A Phase 1/2 Study of MPH966, an Oral Neutrophil Elastase Inhibitor, for Prevention of Graft-versus-host Disease After Allogeneic Hematopoietic Stem Cell Transplantation

The purpose of this study is evaluate the safety and tolerability of MPH966, a neutrophil elastase inhibitor, and its ability to prevent graft-versus-host disease after hematopoietic stem cell transplant.

Start Date01 Sep 2021

Sponsor / Collaborator

Mereo BioPharma Group Plc

[+1]

NCT04539795 / CompletedPhase 1/2IIT

A Phase Ib/II, Single Center, Placebo-Controlled, Randomized, Blinded Study in Adult Patients (> 18 Years) With COVID-19 Respiratory Disease, to Evaluate, Safety, Tolerability and Mechanistic Effect of Alvelestat on Top of Standard of Care (COSTA)

The purpose of this study is to determine the safety, tolerability and pharmacokinetics (PK), and explore the mechanistic and clinical effect of alvelestat (an oral neutrophil elastase inhibitor) orally twice per day for 10 days added to standard of care in adult patients (≥18 years) with COVID-19 respiratory disease.

Start Date25 Jan 2021

Sponsor / Collaborator

The University of Alabama at Birmingham

[+1]

NCT03679598 / CompletedPhase 2IIT

A First in Class Disease Modifying Therapy to Treat Alpha-1 Antitrypsin Deficiency a Genetically Linked Orphan Disease

This is a Phase 2, multicenter, double-blind, randomized (1:1), placebo-controlled, 12-week, proof-of-concept study to evaluate the safety and tolerability as well as the mechanistic effect of oral administration of alvelestat (MPH966) in subjects with confirmed AATD defined as Pi*ZZ, Pi*SZ, Pi*null, or another rare phenotype/genotype known to be associated with either low (serum AAT level <11 μM or <57.2 mg/dL) or functionally impaired AAT including "F" or "I" mutations.

Start Date08 Apr 2019

Sponsor / Collaborator

The University of Alabama at Birmingham

[+2]

100 Clinical Results associated with Alvelestat

100 Translational Medicine associated with Alvelestat

100 Patents (Medical) associated with Alvelestat

Literatures (Medical) associated with Alvelestat

01 Dec 2022·Journal of translational medicineQ2 · MEDICINE

The role of neutrophil elastase in aortic valve calcification

Q2 · MEDICINE

ArticleOA

Author: Huang, Qin ; Liu, Yan ; Li, Xiaorong ; Li, Jin ; Xiang, Yi ; Zhu, Mengying ; Shi, Qiong ; Jiang, Peng ; Weng, Yaguang ; Wang, Yue ; An, Liqin

Abstract:

Background:

Calcific aortic valve disease (CAVD) is the most commonly valvular disease in the western countries initiated by inflammation and abnormal calcium deposition. Currently, there is no clinical drug for CAVD. Neutrophil elastase (NE) plays a causal role in inflammation and participates actively in cardiovascular diseases. However, the effect of NE on valve calcification remains unclear. So we next explore whether it is involved in valve calcification and the molecular mechanisms involved.

Methods:

NE expression and activity in calcific aortic valve stenosis (CAVD) patients (n = 58) and healthy patients (n = 30) were measured by enzyme-linked immunosorbent assay (ELISA), western blot and immunohistochemistry (IHC). Porcine aortic valve interstitial cells (pVICs) were isolated and used in vitro expriments. The effects of NE on pVICs inflammation, apoptosis and calcification were detected by TUNEL assay, MTT assay, reverse transcription polymerase chain reaction (RT-PCR) and western blot. The effects of NE knockdown and NE activity inhibitor Alvelestat on pVICs inflammation, apoptosis and calcification under osteogenic medium induction were also detected by RT-PCR, western blot, alkaline phosphatase staining and alizarin red staining. Changes of Intracellular signaling pathways after NE treatment were measured by western blot. Apolipoprotein E−/− (APOE−/−) mice were employed in this study to establish the important role of Alvelestat in valve calcification. HE was used to detected the thickness of valve. IHC was used to detected the NE and α-SMA expression in APOE−/− mice. Echocardiography was employed to assess the heat function of APOE−/− mice.

