On 19 July 2024, Gedeon Richter announced that the European Medicines Agency (EMA) accepted its marketing authorisation applications (MAAs) for its denosumab biosimilars for all indications of Regeneron’s Xgeva® and Prolia®. Gedeon Richter’s denosumab biosimilars are the first monoclonal antibodies in the company’s biosimilar portfolio.

These acceptances follow the approval of Sandoz’s Jubbonti® and Wyost® (denosumab) in Europe in May 2024 and the EMA’s acceptance of MAAs for denosumab biosimilars of Fresenius Kabi (FKS518, May 2024) and Shanghai Henlius Biotech/Organon (HLX14, May 2024).

Denosumab biosimilars have also been approved in the US (Sandoz’s Jubbonti® and Wyost®) and in China (Boan Biotech’s Byoubei® and Boluojia® and Mabwell’s Mailishu® and Maiweijian^TM).

On 16 July 2024, Sandoz announced the Canadian launch of Wyost® (denosumab), biosimilar to Amgen’s Xgeva®.  Wyost® is available as a 120 mg subcutaneous injection for use every four weeks.

Wyost® was the first denosumab biosimilar approved in Canada in March 2024 for all Xgeva® indications, including the prevention of bone fractures in bone metastatic cancers and treatment of bone giant cell tumours in adults.  This followed the Canadian approval of Sandoz’s Jubbonti®, biosimilar to Amgen’s Prolia® (denosumab) in February 2024 for osteoporosis and increasing bone mass.

Sandoz’s Wyost® and Jubbonti® were the first denosumab biosimilars approved in the US in March 2024.  Following the April 2024 resolution of US BPCI proceedings commenced by Amgen against Sandoz in May 2023, Jubbonti® and Wyost® are expected to launch in the US from 31 May 2025.

On 11 July 2024, Fresenius Kabi announced that its Marketing Authorisation Applications (MAAs) for denosumab have been accepted for review by the European Medicines Agency (EMA) as biosimilars to, and for all indications of, Amgen’s Prolia® and Xgeva®.

This comes after Fresenius’ BLA for denosumab was accepted for review by the US FDA on 27 May 2024, as biosimilar to Amgen’s Prolia®.  In June 2024, Fresenius presented results of a Phase 3 study demonstrating biosimilarity of its FKS518 (denosumab) with Amgen’s Prolia®.

Denosumab biosimilars have been approved in the US and EU (Sandoz’s Jubbonti® and Wyost®) and in China (Boan Biotech’s Byoubei® and Boluojia® and Mabwell’s Mailishu® and Maiweijian^TM).

Alvotech announced positive topline results from a confirmatory clinical study for AVT03 (denosumab), biosimilar to Amgen’s Prolia® and Xgeva®. The study, involving 532 postmenopausal women with osteoporosis, met its primary endpoints, demonstrating clinical similarity in efficacy, safety, immunogenicity, and pharmacokinetics (PK) between AVT03 and Prolia®. Positive results from two additional PK studies comparing AVT03 with Prolia® and Xgeva® also showed equivalent safety and tolerability.  

Alvotech’s announcement states that it expects to file marketing applications for AVT03 in major global markets later in 2024. 

This comes after Alvotech’s announcement last month that it has expanded its current partnership with STADA to include AVT03 for EU, UK and Switzerland. 

Denosumab biosimilars have been approved in the US and EU (Sandoz’s Jubbonti® and Wyost®) and in China (Boan Biotech’s Byoubei® and Boluojia® and Mabwell’s Mailishu® and Maiweijian^TM).

On 11 June 2024, Alvotech announced that it has expanded its current partnership with STADA to include AVT03  (denosumab), biosimilar to Amgen’s Prolia®/Xgeva®.   

Under the agreement, STADA will be the sponsor of the Alvotech developed product, with semi-exclusive rights to commercialise AVT03 in Europe, Switzerland and the UK and exclusive rights in certain Central Asian and Middle Eastern countries. 

The companies’ November 2019 strategic partnership already covers: 

• Hukyndra® (AVT02), a high concentration biosimilar to AbbVie’s Humira® (adalimumab), first launched in Europe in June 2022 and in Switzerland in September 2022; and  
• Uzprovo® (AVT04), biosimilar to Janssen’s Stelara® (ustekinumab), EU-approved in January 2024 and expected to launch following the expiry of Stelara’s SPC in July 2024. 

Under the June 2024 agreement, STADA’s commercialisation rights to the adalimumab and ustekinumab biosimilars will be extended to Commonwealth of Independent States (CIS).  Alvotech will regain commercial rights from STADA to AVT06, biosimilar to Regeneron’s Eylea (aflibercept), for which positive top-line results were reported in January 2024. 

At the American Society of Clinical Oncology (ASCO) conference, held from 31 May to 4 June 2024, Fresenius Kabi presented results of a Phase 3 study comparing its FKS518 with Amgen’s Prolia® (denosumab) in postmenopausal women with osteoporosis.  FKS518 was shown to have therapeutic equivalence to Prolia®, with similar safety profiles.  

On 27 May 2024, Fresenius Kabi announced that its BLA for denosumab was accepted for review by the US FDA as biosimilar to Prolia®.   

On 28 May 2024, Amgen filed a complaint against Celltrion in the United States District Court for the District of New Jersey alleging infringement of 29 patents relating to denosumab.  The allegations relate to Celltrion’s abbreviated Biologics Licence Application (aBLA) submitted in December 2023 for CT-P41, its biosimilar to Amgen’s Xgeva® and Prolia® (denosumab). 

