A Phase 3, Randomized, Open-label, Parallel-arm, Active-controlled, Multicenter Study to Evaluate Safety and Efficacy of ALXN1850 Versus Asfotase Alfa Administered Subcutaneously in Pediatric Participants (2 to < 12 Years of Age) With Hypophosphatasia (HPP) Previously Treated With Asfotase Alfa

The primary purpose of this study is to assess the safety and tolerability of ALXN1850 versus asfotase alfa in pediatric participants with HPP previously treated with asfotase alfa.

Start Date02 Apr 2024

Sponsor / Collaborator

Alexion Pharmaceuticals, Inc.

NCT05234567 / RecruitingNot Applicable

A Prospective Observational Sub-Study of the Global Hypophosphatasia Registry to Describe the Potential Risk of Immune-Mediated Loss of Pharmacological Effect of Asfotase Alfa in Participants With Hypophosphatasia

In this prospective observational sub-study, participants with pediatric-onset hypophosphatasia (HPP) (perinatal/infantile- or juvenile-onset) of any age will be followed for a minimum of 5 years at sites in the United States and potentially 1 or 2 other countries.

Start Date17 Mar 2022

Sponsor / Collaborator

Alexion Pharmaceuticals, Inc.

NCT04189315 / WithdrawnPhase 4

A Phase 4, Randomized, Multicenter, Open-Label, 2-Dosage Regimen, Safety and Tolerability, Efficacy, Pharmacokinetic, and Pharmacodynamic Study of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia

The study will evaluate safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of 2 different doses (approved dose and lower dose) of asfotase alfa in adult participants with pediatric-onset hypophosphatasia (HPP).

Start Date01 Apr 2020

Sponsor / Collaborator

Alexion Pharmaceuticals, Inc.

100 Clinical Results associated with Asfotase alpha

100 Translational Medicine associated with Asfotase alpha

100 Patents (Medical) associated with Asfotase alpha

128

Literatures (Medical) associated with Asfotase alpha

01 Dec 2023·JBMR plus

The Effect of Asfotase Alfa on Plasma and Urine Pyrophosphate Levels and Pseudofractures in a Patient With Adult‐Onset Hypophosphatasia

Author: Kato, Hajime ; Hoshino, Yoshitomo ; Kinoshita, Yuka ; Ito, Nobuaki ; Tachikawa, Kanako ; Makita, Noriko ; Watanabe, So ; Murata, Hiroaki ; Osaki, Keiichi ; Hidaka, Naoko ; Michigami, Toshimi ; Kimura, Soichiro ; Sunouchi, Takashi ; Nangaku, Masaomi ; Sekiyama, Takashi

ABSTRACT:

Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue‐nonspecific alkaline phosphatase. Adult‐onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first‐line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64‐year‐old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6‐minute walk test (525 to 606 m). The EQ‐5D‐5L index was also improved (0.757 to 0.895). Within a follow‐up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

01 Oct 2023·Bone

Effects of asfotase alfa in adults with pediatric-onset hypophosphatasia over 24 months of treatment

Article

Author: Genest, Franca ; Petryk, Anna ; Seefried, Lothar ; Veith, Marina

BACKGROUND:

Hypophosphatasia (HPP) is a rare, heritable metabolic disorder caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Asfotase alfa (AA) is a human recombinant TNSALP that promotes bone mineralization and is approved to treat eligible patients with HPP.

METHODS:

This prospective single-center observational study evaluated AA in adults with pediatric-onset HPP over 2 years of treatment (ClinicalTrials.govNCT03418389). Primary outcomes evaluated physical function; secondary outcomes assessed quality of life (QoL) and pain.

RESULTS:

The study included 17 females and 5 males (mean age: 48.7 years). Median distance walked in the 6-Minute Walk Test increased significantly from baseline to 12 months (P = 0.034) and results were sustained. Median Timed Up and Go test time significantly decreased from baseline at 12 (P = 0.003) and 24 months (P = 0.005), as did the median chair rise time test at 12 (P = 0.003) and 24 months (P < 0.002). The change from baseline in usual gait speed was significant at 12 (P = 0.003) and 24 months (P = 0.015). Mean dominant and nondominant hand grip strength improved at 24 months (P = 0.029 and P = 0.019, respectively). Median Short Form 36 Physical Component Summary scores significantly improved from baseline at 12 (P = 0.012) and 24 (P = 0.005) months, and median Lower Extremity Functional Scale scores improved from baseline at 12 (P = 0.001) and 24 (P = 0.002) months. No significant change was noted in pain level at these timepoints. While injection site reactions occurred in 86.4 % of the participants, there were no severe side effects or safety findings.

