Roche Showcases Robust Neuroscience Pipeline with New Clinical Data at AAN 2019

From May 4 to 10, at the 71st Annual Meeting of the American Academy of Neurology (AAN) held in Philadelphia, Pennsylvania, the Roche Group prominently released the latest research data on multiple drugs targeting neurological disorders, including spinal muscular atrophy (SMA), neuromyelitis optica spectrum disorder (NMOSD), Huntington’s disease (HD), Alzheimer’s disease (AD), multiple sclerosis (MS), and Duchenne muscular dystrophy (DMD). This comprehensive presentation highlighted Roche’s robust product pipeline in neuroscience and its sustained commitment to research and development in this field.

Dr. Sandra Horning, Chief Medical Officer and Head of Global Product Development at Roche, stated, “There is an urgent need for treatments for neurological disorders such as SMA, HD, and NMOSD, meaning that every R&D effort represents a significant step forward. We remain committed to investing in research and collaborations, with the aim of developing new therapeutic options for these conditions that severely impair quality of life. We are pleased to contribute to a better understanding of these diseases and clinical progress at this year’s AAN Annual Meeting, thereby helping patients and families affected by these debilitating conditions.”

Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) is a severe, progressive neuromuscular genetic disorder. Patients with SMA experience significant decline or loss of motor function, including the ability to walk, eat, or breathe, and face an increased risk of mortality [1]. It is one of the most common rare diseases and the leading genetic cause of infant mortality, with an incidence of 1 in 11,000 live births [2]. Risdiplam is an investigational oral survival motor neuron 2 (SMN2) splicing modifier for the treatment of SMA, designed to increase and maintain SMN protein levels in the central nervous system (CNS) and throughout the body [3].

Latest data from two pivotal studies of risdiplam, FIREFISH and SUNFISH, were disclosed at the AAN. Results from Part 1 (dose-finding) of the FIREFISH study showed that among infants with Type 1 spinal muscular atrophy (SMA) treated with the selected dose of risdiplam for more than 12 months, 41.2% were able to sit independently without support for at least 5 seconds (as assessed by the Gross Motor subscale of the Bayley Scales of Infant and Toddler Development, Third Edition). According to the Hammersmith Infant Neurological Examination Module 2 (HINE-2), 64.7% of infants were able to sit (with or without support), and 52.9% achieved vertical head control. Ultimately, one infant (5.9%) achieved the milestone of standing (bearing weight with support) at the 12-month time point [4]. Event-free survival was maintained in 88.2% of infants [5]. The other pivotal study, SUNFISH, enrolled a broad population of patients with Type 2 and Type 3 SMA, aged 2–25 years, including those unable to sit independently and those with severe scoliosis. Latest data indicated that risdiplam treatment was safe in Part 1 (dose-finding) of the SUNFISH study [6]. