PARIS, Jan. 30, 2020 /PRNewswire/ — Olipudase alfa, an investigational recombinant human acid sphingomyelinase, demonstrated constructive ends in two separate medical trials evaluating olipudase alfa for the remedy of acid sphingomyelinase deficiency (ASMD) in grownup and pediatric sufferers. Olipudase alfa is the primary and solely investigational enzyme substitute remedy in late-stage growth for the remedy of ASMD. No remedies are at present authorised for ASMD.
“These vital outcomes for olipudase alfa mark a serious scientific development for ASMD and an essential step towards offering a possible remedy for grownup and pediatric sufferers who at present don’t have any authorised remedy choices for this devastating illness,” mentioned John Reed, M.D., Ph.D., World Head of Analysis and Improvement at Sanofi. “We look ahead to participating with regulatory authorities to convey this potential new remedy to sufferers.”
Trial in Grownup Sufferers with ASMD (ASCEND)
The randomized Part 2/Three trial enrolled 36 grownup sufferers with ASMD throughout 24 facilities in 16 nations. Sufferers obtained both placebo or olipudase alfa intravenous infusion each two weeks at a dose of as much as 3mg/kg administered each two weeks over 52 weeks.i
The trial contained two impartial major efficacy endpoints to deal with separate vital manifestations of ASMD, progressive lung illness and enlarged spleen, that are outstanding medical options in sufferers with ASMD. The examine protocol defines the trial consequence as constructive if one of many impartial major endpoints was met.
The primary impartial major endpoint measuring enchancment in lung perform, utilizing the % predicted diffusing capability of carbon monoxide (DLco), was met; due to this fact, ASCEND is said constructive. The relative enchancment from baseline to week 52 was 22% for the olipudase alfa arm in contrast with 3% for the placebo arm. The distinction between the 2 remedy arms (19%) was statistically vital (p=0.0004).
The opposite impartial major endpoint measuring the impact of olipudase alfa on spleen measurement, assessed as % change from baseline in multiples of regular (MN) of spleen quantity, was met per the examine protocol. Within the olipudase alfa arm, spleen quantity was decreased by 39.5%, in contrast with a 0.5% enhance within the placebo arm. The distinction between the 2 remedy arms (40%) was statistically vital (p<0.0001).
For the U.S., the spleen quantity endpoint was additional mixed with a patient-reported consequence (PRO) measurement of signs related to enlarged spleen referred to as Splenomegaly Associated Rating (SRS). In comparison with baseline, the SRS was decreased by 8.Zero factors within the olipudase alfa arm and 9.Three factors within the placebo arm (p=0.70); due to this fact, this mixture endpoint was not met.
“These are essential information in a illness with no authorised remedies accessible at present,” mentioned Melissa Wasserstein, MD, Chief, Division of Pediatric Genetic Drugs, Youngsters’s Hospital at Montefiore; Professor of Pediatrics and Genetics, Albert Einstein School of Drugs; and an investigator within the ASCEND trial. “Therapy with olipudase alfa confirmed clinically significant enchancment in pulmonary perform and discount in spleen measurement, vital manifestations of this progressive illness. Each of those findings are constant throughout the medical research with olipudase alfa. The absence of an impact on SRS on this trial requires exploration, in mild of the numerous discount in spleen measurement.”
Over the 52-week interval, all sufferers in each the placebo and olipudase alfa arms skilled no less than one hostile occasion. The variety of occasions was decrease within the olipudase alfa arm (242 occasions) in contrast with the placebo arm (267 occasions). Extreme hostile occasions had been much less frequent within the olipudase alfa arm (Three occasions) in contrast with the placebo arm (13 occasions). There have been 5 severe hostile occasions within the olipudase alfa arm and 11 within the placebo arm, none of which had been remedy associated. There have been no hostile occasions that led to remedy discontinuation or examine withdrawal. The most typical hostile occasions (as outlined by percentages of occasions better than or equal to 2% and variety of sufferers better than or equal to 2 in all olipudase alfa handled sufferers; occurring with increased percentages in olipudase alfa sufferers in comparison with placebo sufferers) seen on this trial had been headache, nasopharyngitis, higher respiratory tract an infection, cough, and arthralgia.
