Cardiac amyloidosis future or investigational therapies: Difference between revisions
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==Overview== | ==Overview== | ||
New therapies targeting the serum amyloid protein (SAP), which is an excellent immunogen and a universal component of all amyloid deposits, using monoclonal antibodies are currently being investigated. | New therapies targeting the serum amyloid protein (SAP), which is an excellent immunogen and a universal component of all amyloid deposits, using monoclonal antibodies are currently being investigated. Additionally, several investigational products targeting ATTR amyloid are being studied in clinical trials. These include small interfering RNA (siRNA) molecules which reduce the production of the amyloid precursor misfolded protein and ATTR stabilization molecules. | ||
==Future or Investigational Therapies== | ==Future or Investigational Therapies== | ||
Potential future treatment options targeting TTR: | |||
* AG10: AG10 is a selective, oral TTR stabilizer which mimic a protective TTR mutation known as T119M. In a phase 2 clinical trial, AG10 was found to be safe and effective. This trial randomized 49 patients with mutant or wild-type TTR amyloid cardiomyopathy with NYHA class II to III symptoms to AG10 400 mg, 800 mg, or placebo twice daily for 28 days, and found the medication to be well tolerated and achieve near-complete stabilization of TTR.<ref>{{Cite web|url=https://www.sciencedirect.com/science/article/pii/S0735109719339208?via%3Dihub|title=Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy|last=Judge|first=Daniel P.|date=10/29/2019|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> A phase 3 trial is ongoing (NCT03458130) | |||
* Patisiran: this is a siRNA molecule which has shown promise in patients with polyneuropathy from hereditary TTR amyloidosis. A cardiac subgroup study showed favorable biomarker results as well.<ref>{{Cite web|url=https://www.nejm.org/doi/10.1056/NEJMoa1716153?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov|title=Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis|last=Adams|first=David|date=10/29/19|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> | |||
* Inoterson | |||
Potential future treatment options targeting the serum amyloid protein (SAP): | |||
* Anti-SAP antibody<ref name="pmid20962779">{{cite journal |author=Bodin K, Ellmerich S, Kahan MC, ''et al.'' |title=Antibodies to human serum amyloid P component eliminate visceral amyloid deposits |journal=[[Nature]] |volume=468 |issue=7320 |pages=93–7 |year=2010 |month=November |pmid=20962779 |pmc=2975378 |doi=10.1038/nature09494 |url=}}</ref> | * Anti-SAP antibody<ref name="pmid20962779">{{cite journal |author=Bodin K, Ellmerich S, Kahan MC, ''et al.'' |title=Antibodies to human serum amyloid P component eliminate visceral amyloid deposits |journal=[[Nature]] |volume=468 |issue=7320 |pages=93–7 |year=2010 |month=November |pmid=20962779 |pmc=2975378 |doi=10.1038/nature09494 |url=}}</ref> | ||
* CPHPC:<ref name="pmid12015594">{{cite journal|author = Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, Lovat LB, Bartfai T, Alanine A, Hertel C, Hoffmann T, Jakob-Roetne R, Norcross RD, Kemp JA, Yamamura K, Suzuki M, Taylor GW, Murray S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins PN | title = Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis | journal = Nature | volume = 417 | issue = 6886 | pages = 254–9 | year = 2002 | pmid = 12015594 | doi = 10.1038/417254a }}</ref> CPHPC, also called R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, is a competitive inhibitor of SAP binding to amyloid fibrils. CPHPC is a [[proline]]-derived small palindromic molecule able to strip amyloid P (AP) from deposits by reducing levels of circulating [[serum amyloid protein]] (SAP). It also cross-links and dimerizes SAP, which is cleared rapidly by the [[liver]]. The SAP-amyloid association has also been identified as a possible drug target for anti-amyloid therapy, with the recent development and first stage clinical trials of CPHPC for [[amyloidosis]]. | * CPHPC:<ref name="pmid12015594">{{cite journal|author = Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, Lovat LB, Bartfai T, Alanine A, Hertel C, Hoffmann T, Jakob-Roetne R, Norcross RD, Kemp JA, Yamamura K, Suzuki M, Taylor GW, Murray S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins PN | title = Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis | journal = Nature | volume = 417 | issue = 6886 | pages = 254–9 | year = 2002 | pmid = 12015594 | doi = 10.1038/417254a }}</ref> CPHPC, also called R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, is a competitive inhibitor of SAP binding to amyloid fibrils. CPHPC is a [[proline]]-derived small palindromic molecule able to strip amyloid P (AP) from deposits by reducing levels of circulating [[serum amyloid protein]] (SAP). It also cross-links and dimerizes SAP, which is cleared rapidly by the [[liver]]. The SAP-amyloid association has also been identified as a possible drug target for anti-amyloid therapy, with the recent development and first stage clinical trials of CPHPC for [[amyloidosis]]. |
Revision as of 21:39, 29 October 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Aarti Narayan, M.B.B.S [3]
Overview
New therapies targeting the serum amyloid protein (SAP), which is an excellent immunogen and a universal component of all amyloid deposits, using monoclonal antibodies are currently being investigated. Additionally, several investigational products targeting ATTR amyloid are being studied in clinical trials. These include small interfering RNA (siRNA) molecules which reduce the production of the amyloid precursor misfolded protein and ATTR stabilization molecules.