CONCLUSIONS:

Adults with pediatric-onset HPP treated with AA experienced marked improvement in functional and QoL outcomes that were observed as early as within 3 months of initial treatment and were sustained over 24 months.

01 Aug 2023·European archives of paediatric dentistry : official journal of the European Academy of Paediatric Dentistry

The impact of enzyme replacement therapy on the oral health manifestations of hypophosphatasia among children: a scoping review

Review

Author: Poirier, B F ; Sethi, S ; Jensen, E D ; Smart, G

PURPOSE:

A scoping review to describe the use of enzyme replacement therapy (ERT) in the form of asfotase alfa to decrease the severity of oral manifestations in children with hypophosphatasia (HPP).

METHODS:

Six databases were searched using keywords and index terms related to "hypophosphatasia," "children," and "enzyme replacement therapy." Duplicates were removed and two independent reviewers screened the titles and abstracts to identify articles for full-text review. Extracted data was summarised narratively.

RESULTS:

The systematic search identified 3548 articles, with 171 suitable for full-text review and a final 22 that met inclusion criteria. Enzyme replacement therapy generally resulted in a reduction in the presence and severity of oral manifestations of HPP. However, numerous studies failed to report specific details regarding the nature of oral health outcomes and there were reported cases of further loss of primary teeth.

CONCLUSIONS:

The available evidence suggests that that ERT in the form of asfotase alfa for HPP in infants and young children leads to improved oral health outcomes. It is recommended that the outcomes are improved with earlier initiation of ERT. Further, well-designed clinical research is required to assess oral health improvements and decreased morbidity associated with the early loss of teeth.

News (Medical) associated with Asfotase alpha

10 May 2024

·www.biospace.com

Be Biopharma Announces New Preclinical Data for Novel B Cell Medicine for the Potential Treatment of Hypophosphatasia

Preclinical research demonstrates that CRISPR/Cas9-based precision B cell gene engineering coupled with artificial intelligence-guided protein design produces active tissue-nonspecific alkaline phosphatase (“ALP”) Data presented at American Society of Gene & Cell Therapy 27th Annual Meeting CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Be Biopharma, Inc. (“Be Bio”), a company pioneering the discovery and development of Engineered B Cell Medicines (BCMs), today presented results from new preclinical research demonstrating production of active ALP by a BCM, which highlights BCMs as a potential treatment for Hypophosphatasia (HPP). Researchers used CRISPR/Cas9 precision gene engineering and artificial intelligence-guided protein design to modify primary human B cells to produce ALP, an enzyme deficient in people living with HPP. The findings were presented during a poster presentation at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting on Friday, May 10, at 12:00pm ET. HPP is a rare genetic disease caused by loss of function mutations in the ALPL gene which leads to deficient ALP activity. People living with HPP can experience wide ranging systemic complications, with impaired bone mineralization, such as rickets/osteomalacia, being a major clinical hallmark of severe disease. The only approved therapy for HPP is an enzyme replacement therapy, asfotase alfa, which requires multiple injections every week and is approved only for use in patients with pediatric-onset forms of HPP. “This study demonstrates how BCMs coupled with artificial intelligence-guided protein design broaden the potential of our medicines to express highly effective conjugated therapeutic proteins such as ALP-Fc fusion proteins,” said Rick Morgan, Chief Scientific Officer. “BCMs are designed to provide constant and durable protein levels without preconditioning, are redosable, and can be applied to a wide range of diseases, including a potential first-in-class medicine for people living with HPP.” In this study, primary human B cells were expanded and precision engineered by CRISPR/Cas9 genome editing with AAV-mediated homology directed repair (HDR) to insert an ALP gene expression cassette into various loci, including CCR5 (a safe harbor locus). Guided by an artificial intelligence-based ALP protein structure design engine, protein constructs were optimized for activity and stability of ALP-Fc fusion proteins. Engineered BCMs secreted active ALP proteins up to 200 ng/1e6 cells/24hr. Robust in vitro phenotypic correction using ALP secreting BCMs (ALP-BCMs) was demonstrated in the MC3T3 osteoblast precursor mineralization model. About Engineered B Cell Medicines – A New Class of Cellular Medicines The B cell is a powerful cell that produces thousands of proteins per cell per second at constant levels, and over decades. Precision genome editing can now be used to engineer B Cells that produce therapeutic proteins of interest, driving a new class of cellular medicines – Engineered B Cell Medicines (BCMs) – with the potential to be durable, allogeneic, redosable, and administered without pre-conditioning. The promise of BCMs could transform therapeutic biologics with broad application — across protein classes, patient populations and therapeutic areas. About Be Biopharma Be Biopharma (“Be Bio”) is pioneering Engineered B Cell Medicines (BCMs) to dramatically improve the lives of patients who are living with Hemophilia B and other genetic diseases, cancer, and other serious conditions. With eyes locked on the patient, our team of purpose-driven scientists, technologists, manufacturing experts and business builders collaborate to create a bold new class of cell therapies. Be Bio was founded in October 2020 by B cell engineering pioneers David Rawlings, M.D., and Richard James, Ph.D., from Seattle Children’s Research Institute. Be Bio is backed by ARCH Venture Partners, Atlas Venture, RA Capital Management, Alta Partners, Longwood Fund, Bristol Myers Squibb, Takeda Ventures, Seattle Children’s Research Institute and others. Since our founding, Be Bio’s investors have committed over $180 million to enable the Company to re-imagine medicine based on the power of B cell therapy. For more information, please visit us at Be.Bio and our LinkedIn page. View source version on businesswire.com: Contacts Investors: ir@be.bio Media: media@be.bio Source: Be Biopharma, Inc. View this news release online at:

