Abaloparatide

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Abaloparatide
Clinical data
Synonyms BA058, BIM-44058
Routes of
administration
Subcutaneous injection
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C174H299N56O49
Molar mass 3,959.65 g·mol−1
3D model (JSmol)

Abaloparatide (brand name TYMLOS), formerly BA058, is a parathyroid hormone-related protein (PTHrP) analog drug used to treat osteoporosis. Like the related drug teriparatide, and unlike bisphosphonates, it is an anabolic (i.e., bone growing) agent.[1] A subcutaneous injection formulation of the drug has completed a Phase III trial for osteoporosis.[2] This single study found a decrease in fractures.[3] In 28 April 2017, it was approved by Food and drug administration (FDA) to treat postmenopausal osteoporosis.

Therapeutics[edit]

Medical use[edit]

Abaloparatide is indicated to treat postmenopausal women with osteoporosis who are more susceptible to bone fractures.[2]

Dosage[edit]

The dose recommended is 80mcg subcutaneous injection once a day, administered in the periumbilical area using a prefilled pen device containing 30 doses.[4]

Warnings and Precautions[edit]

Preclinical studies revealed that abaloparatide systemic daily administration leads to a dose- and time-dependent increase in the incidence of osteosarcoma in rodents.[5] 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.[4][6]

Side Effects[edit]

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.[4]

Pharmacology[edit]

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).[7] 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.[8][9]

History[edit]

Preclinical studies[edit]

Abaloropatide was previously known as BA058 and BIM-44058 while under development. The anabolic effects of abaloparatide on bone were demonstrated in two preclinical studies conducted in ovarectomized rats. Both studies showed increased cortical and trabecular bone volume and density, and trabecular microarchitecture improvement in vertebral and nonvertebral bones after short-term[10] and long-term[11] 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.[12] However, it was also indicated that prolonged abalorapatide-SC treatment leads to increased incidence of osteosarcoma.[5] To date, there is no yet evidence for increased risk of bone tumors due to prolonged abalorapatide systemic administration in humans. Based on this 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.[4]

Clinical Trials[edit]

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.[13] 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.[14] Following the completion of this study, an NDA filed in 2014 was denied by the FDA that requested additional clinical evidence that abaloparatide presents substantial benefits over existing therapies in at least one endpoint.[15]

In the phase III (2011-2014) Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial, a 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).[2] 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.[3]

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).[16] 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 TYMLOS and alendronate therapy reduced significantly the incidence of vertebral and nonvertebral fractures.[17]

A clinical trial assessing the effectiveness of TYMLOS 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 issue a sNDA to expand the use of abaloparatide-SC to treat men with osteoporosis.[18]

In addition to the injectable form of TYMLOS, a transdermal patch is also in development.[1]

Commercialization[edit]

As previously noted, abaloparatide-SC is manufactured by Radius Health, Inc. (Nasdaq: RDUS), a biomedical company based in Waltham, Massachusetts. This company is focused on the development of new therapeutics for osteoporosis, cancer and endocrine diseases. TYMLOS is the only drug currently marketed by Radius Health. RDUS reported that sales for TYMLOS were $3.5million for the third quarter of 2017.[18] The company announced a net loss of $57.8 million, or $1.31 per share for the third quarter of 2017, compared to $19.2 million for the same quarter of 2016.[19] The net loss most likely reflects the substantial expenses associated with the preparation and launching of TYMLOS into the US market in May 2017.

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.[20] 

Regulatory Information[edit]

Radius Health filed a Marketing Authorization Application (MAA) in November 2015,[21] 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.[18]

In February 2016 a NDA was filed to the FDA, Radius NDA for abaloparatide-SC was accepted in May, 2016.[22] A Prescription Drug User Fee Act (PDUFA) date was initially granted in March 30, 2016, but then extended to June 30, 2017.[23] As previously stated, abaloparatide injection (TYMLOS) was approved for use in postmenopausal osteoporosis on April 28, 2017.[6]

Intellectual Property[edit]

Radius Health currently holds three patents on abaloparatide-SC, with expiration dates from 2027-2028.[24] The patents relate to the drug composition (US 8148333), and the drug delivery methods (US 7803770 B2 and US 8748382-B2). 

