An Open-label, Randomized, Active-Controlled, Phase 3 Study of Setrusumab Compared With Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta Types I, III or IV

The primary objective of the study is to evaluate the effect of setrusumab vs intravenous bisphosphonates (IV-BP) on reduction in fracture rate, including morphometric vertebral fractures in pediatric participants.

Start Date14 Jun 2023

Sponsor / Collaborator

Ultragenyx Pharmaceutical, Inc.

NCT05312697 / TerminatedPhase 2

A Phase 2b, Multicenter, Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta

The primary objective of the study is to evaluate bone mineral density (BMD) after 12 months of retreatment with monthly setrusumab in adults with osteogenesis imperfecta (OI).

Start Date28 Apr 2022

Sponsor / Collaborator

Ultragenyx Pharmaceutical, Inc.

[+1]

NCT05125809 / Active, not recruitingPhase 2/3

An Operationally Seamless, Randomized Phase 2/3 Study Consisting of a Phase 2 Single-Blind, Dose-Evaluation Phase and a Phase 3 Double-Blind, Placebo-Controlled Phase to Assess the Efficacy and Safety of Setrusumab in Subjects With Osteogenesis Imperfecta

The primary objectives of the study are to identify a setrusumab dosing strategy in participants with OI and to evaluate the effect of setrusumab vs placebo on reduction in fracture rate.

Start Date21 Feb 2022

Sponsor / Collaborator

Ultragenyx Pharmaceutical, Inc.

[+1]

100 Clinical Results associated with Setrusumab

100 Translational Medicine associated with Setrusumab

100 Patents (Medical) associated with Setrusumab

Literatures (Medical) associated with Setrusumab

01 Jan 2021·Journal of mid-life health

Sclerostin inhibition: A novel target for the treatment of postmenopausal osteoporosis

Review

Author: Aditya, Suruchi ; Rattan, Aditya

Osteoporosis, a widespread skeletal disorder with a substantial economic load, is characterized by increased porosity of the bones resulting in vulnerability to fractures. When activated, the canonical Wnt signaling pathway results in osteoblastogenesis and bone formation. A Wnt ligand forms a complex with low-density lipoprotein receptor-related proteins 5 and 6 (Lrp5/6) and stimulates intracellular signaling cascades, leading to nuclear translocation of β-catenin and transcription of downstream molecules involved in osteoblast differentiation, maturation, and survival. Sclerostin (SOST), a glycoprotein produced by osteocytes, is an extracellular Wnt antagonist that blocks the binding of Wnt ligands to Lrp5/6, preventing the activation of the pathway and osteoblast-mediated bone formation subsequently. Inhibition of SOST represents a new therapeutic paradigm for the treatment of osteoporosis. Monoclonal antibodies to SOST include romosozumab, blosozumab, and setrusumab. With its unique dual effect of increasing bone formation (anabolic action) and decreasing bone resorption, the Food and Drug Administration approved romosozumab, a promising new treatment for postmenopausal osteoporosis. Its efficacy and safety have been established in trials. However, patients at high risk of cardiovascular or cerebrovascular events should not be prescribed romosozumab.

01 Jul 2017·Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral ResearchQ1 · MEDICINE

BPS804 Anti-Sclerostin Antibody in Adults With Moderate Osteogenesis Imperfecta: Results of a Randomized Phase 2a Trial

Q1 · MEDICINE

Article

Author: Jakob, Franz ; Winkle, Peter J ; Devogelaer, Jean-Pierre ; Durigova, Michaela ; Ruckle, Jon ; Seefried, Lothar ; Junker, Uwe ; Goemaere, Stefan ; Hemsley, Sarah ; Glorieux, Francis H

ABSTRACT:

