A comparative analysis of international health technology assessments for novel gene silencing therapies: patisiran and inotersen

National Institute for Health and Care Excellence

Both patisiran and inotersen were recommended by NICE within their marketing authorizations (15,20). The NICE appraisal for patisiran indicated there was evidence suggesting the drug may provide long-term benefits by stopping the progression of hATTR amyloidosis and potentially reversing the condition (20). Clinical experts consulted by NICE explained that “the likelihood of halting or reversing amyloid deposition, and so reducing neuropathy and improving cardiac function, is dependent on the extent of reduction in TTR” levels in the patient (15,20). While the impact on the progression of the disease may vary among patients due to differences in production and turnover of amyloid in the body, the experts consulted believed that, although not validated, most patients would derive a clinically meaningful benefit from a TTR reduction of 80% or more (20). The NICE appraisal noted that in the patisiran group of the phase III trial, APOLLO, the mean reduction of serum TTR over 18 months was 87.8% (20). Additionally, the clinical experts believe that TTR reduction would be sustained over time with continued patisiran treatment because as TTR production is suppressed, the body is able to clear accumulated amyloid deposits (20). Therefore, the committee concluded that the clinical evidence from the APOLLO study showed that patisiran was of considerable benefit to patients and had the potential to stop and reverse disease progression (20). The inotersen group of the phase III NEURO-TTR trial showed a TTR reduction of 74% over 15 months (15). The committee concluded that while inotersen did not decrease serum TTR levels by 80%, it provided a clinical benefit (15). The NICE appraisal reported that inotersen slowed the progression of neuropathy but did not stop progression or reverse the disease (15).

The NICE appraisal reported that patisiran reduced disability and improved HRQoL compared to baseline, which allowed patients to maintain their independence and dignity, resume or continue to carry out daily activities including returning to work, and participating in a more active social and family life (20). The NICE committee consulted patient experts who reported that the benefits seen in the APOLLO trial had “a marked effect on patients’ lives, including regaining a social life, not having to wear incontinence pads, and being able to go to a restaurant without worrying about debilitating bowel symptoms.” The NICE appraisal concluded that there was also evidence suggesting that patisiran may provide long-term HRQoL benefits to patients by stopping and potentially reversing the condition (20). Patient experts consulted during the NICE appraisal for inotersen indicated that slowing disease progression was valuable to them as it may allow them to remain in the earlier stages of disease, with a better quality of life, for longer (15).

The NICE appraisals for both patisiran and inotersen included assessment of the safety profiles of both therapies. The main safety concerns for inotersen highlighted by the NICE committee were related to glomerulonephritis and thrombocytopenia (15). One death in the inotersen arm, from intercranial hemorrhage caused by severe thrombocytopenia, was considered to be related to the study drug (15). After monitoring of platelet levels was implemented, no other severe thrombocytopenia events occurred in the NEURO-TTR trial, and the committee acknowledged that the major safety risks associated with inotersen can be effectively managed with routine monitoring in clinical practice (15). NICE reported the safety profile for patisiran was favorable, with a low stopping rate and no adverse events (AEs) that involved glomerulonephritis (20).

Scottish Medicines Consortium

The SMC assessment reports accepted patisiran and inotersen for use within NHS Scotland based on the substantial improvement in HRQoL associated with both treatments (22,23).

Clinical experts consulted by the SMC considered that patisiran represented a “major therapeutic advancement” and they noted that patisiran improved HRQoL and reduced disability compared to best supportive care (BSC) (22). The clinical experts consulted in the appraisal of inotersen considered it a “therapeutic advancement” that slowed the progression of polyneuropathy (23).

The SMC assessments included patient and clinical engagement (PACE) meetings consisting of patient group representatives and clinical specialists who considered the added value of the ultra-orphan drugs in the context of treatments currently available from NHS Scotland. The PACE meeting concluded that patisiran “has the potential to halt or slow progression of disease and in some cases improves symptoms,” with the expectation of continued clinical improvement as long as TTR levels remain lowered (22). At the PACE meeting for inotersen, it was noted that compared to placebo, inotersen stabilizes progression of polyneuropathy and the corresponding decline in HRQoL (23).

Canadian Agency for Drugs and Technologies in Health

CADTH CDEC recommended based on separate assessments that both patisiran and inotersen be reimbursed for the treatment of polyneuropathy in adult patients with hATTR amyloidosis, under certain conditions (21). CADTH CDEC recognized that both patisiran and inotersen were associated with a statistically significant improvement compared with placebo for the primary and secondary endpoints of each pivotal study, respectively (21).