Results:

The level and activity of NE were evaluated in patients with CAVD and calcified valve tissues. NE promoted inflammation, apoptosis and phenotype transition in pVICs in the presence or absence of osteogenic medium. Under osteogenic medium induction, NE silencing or NE inhibitor Alvelestat both suppressed the osteogenic differentiation of pVICs. Mechanically, NE played its role in promoting osteogenic differentiation of pVICs by activating the NF-κB and AKT signaling pathway. Alvelestat alleviated valve thickening and decreased the expression of NE and α-SMA in western diet-induced APOE−/− mice. Alvelestat also reduced NE activity and partially improved the heart function of APOE−/−mice.

Conclusions:

Collectively, NE is highly involved in the pathogenesis of valve calcification. Targeting NE such as Alvelestat may be a potential treatment for CAVD.

01 Sep 2022·European journal of pharmacology

Novel benzoxazinone derivative as potent human neutrophil elastase inhibitor: Potential implications in lung injury

Article

Author: Sengupta, Sayantan ; Bandyopadhyay, Arun ; Palakodety, Radha Krishna ; Reddy, Jala Ranjith ; Rajesh, Nomula ; Jaiswal, Ashish ; Mukherjee, Pulok ; Mabalirajan, Ulaganathan

Neutrophil elastase, a powerful physiological defence tool, may serve as drug target for diverse diseases due to its bystander effect on host cells like chronic obstructive pulmonary disease (COPD). Here, we synthesised seven novel benzoxazinone derivatives and identified that these synthetic compounds are human neutrophil elastase inhibitor that was demonstrated by enzyme substrate kinetic assay. One such compound, PD05, emerged as the most potent inhibitor with lower IC₅₀ as compared to control drug sivelestat. While this inhibition is competitive based on substrate dilution assay, PD05 showed a high binding affinity for human neutrophil elastase (Kd = 1.63 nM) with faster association and dissociation rate compared to notable elastase inhibitors like ONO 6818 and AZD9668, and its interaction with human neutrophil elastase was fully reversible.Preclinical pharmacokinetic studies were performed in vitro where protein binding was found to be 72% with a high recovery rate, aqueous solubility of 194.7 μM, low permeability along with a favourable hERG. Experiments with cell line revealed that the molecule successfully prevented elastase induced rounding and retracted cell morphology and cell cytotoxicity. In mouse model PD05 is able to reduce the alveolar collapse induced by neutrophil elastase. In summary, we demonstrate the in situ, in vitro and in vivo anti-elastase potential of the newly synthesised benzoxazinone derivative PD05 and thus this could be promising candidate for further investigation as a drug for the treatment of COPD.

01 Feb 2021·Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapieQ2 · MEDICINE

Neutrophil elastase inhibitor (MPH-966) improves intestinal mucosal damage and gut microbiota in a mouse model of 5-fluorouracil–induced intestinal mucositis

Q2 · MEDICINE

Article

Author: Hwang, Tsong-Long ; Hsieh, Pei-Wen ; Ueng, Shir-Hwa ; Chen, Kung-Ju ; Chen, Yu-Li ; Kuo, Liang-Mou

BACKGROUND:

5-Fluorouracil (5-FU)-based chemotherapy is first-line chemotherapy for colorectal cancer. However, 5-FU-induced intestinal mucositis (FUIIM) is a common adverse effect that severely impairs drug tolerance and results in poor patient health.