This 21-week, open-label, phase 2a trial aimed to evaluate the pharmacodynamics and safety of multiple, escalating infusions of BPS804, a neutralizing, anti-sclerostin antibody, in adults with moderate osteogenesis imperfecta (OI). Patients received BPS804 (three escalating doses each separated by 2 weeks [5, 10, and 20 mg/kg]) or no treatment (reference group). The primary efficacy endpoints were mean changes from baseline to day 43 in: procollagen type 1 N-terminal propeptide (P1NP), procollagen type 1 C-terminal propeptide (P1CP), bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and type 1 collagen cross-linked C-telopeptide (CTX-1). Mean change from baseline to day 141 in lumbar spine areal bone mineral density (aBMD) was also assessed. BPS804 safety and tolerability were assessed every 2 weeks. Overall, 14 adults were enrolled (BPS804 group: n = 9, mean age 30.7 years, mean aBMD Z-score –2.6; reference group, n = 5, mean age 27.4 years, mean aBMD Z-score –2.2). In the BPS804 group, P1NP, P1CP, BSAP, and OC were increased by 84% (p < 0.001), 53% (p = 0.003), 59% (p < 0.001), and 44% (p = 0.012), respectively, versus baseline (reference: P1NP, +6% [p = 0.651]; P1CP, +5% [p = 0.600]; BSAP, –13% [p = 0.582]; OC, –19% [p = 0.436]). BPS804 treatment downregulated CTX-1 by 44% from baseline (reference: –7%; significance was not tested for this biomarker), and increased aBMD by 4% (p = 0.038; reference group: +1%; p = 0.138). BPS804 was generally well tolerated. There were 32 adverse events reported in nine patients; none was suspected to be treatment-related. There were no treatment-related fractures. BPS804 stimulates bone formation, reduces bone resorption, and increases lumbar spine aBMD in adults with moderate OI. This paves the way for a longer-term, phase 3 trial into the efficacy, safety, and tolerability of BPS804 in patients with OI. © 2017 American Society for Bone and Mineral Research.

24 Apr 2017·The Journal of clinical investigationQ1 · MEDICINE

Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia

Q1 · MEDICINE

Article

Author: Chivers, Simon ; Seefried, Lothar ; Junker, Uwe ; Hofmann, Christine ; Borah, Babul ; Valentin, Marie-Anne ; Kunstmann, Erdmute ; Jakob, Franz ; Baumann, Jasmin ; Huang, Yue ; Kiese, Beate ; Hemsley, Sarah ; Roubenoff, Ronenn

BACKGROUND:

Hypophosphatasia (HPP) is a rare genetic disorder resulting in variable alterations of bone formation and mineralization that are caused by mutations in the ALPL gene, encoding the tissue-nonspecific alkaline phosphatase (ALP) enzyme.

METHODS:

In this phase IIA open-label, single-center, intra-patient, dose-escalating study, adult patients with HPP received 3 ascending intravenous doses of 5, 10, and 20 mg/kg BPS804, a fully human anti-sclerostin monoclonal antibody, on days 1, 15, and 29, respectively. Patients were followed for 16 weeks after the last dose. We assessed the pharmacodynamics, pharmacokinetics, preliminary efficacy, and safety of BPS804 administrations at specified intervals during treatment and follow-up.

RESULTS:

Eight patients (mean age 47.8 years) were enrolled in the study (6 females, 2 males). BPS804 treatment increased mean ALP and bone-specific ALP enzymatic activity between days 2 and 29. Transient increases in the bone formation markers procollagen type-I N-terminal propeptide (PINP), osteocalcin, and parathyroid hormone as well as a transient decrease in the bone resorption marker C-telopeptide of type I collagen (CTX-1) were observed. Lumbar spine bone mineral density showed a mean increase by day 85 and at end of study. Treatment-associated adverse events were mild and transient.

CONCLUSION:

BPS804 treatment was well tolerated and resulted in increases in bone formation biomarkers and bone mineral density, suggesting that sclerostin inhibition could be applied to enhance bone mineral density, stability, and regeneration in non-life-threatening clinical situations in adults with HPP.

TRIAL REGISTRATION:

Clinicaltrials.gov NCT01406977.

FUNDING:

Novartis Institutes for BioMedical Research, Basel, Switzerland.

News (Medical) associated with Setrusumab

14 Jun 2024

·www.globenewswire.com

Mereo BioPharma Announces Pricing of $50 Million Underwritten Registered Direct Offering of American Depository Shares, Priced At-the-Market