In May 2023, Amgen sued Sandoz in the US over its denosumab biosimilars (Jubbonti® and Wyost®) asserting infringement of 21 denosumab patents.  That dispute was resolved in April 2024, enabling Sandoz to launch Jubbonti® and Wyost® from 31 May 2025 (or earlier in certain undisclosed circumstances).   

Jubbonti® and Wyost® were approved by the FDA on 5 March 2024 for all indications of, and as interchangeable with, Prolia® and Xgeva®, respectively.  No other denosumab biosimilars have received US approval to date. 

On 27 May 2024, Fresenius Kabi announced that its BLA for denosumab has been accepted for review by the US FDA as biosimilar to Amgen’s Prolia®.  The biosimilar is to be indicated for osteoporosis in men and women, including glucocorticoid-induced osteoporosis, and bone loss due to prostate or breast cancer. 

Sandoz’s Wyost® and Jubbonti® were the first denosumab biosimilars approved in the US in March 2024.  Following the April 2024 resolution of US BPCI litigation, commenced by Amgen against Sandoz in May 2023, Jubbonti® and Wyost® are expected to launch in the US from 31 May 2025. 

On 28 May 2024, Amgen commenced BPCIA litigation against Celltrion in the United States District Court for the District of New Jersey, alleging infringement of 29 patents relating to denosumab.  Celltrion applied to the FDA for marketing authorisation of its denosumab biosimilar, CT-P41, in December 2023. 

On 27 May 2024, Samsung Bioepis presented follow-up results from a Phase 3 study on SB16, biosimilar to Amgen’s Prolia® (denosumab).  According to Samsung Bioepis, the study demonstrated that switching postmenopausal osteoporosis patients from Prolia® to SB16 produced comparable results up to 18 months in terms of efficacy, safety and immunogenicity.  The results were presented at the 2024 European Calcified Tissue Society (ECTS) Congress in France. 

12-month results from the Phase 3 study were previously presented at the American Society for Bone and Mineral Research (ASBMR) Annual Meeting in October 2023. 

Denosumab biosimilars have been approved in the US and EU (Sandoz’s Jubbonti® and Wyost®) and in China (Boan Biotech’s Byoubei® and Boluojia® and Mabwell’s Mailishu® and MaiweijianTM).   

On 27 May 2024, Boan Biotech announced that its Boluojia® (BA11021, denosumab injection, 120mg) received marketing approval from China’s National Medical Products Administration (NMPA) as biosimilar to Amgen’s Xgeva®.  Boluojia® is indicated for the treatment of giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity.  Boan Biotech reports that it intends to expand the approved indications for Boluojia® to include bone metastases from solid tumours and multiple myeloma. 

Boan Biotech’s Boyoubei® (BA6101), biosimilar to Amgen’s Prolia® (denosumab), was approved by China’s NMPA in November 2022 for postmenopausal women with osteoporosis at high risk of fractures. 

In January 2024, Boan Biotech completed enrolment for its international, multi-centre, phase 3 studies of Boluojia® and Boyoubei®, which are being conducted simultaneously in Europe, the US and Japan. 

On 24 May 2024, Shanghai Henlius and Organon announced that the European Medicines Agency (EMA) validated Henlius’ and Organon’s applications for denosumab as biosimilars to Amgen’s Prolia® and Xgeva®.  The applications are based on Phase 3 trials confirming HLX14 is equivalent in efficacy, safety, tolerability and immunogenicity to Prolia® in postmenopausal women with osteoporosis at high risk for fracture.

In June 2022, Shanghai Henlius entered into a licence agreement with Organon regarding HLX14 (and pertuzumab) under which Organon has exclusive global commercialisation rights for all countries except China, Hong Kong, Macau and Taiwan.

This news comes two days after the European Commission approved Sandoz’s Wyost® and Jubbonti® as the first EU denosumab biosimilars.

On 22 May 2024, the European Commission approved the first denosumab biosimilars in Sandoz’s Wyost® and Jubbonti®.  The biosimilars were approved with a full indication set mirroring the approved indications of Amgen’s Xgeva® and Prolia® respectively, and have the same dosage form, route of administration, dosing regimen and presentation as the reference medicines.

Sandoz expects to launch the biosimilars in Europe “from November 2025”.

On 5 March 2024, Sandoz’s Wyost® and Jubbonti® became the first denosumab biosimilars approved in the US with interchangeability to the reference products.  As a result of settlement of pending BPCIA proceedings in the US in April 2024, Sandoz can launch its biosimilars in the US from 31 May 2025 (or earlier in certain circumstances).

Jubbonti® was approved in Canada on 20 February 2024.

Other denosumab biosimilars have been approved in China including Prolia® biosimilars Boan Biotech’s Byoubei® (November 2022) and Mabwell’s Mailishu® (March 2023), and Mabwell’s Xgeva® biosimilar Maiweijian^TM (denosumab 120mg) (April 2024). Companies that have denosumab biosimilars under development include Samsung Bioepis, Celltrion, Alvotech, Intas, and Shanghai Henlius Biotech.

On 21 May 2024, Alvotech provided its financial results for Q1 2024, reporting total revenues of US$37 million compared to US$16M for the same quarter in 2023.

