Regulatory Decision Summary for Waylivra (volanesorsen)

The proposed indication for Waylivra (volanesorsen) is for the treatment of familial chylomicronemia syndrome (FCS), a rare genetic disease characterized by extremely high serum triglycerides (TG) which affects an estimate of 3,000-5,000 patients globally, and more than 100 Canadians. FCS is characterized by severe and recurrent abdominal pain, and many patients experience at least one episode of acute pancreatitis, which can be fatal. The generally agreed aim of therapy of FCS is to attempt to reduce TG levels as much as possible (preferably to <8.5 mmol/L [<750 mg/dL], a level considered to reduce the risk of acute pancreatitis). There are no approved therapies for FCS, and available lipid-lowering agents such as fibrates, fish oils, niacin, and statins have minimal effect. Therefore, the disease is currently managed primarily with an extremely restrictive low-fat diet.

To support the safety and efficacy of volanesorsen in FCS, the sponsor relied primarily on a single pivotal clinical trial, study CS6. Supportive data were also provided from a similarly designed trial in patients with severe hypertriglyceridemia, study CS16. Study CS16 recruited 113 patients, of whom only 7 patients had FCS, including 5 who were treated with volanesorsen. Further safety data were obtained from an open-label, single-arm extension study, CS7.

Study CS6 was a 52-week randomized, double-blind, placebo-controlled trial in 66 patients with FCS treated with diet and, in most cases, standard triglyceride-lowering medication. 33 patients were treated with volanesorsen. For the primary efficacy endpoint, after 3 months of treatment with volanesorsen 300 mg once weekly, there was a 77% reduction of fasting TG from baseline (2,267 mg/dL to 590 mg/dL, p<0.0001). Secondary endpoints included the maintenance of effect on TG levels at 12 months, occurrence of acute pancreatitis and abdominal pain, and the proportion of patients with a baseline TG level ≥8.5 mmol/L (≥750 mg/dL) who achieved a TG level <8.5 mmol/L at 3 months. The latter endpoint was achieved by 23 of 30 volanesorsen-treated patients (77%), compared with 3 placebo-treated patients (10%) (p = 0.0001). At 3 months, no significant difference was seen between the volanesorsen and placebo groups in abdominal pain or quality of life. Although a trend was seen for a reduction of pancreatitis events, there were too few events to demonstrate statistical significance.

The assessment of the efficacy of volanesorsen in FCS was complicated by changes to volanesorsen dosing during study CS6, which were necessitated due to safety concerns. During the trial, 2 serious adverse events (SAEs) of severe thrombocytopenia (platelet count <25 000/mm3) occurred amongst 5 discontinuations due to thrombocytopenia in the 33 volanesorsen-treated patients, with no events seen in the placebo group. Overall, 75% of volanesorsen-treated patients experienced thrombocytopenia, compared to 24% of placebo patients. Reductions in platelet counts below 100,000/mm3 occurred in 47% of volanesorsen-treated patients and no placebo-treated patients. Although no serious bleeding events were observed in the 33 volanesorsen-treated patients, non-serious bleeding was common: 49% of volanesorsen-treated patients experienced bleeding events compared to 12% of placebo patients. Consequently, an intensive platelet monitoring and dose reduction/interruption strategy was instituted in study CS6 after the primary efficacy time point at 3 months.

As a result of the safety-mandated platelet monitoring and dose reductions, as well as patient discontinuations, only 6 volanesorsen-treated FCS patients completed the full 52 weeks of study CS6 on the initial weekly 300 mg dose. The results for the primary endpoint of TG reduction at 3 months therefore overestimate the efficacy to be expected with the platelet monitoring and dose reduction risk mitigation measures proposed by the sponsor. Among the minority of patients who were able to remain on the initial dose of 300 mg weekly, fasting TG reductions from baseline to months 6 and 12 were 80% and 76%, respectively. However, among the 13 patients who required dose reduction efficacy was substantially reduced, with TG decreases from baseline of 52% and 40% at months 6 and 12, respectively. This resulted in mean fasting TG levels of 957 mg/dl and 1,120 mg/dl at months 6 and 12, respectively. These mean TG levels are above the threshold generally considered to significantly reduce the risk of pancreatitis (i.e. <8.5 mmol/L/750 mg/dL).

Other safety concerns regarding volanesorsen include local injection site reactions, which occurred in most volanesorsen-treated FCS patients, and not placebo-treated patients. Hypersensitivity reactions have also been reported, as well as flu-like, constitutional symptoms. It was also noted that possible renal effects of volanesorsen, seen with other drugs in this class and observed in the volanesorsen non-clinical studies, have yet to be rigorously assessed in FCS patients.

Overall, the poor tolerability of volanesorsen was a significant issue, and treatment discontinuation was common, such that of the original 33 patients treated with volanesorsen in CS6, only 10 continued in the CS7 extension study. This raised questions regarding the feasibility of long-term volanesorsen treatment of FCS, a life-long condition, particularly in light of the intensive monitoring that was proposed. This also underscored uncertainties regarding the treatments overall effectiveness, at least based on the studies to date.

Chiefly on the basis of concerns regarding the safety of volanesorsen and the adequacy of the proposed risk mitigation measures, along with uncertainty over the appropriateness of the sponsors proposed dosing regimen, Health Canada issued a Notice of Non-compliance (NON) for the Waylivra NDS.

The issues raised in the NON have not been adequately addressed in the Response to the NON. Data to support the efficacy of volanesorsen when administered according to the revised dosing and the appropriateness of the proposed initial dose are still lacking. The impact of the resulting TG lowering by volanesorsen on clinical endpoints of abdominal pain, pancreatitis and overall quality of life remain to be demonstrated.

The adequacy of the proposed thrombocytopenia risk minimization measures of intensive platelet monitoring and dose reductions have not been demonstrated. Notably, SAEs of platelet counts <25,000/mm³ continue to be reported amongst the patients still being treated with volanesorsen despite the proposed intensive platelet monitoring and dosing decrease algorithm. To date, these SAEs have generally been resolved with drug discontinuation and empirical treatment with intravenous glucocorticosteroids, and no deaths or serious bleeding events have been reported amongst the relatively few volanesorsen-treated FCS patients. However, minor bleeding events such as epistaxis and petechiae are common. The fact that the mechanism of volanesorsen-induced thrombocytopenia has not been identified and that predisposing risk factors have not been defined, makes adequate risk mitigation difficult. Among the continuing thrombocytopenia SAEs, onset has been highly variable, occurring up to more than 250 days post-initiation. Cases have occurred despite reduced biweekly dosing and increased weekly platelet monitoring. Additionally, notwithstanding the sponsors suggestion that patient weight is a risk factor, events have occurred in patients as heavy as 111 kilograms.

Based on the information submitted, Health Canada concluded that the risks and uncertainties associated with volanesorsen therapy in FCS patients, particularly the unpredictable events of severe thrombocytopenia, outweigh the evidence of benefit (which is currently limited to incompletely characterized decreases in triglyceride levels). Therefore a NON Withdrawal was recommended.