#amyloidosisJC 10/28/18: Patisiran vs Placebo for hATTR familial polyneuropathy

This installment of #amyloidosisJC focuses on the positive results of a randomized trial comparing the effects of Patisiran to placebo in ATTR amyloidosis patients with primarily amyloid-related neurological disease. Click HERE for a link to the actual article. 

The following is a nice summary of the article written by tonight’s co-moderator, Suresh Balasubramanian, @malignantheme, a hematology/oncology fellow at the Karmanos Cancer Institute
Background: Amyloidosis is a group of diseases characterized by extracellular deposition of fibrils comprised of misfolded proteins and other molecules such as glycosaminoglycans and SAP, resulting in end organ damage. Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominant, multi systemic, progressive, life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The liver is the primary source of circulating tetrameric transthyretin protein. In hATTR, fibrils containing both mutant and wild-type transthyretin deposit as amyloid in peripheral nerves and the heart, kidney, and gastrointestinal tract resulting in polyneuropathy and cardiomyopathy. If left untreated, death typically ensues within 10 years after the onset of symptoms. Historically, management was largely supportive, with the disease-modifying option of liver transplantation available to a select subset of patients.
Patisiran, a hepatically directed investigational RNAi therapeutic agent harnesses the endogenous mechanism that controls the expression of a specific gene, thereby reducing the production of mutant and wild-type transthyretin.
Phase 1 and 2 studies already showed sustained dose related reduction of wild type and mutant transthyretin levels. click HERE for a link to a previous #amyloidosisJC where we discussed this work.

This phase 3 study was designed to compare against the placebo exploring the benefits of lowering transthyretin levels in reducing the rate of progression of neuropathy including other secondary end points related to improvement in quality of life.
Trial Design: Multicenter, randomized, double-blinded, placebo-controlled comparison of patisiran to placebo (2:1 randomization)
19 countries, 44 sites, 225 patients were randomized in 2:1 ratio to receive patisiran (148) vs. placebo (77)  (12/1/2013-1/30/2016)
Key Inclusion criteria:
Male or female of 18 to 80 years of age with a diagnosis of FAP with documented TTR mutation
Have a NIS of 10 to 100
Key Exclusion criteria:
Patients with previous liver transplantation or who were planning to undergo liver transplantation during the trial period
NYHA class of III or IV
Have a serum creatinine >1.5 × ULN
Known primary (immunoglobulin) amyloidosis or leptomeningeal amyloidosis
Anticipated survival is less than 2 years, in the opinion of the Investigator

Stratification:
NIS 5 to 40 vs. 50 to 130
V30M vs. other pathogenic variants
Previous transthyretin stabilizer yes vs. no
Efficacy assessment:
Primary end point:
Change from baseline to 18 months in the modified Neuropathy Impairment Score+7 (mNIS+7)
The mNIS+7 includes the modified NIS (weakness and reflexes), NCS Σ5, QST, as well as autonomic assessment through postural blood pressure
Secondary end point:
Patient-reported QOL will be evaluated using the Norfolk QOL-DN and the EQ-5D.
Disability will be reported by patients using the R-ODS.
Gait speed (10-m walk test, with speed measured in meters per second)
Nutritional status (modified body mass index [BMI]
Patient-reported autonomic symptoms (Composite Autonomic Symptom Score 31; range, 0 to 100, with higher scores indicating more autonomic symptoms).
All efficacy end points were assessed at baseline and at 9 and 18 months, except modified BMI (at baseline and at weeks 12, 27, 51, 66, and 78).
Patient Allocation:

Treatment: Patisiran (0.3 mg per kilogram of body weight) or placebo intravenously over a period of approximately 80 minutes, once every 3 weeks for 18 months.
Notable Patient Characteristics:
Median age in both the groups is 62 yo. 75% in both groups were males. 72% of study populations were whites and only 2% were blacks. 38% of patisiran group and 52% of placebo group patients had V30M mutation. Previous use of tetramer stabilizer, FAP stage, polyneuropathy score and NYHA class were equally balanced between both the groups.
Results:
Primary composite endpoint:
The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group. At 18 months, the least squares mean (±SE) change in mNIS+7 from baseline was −6.0±1.7 with patisiran, as compared with 28.0±2.6 with placebo (least-squares mean difference, −34.0 points; 95% confidence interval [CI], −39.9 to −28.1; P<0.001)
74% in patisiran group vs. 14% in placebo group showed less than 10-point increase from baseline in the mNIS+7 at 18 months

Secondary end points: 
At 18 months, 51% of patisiran group vs. 10% of placebo group had an improvement (decrease from baseline at 18 months) in the Norfolk QOL-DN score.
Improvement relative to baseline was also seen in gait speed in the 10-m walk test (53% of the patisiran group patients vs. 13% placebo group) and motor strength (40% vs. 1%), as determined by the NIS-weakness test at 18 months.
Select Exploratory End Points:
Measures of neuropathy stage also favored patisiran, compared to placebo group.
In the cardiac subpopulation, the geometric mean baseline level of NT-proBNP in patisiran group was 726.9 pg per milliliter (coefficient of variation, 220.3) compared to 711.1 pg per milliliter (coefficient of variation, 190.8%) in the placebo group. At 18 months, the adjusted geometric mean ratio to baseline was 0.89 with patisiran and 1.97 with placebo (ratio, 0.45; P<0.001), representing a 55% difference in favor of patisiran.
Patisiran treatment was also associated with better cardiac structure and function than placebo, including significant differences in mean left ventricular wall thickness (P = 0.02) and longitudinal strain (P = 0.02) at 18 months.
Safety: Similar rates of AEs and SAEs between grps. No thrombocytopenia or renal failure as reported in the other RNAi therapy trial.
Our Analysis:
Sample size definitely substantial for the rare disease.
Response seems to be really promising. However, most endpoints in trial not used in routine clinical practice. So assessing individual patient response will be a challenge.


Relationship between the mNIS+7 response was analyzed with respect to relative serum transthyretin supression: clear correlation with patisiran. But association too loose to be clinically helpful. Further, there was NO association between TTR suppression and clinical response w inotersen…no way to measure misfoled vs normal TTR presently.
Extended follow-up of trials involving RNAi will be needed to fully understand the longer-term clinical benefits and risks of these drugs, as well as durability of such responses. Further, it remains to be determined the optimal use of RNAi therapy in a larger hATTR population, including patients with predominantly cardiac symptoms.
The significant costs associated with the use of these medications are also already being raised as an obstacle to use.

Nevertheless patisiran (and inotersen) should be viewed as a milestone in the management of hATTR amyloidosis, worthy of a spirited online journal club discussion. We also plan to discuss the results of another randomized trial comparing the antisense oligonucleotide inotersen versus placebo in a very similar group of patients, published in the same issue of the New England Journal of Medicine.