Alvotech reports its highlights for Q1/24 as:

• the FDA approval of Selarsdi^TM (AVT04, ustekinumab-aekn), biosimilar to Janssen’s Stelara®, in April 2024;
• its strategic partnership with Quallent for the supply of its high concentration interchangeable Humira® (adalimumab) biosimilar under private label in the US; and
• its May 24 commercial partnership with Dr Reddy’s for the commercialisation of AVT03 (denosumab), biosimilar to Amgen’s Prolia® and Xgeva® in the US, EU and UK.

Regarding its pipeline, Alvotech reports positive top-line results from studies on AVT05 (golimumab) biosimilar to Simponi® and Simponi Aria® and  AVT06 (aflibercept), biosimilar to Eylea® , with the company being “on track to file marketing applications for at least three biosimilar candidates in the second half of this year”.

On 21 May 2024, Alvotech and Dr Reddy’s announced that that they have entered into a licence and supply agreement for the commercialisation of AVT03 (denosumab), biosimilar to Amgen’s Prolia® and Xgeva® in the US, EU and UK.

Under the agreement, Alvotech will develop and manufacture the product and Dr Reddy’s will commercialise it exclusively in the US, and semi-exclusively in the EU and UK.  The agreement provides for an up-front payment to Alvotech, with additional payments upon certain regulatory and commercialisation milestones, plus sales-based payments.

Alvotech announced positive top-line results for AVT03 in January 2024, in a study comparing the pharmacokinetics, safety and tolerability of the biosimilar compared to Prolia® in healthy adults.

On 7 May 2024, Pharma In Focus reported that Arrotex has partnered with Amgen to promote Amgen’s Prolia® (denosumab) in Australia.  It is planned that the partnership “will support the future growth of Prolia in the Australian market, utilising the infrastructure and reach of Arrotex to further the patient, pharmacist and prescriber experience”.  It is unclear when the agreement will take effect.

There are no Prolia® (denosumab) biosimilars approved in Australia to date.  Prolia® biosimilars have been approved in the US (Sandoz’s Jubbonti®, March 2024), Canada (Jubbonti®, February 2024) and China (Boan Biotech’s Byoubei® (November 2022) and Mabwell’s Mailishu® (March 2023)).

On 7 May 2024, Sandoz announced Q1 2024 net sales of USD1.9 billion, with its biosimilars growing 21% to USD 623 million.  The biosimilar growth is said to be driven by Sandoz’s 2023 US/EU launch of Hyrimoz®, biosimilar to AbbVie’s Humira® (adalimumab), and the acquisition of Cimerli®, biosimilar to Genentech’s Lucentis® (ranibizumab), announced in January 2024.  During the reported quarter, Sandoz also launched in Germany the Polpharma-developed Tyruko® (Biogen’s Tysabri®, natalizumab) and obtained US approval for Jubbonti® and Wyost® (Amgen’s Prolia®/Xgeva®, denosumab).

On 29 April 2024, each of Amgen and Sandoz announced that they resolved the US patent litigation regarding Sandoz’s denosumab biosimilars enabling Sandoz to launch Jubbonti® and Wyost® from 31 May 2025, or earlier in certain (undisclosed) circumstances.

This concludes the District Court proceedings Amgen commenced against Sandoz in New Jersey on 1 May 2023 alleging infringement of 21 patents relating to Amgen’s Prolia® and Xgeva®.  The proceedings followed the FDA’s acceptance of Sandoz’s BLA for Jubbonti® and Wyost® in February 2023.

Jubbonti® and Wyost® were approved by the FDA on 5 March 2024 for all indications of, and as interchangeable with, Prolia® and Xgeva®, respectively.  No other denosumab biosimilars have received US approval to date.

In March 2024, the CHMP of the European Medicines Agency adopted a positive opinion for Sandoz’s denosumab biosimilars.  Jubbonti® was approved in Canada on 20 February 2024.  Other denosumab biosimilars have been approved in China: Boan Biotech’s Byoubei® (November 2022) and Mabwell’s Mailishu® (March 2023), both biosimilars to Prolia®, and Mabwell’s Maiweijian^TM (denosumab 120mg) (April 2024), biosimilar to Xgeva®. Companies that have denosumab biosimilars under development include Samsung Bioepis,  Celltrion, Alvotech, Intas, and Shanghai Henlius Biotech.

The Korea Times reports that Celltrion presented the 78-week results of its Phase 3 study of CT-P41, biosimilar to Amgen’s Prolia® (denosumab), at the World Congress on Osteoporosis held in London from 11-14 April 2024.  It is reported that the clinical trial showed CT-P41 has equivalent efficacy, pharmacokinetics and safety to Prolia® in postmenopausal women with osteoporosis.

Celltrion applied to the FDA for marketing authorisation of CT-P41 in December 2023.  The first Prolia® (denosumab) biosimilar approved in the US was Sandoz’s Jubbonti®, on 5 March 2024.

Prolia® (denosumab) biosimilars have been approved in Canada (Sandoz’s Jubbonti® on 20 February 2024) and China (Boan Biotech’s Boyoubei® in November 2022 and Mabwell’s Mailishu® in March 2023).  Other companies have Prolia® biosimilars under development including Samsung Bioepis, Alvotech, Intas, and Shanghai Henlius Biotech.

On 8 April 2024, Samsung Bioepis released its fifth US Biosimilar Market Report.  The quarterly report details average sales price information for US launched biosimilars and market share and price trends.