Cell TherapyGene Therapy

08 Feb 2024

·www.biospace.com

AstraZeneca Full year and Q4 2023 Financial Results

Strong growth and pipeline momentum with three new medicines approved since the third quarter CAMBRIDGE, United Kingdom--(BUSINESS WIRE)-- AstraZeneca: Revenue and EPS summary FY 2023 Q4 2023 % Change % Change $m Actual CER1 $m Actual CER - Product Sales 43,789 2 4 11,323 5 5 - Alliance Revenue2 1,428 89 89 424 69 67 - Collaboration Revenue2 594 (1 ) (1 ) 277 75 74 Total Revenue 45,811 3 6 12,024 7 8 Total Revenue ex COVID-19 45,488 13 15 12,036 16 16 Reported EPS $3.84 81 96 $0.62 7 5 Core3 EPS $7.26 9 15 $1.45 5 7 Financial performance for full year 2023 (Growth numbers at CER) Total Revenue $45,811m, up 6% despite a decline of $3,736m from COVID-19 medicines4 Excluding COVID-19 medicines, Total Revenue increased 15% and Product Sales increased 14% Double-digit Total Revenue growth from Oncology 21%, CVRM 18%, R&I 10%, and Rare Disease 12% Core Product Sales Gross Margin5 of 82%, up two percentage points, reflecting the decline in sales of lower margin COVID‑19 medicines Core Operating Margin of 32% increased by two percentage points including the previously announced gain from an update to the contractual relationships for Beyfortus, totalling $712m and recorded as Core Other operating income. In the quarter, higher SG&A expense drove lower operating margins, partly due to phasing of expenses and increased investment in launches for Airsupra, Wainua and Truqap The Core Tax Rate for the year was 17%. In the fourth quarter, the tax rate was negatively impacted by reviews by tax authorities, administrative appeal processes and other adjustments, offset by a routine intragroup reorganisation of IP, leading to a tax rate of 10% in the quarter Core EPS increased 15% to $7.26 Second interim dividend declared of $1.97 per share, making a total dividend declared for FY 2023 of $2.90 per share Total Revenue and Core EPS in FY 2024 are each expected to increase by a low double-digit to low teens percentage at CER Pascal Soriot, Chief Executive Officer, AstraZeneca, said: "As AstraZeneca celebrates its 25th anniversary, we are pleased to report another year of strong financial performance and scientific progress, with double-digit earnings growth, and investment in exciting areas of science, including antibody drug conjugates and cell therapies, that lay the foundations for long-term success. We expect another year of strong growth in 2024, driven by continued adoption of our medicines across geographies. Our differentiated and growing portfolio of approved medicines, global reach and rich R&D pipeline give us confidence that we will continue to deliver industry-leading growth." Key milestones achieved since the prior results announcement Three first approvals for new molecular entities: Truqap (capivasertib), Wainua (eplontersen), Voydeya (danicopan) US approvals for Truqap plus Faslodex in HR-positive, HER2-negative advanced breast cancer with biomarker alterations (CAPItello-291), and Wainua for ATTRv-PN (NEURO-TTRansform). China approvals for Imfinzi in mBTC (TOPAZ-1) and Beyfortus for prevention of RSV in infants (MEDLEY/MELODY). First approval, in Japan, for Voydeya, as an add-on therapy to Ultomiris or Soliris for PNH with EVH (ALPHA) Enhertu granted Priority Review in the US for patients with metastatic HER2-positive solid tumours Guidance The Company issues its Total Revenue and Core EPS guidance for FY 2024 at CER, based on the average foreign exchange rates through 2023. Total Revenue is expected to increase by a low double-digit to low teens percentage Core EPS is expected to increase by a low double-digit to low teens percentage Collaboration Revenue is expected to increase substantially, driven by success-based milestones and certain anticipated transactions Other operating income is expected to decrease substantially (FY 2023 included a $241m gain on the disposal of Pulmicort Flexhaler US rights, and a $712m one-time gain relating to updates to contractual arrangements for Beyfortus) The Core Tax rate is expected to be between 18-22% The Company is unable to provide guidance on a Reported basis because it cannot reliably forecast material elements of the Reported results, including any fair value adjustments arising on acquisition-related liabilities, intangible asset impairment charges and legal settlement provisions. Please refer to the cautionary statements section regarding forward-looking statements at the