METHODS:

Male C57BL/6 mice were given 5-FU (50 mg/kg/day, i.p.) and treated with MPH-966 (5 and 7.5 mg/kg/day, p.o.) for five days. The body weight loss and the amount of food intake, and histopathological findings were recorded and analyzed. In addition, the neutrophil infiltration, levels of neutrophil serine proteases and pro-inflammatory cytokines, and tight junction proteins expression in intestinal tissues were determined. The ecology of gut microbiota was performed through next-generation sequencing technologies.

RESULTS:

Neutrophil elastase (NE) overexpression is a key feature in FUIIM. This study showed that treatment with the specific NE inhibitor MPH-966 (7.5 mg/kg/day, p.o.) significantly reversed 5-FU-induced loss in body weight and food intake; reversed villous atrophy; significantly suppressed myeloperoxidase, NE, and proteinase 3 activity; and reduced pro-inflammatory cytokine expression in an FUIIM mouse model. In addition, MPH-966 prevented 5-FU-induced intestinal barrier dysfunction, as indicated by the modulated expression of the tight junction proteins zonula occludin-1 and occludin. MPH-966 also reversed 5-FU-induced changes in gut microbiota diversity and abundances, specifically the Firmicutes-to-Bacteroidetes ratio; Muribaculaceae, Ruminococcaceae, and Eggerthellaceae abundances at the family level; and Candidatus Arthromitus abundance at the genus level.

CONCLUSION:

These data indicate that NE inhibitor is a key treatment candidate to alleviate FUIIM by regulating abnormal inflammatory responses, intestinal barrier dysfunction, and gut microbiota imbalance.

News (Medical) associated with Alvelestat

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

11 Jun 2024

·www.globenewswire.com

Ultragenyx and Mereo BioPharma Announce New Phase 2 Data from Phase 2/3 Orbit Study Demonstrating Sustained Reductions in Fracture Rates Following Treatment with Setrusumab (UX143) in Patients with Osteogenesis Imperfecta (OI)