The Q2 2024 Report notes that as of April 2024, the FDA has approved 48 biosimilars, with three of those (Alvotech’s/Teva’s Simlandi® (Humira®, adalimumab), Sandoz’s Jubbonti®/Wyost® (Prolia®/Xgeva®, denosumab) and Fresenius Kabi’s Tyenne® (Actemra®, tocilizumab) approved in the last quarter.  38 of the 48 approved biosimilars have launched in the US.

Samsung Bioepis reports that, on average, biosimilars in the US have gained 53% market share within 3 years post initial launch.  As at Q4 2023, the adalimumab biosimilars share of the US adalimumab market was 4%, although this was up 2% compared with last quarter. The first biosimilar was launched in January 2023 (Amjevita™, Amgen) and multiple additional biosimilars entered the US market in July 2023.

On 8 April 2024, PR Newswire reported Mabwell’s MAIWEIJIAN^TM (denosumab 120mg) (biosimilar to Amgen’s Xgeva®) received marketing approval in China.  MAIWEIJIAN was developed by Mabwell’s wholly owned subsidiary T-mab.  It is approved in China for the treatment of giant cell tumour of the bone that is unresectable or where surgical resection may lead to severe functional impairment.

Results of Mabwell’s Phase III trials were published in JAMA Oncology in February 2024 .  In March 2023, Mabwell announced that it received Chinese marketing approval for Mailishu® (denosumab), biosimilar to Amgen’s Prolia®.

On 5 April 2024, Shanghai Henlius Biotech (SHB) announced that its phase 3 studies confirmed that HLX14 (denosumab) is equivalent in efficacy, safety, tolerability and immunogenicity to Amgen’s Prolia®.  HLX14 will be indicated for the treatment of osteoporosis in postmenopausal women at high risk of fracture.

SHB announced the successful completion of its phase 1 clinical trials of HLX14 in January 2024.

In June 2022, SHB announced its licence agreement with Organon under which Organon received exclusive global commercialisation rights to HLX14, excluding China, Hong Kong, Macau and Taiwan.

On 22 March 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency published the results of its March 2024 meeting.  CHMP adopted a positive opinion for the following Sandoz and Celltrion biosimilars:

• Sandoz’s denosumab biosimilars, Jubbonti® and Wyost®, for all indications of Amgen’s Prolia® and Xgeva® respectively. Jubbonti® and Wyost® were approved in the US on 5 March 2024.
• Celltrion’s Omlyclo® (omalizumab), biosimilar to Novartis’ Xolair®. Celltrion submitted an A-BLA in the US for its omalizumab bioximilar (CT-P39) earlier this month.

Other positive opinions adopted by CHMP include:

• Outlook Therapeutics’ Lytenava^TM (bevacizumab-vikg) for wet AMD.  If approved, Lytenava^TM will be the first available on-label ophthalmic formulation of bevacizumab in the EU (or US).
• Novo Nordisk’s diabetes treatment, Awiqli® (insulin icodec), a long-acting basal insulin given subcutaneously once a week.

An indication extension was recommended for UCB’s previously EU-approved Bimzelx® (bimekizumab) for the treatment of hidradenitis suppurativa.

On 5 March 2024, the FDA approved the first denosumab biosimilars in the US in Sandoz’s Wyost® and Jubbonti®.  The biosimilars are interchangeable with, and approved for all indications of, Amgen’s Xgeva® and Prolia® respectively. 

The US launch date for the newly approved biosimilars is uncertain given ongoing BPCI litigation regarding the products, commenced by Amgen in May 2023 relating to 21 patents. 

The US approval comes weeks after Sandoz announced the approval of Jubbonti® in Canada.  Prolia® biosimilars developed by Boan Biotech and Mabwell were approved in China respectively in November 2022 (BA6101, Byoubei®) and March 2023 (Mailishu®). 

On 4 March 2024, Sandoz announced that Health Canada approved Wyost® as biosimilar to, and for all indications of, Amgen’s Xgeva® (denosumab).

This follows the Canadian approval of Sandoz’s Jubbonti®, biosimilar to Amgen’s Prolia® (denosumab) in February 2024 for osteoporosis and increasing bone mass.

In February 2023 and May 2023 respectively applications for Sandoz’s denosumab biosimilar were accepted by the FDA and EMA.

On 29 February 2024, the Medicines and Healthcare products Regulatory Agency (MHRA) granted marketing authorisation for Xgeva® (denosumab) as a 120mg solution for injection in a prefilled syringe.  This Xgeva PFS product is a high concentration product which is a line extension of the original Xgeva® sold as a vial product containing 120mg solution for injection. 

This is the first product to be authorised by the MHRA via the new International Recognition Procedure (IRP) introduced in January this year.    

The IRP allows the MHRA to accelerate the assessment of new medicines by taking into account pre-existing approvals from Australia, Canada, the European Union, Japan, Switzerland, Singapore and/or the United States.  In fast-tracking the authorisation of the new Xgeva® high concentration formulation, the MHRA considered a positive opinion issued by the European Medicines Agency on 25 January 2024. 

A study sponsored by Mabwell (Shanghai) Bioscience Co Ltd and published in JAMA Oncology reports that the results of Chinese randomized, 53-week, phase III trials of Mabwell’s MW032 with Amgen’s Xgeva® in patients with solid tumor-related bone metastases, confirm biosimilarity in efficacy, safety and population pharmacokinetics.   

In March 2023, Mabwell announced that it received Chinese marketing approval for Mailishu® (denosumab), biosimilar to Amgen’s Prolia®, from the National Medical Products Administration (NMPA) for the treatment of osteoporosis in postmenopausal women at high risk of fracture.