end of this announcement. Currency impact If foreign exchange rates for February 2024 to December 2024 were to remain at the average rates seen in January 2024, it is anticipated that both FY 2024 Total Revenue and Core EPS would incur a low single-digit adverse impact versus the performance at CER. The Company's foreign exchange rate sensitivity analysis is provided in Table 19. Investor Day AstraZeneca will host an Investor Day on 21 May 2024. For more information, see . Table 1: Key elements of Total Revenue performance in Q4 2023 % Change Revenue type $m Actual % CER % Product Sales 11,323 5 5 * Excluding COVID-19 medicines, Q4 2023 Product Sales increased by 14% Alliance Revenue 424 69 67 * $281m for Enhertu (Q4 2022: $188m) * $80m for Tezspire (Q4 2022: $37m) * $41m for Beyfortus (Q4 2022: $nil) Collaboration Revenue 277 75 74 * $245m Lynparza regulatory milestone (Q4 2022: $105m) * $27m Beyfortus sales milestone (Q4 2022: $nil) Total Revenue 12,024 7 8 * Excluding COVID-19 medicines, Q4 2023 Total Revenue increased by 16% Therapy areas $m Actual % CER % Oncology 4,989 23 24 * Strong performance across all key medicines and regions CVRM 2,702 18 18 * Farxiga up 36% (35% at CER), Lokelma up 38%, roxadustat up 27%, Brilinta declined 5% (4% at CER) R&I 1,675 13 13 * Fasenra up 10% (9% CER), Breztri up 72%. Saphnelo and Tezspire also continue to grow rapidly, partially offset by a 16% decline in Symbicort following entry of a generic competitor in the US in the third quarter V&I 413 (64 ) (66 ) * $6m revenue from COVID-19 mAbs and ‑$17m for Vaxzevria, both resulting from historic contracts (Q4 2022: $734m and $95m respectively) * Beyfortus $122m, including $41m of Alliance Revenue for AstraZeneca's share of gross profits outside US, $27m of Collaboration Revenue for a sales milestone and $54m of Product Sales from product supplied to Sanofi Rare Disease 1,971 9 9 * Ultomiris up 39% (38% at CER), partially offset by decline in Soliris of 15% (13% at CER) * Strensiq up 12% (13% at CER) and Koselugo up 46% (48% at CER) reflecting strong patient demand Other Medicines 274 (33 ) (32 ) * Nexium generic competition in Japan Total Revenue 12,024 7 8 Regions inc. COVID-19 $m Actual % CER % US 5,101 7 6 Emerging Markets 2,783 2 8 - China 1,382 16 16 - Ex-China Emerging Markets 1,401 (9 ) 2 Europe 2,880 25 17 Established RoW 1,259 (9 ) (6 ) Total Revenue inc. COVID-19 12,024 7 8 * Growth rates impacted by lower sales of COVID-19 medicines (see table below) Regions ex. COVID-19 $m Actual % CER % US 5,101 12 12 Emerging Markets 2,791 15 22 - China 1,382 16 16 - Ex-China Emerging Markets 1,409 14 27 Europe 2,884 33 25 Established RoW 1,259 4 8 Total Revenue ex. COVID-19 12,036 16 16 Table 2: Key elements of financial performance in Q4 2023 Metric Reported Reported change Core Core change Comments6 Total Revenue $12,024m 7% Actual 8% CER $12,024m 7% Actual 8% CER * Excluding COVID-19 medicines, Q4 2023 Total Revenue increased by 16% * See Table 1 and the Total Revenue section of this document for further details Product Sales Gross Margin 80% +6pp Actual +6pp CER 80% +3pp Actual +2pp CER + In the prior year period, gross margins were reduced due to inventory write-downs and manufacturing contract terminations for Evusheld * Variations in Product Sales Gross Margin can be expected between periods due to product seasonality, foreign exchange fluctuations and other effects R&D expense $3,073m 17% Actual 15% CER $2,914m 15% Actual 14% CER + Increased investment in the pipeline * Core R&D-to-Total Revenue ratio of 24% (Q4 2022: 23%) + Quarterly phasing impact SG&A expense $5,371m 16% Actual 16% CER $4,034m 13% Actual 12% CER + Market development for recent launches and pre-launch activities * Core SG&A-to-Total Revenue ratio of 34% (Q4 2022: 32%) + Quarterly phasing impact Other operating income and expense7 $107m -43% Actual -42% CER $107m -17% Actual -15% CER ‒ Discontinuation of brazikumab development Operating Margin 10% +1pp Actual +1pp CER 23% Stable * See Product Sales Gross Margin, expenses and Other operating income and expense commentary above Net finance expense $337m 7% Actual 3% CER $259m 5% Actual 1% CER + Higher rates on floating debt and bond issuances + Increased Interest expense on income tax balances ‒ Higher interest received on cash and short-term investments Tax rate -7% +9pp Actual +13pp CER 10% Stable ‒ Intragroup purchase of intellectual property + Reviews by tax authorities, administrative appeals and changes to certain