The CADTH report for patisiran included the result of an indirect treatment comparison (ITC) submitted by the manufacturer based on the two phase III studies APOLLO (patisiran) and NEURO-TTR (inotersen) (21). The ITC was conducted using two methods: one using the Bucher method and a second using the matching-adjusted indirect comparison (MAIC) method. Both analyses suggested that patisiran was statistically superior to inotersen for the change from baseline in modified Neuropathy Impairment Score + 7_ionis (mNIS + 7_ionis) and the Norfolk Quality of Life Diabetic Neuropathy Instrument (Norfolk QoL-DN) scores (21). CADTH concluded that while the differences between treatments were statistically significant, the clinical significance of this was unclear, given the lack of published minimum clinical important difference (MCID) values for these outcome measures (21).

Gemeinsamer Bundesausschuss

The G-BA reported a “considerable additional benefit” for patisiran in the treatment of hATTR amyloidosis (19). This is the second highest possible designation from the G-BA, which corresponds to “a considerable improvement in therapy-related benefit, not previously achieved by BSC, such as recovery from disease, a considerable increase in life, long-term relief from severe symptoms, or extensive avoidance of severe side-effects” (28). The G-BA classified the extent of the additional benefit for inotersen as “not quantifiable” (18). This is the lowest possible designation by the G-BA for an orphan treatment, as an “additional benefit” is considered to be proven by the existence of the marketing authorization (28).

The G-BA assessed each study endpoint for the APOLLO and NEURO-TTR clinical trials in terms of statistical significance and clinical relevance. Only the endpoints that met both conditions were taken into consideration in the assessment of the additional therapeutic benefit for each treatment (18,19). The endpoints considered as statistically significant and clinically relevant by the G-BA for patisiran included: gait speed (Ten Meter Walk Test; 10-MWT), health status (EuroQol 5 Dimension Visual Analog Scale; EQ-5D VAS), impairments regarding daily activities (Rasch-built Overall Disability Scale; R-ODS), and HRQoL (Norfolk QoL-DN) (19). These endpoints were regarded as a “considerable addition to the benefits” of patisiran even though the G-BA viewed their bias potential as high due to an imbalance in the number of missing observations for the placebo arm compared to the patisiran arm of APOLLO. The G-BA report explained that although the per-protocol treatment duration was 18 months for both the patisiran and the control arms, the mean treatment duration was longer for patisiran (18 months vs. 15 months), as there were more patients who discontinued in the placebo group (19). The G-BA assessment considered the majority of results from the NEURO-TTR trial “not quantifiable,” with the exception of the physical functioning domain of the 36-Item Short Form Health Survey (SF-36) that measures HRQoL. A “positive effect” was reported for the SF-36, although the G-BA noted uncertainty regarding the possible overestimation of the effect (18).

The G-BA assessed the safety profile of both patisiran and inotersen. From the APOLLO trial, they noted that fewer AEs led to the discontinuation of treatment in the patisiran group than in the placebo group (19). Furthermore, there were more AEs in the placebo arm than in the patisiran arm. As the proportion of patients with at least 15 months treatment duration was higher in the patisiran arm than in the control arm, the G-BA reported the safety results from APOLLO were potentially biased to the disadvantage of patisiran (19). In the safety analysis of the NEURO-TTR trial, the G-BA noted that the higher level of AEs that resulted in discontinuation in the inotersen arm resulted in a “statistically significant disadvantage” for inotersen compared to placebo (18).

Haute Autorité de Santé

In their assessment of the place in therapy, HAS concluded patisiran should be considered a first-line treatment (16). The evaluation of inotersen by HAS concluded the drug should be considered a second-line treatment for patients who are unable to receive patisiran (17).

Neuropathy impairment was described as stabilized or improved at 18 months in the HAS appraisal for patisiran compared to baseline (29). The appraisal for inotersen described the treatment as demonstrating less neuropathy impairment than placebo at 15 months (30). The impact on HRQoL was described as “favorable” in the HAS appraisal for patisiran (29). In the appraisal for inotersen, the impact on HRQoL was described as “modest” (30).

When considering the safety profiles of both drugs, the HAS appraisal for patisiran reported an acceptable safety profile at 18 months that was characterized mainly by infusion-related reactions that were managed by premedication (16,29). The HAS appraisal for inotersen noted the safety profile was characterized by the risk of thrombocytopenia that can be serious or even fatal—it was the cause of one death during the NEURO-TTR study, and the risk of glomerulonephritis which required additional renal function monitoring (17,30). The inotersen appraisal also mentioned the existence of patisiran as an alternative treatment, with a safety profile that was considered to be more favorable in the short term (17,30).