Shanghai Henlius Biotech announced its phase 1 clinical study for its denosumab biosimilar of HLX14, which met the primary endpoint.

Shanghai Henlius Biotech announced commencement of the study in November 2020.  Organon announceda deal in June 2022 for exclusive global commercialisation rights to Shanghai Henlius Biotech’s denosumab and pertuzumab.

The US Food and Drug Administration (FDA) announced that it is adding a Boxed Warning to the prescribing information for Amgen’s Prolia® (denosumab) about the significant risk of developing severe hypocalcemia (very low blood calcium levels) in patients with advanced chronic kidney disease, particularly patients on dialysis.

The FDA announced its investigation into this risk in November 2022.  Prolia® is approved in the US for the treatment of osteoporosis in men and women, and to increase bone mass in patients receiving certain therapies for prostate cancer and breast cancer.

Lotus Pharmaceutical announced that it has entered into a partnership with Intas Pharmaceuticals for the commercialisation of Intas’s Prolia® (denosumab) biosimilar in South Korea, Taiwan and certain markets in South East Asia.  According to the announcement, Intas will be responsible for development, manufacture and supply of the biosimilar, and Lotus will be responsible for the regulatory process and obtain commercialisation rights in those territories.

The Korea Biomedical Review reported that Celltrion has submitted an application for marketing authorisation to the FDA for CT-P41, its biosimilar to Amgen’s Prolia® (denosumab) for the treatment of osteoporosis and related diseases.  The KBR reported that Celltrion has confirmed CT-P41’s equivalence and similarity in a phase III trial, and is seeking approval as an interchangeable biosimilar.

Samsung Bioepis presented new data on its SB16 (denosumab, biosimilar to Amgen’s Prolia®) at the American Society for Bone and Mineral Research (ASBMR) 2023 Annual Meeting being held from October 13 to 16 in Vancouver, BC, Canada.  The SB16 ph I and III studies demonstrate respectively pharmacokinetic bioequivalence and biosimilarity of SB16 to reference denosumab.

Amneal Pharmaceuticals, Inc announced that it has added two denosumab products (biosimilars to Amgen’s Prolia^® and Xgeva^®) to its biosimilar pipeline.  The denosumab products are being developed by mAbxience.  MAbxience is responsibility for development and manufacture and Amneal is responsible for regulatory approval and has exclusive US commercialisation rights.

On 3 October 2022 Amneal Pharmaceuticals announced the US launch of another biosimilar developed by mAbxience: Alymsys® (biosimilar bevacizumab).

The Searle Company Limited announced that it has entered into a license agreement with China’s Mabwell Pharmaceuticals, under which Searle will manufacture, register and license the biosimilar drugs in Pakistan. 

In March 2023, Mabwell announced that it had received Chinese marketing approval for Mailishu®, its denosumab biosimilar, from the National Medical Products Administration (NMPA) for the treatment of osteoporosis in postmenopausal women at high risk of fracture. 

Sandoz announced that the European Medicines Agency (EMA) has accepted marketing authorisation applications (MAA) for its proposed biosimilar denosumab, for regulatory review. The two applications include the approved indications for the originator drugs Prolia^® and Xgeva^®, including osteoporosis in postmenopausal women and in men at increased risk of fractures, treatment-induced bone loss, prevention of skeletal related complications in cancer that have spread to the bone, and giant cell tumor of the bone.

This week Mitsubishi and GlycoNex announced Japanese approval of their phase I clinical trial of SPD8, a denosumab biosimilar to Prolia®

Mitsubishi Gas Chemical Company, Inc. and GlycoNex announced approval to commence a phase I clinical trial of SPD8 denosumab, biosimilar to Amgen’s Prolia®, from the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).  The companies announced that the first patient has now been enrolled.  The double-blind trial will compare SPD8 with Prolia® in healthy postmenopausal women, who will undergo pharmacokinetic and safety assessments.

This month Boan Biotech commenced its phase III clinical trial for its Prolia® denosumab biosimilar.

Amgen announced new data from a real-world study of nearly half of a million postmenopausal women with osteoporosis in the US showing Prolia^® (denosumab) injection reduced fracture risk in patients versus oral alendronate, a frequently prescribed bisphosphonate treatment. Treatment with Prolia® was also associated with greater reductions in fracture risk over time.

The data were presented during an oral presentation at the World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO), in Barcelona, May 4-7, 2023.

Luye Pharma announced that it has enrolled its first subject in an international multi-center Phase 3 clinical study for its internally developed denosumab products (BA6101 and BA1102) to be carried out in Europe, the United States, and Japan. BA6101 and BA1102 are biosimilars to Amgen’s Prolia^® and Xgeva^®, respectively.   Prolia® is indicated for the treatment of osteoporosis, and Xgeva® is indicated for the prevention of skeletal-related events in patients with multiple myeloma and bone metastases from solid tumours, and treatment of giant cell tumour of bone.

BA6101 (Boyoubei®) was approved for marketing in China in November 2022, as the first approved Prolia® biosimilar in the world, and China’s NMPA has accepted Boan’s BLA for approval as an Xgeva^® biosimilar.

On 1 May 2023, Amgen instigated proceedings in the US District Court of New Jersey against Sandoz, Novartis and Lek, alleging infringement of 21 patents relating to Amgen’s Prolia® and Xgeva® (denosumab) products.  Sandoz submitted its aBLA to the FDA in December 2022 (which was accepted on 6 February 2023) seeking approval of its anti-RANKL mAb Prolia® and Xgeva® biosimilar.