Trial in Pediatric Sufferers with ASMD (ASCEND-Peds)
The only arm, open label Part 2 trial enrolled 20 pediatric sufferers (start to <18 years) with ASMD in six nations. Youngsters with quickly progressive neurological illness had been excluded. The first goal of the trial was to judge the security and tolerability of olipudase alfa at a dose of as much as 3mg/kg administered intravenously each two weeks for 64
Over the 64-week remedy interval, all sufferers skilled no less than one hostile occasion. These occasions had been largely delicate and reasonable, with one affected person experiencing a extreme and severe (see beneath) anaphylactic response that was thought-about associated to olipudase alfa. 5 treatment-related severe hostile occasions had been noticed in three sufferers: two instances of transient, asymptomatic alanine aminotransferase (ALT) enhance in a single affected person, one case every of urticaria and rash in a single affected person, and one anaphylactic response in a single affected person. No sufferers needed to completely discontinue remedy attributable to an hostile occasion. The most typical hostile occasions (as outlined by percentages of occasions better than or equal to 2% and variety of sufferers better than or equal to 2 in all olipudase alfa handled sufferers) seen on this trial had been pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache, higher respiratory tract an infection, contusion, belly ache, nasal congestion, rash, urticaria, scratch, and epistaxis.
The examine additionally explored secondary endpoints of progressive lung illness and enlarged spleen. After one yr of remedy (52 weeks), the % predicted DLco elevated by a imply of 33% in 9 sufferers who had been capable of carry out the check at baseline (kids over the age of 5 had been assessed in the event that they had been capable of carry out the check). Moreover, at 52 weeks, the spleen volumes decreased by 49% as assessed by imply MN (particular person affected person decreases ranged from 23% to 61%).
Outcomes from these trials will likely be submitted to future medical conferences and can type the premise of worldwide regulatory submissions anticipated to start the second half of 2021.
Historically known as Niemann-Decide Illness (NPD) Sort A and Sort B, ASMD is a uncommon, progressive and probably life-threatening lysosomal storage dysfunction that outcomes from a poor exercise of the enzyme acid sphingomyelinase (ASM), which is present in particular compartments inside cells referred to as lysosomes and is required to breakdown lipids referred to as sphingomyelin. If ASM is absent or not functioning because it ought to, sphingomyelin can’t be metabolized correctly and accumulates inside cells, finally inflicting cell demise and the malfunction of main organ programs. The deficiency of the lysosomal enzyme ASM is because of mutations within the sphingomyelin phosphodiesterase 1 gene (SMPD1). The estimated prevalence of ASMD is roughly 2,000 sufferers within the U.S., Europe and Japan.
ASMD represents a spectrum of illness brought on by the identical enzymatic deficiency, with two varieties that will characterize reverse ends of a continuum generally known as NPD Sort A and Sort B. NPD Sort A is a quickly progressive neurological type of the illness leading to demise in early childhood attributable to central nervous system issues. NPD Sort B is a severe and probably life-threatening illness that predominantly, however not solely, impacts the lungs, liver, spleen and coronary heart. NPD Sort A/B represents an intermediate type that features various levels of neurologic involvement. One other sort of NPD is NPD Sort C, which is unrelated to ASMD.
About Olipudase alfa
Olipudase alfa is an investigational enzyme substitute remedy designed to exchange poor or faulty ASM, permitting for the breakdown of sphingomyelin. Olipudase alfa is at present being investigated to deal with ASMD Sort A/B and B. Olipudase alfa has not been studied in NPD Sort A sufferers. Olipudase alfa is an investigational agent and the security and efficacy haven’t been evaluated by the U.S. Meals and Drug Administration (FDA), the European Medicines Company (EMA), or some other regulatory authority.
The FDA has granted Breakthrough Remedy designation to olipudase alfa. This designation is meant to expedite the event and evaluation of medicine supposed to deal with severe or life-threatening illnesses and situations. The factors for granting Breakthrough Remedy designation embody preliminary medical proof indicating that the molecule might display substantial enchancment over accessible therapies on a clinically vital endpoint.
The EMA has awarded PRIority MEdicines, also called PRIME, designation to olipudase alfa. This designation is designed to help and expedite the regulatory course of for investigational medicines that will supply a serious therapeutic benefit over present remedies, or profit sufferers with out remedy choices.
Olipudase alfa was awarded the SAKIGAKE designation in Japan. SAKIGAKE is meant to advertise analysis and growth in Japan for revolutionary new medical merchandise that fulfill sure standards, such because the severity of the supposed indication.
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i ; Identifier: NCT02004691
ii ; Identifier: NCT02292654
Posted: January 2020