Denosumab

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Denosumab
Mass / length primary structure 146  kDa
Identifier
External IDs
Drug information
ATC code M05 BX04
Drug class Monoclonal antibody

Denosumab (trade names Prolia ® and XGEVA ® ; manufacturer in both cases Amgen ) is a human monoclonal antibody that mimics the effects of osteoprotegerin (OPG) in bone metabolism . Denosumab is an IgG2 anti-RANKL antibody that binds to RANKL with a very high affinity and thus inhibits its interaction with RANK .

Mode of action

It is known that the regular renewal of the bone matrix is ​​based on a complex interaction of special bone cells: In addition to osteoclasts (responsible for bone resorption) and osteoblasts (responsible for bone formation), osteocytes and so-called "lining cells" also play a role. There is a finely tuned coordination for their various activities. This coordination requires sophisticated intracellular communication pathways that explain the transmission of the coupling signal.

Recent findings in the understanding of bone biology has led to the track of a - formed by the osteoblasts - protein, the so-called R preceptor A ctivator of N uclear Factor K appa B L igand (RANKL), which is considered as a signal transmitter of osteoblasts to osteoclasts. RANKL binds to its receptor RANK, a member of the tumor necrosis factor receptor superfamily , located on the surface of pre - osteoclasts, converts the precursor cells into osteoclasts and thus increases the activity and survival of the cells responsible for bone resorption. RANKL is therefore the primary mediator of bone loss. In the long term, bone loss leads to osteoporosis .

In order to modulate its effect and to maintain the physiological balance, the osteoblasts secrete another protein - osteoprotegerin (OPG), which acts as a "capture" receptor. OPG binds to RANKL, thereby preventing it from interacting with RANK and thus controlling the intensity and duration of the RANKL-induced osteoclast function.

The decoding of this RANK / RANKL / OPG path, which the American biotech company Amgen has been working on together with other scientific laboratories since the mid-1990s, pioneered the development of a clinically applicable RANKL inhibitor: denosumab, a human monoclonal IgG2 -anti-RANKL antibody that mimics the effects of OPG. In contrast to OPG, denosumab is highly selective, i. H. the antibody does not bind to other members of the TNF family and thereby enables the specific inhibition of RANKL activity. An important advantage of the administration of antibodies is that - unlike the recombinant OPG discussed earlier on RANKL inhibition - there is no immune sensitization to OPG.

Therapeutic use

  • Treatment of osteoporosis in postmenopausal women at increased risk of fractures (trade name Prolia ® )
  • Treatment of osteoporosis in men at increased risk of fractures (trade name Prolia ® )
  • Treatment of osteoporosis in men caused by hormone therapy for prostate cancer (trade name Prolia® )
  • Prevention of skeletal complications in adults with bone metastases due to solid tumors (trade name XGEVA ® )
  • Treatment of giant cell tumors of the bone (trade name XGEVA ® )

Since the critical RANKL / RANK signaling pathway exists in all diseases associated with bone loss, denosumab could possibly also be used in male osteoporosis, steroid-induced bone loss and not least in rheumatoid arthritis in addition to postmenopausal diseases . However, the active ingredient has not yet been approved for this ( off-label use ).

Denosumab (60 mg injected subcutaneously every six months) has now been tested in two multicenter, double-blind, randomized placebo-controlled studies with regard to the reduction in osteoporotic fractures . In 734 men (mean 75.3 years) on anti- androgen therapy for prostate cancer , an increase in bone density of 5.6% was found after two years, compared to a bone density decrease of 1.0% in the placebo group . Vertebral body fractures occurred in 1.5% , compared to 3.9% in the placebo group ( relative risk reduction 62%). The second study ("FREEDOM Trial") included 7868 postmenopausal women between 60 and 69 years with osteoporosis . A vertebral body fracture occurred within 36 months in 2.3%, in the placebo group in 7.2% (relative risk reduction 68%). Femoral shaft fractures occurred in 0.7% versus 1.2% in the placebo group (relative risk reduction 40%). The risk of a bone fracture could thus be reduced in both studies by the same order of magnitude as with zoledronate and teriparatide , and slightly more than with the oral aminobisphosphonates .

