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    Tofersen

    DEVELOPMENTS

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    2D Structure
    Also known as: Tofersen
    Molecular Formula
    C230H317N72O123P19S15
    Molecular Weight
    7128  g/mol
    InChI Key
    AZBXTZOFHIRMCD-SIVATHJTSA-N
    Tofersen is under an intrathecally administered antisense oligonucleotide targeting the mutated SOD1 gene that causes amyotrophic lateral sclerosis (ALS). Although there were various causes of ALS, 2% of ALS cases are due to SOD1 mutations, with more than 200 SOD1 mutations documented. Tofersen was granted accelerated approval from the FDA on April 25, 2023, as the first treatment for adults with ALS caused by SOD1 mutation. Continual FDA approval is contingent on clinical benefits from ongoing trials, particularly the Phase 3 ATLAST study in people with presymptomatic SOD1-ALS. Tofersen demonstrated efficacy in reducing the concentration of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks, although the ALS Functional Rating ScaleRevised did not improve. However, it could potentially be due to the short timeframe of tofersen treatment, and more longterm trials are being conducted to confirm this hypothesis.
    Tofersen is an Antisense Oligonucleotide.
    1 2D Structure

    2D Structure

    2 Identification
    2.1 Computed Descriptors
    2.1.1 IUPAC Name
    [(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3S,5R)-3-[[(2R,3S,5R)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-3-[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-3-[hydroxy-[[(2R,3R,4R,5R)-3-hydroxy-4-(2-methoxyethoxy)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphinothioyl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-sulfanylphosphoryl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methoxy-hydroxyphosphinothioyl]oxy-5-(2-amino-6-oxo-1H-purin-9-yl)-4-(2-methoxyethoxy)oxolan-2-yl]methyl [(2R,3R,4R,5R)-2-[[[(2R,3R,4R,5R)-5-(4-amino-5-methyl-2-oxopyrimidin-1-yl)-2-(hydroxymethyl)-4-(2-methoxyethoxy)oxolan-3-yl]oxy-hydroxyphosphinothioyl]oxymethyl]-5-(6-aminopurin-9-yl)-4-(2-methoxyethoxy)oxolan-3-yl] hydrogen phosphate
    2.1.2 InChI
    InChI=1S/C230H317N72O123P19S15/c1-98-52-283(220(314)266-178(98)231)139-42-109(407-430(333,445)373-66-124-114(47-144(391-124)288-60-106(9)201(308)280-228(288)322)412-435(338,450)380-72-129-118(51-148(396-129)296-91-259-151-185(238)247-85-253-191(151)296)416-439(342,454)383-79-135-160(170(360-34-24-350-14)209(400-135)291-55-101(4)181(234)269-223(291)317)417-426(325,326)369-77-133-166(176(366-40-30-356-20)213(402-133)299-94-262-154-188(241)250-88-256-194(154)299)424-443(346,458)385-81-137-162(172(362-36-26-352-16)214(405-137)300-95-263-155-195(300)271-217(242)274-204(155)311)419-427(327,328)368-75-131-164(174(364-38-28-354-18)210(399-131)292-56-102(5)182(235)270-224(292)318)422-441(344,456)382-74-130-158(304)168(358-32-22-348-12)207(398-130)293-62-108(11)203(310)282-230(293)324)120(387-139)64-372-431(334,446)409-111-44-141(285-57-103(6)198(305)277-225(285)319)389-122(111)67-374-432(335,447)410-112-45-142(286-58-104(7)199(306)278-226(286)320)390-123(112)68-375-433(336,448)411-113-46-143(287-59-105(8)200(307)279-227(287)321)392-125(113)69-377-438(341,453)415-117-50-147(295-90-258-150-184(237)246-84-252-190(150)295)394-127(117)70-378-434(337,449)408-110-43-140(284-53-99(2)179(232)267-221(284)315)388-121(110)65-376-437(340,452)414-116-49-146(294-89-257-149-183(236)245-83-251-189(149)294)395-128(116)71-379-436(339,451)413-115-48-145(289-61-107(10)202(309)281-229(289)323)393-126(115)73-381-440(343,455)423-165-132(401-212(175(165)365-39-29-355-19)298-93-261-153-187(240)249-87-255-193(153)298)76-370-429(331,332)420-163-138(406-215(173(163)363-37-27-353-17)301-96-264-156-196(301)272-218(243)275-205(156)312)82-386-444(347,459)425-167-134(403-216(177(167)367-41-31-357-21)302-97-265-157-197(302)273-219(244)276-206(157)313)78-371-428(329,330)418-161-136(404-211(171(161)361-35-25-351-15)297-92-260-152-186(239)248-86-254-192(152)297)80-384-442(345,457)421-159-119(63-303)397-208(169(159)359-33-23-349-13)290-54-100(3)180(233)268-222(290)316/h52-62,83-97,109-148,158-177,207-216,303-304H,22-51,63-82H2,1-21H3,(H,325,326)(H,327,328)(H,329,330)(H,331,332)(H,333,445)(H,334,446)(H,335,447)(H,336,448)(H,337,449)(H,338,450)(H,339,451)(H,340,452)(H,341,453)(H,342,454)(H,343,455)(H,344,456)(H,345,457)(H,346,458)(H,347,459)(H2,231,266,314)(H2,232,267,315)(H2,233,268,316)(H2,234,269,317)(H2,235,270,318)(H2,236,245,251)(H2,237,246,252)(H2,238,247,253)(H2,239,248,254)(H2,240,249,255)(H2,241,250,256)(H,277,305,319)(H,278,306,320)(H,279,307,321)(H,280,308,322)(H,281,309,323)(H,282,310,324)(H3,242,271,274,311)(H3,243,272,275,312)(H3,244,273,276,313)/t109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119+,120+,121+,122+,123+,124+,125+,126+,127+,128+,129+,130+,131+,132+,133+,134+,135+,136+,137+,138+,139+,140+,141+,142+,143+,144+,145+,146+,147+,148+,158+,159+,160+,161+,162+,163+,164+,165+,166+,167+,168+,169+,170+,171+,172+,173+,174+,175+,176+,177+,207+,208+,209+,210+,211+,212+,213+,214+,215+,216+,430?,431?,432?,433?,434?,435?,436?,437?,438?,439?,440?,441?,442?,443?,444?/m0/s1
    2.1.3 InChI Key
    AZBXTZOFHIRMCD-SIVATHJTSA-N
    2.2 Synonyms
    2.2.1 Depositor-Supplied Synonyms

