A Single-arm, Open-label, Phase 4 Study to Evaluate the Safety and Efficacy of Avalglucosidase Alfa in Chinese Participants With Infantile-onset Pompe Disease (IOPD)

This is a single group, 52-week treatment, Phase 4, open-label, single-arm study to assess the safety and efficacy of avalglucosidase alfa IV infusion in male and female Chinese participants with IOPD who are treatment-naïve or were previously treated with ERT.
Study details include:
* The study duration: total study duration is approximately 64 weeks.
* Screening period of up to 8 weeks
* Treatment period of 52 weeks
* Follow-up period of 4 weeks.
* The number of visits will be 30, including 29 site visits and 1 phone call follow-up visit.

Start Date27 Mar 2025

Sponsor / Collaborator

Genzyme Corp.

NCT06121011 / RecruitingNot Applicable

A Global Prospective Observational Registry of Patients With Pompe Disease

This is a global, multicenter, prospective, observational registry of patients with Pompe disease, including those with late-onset pompe disease (LOPD) and infantile-onset pompe disease (IOPD). Both untreated patients and those being treated with an approved therapy for Pompe disease are eligible to participate.
The objectives of the registry are:
* To evaluate the long-term safety of Pompe disease treatments through collection of data that describe the frequency of adverse events (AEs)/serious adverse events (SAEs) occurring in Pompe disease patients
* To evaluate the long-term real-world effectiveness of Pompe disease treatments
* To evaluate the long-term real-world impact of Pompe disease treatments on quality of life (QOL) and patient-reported outcomes (PROs)
* To describe the natural history of untreated Pompe disease

Start Date16 Feb 2024

Sponsor / Collaborator

Amicus Therapeutics, Inc.

NCT05734521 / RecruitingNot Applicable

A Descriptive Safety Study Based on Data Collected From Women and Their Offspring Exposed to Nexviazyme/Nexviadyme (Avalglucosidase Alfa-ngpt/Avalglucosidase Alfa) During Pregnancy and/or Lactation in the Postmarketing Setting

This is a worldwide, descriptive safety study collecting data on women and their offspring exposed to avalglucosidase alfa during pregnancy and/or lactation, to assess the risks of avalglucsodiase alfa on pregnancy and maternal complications and adverse effects in the developing fetus, neonate, and infant.
* Outcomes in exposed infants, including growth and development, will be assessed through at least the first year of life.
* Data will be collected for approximately 10 years.

Start Date26 Oct 2022

Sponsor / Collaborator

Sanofi

100 Clinical Results associated with Avalglucosidase alfa

100 Translational Medicine associated with Avalglucosidase alfa

100 Patents (Medical) associated with Avalglucosidase alfa

Literatures (Medical) associated with Avalglucosidase alfa

01 Dec 2024·Molecular Genetics and Metabolism Reports

Optimizing clinical outcomes: The journey of twins with CRIM-negative infantile-onset Pompe disease on high-dose enzyme replacement therapy and immunomodulation

Article

Author: Fares, Angie H. ; Sharon, Cassie ; Koch, Rebecca L. ; Kishnani, Priya S. ; Fares, Angie H ; Case, Laura E ; Kishnani, Priya S ; Lisi, Matthew T. ; Klinepeter, Amy ; Lisi, Matthew T ; Kirby, Amelia ; Desai, Ankit K ; Koch, Rebecca L ; Case, Laura E. ; Desai, Ankit K.

