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Tofersen

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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

Tofersen

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 Formula	C₂₃₀H₃₁₇N₇₂O₁₂₃P₁₉S₁₅
Molecular Weight	7128 g/mol
XLogP3	-16.7
Hydrogen Bond Donor Count	44
Hydrogen Bond Acceptor Count	168
Rotatable Bond Count	156
Exact Mass	Da
Monoisotopic Mass	Da
Topological Polar Surface Area	2920
Heavy Atom Count	459
Formal Charge	0
Complexity	19900
Isotope Atom Count	0
Defined Atom Stereocenter Count	70
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

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.

Drugs in Development