Targeted Therapeutics for Transthyretin Cardiac Amyloidosis
2019; Lippincott Williams & Wilkins; Volume: 139; Issue: 4 Linguagem: Inglês
10.1161/circulationaha.118.037593
ISSN1524-4539
Autores Tópico(s)Sarcoidosis and Beryllium Toxicity Research
ResumoHomeCirculationVol. 139, No. 4Targeted Therapeutics for Transthyretin Cardiac Amyloidosis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTargeted Therapeutics for Transthyretin Cardiac AmyloidosisProof That Precision Medicine in Heart Failure Is a Possibility? Sanjiv J. Shah, MD Sanjiv J. ShahSanjiv J. Shah Sanjiv J. Shah, MD, Division of Cardiology, Department of Medicine, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 676 N St. Clair St, Ste 600, Chicago, IL 60611. Email E-mail Address: [email protected] Division of Cardiology, Department of Medicine, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL. Originally published21 Jan 2019https://doi.org/10.1161/CIRCULATIONAHA.118.037593Circulation. 2019;139:444–447This article is a commentary on the followingEffects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated AmyloidosisArticle, see p 431Despite the availability of proven treatments for some patients with heart failure (HF), many patients, particularly those with HF and preserved ejection fraction (HFpEF), remain difficult to treat, resulting in persistently high morbidity and mortality in the majority of patients with HF. The lack of effective treatments, disappointing results of many HF randomized clinical trials (RCTs), and variable treatment responses even for proven therapies are all possible reasons for the poor prognosis of HF patients. In the context of this backdrop, it is not surprising that there has been growing interest and enthusiasm for "precision medicine" in order to improve outcomes for patients with the HF syndrome.1,2The intuitive appeal of precision medicine for heterogeneous clinical syndromes such as HF notwithstanding, in reality, achieving the goal of targeted therapeutics can be quite difficult. Indeed, there are those who believe that precision medicine is nothing more than hype that may never be realized because of a number of potential pitfalls.3 There is significant interindividual variation in treatment responses, thereby making it very difficult to identify a responder phenotype in RCTs.3,4 In addition, as a result of the biological complexity of clinical syndromes such as HF, biomarkers, genetic variants, or other diagnostic tests that purportedly identify patients as candidates for specific therapies may be inaccurate and may lead to inappropriate withholding or targeting of therapies. Furthermore, developing precision therapeutics typically requires understanding of the molecular pathogenesis of disease, which is difficult for vaguely defined clinical syndromes such as HF in which access to diseased tissue is not easy. Finally, by targeting therapeutics, we reduce the pool of eligible patients for RCTs, potentially making it difficult to enroll patients in these studies.Given the many potential pitfalls of precision medicine and targeted therapeutics, we may ask ourselves whether it is even worth trying to use novel methods2,5 to classify HF into subgroups that have more homogeneous disease pathophysiology and may respond in a more consistent manner to specific treatments. Fortunately, recent data from transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) RCTs6–8 provide compelling evidence that supports continued efforts for more precise classification of HF.ATTR-CM is an increasingly recognized infiltrative cardiomyopathy that results from the dissociation of the normal tetrameric form of TTR, which causes the release of TTR monomers that are prone to misfolding, thereby leading to TTR amyloid fibril formation and deposition in the myocardium.9 ATTR-CM can be the result of a mutation in the TTR gene (hereditary ATTR-CM), which causes a change in the amino acid sequence of TTR resulting in tetramer dissociation, or incompletely understood age-related misfolding of TTR (wild-type ATTR-CM). Several therapeutics, including patisiran (an RNA interference [RNAi] therapeutic),7 inotersen (an antisense oligonucleotide inhibitor),8 and TTR stabilizers (tafamadis6 and AG1010), are currently in development for ATTR-CM and for ATTR-associated polyneuropathy, the other