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Goodman & Gilman's: Annual FDA Approvals


Brand Name


Pharmacological Class

Transthyretin-directed short interfering RNA1

FDA Indication

Polyneuropathy of hereditary transthyretin-mediated amyloidosis


Inotersen is a single-stranded 2′-O-methoxyethyl–modified antisense oligonucleotide (ASO).44 Patisiran contains small interfering double-stranded ribonucleic acid (siRNA) sequences formulated for targeted delivery to hepatocytes.45 Both are gene-silencing therapies that prevent mRNA molecules from performing the specific translation activity that generates transthyretin (TTR) proteins.44,45 TTR is a serum and cerebrospinal fluid transport protein for vitamin A and thyroxine that is produced in the liver (predominantly), choroid plexus, and retina.76 Disengagement from the translation process leads to rapid degradation of the endogenous TTR mRNA and silencing of the TTR gene.44,45 Inotersen and patisiran were both approved by FDA in 2018 for the treatment of polyneuropathy in adults with hereditary transthyretin-mediated amyloidosis (hTTRA).44,45

Patients with hATTR have mutations of the TTR gene that cause upregulation and misfolding of TTR protein molecules. Accumulation of their dysfunctional degradation fragments into amyloid deposits in the peripheral nervous system, heart, and other tissues results in the disease manifestations associated with hATTR.77 Patients with hATTR typically exhibit progressive GI and autonomic nervous system dysfunction, peripheral polyneuropathy, cardiomyopathy, and nephropathy.77 In patients with hATTR polyneuropathy, downregulation of the mutated gene through either ASO (inotersen) or iRNA (patisiran) mechanisms slows progression of the peripheral neurologic manifestations of the disease by reducing the circulating levels of wild-type and mutant TTR, thereby making fewer dysfunctional degradation fragments available for accumulation.44,45,77-80 Predictably, patients treated with inotersen or patisiran require co-therapy with supplemental vitamin A at the recommended daily dose.44,45

FDA approval of both inotersen and patisiran were granted on the basis of improved objective measures of cranial nerve function, muscle strength, reflexes, touch-pressure and heat-pain sensations, heart rate response to deep breathing, postural blood pressure, and peripheral nerve electrophysiology.44,45 Inotersen was studied in 112 subjects with hATTR polyneuropathy treated for up to 65 weeks (NCT01737398)44,78,80 and patisiran was studied in a similar population of 135 subjects treated for up to 72 weeks (NCT01960348).45 Both therapies demonstrated similar benefits with respect to neuropathy, polyneuropathy, cardiac manifestations, and quality of life.44,45,79-81 The cost of both therapies is expected to be approximately $450,000/year.82

  • Inotersen: Inotersen was granted orphan drug status for the treatment of transthyretin amyloidosis in 2012.21 Inotersen is the fifth drug employing the antisense mechanism to be brought to market in the U.S. and the first TTR-targeted ASO. It was preceded to market by four other ASOs: eteplirsen for Duchenne muscular dystrophy, fomivirsen (discontinued in the U.S.) for cytomegalovirus retinitis, mipomersen for homozygous familial hypercholesterolemia, and nusinersen for spinal muscular atrophy. Inotersen binds to the “sense” strand of mutant and wild-type mRNA coding for the TTR protein and causes its degradation by ribonuclease H.44,78 The dose of inotersen is 284 mg administered as a subcutaneous injection once weekly.44 With repeat weekly dosing, inotersen therapy reduces mean serum TTR by 68%–74%, regardless of TTR mutation.44 The elimination half-life is 32 days.44 Inotersen is metabolized in tissues by endonucleases, forming shorter inactive oligonucleotides that are then metabolized by exonucleases to form nucleotides of various lengths.44 Urine is the main route of elimination for inotersen and its metabolites.44

    Inotersen therapy is associated with serious and potentially life-threatening adverse effects including thrombocytopenia, adverse inflammatory and immune reactions, development of antidrug antibodies, and renal, hepatic, and neurologic toxicities.44 Due to the serious safety risks, prescribing and distribution of inotersen is restricted to the requirements of the Tegsedi REMS Program.83 The REMS program requires prescriber and pharmacy certifications along with patient enrollment. Candidates for initiation of therapy (1) must have sufficient platelets and a urine protein-to-creatinine ratio ≥1000 mg/g; (2) must be able to adhere to the recommended laboratory monitoring before, during, and after discontinuation of therapy; and (3) must be eligible to receive glucocorticoids and potentially other potent immunosuppressive medications to manage serious consequences of therapy if required.

  • Patisiran: Patisiran was granted orphan drug status for transthyretin-mediated amyloidosis in 2012.21 It represents the first-in-class siRNA therapy to win FDA approval.1,84 Patisiran contains TTR-directed double-stranded RNA sequences formulated as nanoparticles.45 The nanoparticles are encapsulated in apolipoprotein E (ApoE)-coated lipid carriers for targeted delivery to ApoE receptors on hepatocytes.45,79,81,85 The structure of patisiran is depicted in Figure P1-3.

    Patisiran reduces the amount of TTR mRNA available for translation by engaging in a natural process of gene downregulation that uses endogenous siRNA molecules to disengage mRNA strands actively involved in gene translation.76,78,81 The sequence of steps to achieve TTR gene silencing by patisiran is roughly as follows: (1) in a series of steps that involve opsonization, ApoE receptor binding, endocytosis, ionization, and finally membrane fusion, patisiran siRNA sequences are released from their lipid encapsulation into the cytoplasm of hepatocytes,78,85 (2) the patisiran siRNA sequences are taken up by the cytoplasmic RNA-induced silencing complex (RISC), (3) the patisiran siRNA double-strands are unwound, (4) argonaute-2 (Argo-2) cleaves and discards the patisiran siRNA passenger (sense) strand, (5) the remaining patisiran (antisense) siRNA strand guides the RISC complex to its complementary mRNA sequence where it binds to a conserved sequence in the 3′(untranslated) region of both mutant and wild-type TTR mRNA, and (6) Argo-2 within the RISC/siRNA complex then frees the TTR mRNA to cause its rapid degradation.85-87

    Patisiran therapy is administered as a 0.3-mg/kg (max 30 mg) IV infusion over ~80 minutes every 3 weeks.45 With repeat dosing, therapy with patisiran reduces mean serum TTR by approximately 80%–90% regardless of TTR mutation.45 Steady state is reached by 24 weeks of treatment.45 Patisiran is formulated as a lipid complex specifically for targeted distribution primarily to the liver. The half-life for elimination is 3.2 ± 1.8 days.45 As for endogenous RNA, patisiran is mainly cleared through metabolism by nucleases to nucleotides of various lengths.45 Patisiran has not been studied in patients with severe renal impairment, in those with moderate or severe hepatic impairment, or in liver transplant recipients. Infusion reactions necessitate the use of corticosteroid, acetaminophen, and both H1- and H2-antihistamine premedications prior to patisiran administration.45 Infusion reactions are managed by immediately slowing or interrupting the infusion. Other serious premarket adverse reactions included atrioventricular (AV) heart block, including three cases of complete AV block, and vision abnormalities.45 Antidrug antibodies were detected in seven of 194 premarket test subjects.45

Figure P1-3

Structure of patisiran88 (PubChem SID: 350082694). Abbreviations of modified RNA: Um, 2'-O-methyluridine; Cm, 2'-O-methylcytidine.

Further Reading in Goodman & Gilman’s