CAMBRIDGE, Mass. ? October 27, 2020??Olipudase alfa, an?investigational?recombinant human acid sphingomyelinase, demonstrated significant improvement in lung function and spleen volume in patients with acid sphingomyelinase deficiency (ASMD).?Results from?two separate clinical trials of adult and pediatric patients?were?presented at the American Society of Human Genetics (ASHG) 2020 Virtual Meeting this week and?will form the basis of global regulatory submissions expected to begin in the second half of 2021.

Historically referred to as Niemann-Pick Disease (NPD) type A and type B, ASMD is a rare, lysosomal storage disease that results from a deficient activity of the enzyme acid sphingomyelinase (ASM), which is found in special compartments within cells called lysosomes and is required to breakdown lipids called sphingomyelin. If ASM is absent or not functioning as it should, sphingomyelin cannot be metabolized properly and accumulates within cells, eventually causing cell death and the malfunction of major organ systems. The deficiency of the lysosomal enzyme ASM is due to disease-causing variants in the sphingomyelin phosphodiesterase 1 gene (SMPD1). The overall global estimated incidence of ASMD is 0.4-0.6 in 100,000 births.^i,ii

?ASMD is a progressive and potentially life-threatening genetic disease with no approved treatment options,??said Melissa Wasserstein, MD, Chief, Division of Pediatric Genetic Medicine, Children's Hospital at Montefiore; Professor of Pediatrics and Genetics, Albert Einstein College of Medicine.??Results from both the adult and pediatric clinical trials with olipudase alfa clearly demonstrate the potential of this investigational therapy to impact visceral manifestations of ASMD and have a meaningful impact on the lives of those impacted by this devastating disease.?

Data in Adult Patients with ASMD (ASCEND)

The Phase 2/3 trial randomized 36 adult patients with ASMD type B to receive either placebo or olipudase alfa up to 3 mg/kg administered via intravenous infusion every two weeks for 52 weeksiii?to evaluate treatment impact on pulmonary function and spleen and liver volume.?An open-label, single-arm extension of this study is ongoing to evaluate the long-term efficacy and safety of olipudase alfa.

Lung function at 52 weeks:

• Olipudase alfa significantly improved lung function by 22% from baseline compared to 3% for patients receiving placebo (p=0.0004), as measured by?percent predicted diffusing capacity of carbon monoxide (DL_CO).

Spleen volume and Splenomegaly Related Score (SRS)?at 52 weeks:

• Olipudase alfa significantly reduced spleen volume by 39.5% compared with a 0.5% increase in the placebo arm (p<0.0001), as assessed by percent change from baseline in multiples of normal (MN) of spleen volume.
• For the US, this was combined with the SRS, a patient-reported outcome (PRO) measurement that evaluated patient symptoms associated with an enlarged spleen. There was no meaningful difference between the treatment and placebo arms (8.0 point decrease for olipudase alfa vs. 9.3 point reduction for placebo; p=0.70); therefore this combination endpoint was not met for the US.
• Our analysis of the SRS data did not find a correlation with spleen volume at baseline, nor was the change in SRS correlated with the change in spleen volume at week 52.

Liver volume and platelet count at 52 weeks (pre-specified secondary endpoints):

• Olipudase alfa reduced liver volume by 31.7%,?compared with a 1.4% decrease in the placebo arm, as measured by percent change from baseline in?MN?of liver volume.
• Mean platelet counts improved by 16.8% in olipudase alfa versus 2.5% in placebo-treated patients.

Overall safety and tolerability profile at 52 weeks:

• All patients in the placebo and olipudase alfa arms experienced at least one adverse event (AE). The number of events was lower in the olipudase alfa arm (242 events) compared with the placebo arm (267 events).
• Severe AEs were less frequent in the olipudase alfa arm (3 events) compared with the placebo arm (13 events).
• There were five serious AEs in the olipudase alfa arm and 11 in the placebo arm, none of which were treatment related. There were no adverse events that led to treatment discontinuation or study withdrawal.
• Infusion associated reactions were mild to moderate, with 44% of?olipudase alfa patients and 33% of placebo patients experiencing infusion-related reactions.
• The most common AEs in the trial were headache, nasopharyngitis, upper respiratory tract infection, cough, and arthralgia (as defined by percentages of events = 2% and number of olipudase alfa treated patients = 2).
• Treatment-induced anti-drug antibodies occurred in 22% of olipudase alfa patients.