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

References[edit]

  1. ^ a b H. Spreitzer (18 January 2016). "Neue Wirkstoffe – Abaloparatid". Österreichische Apothekerzeitung (in German) (2/2016): 12. 
  2. ^ a b c 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
  3. ^ a b Miller, PD; Hattersley, G; Riis, BJ; Williams, GC; Lau, E; Russo, LA; Alexandersen, P; Zerbini, CA; Hu, MY; Harris, AG; Fitzpatrick, LA; Cosman, F; Christiansen, C; ACTIVE Study, Investigators. (16 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. 
  4. ^ a b c d "Drugs@FDA: FDA Approved Drug Products". www.accessdata.fda.gov. Retrieved 2017-11-03. 
  5. ^ a b Jolette, Jacquelin; Attalla, Bassem; Varela, Aurore; Long, Gerald G.; Mellal, Nacera; Trimm, Sabile; Smith, Susan Y.; Ominsky, Michael S.; Hattersley, Gary (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: RTP. 86: 356–365. doi:10.1016/j.yrtph.2017.04.001. ISSN 1096-0295. PMID 28389324. 
  6. ^ a b Radius Inc, Press Release, April 2017. "FDA Approves Radius Health's TYMLOS™ (abaloparatide), a Bone Building Agent for the Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture". Retrieved 2017-11-03. 
  7. ^ Tella, Sri Harsha; Kommalapati, Anuhya; Correa, Ricardo (2017-05-31). "Profile of Abaloparatide and Its Potential in the Treatment of Postmenopausal Osteoporosis". Cureus. 9 (5): e1300. doi:10.7759/cureus.1300. ISSN 2168-8184. PMC 5493470Freely accessible. PMID 28680788. 
  8. ^ Pioszak, Augen A.; Parker, Naomi R.; Gardella, Thomas J.; Xu, H. Eric (2009-10-09). "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): 28382–28391. doi:10.1074/jbc.M109.022905. ISSN 0021-9258. PMC 2788887Freely accessible. PMID 19674967. 
  9. ^ Tay, D.; Cremers, S.; Bilezikian, J. P. (2017-10-19). "Optimal dosing and delivery of PTH and its analogues for osteoporosis and hypoparathyroidism - translating the pharmacology". British Journal of Clinical Pharmacology. doi:10.1111/bcp.13455. ISSN 1365-2125. PMID 29049872. 
  10. ^ Bahar, Hila; Gallacher, Kyla; Downall, Julie; Nelson, Carol A.; Shomali, Maysoun; Hattersley, Gary (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. ISSN 0171-967X. PMC 5055567Freely accessible. PMID 27395059. 
  11. ^ Varela, Aurore; Chouinard, Luc; Lesage, Elisabeth; Smith, Susan Y.; Hattersley, Gary (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. ISSN 1523-4681. PMID 27748532. 
  12. ^ Varela, Aurore; Chouinard, Luc; Lesage, Elisabeth; Guldberg, Robert; Smith, Susan Y.; Kostenuik, Paul J.; Hattersley, Gary (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. ISSN 1873-2763. PMID 27894941. 
  13. ^ "Phase 2 Dose-finding Study to Evaluate the Effects of BA058 in the Treatment of Postmenopausal Women With Osteoporosis - Full Text View - ClinicalTrials.gov". Retrieved 2017-11-04. 
  14. ^ Leder, Benjamin Z.; O'Dea, Louis St L.; Zanchetta, José R.; Kumar, Prasana; Banks, Kathleen; McKay, Kathleen; Lyttle, C. Richard; Hattersley, Gary (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. ISSN 1945-7197. PMID 25393645. 
  15. ^ Radius Health Inc (December 31, 2014). "Annual Report on Form 10-K For the Fiscal Year Ended". 
  16. ^ "Twenty Four Month Extension Study of BA058-05-003 - Full Text View - ClinicalTrials.gov". Retrieved 2017-11-04. 
  17. ^ Cosman, Felicia; Miller, Paul D.; Williams, Gregory C.; Hattersley, Gary; Hu, Ming-Yi; Valter, Ivo; Fitzpatrick, Lorraine A.; Riis, Bente Juel; Christiansen, Claus (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. ISSN 1942-5546. PMID 28160873. 
  18. ^ a b c Inc., Radius Health. "Radius Health Reports Third Quarter 2017 Financial and Operating Results and Provides Business Update". GlobeNewswire News Room. Retrieved 2017-11-03. 
  19. ^ Radius Inc, Press Release, Nov 2017. "Radius Health Reports Third Quarter 2017 Financial and Operating Results and Provides Business Update". Yahoo Finances. Retrieved 2017-11-03. 
  20. ^ "Radius Health Announces License and Development Agreement for Abaloparatide-SC with Teijin Limited in Japan". Retrieved 2017-11-03. 
  21. ^ "Radius Health Has Submitted a Marketing Authorization Application for the Investigational Drug Abaloparatide-SC for the Treatment of Postmenopausal Osteoporosis in Europe". Retrieved 2017-11-03. 
  22. ^ "Radius Announces FDA Acceptance for Filing of New Drug Application for Abaloparatide-SC for the Treatment of Postmenopausal Women with Osteoporosis". Retrieved 2017-11-04. 
  23. ^ FDA (Apr 27, 2017). "NDA Approval Letter". 
  24. ^ "Abaloparatide | Patents | Expiry | Expiration | Dates | PharmaCompass.com". www.pharmacompass.com. Retrieved 2017-11-03.