14-month data show treatment with setrusumab resulted in a large, sustained 67% reduction in annualized fracture rate and persistent median annualized fracture rate of 0.00 (p=0.0014) Treatment resulted in continued, substantial improvements in bone mineral density (BMD) with a mean increase from baseline of 22% (p<0.0001) and a mean improvement in Z-score of +1.25 (p<0.0001) NOVATO, Calif. and LONDON, June 11, 2024 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE) and Mereo BioPharma Group plc (NASDAQ: MREO) today announced positive 14-month results from the Phase 2 portion of the ongoing Phase 2/3 Orbit study (NCT05125809) demonstrating that, as of a May 24, 2024 data cut-off date, treatment with setrusumab (UX143) continued to significantly reduce incidence of fractures in patients with OI with at least 14 months of follow-up. Treatment with setrusumab also resulted in ongoing and meaningful improvements in lumbar spine bone mineral density (BMD) at month 12 without evidence of plateau. The large reduction in annualized radiologically confirmed fracture rate previously reported in patients treated for a minimum of 6 months was sustained in patients treated for at least 14 months with a high degree of significance. The median annualized rate of radiologically confirmed fractures across all 24 patients in the 2 years prior to treatment was 0.72. Following a mean treatment duration period of 16 months, the median annualized fracture rate was reduced 67% to 0.00 (p=0.0014; n=24). The annualized fracture rate excluded morphometric vertebral fractures and fractures of the fingers, toes, skull, and face, consistent with the Phase 3 study primary efficacy endpoint. “All indications are that setrusumab is having the effect we hoped for, safely reducing the incidence of fractures and improving BMD in patients with OI,” said Gary S. Gottesman, M.D., Professor of Pediatrics and Medicine, Washington University School of Medicine. “The anti-sclerostin antibody appears effective even after a year and remarkably, patients continue to make measurable gains, suggesting we will see an ongoing response over the long term.” The reduction in annualized fracture rates was associated with continued, clinically meaningful increases in BMD. Tests conducted at the 12-month timepoint demonstrated that treatment with setrusumab resulted in a mean increase in lumbar spine BMD from baseline of 22% (p<0.0001, n=19) across all age groups (5 to < 26 years old), a further improvement from 14% observed at 6 months of treatment. This increase in BMD is reflected in the change from the mean baseline lumbar spine BMD Z-score of -1.73 to -0.49 at 12 months across all age groups, a substantial normalization in Z-score of +1.25 (p<0.0001, n=18). This is further improved from the mean 6-month Z-score change of +0.85. The improvements in BMD and Z-scores were significant and consistent across all OI sub-types studied. “The clinically meaningful continued improvement in BMD suggests that new and stronger bone is being created that has resulted in an important reduction in fractures across age groups and types of OI,” said Eric Crombez, M.D., chief medical officer at Ultragenyx. “With our phase 3 Orbit and Cosmic studies fully enrolled we now look forward to the possibility to bring this potential new treatment to a larger number of patients living with OI.” As of the data cut-off, there were no treatment-related serious adverse events observed in the study. Reported adverse events were generally consistent with those observed in the Asteroid study with infusion-related events and headache determined to be the most common adverse events related to the study drug. As of the data cut-off, there were no reported hypersensitivity reactions related to setrusumab. More detailed 14-month data will be presented at a future scientific meeting. About the Setrusumab Phase 3 ProgramUltragenyx is developing setrusumab in pediatric and young adult patients across OI sub-types I, III and IV with two late-stage trials: the pivotal Phase 2/3 Orbit study and Phase 3 Cosmic study. The global, seamless Phase 2/3 Orbit study is evaluating the effect of setrusumab on clinical fracture rate in patients aged 5 to 25 years. In the Phase 2 portion, 24 patients were randomized 1:1 to receive setrusumab at one of two doses to determine the optimal dosing strategy for Phase 3. All patients from the 40 mg/kg dosing cohort have been transitioned to 20 mg/kg of setrusumab. The pivotal Phase 3 portion of the study has enrolled an additional 158 patients at 45 sites across 11 countries, with subjects randomized 2:1 to receive setrusumab or placebo, and a primary efficacy endpoint of annualized clinical fracture rate. All patients will transition to an extension period and receive open-label setrusumab after the Phase 3 primary analysis is complete. The global Phase 3 Cosmic study is an open-label, randomized, active-controlled study in patients aged 2 to <7 years. Patients are randomized 1:1 to receive setrusumab or intravenous bisphosphonates (IV-BP) therapy to evaluate reduction in total fracture rate. The Cosmic study has enrolled 69 patients at 21 sites across 7 countries. About Osteogenesis Imperfecta (OI)Osteogenesis Imperfecta (OI) includes a group of genetic disorders impacting bone metabolism. Approximately 85% to 90% of OI cases are caused by genetic variants in the COL1A1 or COL1A2 genes, leading to either reduced or abnormal collagen and changes in bone metabolism. The collagen mutations in OI can result in increased bone brittleness, which contributes to a high rate of fractures. Patients with OI also exhibit inadequate production of new bone and excess bone resorption, resulting in decreased bone mineral density, bone fragility and weakness. OI can also lead to bone deformities, abnormal spine curvature, pain, decreased mobility, and short stature. No treatments are globally approved for OI, which affects approximately 60,000 people in commercially accessible geographies. About Setrusumab (UX143)Setrusumab is a fully human monoclonal antibody that inhibits sclerostin, a negative regulator of bone formation. Blocking sclerostin is expected to increase new bone formation, bone mineral density and bone strength in OI. In mouse models of OI, the use of anti-sclerostin antibodies was shown to increase bone formation, improve bone mass to normal levels, and