major manifestation of the hereditary form of the disease. Most patients with ATTR-CM with HF have a relatively preserved ejection fraction (until late in the disease process) and typically fall under the umbrella of HFpEF, especially because these patients have increased left ventricular wall thickness and are often elderly. Although still underdiagnosed, ATTR-CM is increasingly recognized as a cause of HFpEF, especially as a result of advances in imaging with characteristic findings on echocardiography (speckle-tracking imaging demonstrating a relative sparing of longitudinal strain at the apex compared with the base), cardiac magnetic resonance (difficulty nulling the myocardium on delayed gadolinium enhancement imaging and high extracellular volume fraction on T1 mapping), and bone scintigraphy (eg, elevated ratio of heart to contralateral lung uptake on 99m-technetium pyrophosphate scanning). However, the development of each of these imaging techniques for ATTR-CM was based at least initially on pathological confirmation of TTR protein within amyloid deposits on endomyocardial biopsy samples. Thus, the identification of the ATTR-CM subgroup of HFpEF (particularly in patients with wild-type ATTR-CM or hereditary TTR amyloid [ATTR] with predominant cardiac manifestations [eg, the V122I mutation, which is present in 3%–4% of individuals with African ancestry]) was based on pathological tissue analysis of the primary diseased organ: the heart.Patients who develop HF as a result of ATTR-CM have a high morbidity and mortality, with progressive decline in functional status and quality of life and a high rate of hospitalization and premature death.9 The recently completed ATTR-ACT trial (Transthyretin Amyloid Cardiomyopathy Tafamidis Study) of the oral TTR stabilizer tafamadis demonstrated reduced all-cause mortality and cardiovascular hospitalizations, along with prevention of a rapid decline in 6-minute walk test distance and quality of life.6 In this issue of Circulation, Solomon and colleagues11 report the results of a prespecified subgroup analysis of the APOLLO trial7 (A Phase 3 Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Patisiran [ALN-TTR02] in Transthyretin-Mediated Polyneuropathy) of the RNAi therapeutic patisiran in patients with hereditary ATTR polyneuropathy. The prespecified cardiac subgroup included enrolled patients who had increased left ventricular wall thickness (≥13 mm) but no history of hypertension or aortic valve disease. The subgroup analysis demonstrated that patisiran, compared with placebo, reduced left ventricular wall thickness, improved left ventricular longitudinal strain, increased cardiac output, and lowered N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Lowering of NT-proBNP with patisiran was also seen in the overall APOLLO trial. Finally, there was a suggestion of improved cardiac outcomes in the patisiran group compared with the placebo group. These findings led the authors to conclude that patisiran may be helpful in halting the cardiac progression and thereby may lead to improved outcomes in patients with ATTR-CM.Although the study findings are compelling, several questions remain. The APOLLO trial enrolled only patients with hereditary ATTR polyneuropathy. Although the cardiac subgroup was prespecified, the findings were generated in a post hoc, exploratory analysis, and the sample size was relatively small (90 patisiran-treated patients versus 36 placebo-treated patients). In addition, the APOLLO trial was started before the broad recognition of bone scintigraphy as a diagnostic test for ATTR-CM. Future studies of hereditary ATTR polyneuropathy will have an easier time determining which of the enrolled patients truly have cardiac involvement via the use of scintigraphy for more accurate diagnosis of ATTR-CM. Furthermore, although a history of known cardiac involvement was not an exclusion criterion per se, those with New York Heart Association class III or greater symptoms were excluded. APOLLO also did not include the more prevalent wild-type form of ATTR-CM. Therefore, we do not know if patisiran is effective in patients with hereditary ATTR-CM with more advanced cardiac disease or in patients with wild-type ATTR-CM. The Table, which compares patient characteristics among the APOLLO cardiac subgroup,11 the ATTR-ACT