15 November, 2018

#amyloidosisJC 11/18/18: Tafamidis for ATTR amyloidosis!

The following is a GUEST-POST composed by Dr. Sascha Tuchman, a friend and colleague from the University of North Carolina in Chapel Hill, NC. Dr Tuchman will be co-moderating the final pre-ASH 2018 #amyloidosis journal club (#amyloidosisJC) with Untangling Amyloidosis 208 Trainee Travel Grant Awardee Dr. Sam Rubinstein

Dr Tuchman
Dr Rubinstein


For basic information on transthyretin (TTR) and how it forms amyloidosis, please refer to the background information in recent blog post dated 10/28/18, which summarized the APOLLO study of patisiranin hereditary transthyretin polyneuropathy.  Drugs like patisian work to suppress TTR synthesis by the liver (“A” in the below diagram). Another area of research interest has been in TTR stabilizers. If we refer to the image below, we see that TTR circulates in blood as a tetramer, meaning a single molecule made up of four pieces of TTR joined together. The TTR tetramer dissociates, resulting in single TTR pieces (monomers).  Those monomers can deposit in organs and form amyloid.  The theory behind TTR stabilizers is that making it harder for the tetramers to dissociate means there are fewer TTR monomers available to form amyloidosis (“B” in the below diagram). The “B” approach was first successfully tested using the drug diflunisal in patients with TTR neuropathy (Berk J et al., JAMA 2013).  The current “ATTR-ACT” study examined the oral TTR stabilizer tafamidis in patients with TTR amyloid cardiomyopathy.


Phase 3, international study of 441 patients with biopsy-proven TTR cardiac amyloidosis. Placebo-controlled and double-blinded.  Patients had to have clinical evidence of active heart failure, but less severe than symptomatic at rest (NYHA class <4).  Severe impairment of liver/kidney function or nutritional status precluded participation.  Patients were prohibited from receiving other TTR-directed agents such as diflunisal or doxycycline during study participation. 

Patients received either 80 or 20 mg of tafamidis daily orally or placebo (randomized in a 2:1:2 ratio). Stratified by TTR mutational status (wild-type vs mutated) and baseline NYHA class. Treatment was for 30 months and on completion, patients could opt to continue on to an extension study including open label tafamidis.

The primary endpoint was all-cause mortality followed by cardiovascular-related hospitalizations.  The planned sample size of 400 patients was 90% powered to detect a 30% reduction in mortality and in cardiovascular-related hospitalizations from 2.5 to 1.5 over the 30 months on study.


548 patients screened and 441 randomized. 264 patients received tafamidis and 177 placebo. ~24% in both groups had mutated TTR, with a similar frequency of specific TTR mutations in each group. Other baseline factors were similar, including NYHA class, NT-proBNP, and body mass index (BMI).

Both mortality and frequency of cardiovascular-related hospitalizations were improved with tafamidis. Specifically the hazard ratio for all-cause mortality was 0.7 (95% CI 0.51-0.96) and the relative risk for hospitalizations was 0.68 (0.56-0.81).  The mortality benefit appeared after approximately 18 months on study. Benefits were consistent across all subgroups except NYHA class 3 CHF, in which mortality was the same but rate of hospitalizations was higher for tafamidis.
Functional measures of the heart also showed a slower decline with tafamidis than placebo, such as distance walked in 6 minute walk test and patient-reported symptoms.

There were no significant adverse events for tafamidis, and discontinuation from study as a result of adverse events was more common for placebo-treated than tafalidis-treated patients.


Tafamidis reduced mortality and cardiovascular-related hospitalization in patients with cardiomyopathy resulting from either wild-type or mutated TTR.  Markers of heart function such as 6 minute walk test and NT-proBNP suggest that tafamidis doesn’t stop the disease, rather it slows its progression.


Tafamidis is clearly a game-changer in the sense that it’s the first medication that will likely be FDA-approved for TTR cardiomyopathy. However, the fact that the disease still progresses indicates that more needs to be done. In particular, combining tafamidis with drugs that perturb other aspects of TTR formation could be promising. (Recall in the diagram above that tafamidis is a “B” drug.  Other drugs such as patisiran and inotersen are “A” drugs.  Combining a B drug with an A drug and/or a C drug may improve the benefit overall to patients with these diseases by further slowing or even reversing damage caused to the heart by TTR.)

EDITOR'S ADDENDUM: looking forward to this week's installment of #amyloidosisJC, at 8 pm EST on Sunday November 18, 2018. Remember to use the #amyloidosisJC hashtag when you log on! Also, hoping to see you in San Diego for the Untangling Amyloidosis 2018 Friday Satellite Symposium. Turns out Dr Tuchman is joining the faculty speaker roster! 

02 November, 2018

#amyloidosisJC 11/4/18: Daratumumab as therapy for AL amyloidosis

We will be discussing this short, sweet, yet practice-changing article demonstrating the significant therapeutic efficacy of daratumumab in a series of patients with AL amyloidosis. Since this publication, there have been numerous other abstracts and a few publications expanding on these findings. We'll discuss them all on Sunday night, 11/4/18, at 8 pm EST.

click HERE for a link to a similar series we just published with colleagues at the Cleveland Clinic, and HERE for an article by Dr Vaishali Sanchorawala (@vsanchorawala) summarizing other data on this topic presented last year at #ASH17

Tweet ya Sunday. I'll be logging in from ALBANIA. Pix of Tirana and from the 13th Congress of the Albanian Association of Hematology to follow. 

28 October, 2018

#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

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.

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.