The researchers at the Institute for Molecular Biotechnology (IMBA) in Vienna discovered in 2010 that the protein RANKL, actually a key molecule in bone metabolism, is also responsible for the development of hormone-dependent breast cancer . In 2012, the US Department of Defense presented the IMBA with the annual "Innovator Award" for research into breast cancer, which is well-funded. The Austrian breast cancer research was funded with 7.4 million dollars.

Admission status

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive assessment in December 2009. Accordingly, denosumab was approved in May 2010 under the trade name Prolia ® in the European Union (as well as in Norway, Iceland and Liechtenstein) for the treatment of osteoporosis in women with an increased risk of bone fractures. The US Food and Drug Administration (FDA) followed suit in June 2010 with approval for denosumab (osteoporosis in women). On September 20, 2012, the FDA approved denosumab for the treatment of osteoporosis in men at increased risk of fractures. Approval for this indication within the EU is still pending. Since September 1, 2015, Prolia has also been approved for the treatment of osteporosis for men in Switzerland.

In November 2010, the Food and Drug Administration approved denosumab (trade name: XGEVA ® ) for the United States for the prevention of skeletal complications in patients with bone metastases from solid tumors. In July 2011 the European Medicines Agency (EMA) approved XGEVA ® for the prevention of skeletal complications in bone metastases from solid tumors for the EU . In June 2013, Amgen received FDA approval for XGEVA ® for the treatment of giant cell tumors of the bone. Denosumab is the first FDA-approved drug for this rare disease.

Risks

According to EMA, the most common side effects are: urinary tract infections, upper respiratory tract infections , cataracts, constipation, rash, sciatica, and joint pain.

A smaller study found an increased risk of cancer and serious infections, but this was not statistically significant. The Cummings et al. with women suffering from osteoporosis showed significantly higher rates of eczema and hospital admissions for skin infections. A possible connection is that RANKL, as a target of denosumab, is also expressed on immune cells, but the significance of RANKL there is not yet known.

In September 2012, the manufacturer Amgen sent out a Rote-Hand-Brief regarding severe symptomatic hypocalcemia (including cases with fatal outcome) in patients treated with XGEVA ® (denosumab). In February 2013, the manufacturer issued a Rote-Hand-Brief informing about the risk of atypical femoral fractures in patients treated with Prolia ® (denosumab). Another “Red Hand Letter” from the manufacturer (see above) provided information on jaw osteonecrosis as a further possible side effect in September 2014. Prescribers were advised that patients with accompanying risk factors should undergo a dental examination before the first dose. After the administration, tooth extraction may only be performed under antibiotic protection with plastic wound closure.

A rebound effect was observed after the drug was discontinued .

Others

Thomson Reuters estimates that denosumab would have annual worldwide sales of $ 3.3 billion in 2014. According to Reuters, Prolia ® had sales of $ 744 million in 2013.

In November 2010, denosumab received the Scrip Award as the best new drug of the year from SCRIP , the leading international publication for healthcare market analysis.

In 2011, Amgen received the Galenus Prize in the Primary Care category for denosumab .