Infantile-onset Pompe disease (IOPD) is caused by a deficiency in the enzyme acid alpha-glucosidase (GAA). It is characterized by severe and progressive hypertrophic cardiomyopathy and muscle weakness with death in the first 2 years of life if left untreated. Enzyme replacement therapy (ERT) with alglucosidase-alfa is lifesaving, but its effectiveness is influenced by the patient's cross-reactive immunologic material (CRIM) status, dose of ERT, and the development of high antibody titers, which can reduce the therapy's efficacy. The inability of CRIM-negative IOPD patients to produce native GAA exposes them to a high risk of development of anti-rhGAA IgG antibody titers, leading to treatment failure. We present the case of CRIM-negative dizygotic twins treated with high-dose alglucosidase-alfa (40 mg/kg/week), initiated at 28 days (Twin A) and 44 days (Twin B). Both twins received immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG to mitigate antibody response. Initial evaluations revealed elevated left ventricular mass index (LVMI) and elevated biomarkers (urine glucose tetrasaccharide (Glc₄), creatine kinase (CK), and aspartate aminotransferase (AST)) in both twins. Following treatment, cardiac function and biomarkers normalized within several months, with a slight delay in Twin B compared to Twin A, likely attributed to the later initiation of ERT. Both twins safely tolerated ITI, achieving immune tolerance with low antibody titers. At 28 months, the twins transitioned to avalglucosidase-alfa (40 mg/kg every other week (EOW)), which was well tolerated without an increase in antibody titers. At 39 months, both twins exhibited normal cardiac function, LVMI, and biomarkers. Motor skills continued to improve, though some kinematic concerns persisted. These cases underscore the importance of early, high-dose ERT combined with ITI in managing CRIM-negative IOPD. While transitioning to avalglucosidase-alfa at 40 mg/kg/EOW was beneficial and well-tolerated in our patients, further studies are needed to confirm its long-term efficacy compared to the high-dose weekly 40 mg/kg alglucosidase-alfa.

01 Nov 2024·Molecular Genetics and Metabolism

Pompe disease: Unmet needs and emerging therapies

Review

Author: George, Kelly A ; Berger, Kenneth I ; Anding, Allyson L ; George, Kelly A. ; Zhang, Tracy Y. ; Tomassy, Giulio S ; Sardi, S. Pablo ; Berger, Kenneth I. ; Sardi, S Pablo ; Zhang, Tracy Y ; van der Flier, Arjan ; Anding, Allyson L. ; Tomassy, Giulio S.

Pompe disease is a debilitating and life-threatening disease caused by aberrant accumulation of glycogen resulting from reduced acid alpha-glucosidase activity. The first treatment for Pompe disease, the enzyme replacement therapy, Myozyme® (recombinant human acid alpha-glucosidase, alglucosidase alfa), is a lifesaving treatment for the most severe form of the disease and provided clinically meaningful benefits to patients with milder phenotypes. Nonetheless, many patients display suboptimal responses or clinical decline following years of alglucosidase alfa treatment. The approval of avalglucosidase alfa (Nexviazyme®) and cipaglucosidase alfa (Pombiliti®) with miglustat (Opfolda®) represents a new generation of enzyme replacement therapies seeking to further improve patient outcomes beyond alglucosidase alfa. However, the emergence of a complicated new phenotype with central nervous system involvement following long-term treatment, coupled with known and anticipated unmet needs of patients receiving enzyme replacement therapy, has prompted development of innovative new treatments. This review provides an overview of the challenges of existing treatments and a summary of emerging therapies currently in preclinical or clinical development for Pompe disease and related lysosomal storage disorders. Key treatments include tissue-targeted enzyme replacement therapy, which seeks to enhance enzyme concentration in target tissues such as the central nervous system; substrate reduction therapy, which reduces intracellular glycogen concentrations via novel mechanisms; and gene therapy, which may restore endogenous production of deficient acid alpha-glucosidase. Each of these proposed treatments shows promise as a future therapeutic option to improve quality of life in Pompe disease by more efficiently treating the underlying cause of disease progression: glycogen accumulation.

01 Nov 2024·Brain and Development

Long-term observation of patients with advanced late-onset Pompe disease undergoing enzyme replacement therapy: A 15-year observation in a single center

Article

Author: Unuma, Atsushi ; Katsuta, Wakana ; Takizawa, Hotake ; Takahashi, Yuji ; Sato, Noriko ; Miyagi, Kenji ; Hara, Takatoshi ; Mori-Yoshimura, Madoka ; Yorimoto, Keisuke ; Oya, Yasushi