deferred tax balances * Variations in the tax rate can be expected between periods EPS $0.62 7% Actual 5% CER $1.45 5% Actual 7% CER * Further details of differences between Reported and Core are shown in Table 14 Table 3: Pipeline highlights since prior results announcement Event Medicine Indication / Trial Event Regulatory approvals and other regulatory actions Truqap HR-positive HER2-negative advanced breast cancer with biomarker alterations (CAPItello-291) Regulatory approval (US) Imfinzi Biliary tract cancer (TOPAZ-1) Regulatory approval (CN) Wainua ATTRv-PN (NEURO-TTRansform) Regulatory approval (US) Beyfortus RSV (MELODY-MEDLEY) Regulatory approval (CN) Voydeya PNH with EVH (ALPHA) Regulatory approval (JP) Regulatory submissions or acceptances* Lynparza gBRCA breast cancer (adjuvant) (OlympiA) Regulatory submission (CN) Lynparza + Imfinzi Endometrial cancer (1st-line) (DUO-E) Regulatory submission (US, EU, JP) Enhertu HER2-expressing tumours (DESTINY-PanTumor02, DESTINY-Lung01, DESTINY-CRC02) Regulatory submission (US), Priority Review (US) Enhertu HER2+/HER2-low gastric (1st-line) (DESTINY-Gastric01) Regulatory submission (CN) Imfinzi + Imjudo NSCLC (neoadjuvant) (AEGEAN) Regulatory submission (EU) Wainua ATTRv-PN (NEURO-TTRansform) Regulatory submission (EU) Fasenra EGPA (MANDARA) Regulatory submission (US, EU, JP) Ultomiris NMOSD (CHAMPION-NMOSD) Regulatory submission (US) Ultomiris gMG Regulatory submission (CN) Major Phase III data readouts and other developments Imfinzi NSCLC (unresectable, Stg. III) (PACIFIC-2) Primary endpoint not met acoramidis 8 ATTR-CM Primary endpoint met *US, EU and China regulatory submission denotes filing acceptance Upcoming pipeline catalysts For a table of anticipated timings of key trial readouts, please refer to page 3 of the Clinical Trials Appendix, available on . Table 4: Phase III trials started since 1 January 2023 Medicine Trial name Indication datopotamab deruxtecan AVANZAR NSCLC (1st-line) TROPION-Lung07 Non-squamous NSCLC (1st-line) TROPION-Breast04 Neoadjuvant/adjuvant triple-negative or HR-low/HER2-negative breast cancer TROPION-Breast05 PD-L1-positive locally recurrent inoperable or metastatic TNBC camizestrant CAMBRIA-1 HR-positive/HER2-negative adjuvant breast cancer CAMBRIA-2 HR-positive/HER2-negative adjuvant breast cancer Truqap CAPItello-292 HR-positive/HER2-negative advanced breast cancer volrustomig eVOLVE-Cervical High-risk locally advanced cervical cancer eVOLVE-Lung02 mNSCLC (1st-line) with PD-L1 <50% eVOLVE-Meso Unresectable malignant pleural mesothelioma (1st-line) eVOLVE-HNSCC Unresected, locally advanced HNSCC rilvegostomig ARTEMIDE-Biliary01 BTC with curative intent saruparib EvoPAR-PR01 HRRm and Non-HRRm mCSPC zibo/dapa ZENITH High Proteinuria CKD with high proteinuria Saphnelo DAISY Systemic sclerosis baxdrostat BaxHTN Uncontrolled, including treatment-resistant, hypertension Tezspire CROSSING Eosinophilic oesophagitis Breztri LITHOS Mild to moderate asthma ATHLOS COPD pMDI portfolio HFO1234ze + Breztri COPD HFO1234ze Mucociliary clearance in healthy volunteers HFO1234ze Asthma tozorakimab MIRANDA COPD ipavibart (AZD3152) SUPERNOVA COVID-19 prophylaxis Ultomiris ARTEMIS Cardiac surgery-associated acute kidney injury ALXN2220 DepleTTR-CM Transthyretin amyloid cardiomyopathy efzimfotase alfa (ALXN1850) HICKORY Hypophosphatasia Corporate and business development In November 2023, AstraZeneca launched Evinova, with an ambition to become a leading provider of digital health solutions to better meet the needs of healthcare professionals, regulators and patients. Evinova will prioritise bringing to market established and scaled digital technology solutions already being used globally by AstraZeneca to optimise clinical trial design and delivery. Globally-leading clinical research organisations Parexel and Fortrea have entered into agreements to offer Evinova digital health solutions to their wide customer base. In December 2023, AstraZeneca entered into a definitive agreement to acquire Icosavax, Inc (Icosavax). The acquisition strengthens AstraZeneca's late-stage pipeline with Icosavax's lead investigational vaccine candidate, IVX-A12, a potential first-in-class, Phase III-ready, combination VLP vaccine that targets both RSV and hMPV. RSV and hMPV are both leading causes of severe respiratory infection and hospitalisation in adults 60 years of age and older and those with chronic conditions such as cardiovascular, renal and respiratory disease. Subject to