Tandvårds-och Läkemedelsförmånsverket

In their overall assessment of patisiran and inotersen, TLV made the assessment that “it is not possible to say that one drug is better than the other in terms of treatment effect” (31). TLV reported that patisiran showed statistically significant and clinically relevant positive effects for the primary, secondary, and exploratory endpoints of the APOLLO, including patient-reported outcomes (25). They further noted a sustained effect of patisiran in the long term based on the follow-up data to 36 months (25). The TLV analysis of inotersen reported statistically significant and clinically relevant positive effects for the primary composite endpoint from NEURO-TTR compared to placebo (26). TLV noted sustained efficacy for inotersen over the 15-month period of the NEURO-TTR study (26).

The TLV assessment of patisiran did not include any assessment or conclusion on the safety profile of patisiran (25). The assessment for inotersen indicated that while regular monitoring of platelet counts and renal and liver function is mandatory, there remains a risk of serious side effects with inotersen treatment compared to placebo (26).

Institute for Clinical and Economic Review

ICER reported a “moderate certainty of a substantial net health benefit with high certainty of at least a small net health benefit compared to best supportive care” for patisiran (24). As a result, they rated the net health benefit for patisiran as incremental or better than that of BSC, leading to a grade of B+ in the ICER evidence rating matrix (24). ICER reported a “moderate certainty of a comparable, small or substantial net health benefit for inotersen relative to BSC, with high certainty of at least a comparable net health benefit” (24). As a result, they rate the net health benefit for inotersen as comparable or better to that of BSC (ICER evidence rating matrix: C+) (24).

In their appraisal, ICER concluded that patisiran was associated with an improvement from baseline in neuropathy symptoms (24). Additionally, for the exploratory endpoint of neuropathy stage (disease progression), ICER noted that patients treated with patisiran were stable or improved compared to BSC in the APOLLO trial (24). The ICER appraisal of inotersen concluded that patients treated with the drug did not experience an improvement from baseline in neuropathy symptoms, but rather exhibited a slowing in worsening of neuropathy and stabilized neuropathy-related HRQoL relative to placebo (24). The report noted that the delay of neuropathy progression due to treatment with inotersen was sustained for 2 years; however, ICER indicated the stability in neuropathy-related HRQoL may not be durable. Additionally, ICER reported there was no evidence of improved stabilization of disease progression, as measured by polyneuropathy disability (PND) score, for patients treated with inotersen as compared to BSC (24).

ICER considered the safety profiles of both drugs and noted a “low-moderate” risk safety profile due to concomitant steroid administration for patisiran (24). Additionally, ICER reported a decreased frequency of AEs compared to BSC and no difference in mortality between treatment arms in APOLLO. As all deaths in the patisiran arm were cardiovascular in nature, a possible safety signal of complete heart block was reported; however, this finding was qualified by the statement that heart block can be observed in hATTR amyloidosis patients with cardiomyopathy. Finally, ICER noted that the post hoc analysis in patients with cardiac involvement demonstrated a statistically significant reduction in the composite rate of all-cause hospitalization and mortality in the patisiran arm compared to the BSC arm (24).

When considering the safety profile from the NEURO-TTR trial, ICER concluded that there were potential safety signals due to thrombocytopenia and glomerulonephritis in patients treated with inotersen (24). Uncertainty regarding the safety of inotersen treatment was reported given that all deaths in the NEURO-TTR trial occurred in the inotersen arm, and one patient death was considered possibly drug related. ICER suggested that the enhanced monitoring protocol added to the trial may offer assurance that the risk of thrombocytopenia may be manageable (24).

Infarmed

Infarmed recommended patisiran be reimbursed for the full indication in hATTR amyloidosis patients with stage 1 or stage 2 polyneuropathy (32). The report for inotersen recommended reimbursement for the treatment of patients with hATTR amyloidosis stage 2 polyneuropathy and patients in stage 1 who do not respond, who are intolerant, or ineligible for previous pharmacological treatment with tafamidis (33).

Both reports noted that while the magnitude of treatment effect was not possible to quantify, respectively, it may be considered substantial. The assessment of patisiran did not raise any safety concerns (32). The assessment of inotersen reported important toxicity problems that should be monitored (33).

Agencia Española de medicamentos y productos sanitarios

The AEMPS reports for patisiran and inotersen noted the lack of direct comparative studies between either treatment. Despite documenting the limitations of comparing the differences in endpoints (mNIS+7 vs. mNIS+7_ionis), the reports noted that an unadjusted indirect comparison showed an apparent greater effect of patisiran over inotersen on neuropathy (34,35). The report for patisiran also noted a difference in safety profiles between the two treatments characterized by infusion reactions and ocular alterations for patisiran; and thrombocytopenia, risk of bleeding, and glomerulonephritis for inotersen (34).

Summary of the clinical and comparative economic evidence of the HTA appraisal

The summary of the clinical and comparative pharmacoeconomic evidence from the HTAs reports is presented in Table II.