Amgen is asserting that Sandoz/Novartis/Lek failed to comply with the BPCIA 42 U.S.C. § 262(l)(2)(A) “patent dance” requirements, and is seeking declaratory judgement under § 262(l)(9)(C).

Interestingly, of the 21 patents in suit, there are 2 product patents, and 19 process patents including many to media related “inventions”.

The asserted patents (and the nature of the patent, according to Amgen) are:

• 7,364,736 (“the ’736 Patent”) – denosumab sequence patent
• 7,928,205 (“the ’205 Patent”) – process (reduction/oxidation reagent + (optionally) a chaotopric agent)
• 8,058,418 (“the ’418 Patent”) – product patent;
• 9,012,178 (“the ’178 Patent”) – methods of culturing mammalian cells to express protein in a serum free media
• 9,133,493 (“the ’493 Patent”) – methods of culturing mammalian cells (tyrosine and cysteine feeds)
• 9,228,168 (“the ’168 Patent”) – methods of stabilizing feed media (pyruvate)
• 9,320,816 (“the ’816 Patent”) – methods of treating cell culture media (UV C light and filtration)
• 9,328,134 (“the ’134 Patent”) – methods of making proteins with modified glycosylation profile
• 9,359,435 (“the ’435 Patent”) – methods of modulating glycoform content (mannose)
• 9,481,901 (“the ’901 Patent”) – methods of influencing high mannose glycoform content (mannose sugars)
• 10,167,492 (“the ’492 Patent”) – methods of influencing fucosylated glycan content
• 10,513,723 (“the ’723 Patent”) – methods of influencing high mannose glycoform content
• 10,583,397 (“the ’397 Patent”) – systems and methods to control filtration
• 10,822,630 (“the ’630 Patent”) – methods of influencing fucosylated glycan content
• 10,894,972 (“the ’972 Patent”) – methods of influencing high mannose glycoform content (mannose sugars)
• 11,077,404 (“the ’404 Patent”) – systems and methods to control filtration
• 11,098,079 (“the ’079 Patent”) – methods of using a charged depth filter
• 11,130,980 (“the ’980 Patent”) – methods of regulating high mannose glycoform content (monensin)
• 11,254,963 (“the ’963 Patent”) – methods of influencing high mannose glycoform content
• 11,299,760 (“the ’760 Patent”) – methods of regulating high mannose glycoform content (monensin)
• 11,434,514 (“the ’514 Patent”) – methods of influencing high mannose glycoform content (mannose sugars).

Given the timing of Sandoz’s submission, in the ordinary course of events its approval will precede expiry of US patent no. 7364736 to the denosumab antibody in February 2025.

Prolia® is indicated for the treatment of osteoporosis, and Xgeva® is indicated for the prevention of skeletal-related events in patients with multiple myeloma and bone metastases from solid tumours; and treatment of giant cell tumour of bone.

Mabwell announced that it received Chinese marketing approval for Mailishu® (denosumab), biosimilar to Amgen’s Xgeva®/Prolia®, from the National Medical Products Administration (NMPA) for the treatment of osteoporosis in postmenopausal women at high risk of fracture.  It is the world’s second approved denosumab biosimilar.  Mailishu was developed by Mabwell’s wholly-owned subsidiary T-mab.

This announcement comes only 10 days after the NMPA accepted Boan Biotech’s BLA for its denosumab BA1102, biosimilar to Amgen’s Xgeva®/Prolia®.

Luye Pharma Group announced that the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) accepted the BLA submitted by Luye’s subsidiary Boan Biotech for denosumab (BA1102), biosimilar to Amgen’s Xgeva®. It is indicated for the treatment of bone metastases from solid tumors and patients with multiple myeloma, to delay or reduce the risk of skeletal-related events, and for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

In late 2022, Boan Biotech previously announced the apprA approval and launch of its Boyoubei® (denosumab, biosimilar to Amgen’s Prolia®), for the treatment of postmenopausal women with osteoporosis with high risk of fractures.

Sandoz announced that FDA accepted its BLA for anti-RANKL mAb, biosimilar denosumab.  The application includes all indications included in the Amgen reference products Prolia® and Xgeva®.

BeiGene announced that the National Reimbursement Drug List released by China’s NMPA has been updated to include four new indications for its PD-1 inhibitor tislelizumab.  BeiGene’s Xgeva® (denosumab) was also renewed in the NRDL.  These updates will take effect from 01 March 2023.

Luye Pharma announced that its subsidiary Boan Biotech has signed an agreement with CP Pharmaceutical Qingdao Co., Ltd. (CP Qingdao) to grant CP Qingdao the right to commercialise Boyoubei® (biosimilar denosumab) in mainland China.  Boyoubei was approved by China’s NMPA in November 2022.

A new study published in the Journal of Orthopaedic Translation reported that LY06006 (biosimilar denosumab) might be an effective treatment for osteoporosis.  The study also reported that LY06006 was generally safe and well tolerated without unexpected reactions, similar to Prolia® (denosumab).

The FDA announced that it is investigating the risk of severe hypocalcemia with serious outcomes in patients with advanced kidney disease on dialysis treated with Amgen’s Prolia® (denosumab).  According to the announcement, FDA’s review of interim results of ongoing safety studies suggested an increased risk of hypocalcemia in patients with advanced kidney disease, and a substantial risk with serious outcomes including hospitalization and death.

