Sprifermin - Misplaced Pages

Human recombinant FGF18 Pharmaceutical compound

Sprifermin
Clinical data
Other names	AS-902330; rhFGF18; L-Methionyl(human fibroblast growth factor 18 (FGF-18, zFGF5)-(1-169)-peptide)
Identifiers
CAS Number	890058-52-3
UNII	UEJ4E476ZP
Chemical and physical data
Formula	C₈₇₆H₁₃₉₆N₂₅₈O₂₅₆S₆
Molar mass	19830.71 g·mol
3D model (JSmol)	Interactive image
SMILES CC(C)(NC(=O)(CCCNC(=N)N)NC(=O)(CCCNC(=N)N)NC(=O)CNC(=O)(CC(C)C)NC(=O)(NC(=O)(CCC(=O)N)NC(=O)(NC(=O)(Cc1cnc1)NC(=O)(CCCCN)NC(=O)CNC(=O)(CO)NC(=O)(NC(=O)(CCCNC(=N)N)NC(=O)(CO)NC(=O)(Cc2ccc(O)cc2)NC(=O)(CC(C)C)NC(=O)(CCC(=O)N)NC(=O)(Cc3ccc(O)cc3)NC(=O)(CC(C)C)NC(=O)(CCCNC(=N)N)NC(=O)(CC(C)C)NC(=O)(CCC(=O)N)NC(=O)(CCCCN)NC(=O)(CCCNC(=N)N)NC(=O)(CO)NC(=O)(NC(=O)(CC(=O)O)NC(=O)(CC(=O)O)NC(=O)(CCCNC(=N)N)NC(=O)(C)NC(=O)(CCCNC(=N)N)NC(=O)(NC(=O)(CCC(=O)N)NC(=O)(CC(=O)N)NC(=O)(CCC(=O)O)NC(=O)(NC(=O)(Cc4cnc4)NC(=O)(NC(=O)(CCCNC(=N)N)NC(=O)(Cc5ccccc5)NC(=O)(CC(=O)O)NC(=O)(NC(=O)(CC(=O)N)NC(=O)(CCC(=O)O)NC(=O)(CCC(=O)O)NC(=O)(N)CCSC)C(C)C)(C)CC)C(C)C)(C)O)C(C)C)(C)O)(C)CC)C(C)C)C(=O)N(CO)C(=O)N(C)C(=O)N(CCCNC(=N)N)C(=O)NCC(=O)N(CCC(=O)O)C(=O)N(CC(=O)O)C(=O)NCC(=O)N(CC(=O)O)C(=O)N(CCCCN)C(=O)N(Cc6ccc(O)cc6)C(=O)N(C)C(=O)N(CCC(=O)N)C(=O)N(CC(C)C)C(=O)N(CC(C)C)C(=O)N(C(C)C)C(=O)N(CCC(=O)O)C(=O)N((C)O)C(=O)N(CC(=O)O)C(=O)N((C)O)C(=O)N(Cc7ccccc7)C(=O)NCC(=O)N(CO)C(=O)N(CCC(=O)N)C(=O)N(C(C)C)C(=O)N(CCCNC(=N)N)C(=O)N((C)CC)C(=O)N(CCCCN)C(=O)NCC(=O)N(CCCCN)C(=O)N(CCC(=O)O)C(=O)N((C)O)C(=O)N(CCC(=O)O)C(=O)N(Cc8ccccc8)C(=O)N(Cc9ccc(O)cc9)C(=O)N(CC(C)C)C(=O)N%10CSSC(NC(=O)(CCC(=O)O)NC(=O)(CCCCN)NC(=O)(CO)NC(=O)(NC(=O)CNC(=O)(CC(=O)O)NC(=O)%11CCCN%11C(=O)(CCCCN)NC(=O)CNC(=O)(NC(=O)(CC(C)C)NC(=O)(CCCCN)NC(=O)CNC(=O)(CCCCN)NC(=O)(CCCNC(=N)N)NC(=O)(CC(=O)N)NC(=O)(CCSC)NC%10=O)C(C)C)(C)O)C(=O)N(C(C)C)C(=O)N(Cc%12ccccc%12)C(=O)N((C)CC)C(=O)N(CCC(=O)O)C(=O)N(CCCCN)C(=O)N(C(C)C)C(=O)N(CC(C)C)C(=O)N(CCC(=O)O)C(=O)N(CC(=O)N)C(=O)N(CC(=O)N)C(=O)N(Cc%13ccc(O)cc%13)C(=O)N((C)O)C(=O)N(C)C(=O)N(CC(C)C)C(=O)N(CCSC)C(=O)N(CO)C(=O)N(C)C(=O)N(CCCCN)C(=O)N(Cc%14ccc(O)cc%14)C(=O)N(CO)C(=O)NCC(=O)N(Cc%15cc%16ccccc%15%16)C(=O)N(Cc%17ccc(O)cc%17)C(=O)N(C(C)C)C(=O)NCC(=O)N(Cc%18ccccc%18)C(=O)N((C)O)C(=O)N(CCCCN)C(=O)N(CCCCN)C(=O)NCC(=O)N(CCCNC(=N)N)C(=O)N%19CCC%19C(=O)N(CCCNC(=N)N)C(=O)N(CCCCN)C(=O)NCC(=O)N%20CCC%20C(=O)N(CCCCN)C(=O)N((C)O)C(=O)N(CCCNC(=N)N)C(=O)N(CCC(=O)O)C(=O)N(CC(=O)N)C(=O)N(CCC(=O)N)C(=O)N(CCC(=O)N)C(=O)N(CC(=O)O)C(=O)N(C(C)C)C(=O)N(Cc%21cnc%21)C(=O)N(Cc%22ccccc%22)C(=O)N(CCSC)C(=O)N(CCCCN)C(=O)N(CCCNC(=N)N)C(=O)N(Cc%23ccc(O)cc%23)C(=O)N%24CCC%24C(=O)N(CCCCN)C(=O)NCC(=O)N(CCC(=O)N)C(=O)N%25CCC%25C(=O)N(CCC(=O)O)C(=O)N(CC(C)C)C(=O)N(CCC(=O)N)C(=O)N(CCCCN)C(=O)N%26CCC%26C(=O)N(Cc%27ccccc%27)C(=O)N(CCCCN)C(=O)N(Cc%28ccc(O)cc%28)C(=O)N((C)O)C(=O)N((C)O)C(=O)N(C(C)C)C(=O)N((C)O)C(=O)N(CCCCN)C(=O)O

