, to treat, as an adjunct to diet, adult patients with familial chylomicronaemia syndrome [17].
Oct 17Granted a Promising Innovative Medicine (PIM) designation by the MHRA [16].
Aug 17Filed in US [15].
Jul 17Filed in EU [14].
Jul 16Granted orphan designation in EU for the treatment of familial partial lipodystrophy (FLP), a rare lipid disorder characterised by abnormal fat distribution across the body and a range of metabolic abnormalities, including sever TIIDM, high triglycerides and accumulation of fat in the liver [10].
May 16Ionis Pharmaceuticals says safety issues of thrombocytopenia recently appeared unexpectedly among some patients enrolled in a ApoCIII trial for volanesorsen [9].
Jan 16The European (Jan 14) and US (Jul 15) regulatory agencies have granted Orphan Drug Designation to volanesorsen for the treatment of patients with FCS [8].
Dec 15Isis Pharmaceuticals is now called Ionis Pharmaceuticals [7].
Jul 15US FDA grants Orphan Drug Designation to volanesorsen (ISIS-APOCIIIRx) for the treatment of pts with FCS [6].
Mar 15P3 trials intended to include UK, although not yet recruiting [5].
Aug 14Phase 3 NCT02211209 initiated, due to complete April 2016 [2].

Category

Antisense oligonucleotide targeting apoC-III, which is a liver-produced protein that regulates serum triglycerides. Given once weekly.
FCS is a rare, serious genetic disorder that is often associated with triglyceride levels higher than 2,000 mg/dL, because of a lack of lipase, the enzyme that clears TGs from the blood. It affects one person in a million. [1,3]
Type 1 hyperlipoproteinaemia (familial chylomicronemia syndrome)
Subcutaneous injection

Further information

Yes

Trial or other data

Aug 19PIII APPROACH study is published; the 52 week RCT (n=66) found antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen resulted in 77% decrease (p<0.001) in mean triglyceride levels (-19.3 mmol/L) vs. 18% increase with placebo (+1.0 mmol/L). Thrombocytopenia and injection-site reactions were common ADRs [22].
Mar 17Akcea Therapeutics, a wholly owned subsidiary of Ionis Pharmaceuticals, announces that the pivotal PIII APPROACH study of volanesorsen met its primary endpoint of reducing triglyceride levels in patients with FCS, but the safety data also stoked fears that declines in platelet counts could affect antisense therapies. APPROACH is a randomized, double-blind, placebo-controlled, 52-week study in 66 patients. Average incoming triglyceride level of patients in the study was 2,209 mg/dL. For the primary endpoint of the study, volanesorsen-treated patients (n=33) achieved a statistically significant (p<0.0001) mean reduction in triglycerides of 77% from baseline after 3 months of treatment, compared to a mean increase of 18% in placebo-treated patients (n=33). This represented a mean absolute reduction of 1,712 mg/dL in treated patients. The treatment effect observed was sustained over the 52-week treatment period. 50% of the treated patients who entered the study with triglycerides ≥750 mg/dL achieved triglyceride levels less than 500 mg/dL after 3 months of treatment. By comparison, none of the placebo-treated patients achieved this level (p<0.003). Volanesorsen-treated patients with the highest documented frequency of pancreatitis attacks suffered no attacks during the 52-week treatment period (p=0.02). A reduction in abdominal pain was observed in volanesorsen-treated patients compared to placebo-treated patients [13].
Dec 16In the COMPASS study, data suggest the effect of volanesorsen is clinically meaningful. After 13 weeks of treatment, 82% of patients in the volanesorsen arm had triglyceride levels of 500 mg/dl or less. Only 14% of subjects in the placebo cohort hit this level. Ionis is particularly interested in a subset of patients with FCS. Going into the trial, the seven FCS patients had triglyceride levels of 2,280 mg/dl on average. After 13 weeks of treatment, triglyceride levels in three of the five FCS patients who received volanesorsen had fallen to 500 mg/dl or less. Overall, triglyceride levels among FCS patients in the volanesorsen arm fell 73%, compared to a 70% increase in the two-patient placebo arm [12].
Dec 16PIII randomized, double-blind, placebo-controlled, 26-week COMPASS study met its primary endpoint in patients with severe hypertriglyceridemia (mean baseline triglyceride level 1,261 mg/dl). Volanesorsen-treated patients achieved a mean reduction in triglycerides of 71.2% from baseline (n=75) compared with 0.9% in placebo-treated patients (n=38), p<0.0001 [11].
Mar 15COMPASS P3 randomised controlled trial initiated in patients with severely elevated triglycerides (>= 5.7 mmol/l) vs. placebo; primary outcome is percent change in fasting triglycerides at 13 weeks from baseline: expected enrolment 75 across North America and the EU, expected completion Dec 15 [4,5].
Aug 14P3 study initiated [NCT02211209]: a randomised, double-blind, placebo-controlled, six month study in approximately 50 patients diagnosed with FCS. The study will evaluate the efficacy and safety of a 300 mg once-weekly SC dose of ISIS-APOCIIIRx. The primary endpoint of the study is percent change in fasting triglycerides from baseline after three months of dosing [1].

Evidence based evaluations

WaylivraFamilial partial lipodystrophy (FPL)

Information

Waylivra
Licence extension / variation
Akcea Therapeutics
Ionis Pharmaceuticals

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes

Category

Antisense oligonucleotide targeting apoC-III, which is a liver-produced protein that regulates serum triglycerides. Given once weekly.
Prevalence of FPL is 1-9 per 100 000 people [4]. Lipodystrophy is associated with clinical features of insulin resistance [3]. Complications include steatohepatosis, type 2 diabetes and severe dyslipidaemia [3]. Dietary changes to a low fat, low calorie diet are the mainstay of treatment [3]. Two centres in the UK offer testing for this condition [1].
Familial partial lipodystrophy (FPL)
Subcutaneous