China’s NMPA approved Luye Pharma subsidiary Boan Biotech’s Boyoubei® (denosumab biosimilar) for the treatment of postmenopausal women with osteoporosis at high risk of fractures.  Boyoubei® is the first biosimilar to Prolia® (the originator of denosumab) approved for marketing anywhere in the world.  Boan Biotech is developing Boyoubei for global sale.

Amgen announced that it will present data across its portfolio at the American College of Rheumatology Convergence on 10-14 November 2022, including data for Amgevita® (biosimilar adalimumab), Enbrel® (biosimilar etanercept) and Prolia® (biosimilar denosumab).

Biocon Biologics announced that it will license its ustekinumab and denosumab biosimilars to Yoshindo for Japan.  Yoshindo will pay an upfront licence fee and further payments over the next few years as certain development milestones are achieved. Biocon Biologics estimates the market opportunity for the two biosimilars in Japan to be US$700m.

Sandoz announced the results of its Ph I/III trials of its biosimilar denosumab.  Sandoz reported that the results confirm that the biosimilar matches the pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity of the reference product.

Lupin and DKSH announced that they have signed an exclusive licensing and supply agreement to market five of Alvotech’s biosimilar products in the Philippines.  The biosimilars include AVT03 (biosimilar denosumab – Prolia® and Xgeva®), AVT05 (biosimilar golimumab/Simponi®) and AVT06 (biosimilar aflibercept/Eylea®) as well as two undisclosed proposed biosimilars for immunology and oncology.

Alvotech announced that it has commenced a confirmatory patient study for AVT03 (biosimilar to Prolia® and Xgeva®, denosumab).  The objective of the study is to demonstrate clinical similarity of AVT03 to Prolia® in terms of efficacy, safety, immunogenicity and pharmacokinetics in postmenopausal women with osteoporosis.  The results from this trial will be used to extrapolate to additional Xgeva® indications.  Alvotech commenced phase I trials for denosumab in July 2022.

Lupin announced that it has entered into an exclusive licensing agreement with I’rom Group for biosimilar denosumab in Japan.  Under the agreement, I’rom and Lupin will together conduct clinical trials and obtain registration, and I’rom will then exclusively distribute and market the product in Japan.

It has been reported that a Ph III clinical trial of Qilu Pharmaceutical’s biosimilar denosumab, QL1206, showed beneficial effects in post-menopausal Chinese women with osteoporosis and high fracture risk.  After twelve months, subjects who received QL1206 showed significantly improved bone mineral density in the lumbar spine, total hip, femoral neck and trochanter compared to placebo.

Alvotech announced that it has initiated a pharmacokinetic study for AVT03 (denosumab, biosimilar to Prolia®/Xgeva®).  The study will assess the pharmacokinetics, safety and tolerability of AVT03 compared to Prolia® in healthy adult male subjects.

Alvotech’s portfolio also includes AVT02 (high concentration adalimumab/biosimilar to Humira®) which launched in Canada in April 2022 and Europe in June 2022 and is expected to launch in the US from July 2023; AVT04 (ustekinumab/biosimilar candidate to Stelara®) for which Alvotech recently announced positive topline results; AVT04 (aflibercept/biosimilar candidate to Eylea®), golimumab/biosimilar to Simponi® and omalizumab/biosimilar to Xolair®.

The results of a phase III study of Iranian biopharmaceutical company AryoGen Pharmed’s denosumab biosimilar Arylia in osteoporosis patients showed that its efficacy and safety were not inferior to Amgen’s Prolia®.

Organon announced that it has entered into a licence agreement with Shanghai Henlius Biotech regarding biosimilars to Perjeta^® (pertuzumab, HLX11) and Prolia^®/Xgeva^® (denosumab, HLX14).  Under the agreement, Organon has exclusive global commercialisation rights “except for China; including Hong Kong, Macau and Taiwan”.  The agreement also includes an option for an exclusive licence for global commercialisation rights to a biosimilar to BMS’ Yervoy® (ipilimumab).

Amgen released its Q1 2022 financial results, reporting a 6% increase in YoY revenues. Amgen reported a 12% increase in Prolia® (denosumab) sales, a 7% decrease in Enbrel® (etanercept) sales, a 2% increase in Amgevita™ (biosimilar adalimumab) sales and a 40% decrease in Kanjinti® (biosimilar trastuzumab) sales.

Vizient announced that remdesivir has replaced Humira® (adalimumab) as the most expensive drug by total member spend in its Winter 2022 Market Outlook.  Pembrolizumab, ustekinumab, ocrelizumab, denosumab, infliximab, nivolumab and tocilizumab also featured in the top 10 most expensive drugs by member spend.

Hikma Pharmaceuticals and Gedeon Richter announced that they have entered into an exclusive license agreement to commercialise Gedeon Richter’s proposed denosumab biosimilar in the United States.

Alvotech and Oaktree Acquisition Corp. II announced that they have entered into a merger agreement for the creation of a publicly-traded global biopharmaceutical company. Alvotech is led by a team of highly experienced biopharma leaders, including Mark Levick as CEO, Anil Okay as CCO, and Philip Caramanica as Chief IP Counsel and Deputy General Counsel. The merger is expected to deliver gross proceeds to Alvotech in excess of USD$450 million.  Alvotech currently has seven products in its pipeline, including a biosimilar candidate to Humira® (adalimumab), Stelara® (ustekinumab), Eylea® (aflibercept), Prolia®/Xgeva® (denosumab) and Simponi®/Simponi ARIA® (golimumab).

