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    Abaloparatide

    From Mdwiki - Reading time: 14 min
    Abaloparatide
    Names
    Trade namesTymlos, Eladynos[1]
    Other namesBA058, BIM-44058
    • L-alanyl-L-valyl-L-seryl-L-α-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-α-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-α-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-α-glutamyl-L-leucyl-L-leucyl-L-α-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-L-alaninamide
    Clinical data
    Drug classParathyroid hormone-related protein (PTHrP) analog[2]
    Main usesOsteoporosis after menopause[2]
    Side effectsPalpitations, lightheadedness, nausea, headache, tiredness, upper abdominal pain[2][3]
    Routes of
    use    		Subcutaneous injection[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa617038
    Legal
    Legal status
    Chemical and physical data
    FormulaC174H299N56O49
    Molar mass3959.649 g·mol−1
    3D model (JSmol)
    • CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC(C)(C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](Cc2cnc[nH]2)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](Cc3cnc[nH]3)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C)N
    • InChI=1S/C174H300N56O49/c1-26-93(20)136(228-165(274)126(80-232)224-141(250)101(39-28-32-56-176)200-129(236)78-195-140(249)100(38-27-31-55-175)201-161(270)123(73-133(243)244)223-160(269)121(71-98-76-190-82-197-98)220-158(267)118(68-90(14)15)216-155(264)114(64-86(6)7)213-148(257)107(45-50-127(180)234)207-159(268)120(70-97-75-189-81-196-97)219-151(260)111(49-54-132(241)242)209-164(273)125(79-231)225-167(276)135(92(18)19)227-139(248)94(21)179)168(277)210-108(46-51-128(181)235)149(258)222-124(74-134(245)246)162(271)217-112(62-84(2)3)152(261)205-105(44-37-61-194-173(187)188)143(252)203-103(42-35-59-192-171(183)184)142(251)204-104(43-36-60-193-172(185)186)144(253)206-110(48-53-131(239)240)150(259)214-115(65-87(8)9)154(263)215-113(63-85(4)5)153(262)208-109(47-52-130(237)238)147(256)202-102(40-29-33-57-177)145(254)211-116(66-88(10)11)156(265)218-119(69-91(16)17)166(275)230-174(24,25)170(279)226-106(41-30-34-58-178)146(255)212-117(67-89(12)13)157(266)221-122(72-99-77-191-83-198-99)163(272)229-137(96(23)233)169(278)199-95(22)138(182)247/h75-77,81-96,100-126,135-137,231-233H,26-74,78-80,175-179H2,1-25H3,(H2,180,234)(H2,181,235)(H2,182,247)(H,189,196)(H,190,197)(H,191,198)(H,195,249)(H,199,278)(H,200,236)(H,201,270)(H,202,256)(H,203,252)(H,204,251)(H,205,261)(H,206,253)(H,207,268)(H,208,262)(H,209,273)(H,210,277)(H,211,254)(H,212,255)(H,213,257)(H,214,259)(H,215,263)(H,216,264)(H,217,271)(H,218,265)(H,219,260)(H,220,267)(H,221,266)(H,222,258)(H,223,269)(H,224,250)(H,225,276)(H,226,279)(H,227,248)(H,228,274)(H,229,272)(H,230,275)(H,237,238)(H,239,240)(H,241,242)(H,243,244)(H,245,246)(H4,183,184,192)(H4,185,186,193)(H4,187,188,194)/t93-,94-,95-,96+,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,115-,116-,117-,118-,119-,120-,121-,122-,123-,124-,125-,126-,135-,136-,137-/m0/s1
    • Key:BVISQZFBLRSESR-XSCWXTNMSA-N

    Abaloparatide, sold under the brand name Tymlos among others, is a medication used to treat osteoporosis after menopause.[2][1] In those at high risk, it may decrease the risk of fractures from 5.9% to 3.3%.[3] It should not be used for more than two years.[2] It is used as an injection just under the skin.[2]

    Common side effects palpitations, lightheadedness, nausea, headache, tiredness, and upper abdominal pain.[2][3] Other potential concerns include an increased risk of osteosarcoma, high blood calcium, low blood pressure with standing, and pain at the injection site.[2][3] It is a parathyroid hormone-related protein (PTHrP) analog and works by promoting bone growth.[2]

    Abaloparatide was approved for medical use in the United States in 2017.[2] It was initially denied approval in Europe in 2018;[4] however, was subsequently approved in 2022.[1] As of 2018, it cost about 1,800 USD per month in the United States.[3] As of 2019 it is unclear how its effectiveness compares to the less expensive bisphosphonates.[3]