Sprifermin (INN) (developmental code name AS-902330), is a recombinant human fibroblast growth factor 18 (rhFGF18) analog, which is under development by TrialSpark for the treatment of osteoarthritis. FGF18 and sprifermin act via the Fibroblast Growth Factor Receptor (FGFR) family, with preferential activity via FGFR3c.

Osteoarthritis

In 2020, Merck reported 5-year follow-up data from the Phase 2 clinical trial for knee osteoarthritis (OA). The placebo controlled, multi-center study demonstrated that sprifermin was able to promote statistically significant improvement in cartilage thickness relative to control in a dose-dependent manner, meeting the primary endpoint of the study. The findings suggested the ability of FGF18 to arrest progression to joint replacement, with 0% of patients in the high dose group progressing to Total Knee Replacement (TKR) surgery over the 5 year study period; in contrast, nearly 1 in 10 patients of the high risk subgroup progressed to TKR when treated with the placebo. These findings suggest significant potential of FGF18 as a disease modifying drug for the treatment of OA (DMOAD) and warrant further clinical evaluation.

Sprifermin was well tolerated with no severe adverse events associated with the treatment. Long-term follow up showed that continual injections (up to 12 per year of bilateral treatment) may need to be sustained over a period of multiple years to prevent recurrence of cartilage loss. Improvement in WOMAC, a secondary endpoint, was met for the Subgroup at Risk. Subsequent analysis further demonstrated that a clinically meaningful reduction in the rate of symptomatic progression (WOMAC) was demonstrated in the full trial population and Subgroup at Risk by the high treatment dose.

References

"Inxight Drugs: Sprifermin". National Center for Advancing Translational Sciences.
Gigout A, Guehring H, Froemel D, Meurer A, Ladel C, Reker D, et al. (November 2017). "Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix". Osteoarthritis and Cartilage. 25 (11): 1858–1867. doi:10.1016/j.joca.2017.08.004. PMID 28823647.
"Sprifermin - Merck". Adis Insight. Springer Nature Switzerland AG.
Ornitz DM, Itoh N (2015). "The Fibroblast Growth Factor signaling pathway". Wiley Interdisciplinary Reviews. Developmental Biology. 4 (3): 215–266. doi:10.1002/wdev.176. PMC 4393358. PMID 25772309.
^ Eckstein F, Hochberg MC, Guehring H, Moreau F, Ona V, Bihlet AR, et al. (August 2021). "Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study". Annals of the Rheumatic Diseases. 80 (8): 1062–1069. doi:10.1136/annrheumdis-2020-219181. PMC 8292562. PMID 33962962.
Eckstein F, Hochberg MC, Guehring H, Moreau F, Ona V, Bihlet AR, et al. (August 2021). "Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study". Annals of the Rheumatic Diseases. 80 (8): 1062–1069. doi:10.1136/annrheumdis-2020-219181. PMC 8292562. PMID 33962962.
Conaghan PG, Katz N, Hunter D, Guermazi A, Hochberg M, Somberg K, et al. (June 2023). "Pos1348 Effects of Sprifermin on a Novel Outcome of Osteoarthritis Symptom Progression: Post-Hoc Analysis of the Forward Randomized Trial". Annals of the Rheumatic Diseases. 82 (Suppl 1): 1025–1026. doi:10.1136/annrheumdis-2023-eular.2454. ISSN 0003-4967.