    1. Tofersen

    2.3 Create Date
    2025-03-20
    3 Chemical and Physical Properties
    Molecular Weight 7128 g/mol
    Molecular Formula C230H317N72O123P19S15
    XLogP3-16.7
    Hydrogen Bond Donor Count44
    Hydrogen Bond Acceptor Count168
    Rotatable Bond Count156
    Exact Mass Da
    Monoisotopic Mass Da
    Topological Polar Surface Area2920
    Heavy Atom Count459
    Formal Charge0
    Complexity19900
    Isotope Atom Count0
    Defined Atom Stereocenter Count70
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    4 Drug and Medication Information
    4.1 Drug Indication

    Tofersen is indicated for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This indication is approved under accelerated approval based on the reduction in plasma neurofilament light chain (NfL) observed in patients treated with tofersen. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

    Indications

    5 Pharmacology and Biochemistry
    5.1 FDA Pharmacological Classification
    5.1.1 Active Moiety
    TOFERSEN
    5.1.2 FDA UNII
    2NU6F9601K
    5.1.3 Pharmacological Classes
    Oligonucleotides, Antisense [CS]; Antisense Oligonucleotide [EPC]
    5.2 ATC Code

    N - Nervous system

    N07 - Other nervous system drugs

    N07X - Other nervous system drugs

    N07XX - Other nervous system drugs

    N07XX22 - Tofersen

    ATCvet Code

    QN - Nervous system

    QN07 - Other nervous system drugs

    QN07X - Other nervous system drugs

    QN07XX - Other nervous system drugs

    QN07XX22 - Tofersen

    5.3 Absorption, Distribution and Excretion

    Absorption

    Intrathecal administration of tofersen into the CSF allows tofersen to be distributed from the CSF to central nervous system tissues. The maximum CSF trough concentration occurred at the third dose, which was the last dose of the loading period. There was little to no accumulation for CSF tofersen with monthly dosing after the loading phase. Tofersen is transferred from CSF into the systemic circulation, with a median time to maximum concentration (Tmax) plasma values ranging from 2 to 6 hours. There was no accumulation in plasma tofersen exposure following monthly maintenance dosing.

    Route of Elimination

    The primary route of elimination has not been characterized.

    5.4 Metabolism/Metabolites

    Tofersen is expected to be metabolized through exonuclease (3'- and 5')-mediated hydrolysis and is not a substrate for, or inhibitor, or inducer of CYP450 enzymes.

    5.5 Biological Half-Life

    The effective half-life in CSF is estimated to be 4 weeks.

    5.6 Mechanism of Action

    Tofersen is an antisense oligonucleotide that causes degradation of SOD1 mRNA through binding to SOD1 mRNA, which results in a reduction of SOD1 protein synthesis.