the satisfaction of the conditions in the merger agreement, the acquisition is expected to close in the first quarter of 2024. In December 2023, AstraZeneca entered into a definitive agreement to acquire Gracell Biotechnologies Inc. (Gracell), a global clinical-stage biopharmaceutical company developing innovative cell therapies for the treatment of cancer and autoimmune diseases. The proposed acquisition will enrich AstraZeneca's growing pipeline of cell therapies with GC012F, a novel, clinical-stage FasTCAR-enabled BCMA and CD19 dual-targeting CAR-T therapy, a potential new treatment for multiple myeloma, as well as other haematologic malignancies and autoimmune diseases including systemic lupus erythematosus. The transaction is expected to close in the first quarter of 2024, subject to customary closing conditions, including regulatory clearances, and Gracell shareholder approval. In February 2024, AstraZeneca announced that it is investing $300 million in a state-of-the-art facility in Rockville, Maryland to establish life-saving cell therapy platforms for critical cancer trials and future commercial supply. To align with clinical trial timelines, the site will initially focus on pivotal clinical trial manufacturing of CAR-T cell therapies to meet current clinical supply demand. More than 150 new highly skilled jobs will be created to initially focus on manufacturing T-cell therapies to enable clinical trials to be conducted around the world. Over time, the site may expand its focus to support other therapy areas. Sustainability highlights Through the Sustainable Markets Initiative Health Systems Task Force, AstraZeneca announced an industry-first renewable power agreement in China together with four global healthcare leaders and renewable energy company Envision Energy, resulting in potential annual emissions savings of approximately 120,000 tonnes, the equivalent of taking 25,000 cars off the road. See the Sustainability section in this document for further details. Conference call A conference call and webcast for investors and analysts will begin today, 8 February 2024, at 11:45 UK time. Details can be accessed via astrazeneca.com. Reporting calendar The Company intends to publish its Q1 2024 results on 25 April 2024. To read AstraZeneca's Full Year and Q4 2023 Financial Results press release in full, click here. ______________________________ 1 Constant exchange rates. The differences between Actual Change and CER Change are due to foreign exchange movements between periods in 2023 vs. 2022. CER financial measures are not accounted for according to generally accepted accounting principles (GAAP) because they remove the effects of currency movements from Reported results. 2 Effective 1 January 2023, the Group has updated the presentation of Total Revenue. For further details of the presentation of Alliance Revenue and Collaboration Revenue, see the Basis of preparation and accounting policies section of the Notes to the Condensed consolidated financial statements section. 3 Core financial measures are adjusted to exclude certain items. The differences between Reported and Core measures are primarily due to costs relating to the acquisition of Alexion, amortisation of intangibles, impairments, legal settlements and restructuring charges. A full reconciliation between Reported EPS and Core EPS is provided in Table 13 and Table 14 in the Financial performance section of this document. 4 The COVID-19 medicines are Vaxzevria, Evusheld, and sipavibart (AZD3152) – the COVID-19 antibody currently in development. 5 The calculation of Reported and Core Product Sales Gross Margin (formerly termed as Gross Margin) excludes the impact of Alliance Revenue and Collaboration Revenue. 6 In Table 2, the plus and minus symbols denote the directional impact of the item being discussed, e.g. a ‘+’ symbol next to an R&D expense comment indicates that the item increased the R&D expense relative to the prior year. 7 Income from disposals of assets and businesses, where the Group does not retain a significant ongoing economic interest, continue to be recorded in Other operating income and expense in the Company’s financial statements. 8 Partnered with BridgeBio Pharma Inc (BridgeBio) – AstraZeneca has rights to commercialise acamoridis in Japan View source version on businesswire.com: Contacts US Media Inquiries Brendan McEvoy, +1 302 885 2677 US Media Mailbox: usmediateam@astrazeneca.com Source: AstraZeneca View this news release online at:

