Sefaxersen

Sefaxersen (also known as RO7434656, RG6299, ISIS-696844 and IONIS-FB-LRx) is an investigational antisense oligonucleotide (ASO) drug developed by Roche Holding AG in partnership with Ionis Pharmaceuticals. It targets complement factor B (CFB) to treat complement system-mediated diseases, primarily IgA nephropathy (IgAN) and geographic atrophy (GA) secondary to age-related macular degeneration.^[1][2][3] By inhibiting CFB expression, Sefaxersen reduces harmful inflammation driven by the alternative complement pathway.^[4]

Sefaxersen

Clinical data
Other names	RO7434656, RG6299 , IONIS-FB-LRx, ISIS-696844
Drug class	Antisense oligonucleotide
Legal status
Legal status	Investigational
Identifiers
IUPAC name all-P-ambo-5'-O-(((6-(5-((tris(3-(6-(2-acetamido-2-deoxy-β-D-galactopyranosyloxy)hexylamino)-3-oxopropoxymethyl))methyl)amino-5-oxopentanamido)hexyl))phospho)-2'-O-(2- methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)- 5-methyl-P-thiouridylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5- methyl-P-thiocytidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioadenylyl- (3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl- (3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-2'-deoxy-5- methyl-P-thiocytidylyl-(3'→5')-2'-deoxy-5-methyl-P-thiocytidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2- methoxyethyl)-5-methyl-P-thiocytidylyl-(3'→5')-2'-O-(2- methoxyethyl)-P-thioadenylyl-(3'→5')-2'-O-(2-methoxyethyl)- P-thioguanylyl-(3'→5')-2'-O-(2-methoxyethyl)-5-methylcytidine
CAS Number	2272975-74-1
PubChem SID	485663323
UNII	T87K47QVF3
Chemical and physical data
Formula	C296H445N77O148P20S19
Molar mass	8678.82 g·mol−1
SMILES C(C)(=O)N[C@H]1[C@@H](O[C@@H]([C@@H]([C@@H]1O)O)CO)OCCCCCCNC(CCOCC(COCCC(NCCCCCCO[C@H]1[C@@H]([C@@H](O)[C@@H](O)[C@H](O1)CO)NC(C)=O)=O)(COCCC(NCCCCCCO[C@H]1[C@@H]([C@@H](O)[C@@H](O)[C@H](O1)CO)NC(C)=O)=O)NC(CCCC(=O)NCCCCCCOP(=O)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C=NC=2C(N)=NC=NC12)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)NC(=O)C(=C1)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC=2C(N)=NC=NC12)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC=2C(=O)NC(N)=NC12)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C(=O)NC(=O)C(C)=C1)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C=NC=2C(=O)NC(N)=NC12)OP(=S)(O)OC[C@@H]1[C@H](C[C@@H](O1)N1C(=O)NC(=O)C(C)=C1)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C=NC=2C(N)=NC=NC12)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C=NC=2C(=O)NC(N)=NC12)OCCOC)OP(=S)(O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C(=O)N=C(N)C(=C1)C)OCCOC)O)=O)=O
InChI InChI=1S/C296H445N77O148P20S19/c1-140-91-354(282(398)333-240(140)297)195-81-157(504-524(415,543)462-110-172-159(83-197(482-172)356-93-142(3)242(299)335-284(356)400)506-526(417,545)464-113-175-162(86-200(485-175)359-102-151(12)260(392)350-293(359)409)508-528(419,547)469-116-178-166(90-204(489-178)370-136-328-212-258(370)345-280(312)348-264(212)396)512-531(422,550)467-114-176-163(87-201(486-176)360-103-152(13)261(393)351-294(360)410)509-532(423,551)472-120-182-222(231(447-72-62-434-19)267(491-182)362-97-146(7)246(303)339-288(362)404)515-536(427,555)475-122-186-226(235(451-76-66-438-23)271(495-186)366-101-150(11)250(307)343-292(366)408)518-540(431,559)478-126-188-228(238(454-79-69-441-26)274(498-188)372-138-326-210-253(310)320-133-323-256(210)372)521-541(432,560)479-127-189-229(239(455-80-70-442-27)275(499-189)373-139-329-213-259(373)346-281(313)349-265(213)397)520-534(425,553)471-118-180-217(388)230(446-71-61-433-18)266(490-180)361-96-145(6)245(302)338-287(361)403)170(480-195)108-461-523(414,542)503-158-82-196(355-92-141(2)241(298)334-283(355)399)481-171(158)109-463-525(416,544)505-160-84-198(357-94-143(4)243(300)336-285(357)401)484-174(160)112-466-530(421,549)511-165-89-203(369-135-327-211-257(369)344-279(311)347-263(211)395)488-177(165)115-468-527(418,546)507-161-85-199(358-95-144(5)244(301)337-286(358)402)483-173(161)111-465-529(420,548)510-164-88-202(368-134-324-208-251(308)318-131-321-254(208)368)487-179(164)117-470-533(424,552)514-223-183(492-268(232(223)448-73-63-435-20)363-98-147(8)247(304)340-289(363)405)121-474-537(428,556)516-224-184(493-269(233(224)449-74-64-436-21)364-99-148(9)248(305)341-290(364)406)123-476-538(429,557)517-225-185(494-270(234(225)450-75-65-437-22)365-100-149(10)249(306)342-291(365)407)124-477-539(430,558)519-227-187(496-272(236(227)452-77-67-439-24)367-104-153(14)262(394)352-295(367)411)125-473-535(426,554)513-221-181(497-273(237(221)453-78-68-440-25)371-137-325-209-252(309)319-132-322-255(209)371)119-460-522(412,413)459-57-43-35-31-39-50-314-190(380)45-44-46-194(384)353-296(128-443-58-47-191(381)315-51-36-28-32-40-54-456-276-205(330-154(15)377)218(389)214(385)167(105-374)500-276,129-444-59-48-192(382)316-52-37-29-33-41-55-457-277-206(331-155(16)378)219(390)215(386)168(106-375)501-277)130-445-60-49-193(383)317-53-38-30-34-42-56-458-278-207(332-156(17)379)220(391)216(387)169(107-376)502-278/h91-104,131-139,157-189,195-207,214-239,266-278,374-376,385-391H,28-90,105-130H2,1-27H3,(H,314,380)(H,315,381)(H,316,382)(H,317,383)(H,330,377)(H,331,378)(H,332,379)(H,353,384)(H,412,413)(H,414,542)(H,415,543)(H,416,544)(H,417,545)(H,418,546)(H,419,547)(H,420,548)(H,421,549)(H,422,550)(H,423,551)(H,424,552)(H,425,553)(H,426,554)(H,427,555)(H,428,556)(H,429,557)(H,430,558)(H,431,559)(H,432,560)(H2,297,333,398)(H2,298,334,399)(H2,299,335,400)(H2,300,336,401)(H2,301,337,402)(H2,302,338,403)(H2,303,339,404)(H2,304,340,405)(H2,305,341,406)(H2,306,342,407)(H2,307,343,408)(H2,308,318,321)(H2,309,319,322)(H2,310,320,323)(H,350,392,409)(H,351,393,410)(H,352,394,411)(H3,311,344,347,395)(H3,312,345,348,396)(H3,313,346,349,397)/t157-,158-,159-,160-,161-,162-,163-,164-,165-,166-,167+,168+,169+,170+,171+,172+,173+,174+,175+,176+,177+,178+,179+,180+,181+,182+,183+,184+,185+,186+,187+,188+,189+,195+,196+,197+,198+,199+,200+,201+,202+,203+,204+,205+,206+,207+,214-,215-,216-,217+,218+,219+,220+,221+,222+,223+,224+,225+,226+,227+,228+,229+,230+,231+,232+,233+,234+,235+,236+,237+,238+,239+,266+,267+,268+,269+,270+,271+,272+,273+,274+,275+,276+,277+,278+,523?,524?,525?,526?,527?,528?,529?,530?,531?,532?,533?,534?,535?,536?,537?,538?,539?,540?,541?/m0/s1 Key:LVROOAHWMCVVSC-WSMKVKJMSA-N