BACKGROUNDThere have been few descriptions in the literature on long-term enzyme replacement therapy (ERT) in patients with advanced late-onset Pompe disease (LOPD).OBJECTIVESThis study aimed to assess the efficacy and limitations of ERT in advanced LOPD patients.METHODSWe retrospectively reviewed the clinical courses of patients with advanced LOPD (two juvenile-onset and five adult-onset patients) who were treated with recombinant human alglucosidase alfa to examine improvements achieved with and limitations of ERT until their death or when switching to avalglucosidase alfa occurred.RESULTSAll patients were non-ambulant and ventilator dependent. The duration of follow-up ranged from 3.7 to 15.0 years (median 9.0 years). All patients reported improvements in their lives during the first two or three years of ERT. Vital capacity was clearly improved in patients with relatively spared respiratory function, although it deteriorated after respiratory complications such as pneumothorax. Pinch and grip power tended to be preserved during the treatment period. Muscle CT revealed progression of atrophy and fatty replacement predominantly in the proximal limb muscles without improvement after ERT. Four patients died due to aspergillosis, respiratory failure, ileus, and sudden death of unknown cause.CONCLUSIONSOur findings demonstrate that patients undergoing ERT show certain improvements, even in the advanced stage of Pompe disease. Respiratory complications are lethal even during ERT, and early diagnosis and induction of therapy are critical. Muscle wasting progressed more severely in the proximal limbs, even after ERT.

News (Medical) associated with Avalglucosidase alfa

28 Oct 2024

·www.echemi.com

Merck's RSV Antibody Faces Major Challenges vs. Sanofi's Beyfortus Exhibiting 83% Efficacy in Reducing Hospitalization

While Merck & Co. 's infant respiratory syncytial virus (RSV) antibody clesrovimab is nearing approval, sanofi also won approval last year for its RSV prevention drug beyforts in partnership with astrazeneca. This news undoubtedly brings new hope to the global healthcare industry, especially in the field of RSV vaccines. "We would very much welcome having more participants on board because it increases the scale of the competition," Thomas Triomphe, Sanofi's executive vice president for vaccines, said of the upcoming RSV competition during an analyst call on Friday. He stressed that more players mean more innovation and better healthcare solutions, which is good for the industry as a whole and for patients. Triomphe noted that Merck still has more data on clesrovimab after announcing phase 2b/3 clinical results last week. In the meantime, Sanofi remains "very confident" in the Beyfortus numbers it has released so far, he said. He mentioned that the protection data provided by Beyfortus in six months is very encouraging, as the effect has not diminished. "After six months, we were still seeing 83 percent hospitalization efficacy," he said, adding that he believed "the duration of protection from Beyfortus was significantly more favorable compared to clesrovimab." This data suggests that Beyfortus has a significant advantage in preventing RSV infection. In Merck's infant RSV study, clesrovimab successfully reduced RSV-related hospitalizations and RSV-related lower respiratory tract infection hospitalizations by 84 percent and 91 percent, respectively, over five months compared to placebo. This result is impressive and shows the great potential of clesrovimab in preventing RSV infection. At the trial's primary endpoint, clesrovimab reduced the incidence of RSV-related medical lower respiratory tract infections by 60 percent compared to placebo. This data provides further evidence of the effectiveness of clesrovimab in preventing RSV infection. Sanofi Chief Financial Officer franois-xavier Roger noted in a conference call on Friday that the inherent uncertainty of cross-trial comparisons suggested that existing Beyfortus data showed a reduction of about 75 percent in the incidence of lower respiratory tract infections with clesrovimab compared to 60 percent with Clesrovimab. This data further reinforces Beyfortus' advantage in preventing RSV infection. And, whether or not Merck brings clesrovimab into the 2025-2026 RSV season as planned, "2025 will be a year of growth for Beyfortus," the CFO stressed. He is confident that Beyfortus' sales will grow significantly as it gradually gains market share. Since it was approved last July, Beyfortus has gradually built up its sales profile. In the third quarter of 2024, sales of this preventive antibody reached 645 million euros ($699), an increase of 382% compared to the same period in 2023. Overall, sales of the drug have reached 845 million euros since the beginning of the year, which is close to the best-selling threshold. Sanofi said at the time that Beyfortus quickly fell into a supply crunch shortly after going public last year due to "higher than expected demand." To counter this, Sanofi and its partner Astrazeneca have moved quickly to ensure there is no repeat of the supply crunch in 2024. Recently they added a new filling line and shipped antibody doses ahead of the 2024 RSV season. "There are 20 markets and we don't see any capacity constraints," Triumph said on Sanofi's conference call. "We will increase supply next year and the year after to make sure there are no supply constraints." This initiative demonstrates Sanofi's confidence in the future of Beyfortus and its commitment to meeting the needs of the global market. The comments by Sanofi executives came as the French pharmaceutical company reported a 15.7 per cent rise in third-quarter sales. This growth was mainly driven by the excellent performance of its immunology product Dupixent, which brought in sales of nearly 3.5 billion euros (about $3.8 billion), an increase of about 24 percent over the third quarter of 2023. Sanofi confirmed DuPont's full-year sales target of about 13 billion euros. Elsewhere, newly launched drugs rose 67.1 percent to 727 million euros ($787), led by hemophilia drug Altuviiio, Pompeii disease treatment Nexviazyme and Rezurock for graft-versus-host disease. The strong performance of these new drugs further strengthens Sanofi's position in the field of innovative medicines. Meanwhile, Sanofi's consumer health division, Opella, saw revenue rise 7.9 percent. This growth shows that Sanofi is also making significant progress in consumer health. Earlier this week, Sanofi confirmed it had entered exclusive talks with U.S. private equity firm Clayton, Dubilier & Rice to sell a controlling 50 percent stake in its consumer healthcare business, which is valued at around 16 billion euros. This move will further strengthen Sanofi's financial strength and provide additional financial support for its future expansion.