Drug ApprovalVaccineAcquisitionPhase 3Immunotherapy

24 Oct 2023

·www.biopharmadive.com

An Orbimed-backed biotech launches with $85M and plans for a new kind of DNA medicine

When developing new medicines, drugmakers typically try to make treatments that are more effective, durable or safer than whats already available.If theyre lucky, they can hit on something that meets at least one of those goals. Rampart Bioscience, a new biotechnology company eyeing a way to make better DNA-based medicines, is striving to hit all three.Headquartered in La Jolla, California, Rampart emerged from stealth Tuesday with $85 million in new funding to develop its lead program for a rare inherited condition known as hypophosphatasia.The company is led by Louis Breton and Jeffrey Bartlett, a pair of biotech veterans who last oversaw Calimmune, a cell and gene therapy developer that worked to create new treatments for HIV and other diseases. Calimmune was picked up by CSL Behring in 2017 through a $91 million deal.Their latest endeavor was born after a phone call with David Bonita, a partner with the venture capital fund OrbiMed.OrbiMed previously funded another company developing a treatment for infants whose bones and teeth did not mineralize properly, which would later become Alexion Pharmaceuticals enzyme replacement therapy Strensiq. But the drug is used for severe forms of hypophosphatasia, leaving patients with more moderate symptoms without any options approved by the Food and Drug Administration. Breton and Bartlett wondered: Could they do better?Rampart, which takes its name from a word meaning to fortify, hopes to create a treatment that could be more long-lasting and effective for those patients. The severe form of hypophosphatasia affects an estimated 1 in 100,000 babies, but milder cases likely occur more frequently and later in life.Especially for those who have diseases where it impacts their quality of life, helping them fortify their own bodies ... is a great step, Breton said.Genetic medicines have, especially in the last decade, proven they can dramatically benefit patients with certain inherited conditions. Often, though, their effectiveness has been hampered by limitations of delivery. Rampart believes its approach can address both delivery and the issue of re-dosability, which may be necessary as hypophosphatasia progresses, according to the company.There are many groups that have been working for specific rare diseases on genetic therapies that potentially would be a one-and-done. But in the way of looking at what would be optimal for patients, this provides more flexibility for doctors, Breton said. It's not just the availability of options for patients; it provides much more specificity to their symptoms and some of the aspects of their own disease progression.Rampart is also developing an unspecified number of other programs.Since its inception in 2019, the company has raised $125 million in private financing, including a $40 million seed round from OrbiMed. Joining OrbiMed in the Series A round were investors RA Capital Management and HealthCap.We are very much a product company,“ Bartlett said. But Rampart's near-term milestones also include continuing to develop the platform and collect the kind of data we've been fortunate in getting. '

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R&D Status

Approved

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Indication	Country/Location	Organization	Date
Hypophosphatasia, Infantile	US	Alexion Pharmaceuticals, Inc.	23 Oct 2015
Hypophosphatasia	JP	Alexion Pharmaceuticals, Inc.	03 Jul 2015