See also

Web links

Individual evidence

  1. ↑ E Preisinger: RANK / RANK-Ligand / OPG: A new therapeutic approach in osteoporosis treatment . In: Journal for Mineral Metabolism . 14, No. 4, November 14, 2007, pp. 144-145. Retrieved July 8, 2012.
  2. ↑ Denosumab in postmenopausal women with osteoporosis . medknowledge.de. Archived from the original on May 13, 2012. Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Retrieved July 8, 2012. @1@ 2Template: Webachiv / IABot / www.medknowledge.de
  3. ↑ RANK Ligand Virtual Press Kit . amgen.com. Archived from the original on June 2, 2009. Retrieved July 8, 2012.
  4. ↑ HG Bone, MA Bolognese, CK Yuen et al .: Effects of denosumab on bone mineral density and bone turnover in postmenopausal women . In: The Journal of Clinical Endocrinology and Metabolism . 93, No. 6, June 2008, pp. 2149-2157. PMID 18381571 . Retrieved August 19, 2010.
  5. ↑ a b c Prolia (R) (Denosumab) Granted Marketing Authorization in the European Union . Press release, May 28, 2010.
  6. ↑ a b FDA Approves New Indication For Prolia® (Denosumab) For The Treatment Of Bone Loss In Men With Osteoporosis At High Risk For Fracture . Press release, September 20, 2012.
  7. ↑ a b XGEVA ® (denosumab) Granted Marketing Authorization in the European Union . Press release, July 15, 2011.
  8. ↑ a b "New Medicines" XGEVA®. (PDF; 361 kB) Drugs Commission of the German Medical Association (AkdÄ); Retrieved December 1, 2011.
  9. ↑ a b FDA Approves Amgen's XGEVA® <(denosumab) For The Treatment Of Giant Cell Tumor Of Bone . Press release, June 13, 2013.
  10. ↑ MR Smith, B Egerdie, N Hernández Toriz et al .: Denosumab in men receiving androgen-deprivation therapy for prostate cancer . In: The New England Journal of Medicine . 361, No. 8, August 2009, pp. 745-755. PMID 19671656 . Retrieved August 19, 2010.
  11. ↑ a b SR Cummings, J San Martin, MR McClung et al .: Denosumab for prevention of fractures in postmenopausal women with osteoporosis . In: The New England Journal of Medicine . 361, No. 8, August 2009, pp. 756-765. PMID 19671655 . Retrieved August 19, 2010.
  12. ↑ How hormones can trigger breast cancer (PDF) IMBA press release from September 29, 2010.
  13. ↑ US Department of Defense invests 7.4 million dollars in Austrian breast cancer research ( Memento of the original from January 16, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. , IMBA press release of October 22, 2012. @1@ 2Template: Webachiv / IABot / de.imba.oeaw.ac.at
  14. ↑ Committee for Medicinal Products for Human Use: Summary of Positive Opinion for Prolia (PDF; 39 kB) emea.europa.eu. December 17, 2009. Retrieved July 8, 2012.
  15. ↑ FDA Approves Amgen's Prolia (TM) (Denosumab) for Treatment of Postmenopausal Women With Osteoporosis at High Risk for Fracture . Press release from June 1, 2010.
  16. ↑ FDA Approves Amgen's XGEVA (TM) (Denosumab) for the Prevention of Skeletal-Related Events in Patients with Bone Metastases from Solid Tumors . Press release, November 18, 2010.
  17. ^ Prolia EPAR - Summary for the public . European Medicines Agency (EMA); Retrieved December 1, 2011.
  18. ↑ Xgeva EPAR - Summary for the public . European Medicines Agency (EMA); Retrieved December 1, 2011.
  19. ^ MR McClung, EM Lewiecki, SB Cohen et al .: Denosumab in postmenopausal women with low bone mineral density . In: New England Journal of Medicine , 2006, 354 (8), pp. 821-831, PMID 16495394 .
  20. ↑ S. Khosla: Increasing options for the treatment of osteoporosis . In: New England Journal of Medicine , 2009, 361 (8), pp. 818-820, PMID 19671654 .
  21. ↑ Red Hand Letter from Amgen in September 2012. (PDF) Retrieved on September 4, 2012 .
  22. ↑ Rote-Hand-Brief from Amgen in February 2013 (PDF; 412 kB) Retrieved on February 20, 2013 .
  23. ↑ Prolia® - Osteoporosis drug with risks? Swiss Rheumatism League, accessed on September 11, 2019 .
  24. ^ Prolia®. Specialist information from the Swiss Medicines Compendium®. Amgen Switzerland AG, April 15, 2019, accessed on September 18, 2019 .
  25. ↑ Multiple vertebral body fractures after discontinuation of denosumab (Prolia®). "From the UAW database". In: Deutsches Ärzteblatt. Drug Commission of the German Medical Association, December 1, 2017, accessed on September 18, 2019 .
  26. ↑ Amgen Drug Approved to Fight Osteoporosis . In: New York Times , June 1, 2010. 
  27. ↑ Amgen ends marketing agreement with GSK for osteoporosis drug , Reuters report on the termination of the cooperation with GSK from April 3, 2014, accessed on April 4, 2014.
  28. ↑ Scrip Awards 2010 Winners Announced . Scrip Awards 2010.
  29. ↑ Prolia (TM) (denosumab) Receives Best New Drug Honor at Scrip Awards . Press release from November 4, 2010.
  30. ↑ Galenus von Pergamon Prize 2011 awarded for three top achievements in pharmacology . Press release. Springer medicine.