    Medical uses[edit | edit source]

    Individual had been on Abaloparatide for five months(18-month postoperative image shows full union)

    Abaloparatide is used to treat postmenopausal women with osteoporosis who are at high risk of bone fractures.[5]

    Dosage[edit | edit source]

    It is given as 80 micrograms once daily.[2]

    Side effects[edit | edit source]

    The most common side effects reported by more than 2% of clinical trials subjects are hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain and vertigo.[6]

    Preclinical studies revealed that abaloparatide systemic daily administration leads to a dose- and time-dependent increase in the incidence of osteosarcoma in rodents.[7] However, whether abaloparatide-SC will cause osteosarcoma in humans is unknown. Thus, the use of abaloparatide is not recommended for individuals at increased risk of osteosarcoma. Additionally, its use is not advised for more than 2 years during a patient's lifetime.[6][8]

    Pharmacology[edit | edit source]

    Abaloparatide is 34 amino acid synthetic analog of PTHrP. It has 41% homology to parathyroid hormone (PTH) (1-34) and 76% homology to parathyroid hormone-related protein (PTHrP) (1-34).[9] It works as an anabolic agent for the bone, through selective activation of the parathyroid hormone 1 receptor (PTH1R), a G protein-coupled receptor (GPCR) expressed in the osteoblasts and osteocytes. Abaloparatide preferentially binds the RG conformational state of the PTH1R, which in turn elicits a transient downstream cyclic AMP signaling response towards to a more anabolic signaling pathway.[10][11]

    Like the related drug teriparatide, and unlike bisphosphonates, it is an anabolic (i.e., bone growing) agent.[12]

    Society and culture[edit | edit source]

    Commercialization[edit | edit source]

    Abaloparatide-SC is manufactured by Radius Health, Inc. (RDUS), a biomedical company based in Waltham, Massachusetts. The firm reported that sales for abaloparatide were $3.5 million for the third quarter of 2017.[13]

    In July 2017, Radius Health licensed rights to Teijin Limited for abaloparatide-SC manufacture and commercialization in Japan. Teijin is developing abaloparatide-SC under agreement with Ipsen Pharma S.A.S., and is conducting a phase III clinical trial in Japanese patients with osteoporosis.[14]

    Regulatory approval[edit | edit source]

    The medication was denied approval in Europe in 2018.[4]

    In February 2016 a NDA was filed to the FDA, Radius NDA for abaloparatide-SC was accepted in May, 2016.[15] A Prescription Drug User Fee Act (PDUFA) date was initially granted on March 30, 2016, but then extended to June 30, 2017.[16] As previously stated, abaloparatide injection was approved for use in postmenopausal osteoporosis on April 28, 2017.[8]

    Intellectual property[edit | edit source]

    Radius Health currently holds three patents on abaloparatide-SC, with expiration dates from 2027-2028.[17] The patents relate to the drug composition (US 8148333), and the drug delivery methods (US 7803770 B2 and US 8748382-B2).

    Teijin was granted use of Radius Health's intellectual property in July 2017, for the development, manufacture and commercialization of abaloparatide-sc in Japan.

    Research[edit | edit source]

    Highlights from trials.[18]

    Preclinical studies[edit | edit source]

    Abaloropatide was known as BIM-44058 when it was first discovered at Ipsen and as BA058 while under development. The anabolic effects of abaloparatide on bone were demonstrated in two preclinical studies conducted in ovariectomized rats. Both studies showed increased cortical and trabecular bone volume and density, and trabecular microarchitecture improvement in vertebral and nonvertebral bones after short-term[19] and long-term[20] daily subcutaneous injection of abaloparatide compared to controls. Recent studies indicated a dose-dependent increased in bone mass and strength in long-term abalorapatide treatment.[21] However, it was also found that prolonged abalorapatide-SC treatment leads to increased incidence of osteosarcoma.[7] To date, there is no evidence for increased risk of bone tumors due to prolonged systemic administration in humans. Based on preclinical data, the FDA does not advised the use of abaloparatide-SC for more than 2 years, or in patients with history of Paget disease and/or other conditions that exacerbates the risk of developing osteosarcoma.[6]

    Clinical trials[edit | edit source]