As of 2025, it is in Phase 2/3 trials for IgAN and Phase 2 trials for GA.^[5][6][7][8]

Mechanism of action

Sefaxersen is an antisense oligonucleotide that binds to the messenger RNA (mRNA) of the complement factor B (CFB) gene, preventing CFB protein production.^[3][9] CFB is a key component of the alternative pathway of complement activation, which can drive inflammation and tissue damage in diseases like IgAN and GA.^[3] By reducing CFB levels, Sefaxersen dampens this pathway, aiming to slow disease progression.^[4] This RNA-targeted approach offers precision compared to traditional drugs, making it suitable for complex conditions.^[1][3]

Development

Sefaxersen was developed by Ionis Pharmaceuticals, a pioneer in RNA-targeted therapeutics, in partnership with Roche for late-stage clinical development and potential commercialization.^[2][4] Ionis’ expertise in antisense technology complements Roche’s focus on neurology, rare diseases, and ophthalmology.^[4] Early clinical trials demonstrated that Sefaxersen effectively reduced complement factor B (CFB) levels, supporting its advancement into Phase 2/3 trials for IgA nephropathy (IgAN) and Phase 2 trials for geographic atrophy (GA).^[1][3][10]

Sefaxersen is currently being evaluated in clinical trials for its safety and efficacy in treating the following complement-mediated diseases.^[10]

IgA Nephropathy (IgAN)

Sefaxersen is in Phase 2/3 trials for primary IgA nephropathy (IgAN), a kidney disorder characterized by the deposition of IgA immune complexes in the glomeruli, leading to inflammation and progressive kidney damage.^[1][10][11] Results from Phase 2 trials showed a significant reduction in proteinuria and stabilization of kidney function in treated patients, supporting the continuation of development.^[12] The ongoing Phase 3 trial is focused on evaluating efficacy, safety, and pharmacokinetics in patients at high risk of disease progression.^[11][7]

Geographic Atrophy (GA)

Overactivation of the alternative complement pathway plays a key role in the progression of GA.^[3] In Phase 1 studies involving healthy volunteers, Sefaxersen was shown to reduce systemic CFB levels and overall complement activity, supporting its potential use in GA treatment.^[9][13] Sefaxersen entered Phase 2 trials (NCT03815825) for geographic atrophy (GA), an advanced form of age-related macular degeneration that leads to irreversible vision loss.^[1][10][9] However, further development of Sefaxersen for GA has been discontinued by Ionis Pharmaceuticals.^[14]