Future or Investigational Therapies
Potential future treatment options targeting TTR:
- AG10: AG10 is a selective, oral TTR stabilizer which mimic a protective TTR mutation known as T119M. In a phase 2 clinical trial, AG10 was found to be safe and effective. This trial randomized 49 patients with mutant or wild-type TTR amyloid cardiomyopathy with NYHA class II to III symptoms to AG10 400 mg, 800 mg, or placebo twice daily for 28 days, and found the medication to be well tolerated and achieve near-complete stabilization of TTR.[1] A phase 3 trial is ongoing (NCT03458130)
- Patisiran: this is a siRNA molecule which has shown promise in patients with polyneuropathy from hereditary TTR amyloidosis. A cardiac subgroup study showed favorable biomarker results as well.[2]
- Inoterson
Potential future treatment options targeting the serum amyloid protein (SAP):
- Anti-SAP antibody[3]
- CPHPC:[4] CPHPC, also called R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, is a competitive inhibitor of SAP binding to amyloid fibrils. CPHPC is a proline-derived small palindromic molecule able to strip amyloid P (AP) from deposits by reducing levels of circulating serum amyloid protein (SAP). It also cross-links and dimerizes SAP, which is cleared rapidly by the liver. The SAP-amyloid association has also been identified as a possible drug target for anti-amyloid therapy, with the recent development and first stage clinical trials of CPHPC for amyloidosis.
- Diflunisal[5]
- Eprodisate[6]
- Pomalidomide (analogue of thalidomide)[7][8]
References
- ↑ Judge, Daniel P. (10/29/2019). "Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy". Check date values in:
|date=
(help) - ↑ Adams, David (10/29/19). "Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis". Check date values in:
|date=
(help) - ↑ Bodin K, Ellmerich S, Kahan MC; et al. (2010). "Antibodies to human serum amyloid P component eliminate visceral amyloid deposits". Nature. 468 (7320): 93–7. doi:10.1038/nature09494. PMC 2975378. PMID 20962779. Unknown parameter
|month=
ignored (help) - ↑ Pepys MB, Herbert J, Hutchinson WL, Tennent GA, Lachmann HJ, Gallimore JR, Lovat LB, Bartfai T, Alanine A, Hertel C, Hoffmann T, Jakob-Roetne R, Norcross RD, Kemp JA, Yamamura K, Suzuki M, Taylor GW, Murray S, Thompson D, Purvis A, Kolstoe S, Wood SP, Hawkins PN (2002). "Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis". Nature. 417 (6886): 254–9. doi:10.1038/417254a. PMID 12015594.
- ↑ Sekijima Y, Dendle MA, Kelly JW (2006). "Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis". Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis. 13 (4): 236–49. doi:10.1080/13506120600960882. PMID 17107884. Unknown parameter
|month=
ignored (help) - ↑ Dember LM, Hawkins PN, Hazenberg BP; et al. (2007). "Eprodisate for the treatment of renal disease in AA amyloidosis". The New England Journal of Medicine. 356 (23): 2349–60. doi:10.1056/NEJMoa065644. PMID 17554116. Unknown parameter
|month=
ignored (help) - ↑ Dispenzieri A, Buadi F, Laumann K; et al. (2012). "Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis". Blood. 119 (23): 5397–404. doi:10.1182/blood-2012-02-413161. PMID 22493299. Unknown parameter
|month=
ignored (help) - ↑ Elkinson S, McCormack PL (2013). "Pomalidomide: first global approval". Drugs. 73 (6): 595–604. doi:10.1007/s40265-013-0047-x. PMID 23572409. Unknown parameter
|month=
ignored (help)