BioBlast®

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 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.