LONDON, June 14, 2024 (GLOBE NEWSWIRE) -- Mereo BioPharma Group plc (NASDAQ: MREO) (“Mereo” or the “Company”), a clinical-stage biopharmaceutical company focused on rare diseases, today announced the pricing of an underwritten offering of 12,531,300 of its American Depositary Shares (“ADSs”). Each ADS is being sold at a price of $3.99 per ADS in an underwritten registered direct offering priced at-the-market under Nasdaq rules. The gross proceeds from the offering, before deducting underwriting discounts and commissions and offering expenses, are expected to be approximately $50.0 million. Each ADS represents five ordinary shares of Mereo. The net proceeds of this offering are expected to be used to fund the setrusumab program, including supply and pre-launch activities in Europe, and for working capital and other general corporate purposes. The offering is expected to close on or about June 17, 2024, subject to the satisfaction of customary closing conditions. Participants in the offering include new investors Frazier Life Sciences, Deerfield Management, and Perceptive Advisors, and existing Mereo shareholders, including Rubric Capital Management, Rock Springs Capital, and Janus Henderson Investors along with other leading healthcare-focused institutional investors. Jefferies, Leerink Partners and Cantor are acting as joint book-running managers for the offering. A shelf registration statement on Form S-3 (File No. 333-279433) relating to the offering of the ADSs described above was declared effective by the Securities and Exchange Commission (“SEC”) on May 22, 2024. The offering is being made only by means of a prospectus supplement and the accompanying prospectus that form a part of the registration statement. A final prospectus supplement relating to and describing the terms of the offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. When available, copies of the final prospectus supplement and accompanying prospectus relating to these securities may also be obtained by sending a request to: Jefferies LLC, Attention: Equity Syndicate Prospectus Department, 520 Madison Avenue, New York, NY 10022, by telephone at (877) 821-7388, or by email at prospectus_department@jefferies.com; Leerink Partners LLC, Attention: Syndicate Department, 53 State Street, 40th Floor, Boston, MA 02109, by telephone at (800) 808-7525, ext. 6105 or by email at syndicate@leerink.com; or Cantor Fitzgerald & Co., Attention: Capital Markets, 110 East 59th Street, 6th Floor, New York, New York 10022, or by email at prospectus@cantor.com. This press release does not constitute an offer to sell or a solicitation of an offer to buy any of these securities, nor will there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale is not permitted. About Mereo BioPharma Mereo BioPharma is a biopharmaceutical company focused on the development of innovative therapeutics for rare diseases. The Company has two rare disease product candidates, setrusumab for the treatment of osteogenesis imperfecta (OI) and alvelestat primarily for the treatment of severe alpha-1 antitrypsin deficiency-associated lung disease (AATD-LD). The Company’s partner, Ultragenyx Pharmaceutical, Inc., has completed enrollment in the Phase 3 portion of a pivotal Phase 2/3 pediatric study in young adults (5 to 25 years old) for setrusumab in OI and in the Phase 3 study in pediatric patients (2 to <7 years old) in the first half of 2024. The partnership with Ultragenyx includes potential additional milestone payments of up to $245 million and royalties to Mereo on commercial sales in Ultragenyx territories. Mereo has retained EU and UK commercial rights and will pay Ultragenyx royalties on commercial sales in those territories. Setrusumab has received orphan designation for osteogenesis imperfecta from the EMA and FDA, PRIME designation from the EMA and has pediatric disease designation from the FDA. Alvelestat has received U.S. Orphan Drug Designation for the treatment of AATD and Fast Track designation from the FDA. Following results from ASTRAEUS and ATALANTa in AATD-lung disease, the Company has aligned with the FDA and the EMA on the primary endpoints for a Phase 3 pivotal study which if successful could enable full approval in both the U.S. and Europe. Forward-Looking Statements This press release contains “forward-looking statements” that involve substantial risks and uncertainties. All statements other than statements of historical fact contained herein are forward-looking statements within the meaning of Section 27A of the United States Securities Act of 1933, as amended, and Section 21E of the United States Securities Exchange Act of 1934, as amended. Forward-looking statements usually relate to future events and anticipated revenues, earnings, cash flows or other aspects of our operations or operating results. Forward-looking statements are often identified by the words “believe,” “expect,” “anticipate,” “plan,” “intend,” “foresee,” “should,” “would,” “could,” “may,” “estimate,” “outlook” and similar expressions, including the negative thereof. The absence of these words, however, does not mean that the statements are not forward-looking. These forward-looking statements are based on the Company’s current expectations, beliefs and assumptions concerning future developments and business conditions and their potential effect on the Company. While management believes that these forward-looking statements are reasonable as and when made, there can be no assurance that future developments affecting the Company will be those that it anticipates. All of the Company’s forward-looking statements involve known and unknown risks and uncertainties some of which are significant or beyond its control and assumptions that could cause actual results to differ materially from the Company’s historical experience and its present expectations or projections. Such risks and uncertainties include, among others, the uncertainties inherent in the clinical development process; the Company’s reliance on third parties to conduct and provide funding for its clinical trials; the Company’s dependence on enrollment of patients in its clinical trials; and the Company’s dependence on its key executives. You should carefully consider the foregoing factors and the other risks and uncertainties that affect the Company’s business, including those described in the “Risk Factors” section of its Annual Report on Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in the Company’s subsequent filings with the Securities and Exchange Commission. The Company wishes to caution you not to place undue reliance on any forward-looking statements, which speak only as of the date hereof. The Company undertakes no obligation to publicly update or revise any of our forward-looking statements after the date they are made, whether as a result of new information, future events or otherwise, except to the extent required by law. Mereo BioPharma Contacts: Mereo +44 (0)333 023 7300Denise Scots-Knight, Chief Executive Officer Christine Fox, Chief Financial Officer Burns McClellan (Investor Relations Adviser to Mereo) +01 646 930 4406Lee Roth Investors investors@mereobiopharma.com