trial (which specifically enrolled ATTR-CM patients [both hereditary and wild-type]),6 and an observational study that included hereditary and wild-type ATTR-CM12 demonstrate why this distinction between patient entry criteria is important. The cardiac subgroup in APOLLO was younger and had much less severe HF compared with typical patients with ATTR-CM; therefore, the results of the APOLLO cardiac subgroup analysis may not be generalizable to typical patients with ATTR-CM.Table. Comparison of Baseline Characteristics of the APOLLO Trial (Patisiran) Versus the ATTR-ACT Trial (Tafamadis)APOLLO11Cardiac Subgroup (n=126)ATTR-ACT6 Tafamadis(n=264)ATTR-ACTPlacebo(n=177)Quarta et al12ATTRm(n=36)Quarta et a12ATTRwt(n=56)Age, y*61 (54 to 67)75 (46 to 88)74 (51 to 89)62 (13)76 (6)Male sex, %7891897588Black race, %21415Not reportedNot reportedATTRwt, %076760100ATTRm, %10024241000 Predominant genotypes in patients with ATTRmVal30Met, Ala97Ser, Thr60AlaVal122Ile, Thr60Ala, Ile68LeuVal122Ile, Thr60Ala, Ile68LeuIle68Leu, Glu89Glyn, Val122IleNot applicableHypertension, %055483629NYHA class, % I4097Not reportedNot reported II606157Not reportedNot reported III or IV†030363332NT-proBNP, median (IQR), pg/mL837 (292 to 2354)2996 (1752 to 4862)3161 (1864 to 4825)1636 (770 to 3396)3708 (1807 to 6068)LV ejection fraction, mean (SD), %61 (10)48 (10)49 (10)57 (13)51 (11)Septal wall thickness, mm‡17 (15 to 19)16.7 (3.8)16.2 (3.5)16 (3)17 (3)LV global longitudinal strain, %‡−15.1 (−17.5 to −12.6)−9.3 (3.5)−9.4 (3.6)−15 (4)−11 (3)APOLLO indicates A Phase 3 Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Patisiran (ALN-TTR02) in Transthyretin-Mediated Polyneuropathy; ATTR-ACT, Transthyretin Amyloid Cardiomyopathy Tafamidis Study; ATTRm, hereditary (mutant) transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; IQR, interquartile range; LV, left ventricular; NT-proBNP, N-terminal pro-B-type natriuretic peptide; and NYHA, New York Heart Association.*Reported as median (25th–75th percentile) in the APOLLO and ATTR-ACT trials and mean (SD) in the study by Quarta et al.12†Patients in NYHA classes III and IV were excluded from the APOLLO trial, and patients in NYHA class IV were excluded from the ATTR-ACT trial.‡Reported as median (25th–75th percentile) in the APOLLO trial and mean (SD) in the ATTR-ACT trial and the study by Quarta et al.12Despite the encouraging results of the APOLLO cardiac subgroup analysis, a dedicated phase 3 RCT in ATTR-CM will be necessary to truly determine whether patisiran (or newer-generation RNAi therapeutics) is effective in ATTR-CM. Indeed, a subcutaneous formulation of an RNAi (resuviran) was associated with an increased mortality compared with placebo in patients with hereditary ATTR-CM enrolled in the phase 3 ENDEAVOUR randomized controlled trial (A Phase 3 Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ALN-TTRSC in Patients with TTR-Mediated Familial Amyloidotic Cardiomyopathy),13 which underscores the need to specifically test novel therapeutic classes in patients with ATTR-CM before their use even if they are effective in ATTR-associated polyneuropathy. Other unknowns include: (1) whether combination therapy with an RNAi (to reduce production of TTR) and a TTR stabilizer (to reduce the rate-limiting step of fibril formation) will further improve cardiac structure/function, symptoms, and outcomes in ATTR-CM; and (2) the effect of patisiran in patients with TTR mutations that were underrepresented in APOLLO but are relatively common (eg, V122I).Despite these limitations, the development of ATTR-CM as an increasingly well-recognized cause of HFpEF, along with the encouraging results of recent RCTs, teach us several lessons. First, although HF, particularly HFpEF, is a heterogeneous syndrome, careful determination of its pathogenesis via tissue sampling of the heart and other affected organs may be extremely useful in identifying subgroups with a distinct molecular basis. Prior failed HFpEF RCTs have no doubt included some patients with ATTR-CM and may have included patients with other HFpEF subtypes that require specific therapies that differ from those tested in these RCTs. Second, we should not give up hope on precision medicine but rather continue to strive to develop novel techniques—clinical, molecular, imaging, and statistical—to identify treatable