increase bone strength against fracture force testing to normal levels. In 2019 Mereo BioPharma completed the Phase 2b dose-finding study (Asteroid) for setrusumab in 112 adults with OI. The Asteroid study demonstrated treatment with setrusumab resulted in a clear, dose-dependent and statistically significant effect on bone formation and bone density at multiple anatomical sites among adult participants with OI. Ultragenyx and Mereo BioPharma are collaborating on the development of setrusumab globally based on the collaboration and license agreement between the parties. The companies have developed a comprehensive late-stage program to continue development of setrusumab in pediatric and young adult patients across OI sub-types I, III and IV. About Ultragenyx Pharmaceutical Inc.Ultragenyx is a biopharmaceutical company committed to bringing novel products to patients for the treatment of serious rare and ultrarare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease. The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyx’s strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency. For more information on Ultragenyx, please visit the company's website at: www.ultragenyx.com. 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. In addition to the rare disease programs, Mereo has two oncology product candidates in clinical development. Etigilimab (anti-TIGIT) has completed a Phase 1b/2 basket study evaluating its safety and efficacy in combination with an anti-PD-1 in a range of tumor types including three rare tumors and three gynecological carcinomas – cervical, ovarian, and endometrial and is an ongoing Phase 1b/2 investigator led study at the MD Anderson Cancer Center in clear cell ovarian cancer; Navicixizumab, for the treatment of late line ovarian cancer, has completed a Phase 1 study and has been partnered with Feng Biosciences Inc. in a global licensing agreement that includes milestone payments and royalties. Mereo has entered into an exclusive global license agreement with ReproNovo SA for the development and commercialization of leflutrozole, a non-steroidal aromatase inhibitor. Under the terms of the agreement, ReproNovo, a reproductive medicine company, is responsible for all future development and commercialization of leflutrozole. For more information on Mereo BioPharma, please visit www.mereobiopharma.com. Ultragenyx Forward-Looking Statements and Use of Digital MediaExcept for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations and projections regarding its future operating results and financial performance, business plans and objectives for UX143, expectations regarding the tolerability and safety of UX143, and future clinical and regulatory developments for UX143 are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the uncertainty of clinical drug development and unpredictability and lengthy process for obtaining regulatory approvals, the ability of the company and Mereo BioPharma to successfully develop UX143, the company’s ability to achieve its projected development goals in its expected timeframes, risks related to adverse side effects, risks related to reliance on third party partners to conduct certain activities on the company’s behalf, the potential for any license or collaboration agreement, including the company’s collaboration agreement with Mereo to be terminated, smaller than anticipated market opportunities for the company’s products and product candidates, manufacturing risks, competition from other therapies or products, and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations, the company’s future operating results and financial performance, the timing of clinical trial activities and reporting results from same, and the availability or commercial potential of Ultragenyx’s products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 3, 2024, and its subsequent periodic reports filed with the SEC. In addition to its SEC filings, press releases and public conference calls, Ultragenyx uses its investor relations website and social media outlets to publish important information about the company, including information that may be deemed material to investors, and to comply with its disclosure obligations under Regulation FD. Financial and other information about Ultragenyx is routinely posted and is accessible on Ultragenyx’s Investor Relations website (https://ir.ultragenyx.com/) and LinkedIn website (https://www.linkedin.com/company/ultragenyx-pharmaceutical-inc-/). Mereo BioPharma Forward-Looking StatementsThis 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 Mereo BioPharma’s 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 Mereo BioPharma’s current expectations, beliefs and assumptions concerning future developments and business conditions and their potential effect on Mereo BioPharma. While management believes that these forward-looking statements are reasonable as and when made, there can be no assurance that future developments affecting Mereo BioPharma will be those that it anticipates. All of Mereo BioPharma’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 Mereo BioPharma’s historical experience and its present expectations or projections. Such risks and uncertainties include, among others, the uncertainties inherent in the clinical development process; Mereo BioPharma’s reliance on third parties to conduct and provide funding for its clinical trials; Mereo BioPharma’s dependence on enrollment of patients in its clinical trials; and Mereo BioPharma’s dependence on its key executives. You should carefully consider the foregoing factors and the other risks and uncertainties that affect Mereo BioPharma’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 Mereo’s subsequent filings with the Securities and Exchange Commission. Mereo BioPharma wishes to caution you not to place undue reliance on any forward-looking statements, which speak only as of the date hereof. Mereo BioPharma 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. Contacts Ultragenyx Pharmaceutical Inc. InvestorsJoshua Higa+1-415-475-6370ir@ultragenyx.com MediaCarolyn Wang+1-415-225-5050media@ultragenyx.com Mereo BioPharma Group plc Denise Scots-Knight, Chief Executive OfficerChristine Fox, Chief Financial Officer+44 (0)333 023 7300 Burns McClellan (Investor Relations Advisor to Mereo)Lee Roth +01 646-930-4406investors@mereobiopharma.com