Drug ApprovalClinical ResultVaccine

12 Sep 2024

·endpts.com

FDA revisits new structure for drug review documents, aiming to better explain its decisions

Back in 2019, as part of a program focused on improving documentation and communications for drug approvals, the FDA made a change to how it explains its decisions. At the time, academics and industry criticized the shift because it could potentially reduce the quantity and quality of the documents the agency was releasing about its drug reviews. “We are writing to express our concern with FDA’s proposal to replace individual original reviews with a new integrated review. There is a scientific publishing norm that authorship should be voluntary, and by institutionalizing group authorship, all authors of integrated reviews may not have a chance to voluntarily approve of the text in a document that bears their name,” Fiona Godlee, former editor-in-chief of the BMJ , and Clare Stone, former editor-in-chief of PLOS Medicine , wrote to the FDA in 2019. On Thursday, the FDA sought additional comment on the integrated reviews documentation, which has already been implemented for new molecular entities, original biologic applications, and select efficacy supplements, and is coming soon for other products. The agency is again seeking responses to questions like: “Comparing the integrated review to previous review documentation, is there any information you are having difficulty locating?” The agency acknowledged that the new system is an abbreviated version of what it did before. “This new integrated review document replaces the previous documentation, which included a separate review document authored by each discipline. It also replaces the multidisciplinary review (i.e., Unireview) in which each discipline provided a separate review section but within a single review document,” the FDA explained . But the regulator believes the new format will still provide “sufficient detail” concerning efficacy and its assessment of risk and risk management “as well as a clearer description of FDA’s analysis of the scientific issues raised by the application and the scientific reasoning supporting the benefit-risk determination.” By implementing the new streamlined structure for its documents, the FDA said the internal process is more coordinated, and it’s easier to reach a more diverse audience, including the public, drug sponsors, researchers and others seeking to understand the basis for FDA’s decisions. The FDA released three examples of what the new format looks like, including three integrated review documents for Sanofi’s Nexviazyme , GSK’s Rukobia and Madrigal’s Rezdiffra .