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypophosphatasia, Childhood	Phase 2	US	Alexion Pharmaceuticals, Inc.	06 Jun 2016
Hypophosphatasia, Childhood	Phase 2	DE	Alexion Pharmaceuticals, Inc.	06 Jun 2016
Pyropoikilocytosis, Hereditary	Phase 2	US	Alexion Pharmaceuticals, Inc.	01 Sep 2008
Pyropoikilocytosis, Hereditary	Phase 2	CA	Alexion Pharmaceuticals, Inc.	01 Sep 2008
Pyropoikilocytosis, Hereditary	Phase 2	AE	Alexion Pharmaceuticals, Inc.	01 Sep 2008
Pyropoikilocytosis, Hereditary	Phase 2	GB	Alexion Pharmaceuticals, Inc.	01 Sep 2008

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02306720 (EUPAS13514, Pubmed)	Not Applicable	Hypophosphatasia, Adult serum alkaline phosphatase (ALP) activity \| ALPL variant(s)	190	Asfotase alfa	ebsoutvpnq(hgqnihnubi) = upgbsubajn nowwaafnui (lygvtmsosr )	Positive	08 Mar 2024
ESPE2023	Not Applicable	Hypophosphatasia alkaline phosphatase (ALP) \| PEA \| B6 vitamin	-	Asfotase alfa	mkhdqzylzq(dwlytfphte) = ixsbusvllx xforxrwwir (ejlwklsiqb ) View more	-	21 Sep 2023
NCT01176266 (Pubmed \| J Clin Endocrinol Metab) Manual	Phase 2	Hypophosphatasia	69	Asfotase Alfa	fhpnyfynea(tmqijcpibz) = wfctdqeyll cnadgnpnap (tcbyiwooks ) View more	Positive	01 Jul 2019
NCT01205152 \| EUCTR2009-009369-32-GB (Pubmed) Manual	Phase 2	Hypophosphatasia	11	Asfotase alfa	vkirynghlf(piicbvpoqq) = zgjxrewntw mslixqkebs (cibnykuadd ) View more	Positive	01 Feb 2019
ESPE2018	Not Applicable	Hypophosphatasia ALPL	-	Asfotase Alfa	svkimtejtu(zicgdwfcay) = The patient needed a wheelchair even for in-home movement, suffered from continuous skeletal pain, had undetectable ALP serum levels and extremely high plasma PLP (997 mcg/l) csgejvsphj (idvannvtbw )	-	27 Sep 2018
NCT02797821 (CTgov)	Phase 2	Hypophosphatasia, Childhood	27	Asfotase alfa (Asfotase Alfa 0.5 mg/kg Dose)	swhdbedrbv(xwfgapclnh) = rmservzazl muczpnoyxn (twwrfwgrff, imkqrzqrwx - bokbjrpbem) View more	-	10 Jul 2018
NCT02797821 (CTgov)	Phase 2	Hypophosphatasia, Childhood	27	Asfotase alfa (Asfotase Alfa 2.0 mg/kg Dose)	swhdbedrbv(xwfgapclnh) = mmmmkzkjqv muczpnoyxn (twwrfwgrff, hbowtzcxtn - mvyfveymoi) View more	-	10 Jul 2018
NCT01176266 (ENB-010-10, CTgov)	Phase 2/3	Hypophosphatasia	69	asfotase alfa	skftkihidl(auzwgaqiuw) = zrqpphhsnz puxijoajfx (geyibwuaos, esvkogztqv - kzizdnddms) View more	-	26 Feb 2018
NCT01205152 (CTgov)	Phase 2	Hypophosphatasia	10	asfotase alfa	xxbraknuwp(jdqiewmzzc) = ynybkpjbiu dpjjcqghmd (htfynfjtmp, yxhzaoxtcr - uibetnemhs) View more	-	17 Nov 2017
NCT01163149 (CTgov)	Phase 2	Hypophosphatasia	19	asfotase alfa	aiscrkyqun(wlplijqhex) = ypoufsnava rtcpykredt (enxkhmibzw, lxiosruwsc - dqdemxxjgb) View more	-	18 Sep 2017
NCT01203826 (CTgov)	Phase 2	Hypophosphatasia	12	Asfotase Alfa (Asfotase Alfa Combined)	bnehuzicgc(xrmammzxci) = ynncsswyer qsxspgafre (rwgryuqyly, asdnaxgaob - mdwpallqle)	-	26 Jul 2017
NCT01203826 (CTgov)	Phase 2	Hypophosphatasia	12	Asfotase Alfa (2 mg/kg Asfotase Alfa)	riyqngxfxc(bovdmgodpy) = nabqncbljb pyqkpvkqee (cypckyqpbw, asnfhixudz - oxjxfuadnt) View more	-	26 Jul 2017

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