External links

Sprifermin - AdisInsight

Growth factor receptor modulators

Angiopoietin

Agonists: Angiopoietin 1
Angiopoietin 4

Antagonists: Angiopoietin 2
Angiopoietin 3

Kinase inhibitors: Altiratinib
CE-245677
Rebastinib

Antibodies: Evinacumab (against angiopoietin 3)
Nesvacumab (against angiopoietin 2)

CNTF

Agonists: Axokine
CNTF
Dapiclermin

EGF (ErbB)

EGF (ErbB1/HER1)	Agonists: Amphiregulin Betacellulin EGF (urogastrone) Epigen Epiregulin Heparin-binding EGF-like growth factor (HB-EGF) Murodermin Nepidermin Transforming growth factor alpha (TGFα) Kinase inhibitors: Afatinib Agerafenib Brigatinib Canertinib Dacomitinib Erlotinib Gefitinib Grandinin Icotinib Lapatinib Neratinib Osimertinib Vandetanib WHI-P 154 Antibodies: Cetuximab Depatuxizumab Depatuxizumab mafodotin Futuximab Imgatuzumab Matuzumab Necitumumab Nimotuzumab Panitumumab Zalutumumab
ErbB2/HER2	Agonists: Unknown/none Antibodies: Ertumaxomab Pertuzumab Trastuzumab Trastuzumab deruxtecan Trastuzumab duocarmazine Trastuzumab emtansine Kinase inhibitors: Afatinib Lapatinib Mubritinib Neratinib Tucatinib
ErbB3/HER3	Agonists: Neuregulins (heregulins) (1, 2, 6 (neuroglycan C)) Antibodies: Duligotumab Patritumab Seribantumab
ErbB4/HER4	Agonists: Betacellulin Epigen Heparin-binding EGF-like growth factor (HB-EGF) Neuregulins (heregulins) (1, 2, 3, 4, 5 (tomoregulin, TMEFF))

FGF

FGFR1	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 8, 10 (KGF2), 20) Repifermin Selpercatinib Trafermin Velafermin
FGFR2	Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22) Palifermin Repifermin Selpercatinib Sprifermin Trafermin Antibodies: Aprutumab Aprutumab ixadotin Kinase inhibitors: Infigratinib
FGFR3	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 8, 9, 18, 23) Selpercatinib Sprifermin Trafermin Antibodies: Burosumab (against FGF23)
FGFR4	Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 6, 8, 9, 19) Trafermin
Unsorted	Agonists: FGF15/19

HGF (c-Met)

Agonists: Fosgonimeton
Hepatocyte growth factor

Potentiators: Dihexa (PNB-0408)

IGF

IGF-1

IGF-2

Agonists: Insulin-like growth factor-2 (somatomedin A)

Antibodies: Dusigitumab
Xentuzumab (against IGF-1 and IGF-2)

Others

Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7)

Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1)
Trofinetide

LNGF (p75)

Antibodies: Against NGF: ABT-110 (PG110)
ASP-6294
Fasinumab
Frunevetmab
Fulranumab
MEDI-578
Ranevetmab
Tanezumab

Aptamers: Against NGF: RBM-004

Decoy receptors: LEVI-04 (p75-Fc)

PDGF

Agonists: Becaplermin
Platelet-derived growth factor (A, B, C, D)

RET (GFL)

GFRα1	Agonists: Glial cell line-derived neurotrophic factor (GDNF) Liatermin Kinase inhibitors: Vandetanib
GFRα2	Agonists: Neurturin (NRTN) Kinase inhibitors: Vandetanib
GFRα3	Agonists: Artemin (ARTN) Kinase inhibitors: Vandetanib
GFRα4	Agonists: Persephin (PSPN) Kinase inhibitors: Vandetanib
Unsorted	Kinase inhibitors: Agerafenib