    Phase II trials were initiated in 2008. A 24-week randomized trial was conducted in postmenopausal women with osteoporosis (n=222) assessing bone mass density (BMD) changes as the primary endpoint.[22] Significant BMD increase at doses of 40 and 80 mcg were found in the lumbar spine, femur and hips of abaloparatide-treated participants compared to placebo. Additionally, abaloparatide showed superior anabolic effects on the hips compared to teriparatide.[23]

    In the phase III (2011-2014) Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial, an 18-months randomized, multicenter, double-blinded, placebo-controlled study evaluated the long-term efficacy of abaloparatide compared to placebo and teriparatide in 2,463 postmenopausal women (± 69 years old).[24] Women who received daily injections of abaloparatide experienced substantial reduction in the incidence of fractures compared to placebo. Additionally, greater BMD increase at 6, 12 and 18 months in spinal, hips and femoral bones was observed in abaloparatide compared to placebo and teriparatide-treated subjects.[25]

    Participants who completed 18 months of abaloparatide or placebo in the ACTIVE study were invited to participate in an extended open-labeled study - ACTIVExtend study (2012-2016).[26] Subjects (n=1139) received additional 2 years of 70 mg of alendronate, Vitamin D (400 to 800 IU), and calcium (500–1000 mg) supplementation daily. Combined abaloparatide and alendronate therapy reduced significantly the incidence of vertebral and nonvertebral fractures.[27]

    A clinical trial assessing the effectiveness of abaloparatide in altering spinal bone mineral density (BMD) in male subjects is expected to start in the first quarter of 2018. If successful, Radius Health aims to submit a sNDA to expand the use of abaloparatide-SC to treat men with osteoporosis.[13]

    In addition to the injectable form of abaloparatide, a transdermal patch is also in development.[12]

    References[edit | edit source]