Clinical ResultPhase 3Phase 2License out/inOrphan Drug

30 May 2024

·www.biospace.com

Mereo BioPharma to Participate in Fireside Chat at the Jefferies Global Healthcare Conference

LONDON, May 30, 2024 (GLOBE NEWSWIRE) -- Mereo BioPharma Group plc (NASDAQ: MREO) (“Mereo” or the “Company”), a clinical-stage biopharmaceutical company focused on rare diseases, today announced that Dr. Denise Scots-Knight, Chief Executive Officer, will participate in a Fireside Chat at the Jefferies Global Healthcare Conference on Thursday, June 6, 2024, at 11:00am ET / 04:00pm BST. A live audio webcast of the presentation can be accessed through the Investors section of the Company’s website at . An archived replay of the webcast will be available on the Company’s website for two weeks following the live event. 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. In addition to the rare disease programs, Mereo has two oncology product candidates in clinical development. Etigilimab (anti-TIGIT) has completed a Phase 1b/2 basket study evaluating its safety and efficacy in combination with an anti-PD-1 in a range of tumor types including three rare tumors and three gynecological carcinomas – cervical, ovarian, and endometrial and is an ongoing Phase 1b/2 investigator led study at the MD Anderson Cancer Center in clear cell ovarian cancer; Navicixizumab, for the treatment of late line ovarian cancer, has completed a Phase 1 study and has been partnered with Feng Biosciences Inc. in a global licensing agreement that includes milestone payments and royalties. Mereo has entered into an exclusive global license agreement with ReproNovo SA for the development and commercialization of leflutrozole, a non-steroidal aromatase inhibitor. Under the terms of the agreement, ReproNovo, a reproductive medicine company, is responsible for all future development and commercialization of leflutrozole. For more information on Mereo BioPharma, please visit 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 7300 Denise Scots-Knight, Chief Executive Officer Christine Fox, Chief Financial Officer Burns McClellan (Investor Relations Adviser to Mereo) +01 646 930 4406 Lee Roth Investors investors@mereobiopharma.com

Phase 3License out/inOrphan DrugFast TrackPhase 1

100 Deals associated with Alvelestat

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11863

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Graft vs Host Disease	Phase 2	US	National Center for Advancing Translational Sciences	01 Sep 2021
Graft vs Host Disease	Phase 2	US	Mereo BioPharma Group Plc	01 Sep 2021
Hematologic Neoplasms	Phase 2	US	Mereo BioPharma Group Plc	01 Sep 2021
Hematologic Neoplasms	Phase 2	US	National Center for Advancing Translational Sciences	01 Sep 2021
COVID-19	Phase 2	US	Mereo BioPharma Group Plc	25 Jan 2021
COVID-19 respiratory infection	Phase 2	US	Mereo BioPharma Group Plc	25 Jan 2021
Alpha 1-Antitrypsin Deficiency	Phase 2	US	Mereo BioPharma Group Plc	08 Apr 2019
Bronchiolitis Obliterans	Phase 2	US	National Cancer Institute	28 Apr 2016
Chronic graft-versus-host disease	Phase 2	US	National Cancer Institute	28 Apr 2016
Cystic Fibrosis	Phase 2	DK	AstraZeneca PLC	01 Oct 2008