subgroups and then investigate them further to determine their molecular basis. Finally, earlier recognition of ATTR-CM is essential. In APOLLO, as shown in the Table, patients in the cardiac subgroup who appeared to respond to patisiran had less advanced disease compared with patients with typical ATTR-CM.6,12 In addition, in ATTR-ACT, the patients in New York Heart Association class II appeared to respond the best to tafamadis.6 Systematic, automated screening of repositories of echocardiograms and ECGs using deep machine learning and computer vision techniques14 and screening at-risk patients with bone scintigraphy,9 ATTR-specific biomarkers,15 or genetic testing may allow earlier identification of patients with ATTR-CM.In conclusion, in a prespecified cardiac subgroup analysis of the APOLLO trial, patisiran was associated with improvements in cardiac structure/function, NT-proBNP, and outcomes. Although not definitive, these findings are encouraging for further development of patisiran for ATTR-CM. Potentially even more intriguing, however, is the possibility that the results of trials such as APOLLO and ATTR-ACT foretell a future of more successful applications of precision medicine to HF syndromes.DisclosuresDr Shah is supported by grants from the National Institutes of Health (R01 HL140731, R01 HL120728, and R01 HL107577) and the American Heart Association (16SFRN28780016 and 15CVGPSD27260148) and by Actelion, AstraZeneca, Corvia, and Novartis; and has received consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ionis, Ironwood, Merck, Novartis, Pfizer, Sanofi, and United Therapeutics.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circSanjiv J. Shah, MD, Division of Cardiology, Department of Medicine, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, 676 N St. Clair St, Ste 600, Chicago, IL 60611. Email sanjiv.[email protected]eduReferences1. Pitt GS. Cardiovascular precision medicine: hope or hype?Eur Heart J. 2015; 36:1842–1843. doi: 10.1093/eurheartj/ehv226CrossrefMedlineGoogle Scholar2. Shah SJ. Precision medicine for heart failure with preserved ejection fraction: an overview.J Cardiovasc Transl Res. 2017; 10:233–244. doi: 10.1007/s12265-017-9756-yCrossrefMedlineGoogle Scholar3. Senn S. Individual therapy: new dawn or false dawn?Ther Innov Regul Sci. 2001; 35:1479–1494.Google Scholar4. Senn S. Individual response to treatment: is it a valid assumption?BMJ. 2004; 329:966–968. doi: 10.1136/bmj.329.7472.966CrossrefMedlineGoogle Scholar5. Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, Bonow RO, Huang CC, Deo RC. 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Dittloff K, Iezzi A, Zhong J, Mohindra P, Desai T and Russell B (2021) Transthyretin amyloid fibrils alter primary fibroblast structure, function, and inflammatory gene expression, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00073.2021, 321:1, (H149-H160), Online publication date: 1-Jul-2021. Manolis A, Manolis A, Manolis T and Melita H (2019) Cardiac amyloidosis: An underdiagnosed/underappreciated disease, European Journal of Internal Medicine, 10.1016/j.ejim.2019.07.022, 67, (1-13), Online publication date: 1-Sep-2019. Shah S (2019) 20th Annual Feigenbaum Lecture: Echocardiography for Precision Medicine—Digital Biopsy to Deconstruct Biology, Journal of the American Society of Echocardiography, 10.1016/j.echo.2019.08.002, 32:11, (1379-1395.e2), Online publication date: 1-Nov-2019. Oghina S, Josse C, Bézard M, Kharoubi M, Delbarre M, Eyharts D, Zaroui A, Guendouz S, Galat A, Hittinger L, Fanen P, Teiger E, Mouri N, Montestruc F and Damy T (2021) Prognostic Value of N-Terminal Pro-Brain Natriuretic Peptide and High-Sensitivity Troponin T Levels in the Natural History of Transthyretin Amyloid Cardiomyopathy and Their Evolution after Tafamidis Treatment, Journal of Clinical Medicine, 10.3390/jcm10214868, 10:21, (4868) Related articlesEffects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated AmyloidosisScott D. Solomon, et al. Circulation. 2019;139:431-443 January 22, 2019Vol 139, Issue 4 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.037593PMID: 30664380 Originally publishedJanuary 21, 2019 Keywordsamyloidosisheart failureEditorialsprecision medicinePDF download Advertisement SubjectsHeart FailurePrecision Medicine
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