    1. ↑ 1.0 1.1 1.2 "Eladynos". European Medicines Agency. 12 October 2022. Archived from the original on 3 March 2021. Retrieved 6 October 2023.
    2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 "Abaloparatide Monograph for Professionals". Drugs.com. Archived from the original on 5 March 2021. Retrieved 17 July 2021.
    3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Benjamin F. Simmons, I. I. I.; Caprio, Anthony J. (15 February 2019). "Abaloparatide (Tymlos) for Osteoporosis". American Family Physician. 99 (4): 260–261. ISSN 0002-838X. Archived from the original on 20 January 2021. Retrieved 17 July 2021.
    4. ↑ 4.0 4.1 "Eladynos". Archived from the original on 3 March 2021. Retrieved 17 July 2021.
    5. ↑ "Drug Trial Snapshot: Tymlos". U.S. Food and Drug Administration (FDA). 2019-02-09. Archived from the original on 2019-06-12. Retrieved 2019-07-26. Public Domain This article incorporates text from this source, which is in the public domain.
    6. ↑ 6.0 6.1 6.2 "Drugs@FDA: FDA Approved Drug Products". www.accessdata.fda.gov. Archived from the original on 2017-06-29. Retrieved 2017-11-03.
    7. ↑ 7.0 7.1 Jolette J, Attalla B, Varela A, Long GG, Mellal N, Trimm S, et al. (June 2017). "Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34)". Regulatory Toxicology and Pharmacology. 86: 356–365. doi:10.1016/j.yrtph.2017.04.001. PMID 28389324.
    8. ↑ 8.0 8.1 "FDA Approves Radius Health's TYMLOS (abaloparatide), a Bone Building Agent for the Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture" (Press release). Radius Inc. 28 April 2017. Archived from the original on 2017-11-04. Retrieved 2017-11-03.
    9. ↑ Tella SH, Kommalapati A, Correa R (May 2017). "Profile of Abaloparatide and Its Potential in the Treatment of Postmenopausal Osteoporosis". Cureus. 9 (5): e1300. doi:10.7759/cureus.1300. PMC 5493470. PMID 28680788.
    10. ↑ Pioszak AA, Parker NR, Gardella TJ, Xu HE (October 2009). "Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides". The Journal of Biological Chemistry. 284 (41): 28382–91. doi:10.1074/jbc.M109.022905. PMC 2788887. PMID 19674967.
    11. ↑ Tay D, Cremers S, Bilezikian JP (February 2018). "Optimal dosing and delivery of parathyroid hormone and its analogues for osteoporosis and hypoparathyroidism - translating the pharmacology". British Journal of Clinical Pharmacology. 84 (2): 252–267. doi:10.1111/bcp.13455. PMC 5777439. PMID 29049872.
    12. ↑ 12.0 12.1 Spreitzer H (18 January 2016). "Neue Wirkstoffe – Abaloparatid". Österreichische Apothekerzeitung (in German) (2/2016): 12.{{cite journal}}: CS1 maint: unrecognized language (link)
    13. ↑ 13.0 13.1 Inc., Radius Health. "Radius Health Reports Third Quarter 2017 Financial and Operating Results and Provides Business Update". GlobeNewswire News Room. Archived from the original on 2017-11-07. Retrieved 2017-11-03.
    14. ↑ "Radius Health Announces License and Development Agreement for Abaloparatide-SC with Teijin Limited in Japan" (Press release). Archived from the original on 2017-11-07. Retrieved 2017-11-03.
    15. ↑ "Radius Announces FDA Acceptance for Filing of New Drug Application for Abaloparatide-SC for the Treatment of Postmenopausal Women with Osteoporosis" (Press release). Archived from the original on 2017-11-07. Retrieved 2017-11-04.
    16. ↑ "NDA Approval Letter". FDA. Apr 27, 2017. Archived from the original on May 2, 2017. Retrieved May 2, 2017.
    17. ↑ "Abaloparatide | Patents | Expiry | Expiration | Dates |". PharmaCompass.com. Archived from the original on 2017-11-07. Retrieved 2017-11-03.
    18. ↑ Brent, Mikkel Bo (15 October 2021). "Abaloparatide: A review of preclinical and clinical studies". European Journal of Pharmacology. 909: 174409. doi:10.1016/j.ejphar.2021.174409. ISSN 0014-2999. Retrieved 6 October 2023.
    19. ↑ Bahar H, Gallacher K, Downall J, Nelson CA, Shomali M, Hattersley G (November 2016). "Six Weeks of Daily Abaloparatide Treatment Increased Vertebral and Femoral Bone Mineral Density, Microarchitecture and Strength in Ovariectomized Osteopenic Rats". Calcified Tissue International. 99 (5): 489–499. doi:10.1007/s00223-016-0171-1. PMC 5055567. PMID 27395059.
    20. ↑ Varela A, Chouinard L, Lesage E, Smith SY, Hattersley G (January 2017). "One Year of Abaloparatide, a Selective Activator of the PTH1 Receptor, Increased Bone Formation and Bone Mass in Osteopenic Ovariectomized Rats Without Increasing Bone Resorption". Journal of Bone and Mineral Research. 32 (1): 24–33. doi:10.1002/jbmr.3003. PMID 27748532.
    21. ↑ Varela A, Chouinard L, Lesage E, Guldberg R, Smith SY, Kostenuik PJ, Hattersley G (February 2017). "One year of abaloparatide, a selective peptide activator of the PTH1 receptor, increased bone mass and strength in ovariectomized rats". Bone. 95: 143–150. doi:10.1016/j.bone.2016.11.027. PMID 27894941.
    22. ↑ Clinical trial number NCT00542425 for "Phase 2 Dose-finding Study to Evaluate the Effects of BA058 in the Treatment of Postmenopausal Women With Osteoporosis" at ClinicalTrials.gov
    23. ↑ Leder BZ, O'Dea LS, Zanchetta JR, Kumar P, Banks K, McKay K, et al. (February 2015). "Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis". The Journal of Clinical Endocrinology and Metabolism. 100 (2): 697–706. doi:10.1210/jc.2014-3718. PMID 25393645.
    24. ↑ Clinical trial number NCT01343004 for "Phase III Study to Evaluate the Safety and Efficacy of BA058 for Prevention of Fracture in Postmenopausal Women" at ClinicalTrials.gov
    25. ↑ Miller PD, Hattersley G, Riis BJ, Williams GC, Lau E, Russo LA, et al. (August 2016). "Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial". JAMA. 316 (7): 722–33. doi:10.1001/jama.2016.11136. PMID 27533157.
    26. ↑ Clinical trial number NCT01657162 for "Twenty Four Month Extension Study of BA058-05-003" at ClinicalTrials.gov
    27. ↑ Cosman F, Miller PD, Williams GC, Hattersley G, Hu MY, Valter I, et al. (February 2017). "Eighteen Months of Treatment With Subcutaneous Abaloparatide Followed by 6 Months of Treatment With Alendronate in Postmenopausal Women With Osteoporosis: Results of the ACTIVExtend Trial". Mayo Clinic Proceedings. 92 (2): 200–210. doi:10.1016/j.mayocp.2016.10.009. PMID 28160873.

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