?These are powerful data evidenced by statistically significant improvement in lung function and spleen ?volume and clinically meaningful reduction in liver volume,??said Karin Knobe, Head of Development of Rare Diseases and Rare Blood Disorders at Sanofi. ?The totality of the study data shows olipudase alfa has the potential to provide meaningful improvements to adults who have lived with a debilitating rare disease for decades.?

Data in Pediatric Patients with ASMD (ASCEND-Peds)

This single arm, open label Phase 2 trial of 20 pediatric patients?(birth to <18 years) with ASMD ?without acute or rapidly progressive neurological abnormalities?evaluated the safety and tolerability of olipudase alfa up to 3 mg/kg administered intravenously every two weeks for 64 weeks.iv?All 20 patients completed the study and continue in an extension trial.

Safety data at 64 weeks:

• All patients?treated with olipudase alfa in the trial experienced?treatment-emergent AEs that were mostly mild or moderate.
• Eleven patients had infusion-associated reactions. The most frequent were: urticaria (4 patients), pyrexia (7 patients) and vomiting (6 patients).
• Five treatment-related serious adverse events were observed in three patients: two cases of transient, asymptomatic alanine aminotransferase (ALT) increase in one patient, one case each of urticaria and rash in one patient, and one anaphylactic reaction in one patient.
• No patients had to permanently discontinue treatment due to an adverse event.
• The most common AEs? were pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache, upper respiratory tract infection, contusion, abdominal pain, nasal congestion, rash, urticaria, scratch, and epistaxis (as defined by percentages of events =2% and number of olipudase alfa-treated patients =2).

Also presented were 52-week exploratory efficacy results, defined as secondary objectives in the trial, measuring lung function, spleen and liver volume, and patient growth. These results showed improvement in these clinically relevant disease endpoints.

• Percent predicted?DL_CO?increased by a mean of?33%?(32.9%?+?29.1%)?in nine patients who were able to perform the test at baseline (children over the age of five were assessed if they were able to perform the test).
• Spleen volume decreased by 49% (49.2%?+?9.7%) and liver volume by 41% (40.6%?+?9.4%),?as assessed by mean MN.
• Fifteen patients (78.9%) improved in the Height Z-score category, and four (21.1%) patients remained in the same category.
• Platelet count increased 34% (34.0%?+36.42%).

About ASMD

ASMD represents a spectrum of disease caused by the same enzymatic deficiency, with two types that may represent opposite ends of a continuum, sometimes referred to as ASMD type A and ASMD type B. ASMD type A is a rapidly progressive neurological form of the disease resulting in death in early childhood due to CNS complications. ASMD type B, is a serious and potentially life-threatening disease that predominantly, but not only, impacts the lungs, liver, spleen and heart. ASMD type A/B represents an intermediate form that includes varying degrees of neurologic involvement. Patients with ASMD type A/B or ASMD type B were studied in the ASCEND trial program. Another type of NPD is NPD type C, which is unrelated to ASMD.

About olipudase alfa

Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM, allowing for the breakdown of sphingomyelin. Olipudase alfa is currently being investigated to treat non-CNS manifestations of ASMD. Olipudase alfa has not been studied in ASMD type A patients.

Olipudase alfa?is currently under clinical investigation and its safety and efficacy have not been evaluated by any regulatory authority worldwide.

The FDA has granted Breakthrough Therapy designation to olipudase alfa. This designation is intended to expedite the development and review of drugs intended to treat serious or life-threatening diseases and conditions. The criteria for granting Breakthrough Therapy designation include preliminary clinical evidence indicating that the molecule may demonstrate substantial improvement on a clinically significant endpoint over available therapies.

The EMA has awarded PRIority MEdicines, also known as PRIME, designation to olipudase alfa. This designation is designed to aid and expedite the regulatory process for investigational medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.

Olipudase alfa was awarded the SAKIGAKE designation in Japan. SAKIGAKE is intended to promote research and development in Japan for innovative new medical products that satisfy certain criteria, such as the severity of the intended indication.