Accelerated Approval

25 Jul 2024

·www.fiercepharma.com

With capacity upgrades ready to roll, Sanofi stands firm on blockbuster sales goal for RSV drug in 2024

Beyfortus, which was approved last summer, delivered 547 million euros for all of 2023. Sanofi expects the drug to become a blockbuster in 2024. While manufacturing and supply hitches have troubled the rollout of Sanofi’s key respiratory syncytial virus (RSV) drug, the near-term expected approval of a pair of new filling lines is giving the French pharma assurance that its AstraZeneca-partnered antibody Beyfortus can breach the billion-dollar threshold before the year is out. “We’re confident that Beyfortus will be a blockbuster in 2024,” Thomas Triomphe, Sanofi’s executive vice president of vaccines, said on a call with analysts Thursday. With the first Beyfortus shipment in the Northern Hemisphere expected to occur in the third quarter, Sanofi figures the last three months of the year will represent the antibody’s biggest sales season, the company’s chief financial officer, François Roger, added on the call. That fourth-quarter sales boost is likely to come courtesy of both the seasonality of RSV and the expected approval of two new filling lines in September, Roger explained. Beyfortus, which was approved last summer, delivered 547 million euros for all of 2023. Despite the antibody’s popularity out of the gate, the immunization quickly ran up against supply constraints, with the Centers for Disease Control and Prevention in October urging doctors to prioritize 100-mg doses for infants at the highest risk of RSV disease. At the time, Sanofi said it was working with AstraZeneca to “accelerate additional supply” and explore “a number of actions” to beef up the partners’ manufacturing network. Now, Sanofi is “exactly on track” with its plan to activate more filling capacity around September, Triomphe said Thursday. “We believe that there’s reason to be confident about the accelerated approval process of those lines and the fact that we’ll be able to move forward with this update for the 2024 RSV season,” he said. The executives’ comments came as Sanofi reported a roughly 10% overall sales increase to 10.75 billion euros (about $11.6 billion) in the second quarter. Much of that growth was driven by immunology superstar Dupixent, which set a new quarterly record by growing sales 29% to 3.3 billion euros ($3.6 billion) over the second three months of the year. All told, Sanofi continues to expect its immunology stalwart to generate roughly 13 billion euros in 2024, according to an earnings release. Elsewhere, Sanofi's new pharma launches grew a whopping 80.4%, bringing home total sales of 689 million euros ($746.9 million). That group includes Altuviiio in hemophilia A, Nexviazyme in Pompe disease, Rezurock in graft-versus-host disease and Sarclisa in multiple myeloma. Meanwhile, Sanofi’s vaccines sales dipped 4.8%, though revenues were overall stable once the effects of 2023’s COVID-19 sales were removed from the equation, CEO Paul Hudson said on the company’s call. Thanks to its strong performance so far in 2024, Sanofi is upgrading its earnings per share (EPS) guidance, which it now expects to be stable at constant currencies. The company previously expected EPS to decrease by a low single-digit percentage.

Drug ApprovalVaccine

100 Deals associated with Avalglucosidase alfa

External Link

KEGG	Wiki	ATC	Drug Bank
D11744	Avalglucosidase alfa	A16AB07	DB16099

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Glycogen Storage Disease Type II	US	Genzyme Corp.	06 Aug 2021

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Glycogen Storage Disease Type II	Phase 3	RU	Genzyme Corp.	02 Nov 2016
Glycogen Storage Disease Type II	Phase 3	CH	Genzyme Corp.	02 Nov 2016
Glycogen Storage Disease Type II	Phase 3	MX	Genzyme Corp.	02 Nov 2016
Glycogen Storage Disease Type II	Phase 3	TR	Genzyme Corp.	02 Nov 2016
Glycogen Storage Disease Type II	Phase 3	BR	Genzyme Corp.	02 Nov 2016
Glycogen Storage Disease Type II	Phase 3	AR	Genzyme Corp.	02 Nov 2016

