Chemistry:Abaloparatide

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Short description: Pharmaceutical medication
Abaloparatide
Clinical data
Trade namesTymlos
Other namesBA058, BIM-44058
AHFS/Drugs.comMonograph
MedlinePlusa617038
License data
Routes of
administration		Subcutaneous injection
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC174H299N56O49
Molar mass3959.649 g·mol−1
3D model (JSmol)

Abaloparatide, sold under the brand name Tymlos among others, is a parathyroid hormone-related protein (PTHrP) analog medication used to treat osteoporosis.[1] It is an anabolic (i.e., bone growing) agent.[3]

The most common side effects include hypercalciuria (high calcium levels in the urine) and dizziness.[2] Other common side effects include back pain, nausea, headache, joint pain, high blood pressure, reactions at the injection site, and palpitations (a forceful heartbeat that may be rapid or irregular).[2]

Abaloparatide was approved for medical use in the United States in April 2017,[1][4][5][6][7] and in the European Union in December 2022.[2]

Medical uses

Abaloparatide is indicated to treat postmenopausal women with osteoporosis at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy.[1][2][5]

In the US it is also indicated for the treatment to increase bone density in men with osteoporosis at high risk of fracture or in people who have failed or are intolerant to other available osteoporosis therapy.[1][8]

Side effects

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.[1]

Preclinical studies revealed that abaloparatide systemic daily administration leads to a dose- and time-dependent increase in the incidence of osteosarcoma in rodents.[9] It is unknown if abaloparatide will cause osteosarcoma in humans.[1]<

Pharmacology

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).[10] 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.[11][12]

History

Preclinical studies

Abaloropatide was invented at Ipsen.[13] It was known as BIM-44058 during pre-clinical studies and as BA058 while under clinical 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[14] and long-term[15] 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.[16]

Clinical Trials

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.[17] 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.[18]

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).[19] 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.[20]

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).[21] 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.[22]

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.[23]

In addition to the injectable form of abaloparatide, a transdermal patch is also in development.[3]

Society and culture

Legal status

Radius Health filed a Marketing Authorization Application (MAA) in November 2015,[24] which was validated in December 2015, and still under regulatory assessment by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). As in July 2017, the CHMP issued a second Day-180 List of Outstanding Issues, which Radius is addressing with the CHMP.[23]

In February 2016 a NDA was filed to the FDA, Radius NDA for abaloparatide-SC was accepted in May 2016.[25] A Prescription Drug User Fee Act (PDUFA) date was initially granted on 30 March 2016, but then extended to 30 June 2017.[26]

On 13 October 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Eladynos, intended for the treatment of osteoporosis in postmenopausal women at increased risk of fracture.[27] The applicant for this medicinal product is Radius Health Ireland Ltd.[27] Abaloparatide was approved for medical use in the European Union in December 2022.[2][28]

Intellectual Property

Radius Health holds three patents on abaloparatide-SC, with expiration dates from 2027 to 2028.[29] The patents relate to the drug composition (US 8148333), and the drug delivery methods (US 7803770 B2 and US 8748382-B2).

Economics

Abaloparatide-SC is manufactured by Radius Health, Inc, a biomedical company based in Boston, Massachusetts.[23] The firm reported that sales for abaloparatide were $3.5 million for the third quarter of 2017.[23]

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.[30]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Tymlos- abaloparatide injection, solution". 28 December 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=712143d9-e21e-4013-bb3b-3426a21060a8. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "Eladynos EPAR". 12 October 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/eladynos. 
  3. ↑ 3.0 3.1 "Neue Wirkstoffe – Abaloparatid" (in de). Österreichische Apothekerzeitung (2/2016): 12. 18 January 2016. 
  4. ↑ "Tymlos Subcutaneous Injection". 8 June 2017. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208743Orig1s000TOC.cfm. 
  5. ↑ 5.0 5.1 "Drug Trial Snapshot: Tymlos". U.S. Food and Drug Administration (FDA). 9 February 2019. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-tymlos.  This article incorporates text from this source, which is in the public domain.
  6. ↑ "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 4 November 2017. Retrieved 3 November 2017.
  7. ↑ "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 Health. 28 April 2017. Retrieved 3 March 2023 – via GlobeNewswire.
  8. ↑ "Radius Health's Tymlos (abaloparatide) Receives U.S. FDA Approval as a Treatment to Increase Bone Density in Men with Osteoporosis at High Risk for Fracture". Radius (Press release). 21 December 2022. Retrieved 3 March 2023.
  9. ↑ "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. June 2017. doi:10.1016/j.yrtph.2017.04.001. PMID 28389324. 
  10. ↑ "Profile of Abaloparatide and Its Potential in the Treatment of Postmenopausal Osteoporosis". Cureus 9 (5): e1300. May 2017. doi:10.7759/cureus.1300. PMID 28680788. 
  11. ↑ "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. October 2009. doi:10.1074/jbc.M109.022905. PMID 19674967. 
  12. ↑ "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. February 2018. doi:10.1111/bcp.13455. PMID 29049872. 
  13. ↑ US Patent US 6,544,949 B1, "Analogs of Parathyroid Hormone", 8 April 2003, Inventor: Zheng Xin Dong
  14. ↑ "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. November 2016. doi:10.1007/s00223-016-0171-1. PMID 27395059. 
  15. ↑ "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. January 2017. doi:10.1002/jbmr.3003. PMID 27748532. 
  16. ↑ "One year of abaloparatide, a selective peptide activator of the PTH1 receptor, increased bone mass and strength in ovariectomized rats". Bone 95: 143–150. February 2017. doi:10.1016/j.bone.2016.11.027. PMID 27894941. 
  17. ↑ 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
  18. ↑ "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. February 2015. doi:10.1210/jc.2014-3718. PMID 25393645. 
  19. ↑ 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
  20. ↑ "Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial". JAMA 316 (7): 722–33. August 2016. doi:10.1001/jama.2016.11136. PMID 27533157. 
  21. ↑ Clinical trial number NCT01657162 for "Twenty Four Month Extension Study of BA058-05-003" at ClinicalTrials.gov
  22. ↑ "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. February 2017. doi:10.1016/j.mayocp.2016.10.009. PMID 28160873. 
  23. ↑ 23.0 23.1 23.2 23.3 "Radius Health Reports Third Quarter 2017 Financial and Operating Results and Provides Business Update" (Press release). Radius Health. 2 November 2017. Retrieved 3 November 2017 – via GlobeNewswire.
  24. ↑ "Radius Health Has Submitted a Marketing Authorization Application for the Investigational Drug Abaloparatide-SC for the Treatment of Postmenopausal Osteoporosis in Europe" (Press release). Retrieved 3 November 2017.
  25. ↑ "Radius Announces FDA Acceptance for Filing of New Drug Application for Abaloparatide-SC for the Treatment of Postmenopausal Women with Osteoporosis" (Press release). Retrieved 4 November 2017.
  26. ↑ "NDA Approval Letter". FDA. 27 April 2017. https://www.accessdata.fda.gov. 
  27. ↑ 27.0 27.1 "Eladynos: Pending EC decision". 13 October 2022. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/eladynos-0.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  28. ↑ "Eladynos Product information". https://ec.europa.eu/health/documents/community-register/html/h1706.htm. 
  29. ↑ "Abaloparatide". PharmaCompass.com. https://www.pharmacompass.com/patent-expiry-expiration/abaloparatide. 
  30. ↑ "Radius Health Announces License and Development Agreement for Abaloparatide-SC with Teijin Limited in Japan" (Press release). Retrieved 3 November 2017.



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