Phase 3Orphan DrugFast Track

13 Jun 2024

·www.fiercebiotech.com

Ultragenyx wins surrogate endpoint debate, securing green light to seek FDA approval of gene therapy

Ultragenyx Pharmaceutical began a public offering of up to $350 million of its common stock after reporting a pipeline update. Ultragenyx Pharmaceutical's work to get the FDA to recognize a biomarker as a surrogate endpoint looks to have paid off. With the agency agreeing the biomarker is a reasonable surrogate endpoint, Ultragenyx is preparing to file for approval of its Sanfilippo syndrome gene therapy around the end of the year. A pivotal trial of the UX111 AAV gene therapy was already underway when Ultragenyx acquired global rights to the program from Abeona Therapeutics in 2022. Ultragenyx reported data from the study earlier this year but was unsure whether the FDA would accept a filing based on cerebral spinal fluid (CSF) heparan sulfate (HS). The biotech made its case at a Reagan-Udall Foundation event attended by FDA staff. Wednesday, Ultragenyx said it had reached an agreement with the agency on the use of the biomarker as a surrogate endpoint for accelerated approval. The biotech now plans to finalize the details of its filing at a meeting with the FDA and apply for approval either late in 2024 or early in 2025. Ultragenyx intends to base the submission on data from the ongoing pivotal study of UX111. In February, the rare disease specialist reported that levels of CSF HS fell within one month after treatment with the gene therapy. Ultragenyx reported declines in the biomarker in all 17 people with Sanfilippo, a fatal lysosomal storage disease also known as MPS IIIA, in its modified intention-to-treat group. The biotech correlated reductions in CSF HS exposure to changes in cognitive function. When looking at cognitive function, Ultragenyx said it saw “a positive rate of change indicating either stability or gains from baseline in 16 of the 17 patients during the expected window of plateau into decline.” Ultragenyx’s filing will show whether the FDA views the biomarker results and signs of clinical efficacy as enough for accelerated approval. But, while that big test is yet to come, securing the green light to file for approval is still another milestone in Ultragenyx’s push to quickly expand its portfolio of approved drugs. The biotech plans to file for approval of its DTX401 gene therapy in glycogen storage disease type Ia next year and is closing in on phase 3 data for its brittle bone disease drug setrusumab. Winning approval for the candidates, and securing the resulting revenues and priority review vouchers, is part of Ultragenyx’s plan for becoming profitable by 2026. Bringing UX111 to market will also increase Ultragenyx’s outgoings, though. The company will pay Abeona up to $30 million in commercial milestones following regulatory approval of the product. Abeona is also in line to receive tiered royalties of up to 10% on net sales. Ultragenyx began a public offering of up to $350 million of shares of its common stock after reporting the update on UX111.