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01898364, NCT02032524 (NEO1/NEO-EXT Studies, AAN2024)	Not Applicable	Glycogen Storage Disease Type II	24	Avalglucosidase Alfa 5 mg/kg/every other week	wlkbfydjzx(fdfpkxxxcd) = rzfjuxmrsw tklqujzkqk (peaaxfafyt, 26.0) View more	Positive	09 Apr 2024
				Avalglucosidase Alfa 10 mg/kg/every other week	wlkbfydjzx(fdfpkxxxcd) = jrwkmezyft tklqujzkqk (peaaxfafyt, 19.3) View more
NCT02032524 (NEO1 and NEO-EXT \| NEO-EXT, CTgov)	Phase 2	Glycogen Storage Disease Type II	19	Avalglucosidase Alfa (Group 1: Avalglucosidase Alfa 5 mg/kg)	atavfwgkuj(svbqmhmqib) = ekivutxyup gclojvcmko (rdudarxsck, iggqzdcrot - rqymioqygt) View more	-	01 Mar 2024
				Avalglucosidase Alfa (Group 1: Avalglucosidase Alfa 10 mg/kg)	atavfwgkuj(svbqmhmqib) = vbacyqfesc gclojvcmko (rdudarxsck, gkzaiksidi - irrknfoach) View more
NCT02782741 (COMET, pubmed) Manual	Phase 3	Glycogen Storage Disease Type II First line	100	Avalglucosidase alfa	(tlljtxakav) = upyejlteyz ipneagrtyc (yiiyzbphbd, 1.05) View more	Positive	10 Apr 2023
				Alglucosidase alfa (switched to avalglucosidase alfa after 49 weeks)	(tlljtxakav) = ozfjczalkp ipneagrtyc (yiiyzbphbd, 1.12) View more
NCT02782741 (COMET, MDA2023) Manual	Phase 3	Glycogen Storage Disease Type II	100	Avalglucosidase alfa 20 mg/kg (AVAL-arm)	vzjygofzyt(tfqdmcakxy) = reqjiwmxuy nqqvnptwzg (nwilmywvnq, 9.60) View more	Positive	19 Mar 2023
				Alglucosidase alfa 20 mg/kg (Switch-arm)	vzjygofzyt(tfqdmcakxy) = njxolwrkpr nqqvnptwzg (nwilmywvnq, 10.42) View more
NCT02782741 (COMET, EAN)	Phase 3	Glycogen Storage Disease Type II	-	Avalglucosidase alfa	(hfxfzrxfaj) = vvzpmktjsx ajeuzuzopp (ymkrselosl, 9.93)	Positive	18 Jun 2021
				Alglucosidase alfa	(hfxfzrxfaj) = prcjxuumiy ajeuzuzopp (ymkrselosl, 10.40)
NCT02782741 (COMET, CTgov)	Phase 3	Glycogen Storage Disease Type II	101	PAP+Avalglucosidase Alfa (PAP: Avalglucosidase Alfa)	zeodfvoqjm(gskwfkvoog) = eufnipaafq dssaydysjw (xkibuvjgcj, excuzvrasz - nbajdakxkh) View more	-	08 Apr 2021
				PAP+Alglucosidase Alfa (PAP: Alglucosidase Alfa)	zeodfvoqjm(gskwfkvoog) = ojcgbnoymx dssaydysjw (xkibuvjgcj, dyzuiqpbsd - knjtrkvmdv) View more
NCT01898364 (Pubmed) Manual	Phase 1	Glycogen Storage Disease Type II	24	avalglucosidase alfa (Naïve patients)	(oasmjusfwk) = no deaths/life-threatening serious adverse events (SAEs). ojvjxxnmra (lcomrjivwj ) View more	Positive	01 Mar 2019
				Alglucosidase Alfa (Switch patients)
NCT01898364 (I4.011, AAN2016)	Phase 1	Glycogen Storage Disease Type II	24	NeoGAA 5mg/kg	rlksaxpnen(fvepoqdqaa) = minimal changes vitmyortrk (mqswnnkzsa ) View more	-	05 Apr 2016
				NeoGAA 10mg/kg
NCT01898364 (S38.006, AAN2016)	Phase 1	Glycogen Storage Disease Type II	24	NeoGAA 5mg/kg	khupwczyvb(mevugypgsr) = showed minimal changes across groups and all dose levels fiwbbixifa (myctbebuow ) View more	Positive	05 Apr 2016
				NeoGAA 10mg/kg

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