Korea Biomedical Review reported that Dong-A ST has completed patient enrolment for Ph III trials of DMB-3115 (proposed denosumab biosimilar) in patients with moderate to severe chronic plaque psoriasis.

Celltrion announced its Q3 2021 financial results. Celltrion reported that Remsima® (infliximab biosimilar) has obtained a 53% market share in Europe and 21% market share in Japan. Celltrion reported that Truxima® (rituximab biosimilar) has obtained a 40% market share in Europe and Herzuma® (trastuzumab biosimilar) has obtained a 14% market share in Europe. Celltrion also reported that it expects to launch biosimilar bevacizumab in 2022, biosimilar ustekinumab in 2023, biosimilar omalizumab and aflibercept in 2024 and biosimilar denosumab in 2025.

India’s DCGI granted marketing authorisation for Enzene Bioscience’s biosimilar denosumab.

Amgen released its Q2 2021 financial results, reporting double digit volume growth for Prolia® (denosumab), Repatha® (evolocumab), Mvasi® (biosimilar bevacizumab) and Kanjinti® (biosimilar trastuzumab).

Theramex UK announced it has entered into an agreement with Enzene Biosciences for the commercialisation of a biosimilar denosumab. Under the agreement, Enzene will supply Theramex with the product for commercialisation in Europe, the UK, Switzerland and Australia.

Celltrion released its Q1 2020 financial results, reporting that YoY sales of Celltrion biosimilars increased by 23%.  Celltrion announced that it is planning to complete Ph III trials of biosimilar bevacizumab in the first half of 2021, and that ustekinumab, aflibercept, omalizumab and denosumab candidates remain in Ph III trials.

Huons Lab announced it has reached an agreement with PanGen Biotech for the development of biosimilar denosumab. Under the agreement, Huons Lab will gain access to PanGen Biotech’s cell line manufacturing and purification technology.

Cipla and Alvotech announced that they have expanded their partnership for the marketing and distribution of four biosimilar medicines in Australia and New Zealand. The agreement includes biosimilar aflibercept, ustekinumab, denosumab and golimumab candidates. This agreement is in addition to the previous agreement between Alvotech and Cipla for the commercialisation of AVT02 (biosimilar adalimumab candidate).

Health care performance improvement company Vizient releases its Winter 2021 Pharmacy Market Outlook. Vizient projected that the greatest price increases to members would occur in Humira® (adalimumab), with a 7.5% price increase predicted over the next 18 months. Adalimumab also topped the list of greatest total spend by product among Vizient members, followed by pembrolizumab, rituximab, infliximab, ustekinumab, nivolumab and denosumab. New figures also showed trastuzumab biosimilars have captured a significant market share, contributing to 39% of cost to members in September 2020.

Celltrion announces it has submitted an investigational new drug application for Ph III trials of CT-P41 (proposed denosumab biosimilar).

Samsung Bioepis announces it has commenced Ph III trials of SB16 (proposed denosumab biosimilar) in women with postmenopausal osteoporosis.

Novartis released its annual report ‘Meet Novartis Management 2020‘. In the report, Novartis announced that GP2411 (biosimilar denosumab candidate) has commenced Ph III trials. Novartis has also indicated it  has planned launches for biosimilar adalimumab and natalizumab in 2021-2023 and denosumab in 2024-2026.

Samsung Bioepis announces it has commenced Ph I trials for SB16 (proposed denosumab biosimilar).

Shanghai Henlius Biotech announces it has commenced Ph I trials for HLX14 (proposed denosumab biosimilar).

Rheumatology Advisor reports a study sponsored by China’s National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation demonstrates that delayed administration of subsequent denosumab doses by greater than 16 weeks is associated with increased risk for vertebral fracture. This risk was observed in both the short delay (4-16 weeks) and the long delay (>16 weeks) groups. Additionally, there was a significant correlation between delayed subsequent injections and major osteoporotic fractures.

Korea Biomedical Review reports that Celltrion will commence Ph I clinical trials of CT-P41 (biosimilar denosumab candidate) in September.

BeiGene announces its has begun commercialising Xgeva® (denosumab) in China. Xgeva® was developed by Amgen, and is the first of the products to be commercialised by BeiGene under a January 2020 agreement.

Shanghai Henlius Biotech announces that China’s National Medical Products Administration has approved its IND application for HLX14, a proposed denosumab biosimilar. 

JHL Biotech announces that the first group of subjects in the Australian randomised Ph I trials of JHL1266 (proposed denosumab) have been dosed.

Shanghai Henlius Biotech announces China’s National Medical Administration had accepted its Investigational New Drug application for HLX14 (denosumab). HLX14 is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture.

Sandoz announces commencement of patient enrolment in Ph I/III trials of proposed biosimilar denosumab. A total of 520 osteoporosis patients will be enrolled in the 52 week study.

Shanghai Biomabs commences Ph I trials of biosimilar denosumab candidate.

Qilu commences Ph 1 trials of biosimilar denosumab candidate.

Australia’s Neuclone discloses the 5th product in its pipeline is biosimilar denosumab, which is at the pre-clinical stage.

Iranian biopharmaceutical company AryoGen Pharmed commences phase III denosumab trials comparing the efficacy and safety of AryoGen’s 60mg denosumab and Amgen’s 60mg denosumab among osteoporotic post-menopausal women.