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04539795 (COSTA, Corporate Publications) Manual	Phase 1/2	COVID-19	15	Alvelestat	ithlffklva(uhfjvubzps) = ggqfvsxxeq aqlhsxtxao (rwsanjdxxk ) View more	Positive	22 Dec 2021
				Placebo	znebpvzsak(fpvbsqfvzl) = brdjsovnev zbwyxjfnvf (jzsgacbyzq ) View more
NCT02597101 (CTgov)	Phase 2	Diabetes Mellitus, Type 2 \| Insulin Resistance \| Obesity	14	placebo+metformin+saxagliptin (Placebo)	bytuzfdilf(ykulpttpiq) = igmydksczy rtuunnaszd (kvnzsjuppi, mbziadigua - lbdfozimnt) View more	-	13 May 2021
				AZD9668+metformin+saxagliptin (AZD9668)	bytuzfdilf(ykulpttpiq) = ksfjonmhuz rtuunnaszd (kvnzsjuppi, aiidvhpksb - oizdnehqzt) View more
NCT00949975 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	838	AZD9668 (5 mg AZD9668)	pwbxgjnphc(kseiastrdi) = cdpardfgbk fftvwyfkak (tqysdojlon, ulsvrsjlqo - tjeukorbyl) View more	-	03 Aug 2012
				AZD9668 (20 mg AZD9668)	pwbxgjnphc(kseiastrdi) = gtwkkjapht fftvwyfkak (tqysdojlon, yzgsqbyppr - uucnwyzwmr) View more
NCT01023516 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	615	AZD9668 (60 mg AZD9668)	zriqpyklde(wfogdvwgro) = nbumcsaoxo jqouhurkuz (iioxozgeln, opzjxtebov - rmtigzmawq) View more	-	03 Aug 2012
				Placebo (Placebo)	zriqpyklde(wfogdvwgro) = nmiubzyyzk jqouhurkuz (iioxozgeln, bitwbsmphr - fccfnxsjrh) View more
NCT00769119 (CTgov)	Phase 2	Bronchiectasis	38	AZD9668 (AZD9668)	vrydewicln(uvnsktxpva) = xvfmpownjz kvppuyxkgn (ocokygnrne, zhwraqglpk - rahppupvng) View more	-	25 Jul 2012
				Placebo (Placebo)	vrydewicln(uvnsktxpva) = nqbhfbmhkk kvppuyxkgn (ocokygnrne, hfrulalytj - ktbwyornof) View more
NCT00757848 (CTgov)	Phase 2	Cystic Fibrosis	56	AZD9668 (AZD9668)	krdqtioagy(cylnicajja) = rlzvlbhzcv dvskbnmlyz (ycdrsfldqx, swrqktvwcm - ubivxwkrmq) View more	-	25 Jul 2012
				AZD9668 Placebo equivalent (Placebo)	krdqtioagy(cylnicajja) = jemtmxjlkk dvskbnmlyz (ycdrsfldqx, jmzhjewpxa - ciythnweof) View more
NCT01054170 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	52	AZD9668 (AZD9668)	vqynwuftkn(oydpghrhcr) = lyvlkcvtyw hkofbhxjif (hjsqrcnszt, gehzocxvzi - vsilzscweg) View more	-	25 Jul 2012
				placebo (Placebo)	vqynwuftkn(oydpghrhcr) = ebcaemyykt hkofbhxjif (hjsqrcnszt, dxnwklupci - czfhawtbdb) View more
NCT00703391 (CTgov)	Phase 2	Pulmonary Disease, Chronic Obstructive	18	AZD9668 (AZD9668)	cebgqaleiv(ydyswomidr) = swnqmjvfom vvxhdyhrrv (ukgrxwkgzr, lndwxokicl - uxlrnmsvuk) View more	-	29 Dec 2010
				placebo (Placebo)	cebgqaleiv(ydyswomidr) = niyptcaibk vvxhdyhrrv (ukgrxwkgzr, vjjxpldtqg - ntztbdgghu) View more

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