Phase 3Gene TherapyPriority Review

13 Jun 2024

·firstwordpharma.com

Ultragenyx preps US filing for Sanfilippo syndrome gene therapy

Ultragenyx Pharmaceutical announced plans to file for accelerated approval of its gene therapy UX111 for the rare, fatal lysosomal storage disease Sanfilippo syndrome type A (MPS IIIA). The decision follows the FDA agreeing that levels of the biomarker heparan sulfate in cerebral spinal fluid (CSF-HS) can serve as a reasonable surrogate endpoint to support the application.The biotech stated it will finalise details of the planned US regulatory filing with the FDA, and aims to submit before the end of 2024 or early 2025. It acquired exclusive global rights to the investigational AAV gene therapy, formerly known as ABO-102, through a $30-million deal with Abeona Therapeutics in 2022.Alignment with FDA"Gaining alignment with the FDA that CSF heparan sulfate is a relevant biomarker to enable accelerated approval in Sanfilippo syndrome is a pivotal moment for the community and paves the way for treatments for all fatal types of neuronopathic mucopolysaccharidoses," said Ultragenyx CEO Emil Kakkis.The announcement follows clinical data updates presented this past February from the pivotal TRANSPHER A study evaluating the one-time intravenous infusion. As of an August 2023 data cutoff, treatment with UX111 led to rapid and sustained reductions in CSF-HS that correlated with stabilisation or gains in cognitive function across 17 modified intent-to-treat patients."The data supported durable clinical benefit," Barclays analyst Geena Wang said in a note to clients at the time. Wang added she was "optimistic on the FDA's openness and flexibility for accelerated approval paths in rare disease" based on prior agency comments.Meanwhile, Ultragenyx is also preparing regulatory submissions for its DTX401 gene therapy in glycogen storage disease type 1a next year and recently reported longer-term Phase II data for its anti-sclerostin antibody setrusumab, partnered with Mereo BioPharma, in the rare inherited brittle bone disease osteogenesis imperfecta.

Gene TherapyClinical ResultPhase 2

100 Deals associated with Setrusumab

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Osteogenesis Imperfecta	Phase 3	US	Ultragenyx Pharmaceutical, Inc.	14 Mar 2023
Osteogenesis Imperfecta	Phase 3	CA	Ultragenyx Pharmaceutical, Inc.	14 Mar 2023
Osteogenesis Imperfecta	Phase 3	FR	Ultragenyx Pharmaceutical, Inc.	14 Mar 2023
Osteogenesis Imperfecta	Phase 3	IT	Ultragenyx Pharmaceutical, Inc.	14 Mar 2023
Osteogenesis Imperfecta	Phase 3	NL	Ultragenyx Pharmaceutical, Inc.	14 Mar 2023
Osteogenesis Imperfecta	Phase 3	PL	Ultragenyx Pharmaceutical, Inc.	14 Mar 2023
Osteogenesis Imperfecta, Type 3	Phase 2	US	Ultragenyx Pharmaceutical, Inc.	11 Sep 2017
Osteogenesis Imperfecta, Type 3	Phase 2	CA	Ultragenyx Pharmaceutical, Inc.	11 Sep 2017
Osteogenesis Imperfecta, Type 3	Phase 2	DK	Ultragenyx Pharmaceutical, Inc.	11 Sep 2017
Osteogenesis Imperfecta, Type 3	Phase 2	FR	Ultragenyx Pharmaceutical, Inc.	11 Sep 2017

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05125809 (Orbit, GlobeNewswire) Manual	Phase 2/3	Osteogenesis Imperfecta	24	Setrusumab	rhzmcpolfu(zlzarmeuao) = akqmxemoja wpnsyznivg (thqgfupdac ) View more	Positive	11 Jun 2024
NCT05125809 (Orbit, Corporate Publications) Manual	Phase 2	Osteogenesis Imperfecta	24	Setrusumab	amiqmsxyas(qpaygsejrg) = 0.72 in the 2 years prior to treatment was reduced to 0.00 (n=24, p=0.042) during the mean treatment duration period of 9 months vbayiarwhf (prtobmdjiy ) View more	Positive	14 Oct 2023
NCT03118570 (CTgov)	Phase 2	Osteogenesis Imperfecta, Type IV \| Osteogenesis Imperfecta, Type 3	112	Vitamin D+zoledronic acid (optional)+setrusumab (Setrusumab 20 mg/kg (Blinded))	nfyhfpwgcc(gtkckvkulw) = tynhjjvxej jwshsldrxz (tcboluvrlg, wvvxhpcvmr - cqvjrhdodq) View more	-	02 Mar 2022
NCT03118570 (CTgov)	Phase 2		112	Vitamin D+zoledronic acid (optional)+setrusumab (Setrusumab 8 mg/kg (Blinded))	nfyhfpwgcc(gtkckvkulw) = wunhknmhgo jwshsldrxz (tcboluvrlg, kmfiykaqjc - bjroojtpwc) View more	-	02 Mar 2022
NCT01417091 (Pubmed) Manual	Phase 2	Osteogenesis Imperfecta	14	BPS804	zlvteitssk(rvjgzcsdue) = lirlcinldh ovkifgmkvx (nqxxdehsse ) View more	Positive	01 Jul 2017
NCT01417091 (Pubmed) Manual	Phase 2	Osteogenesis Imperfecta	14	no treatment	zlvteitssk(rvjgzcsdue) = bozughpapv ovkifgmkvx (nqxxdehsse ) View more	Positive	01 Jul 2017

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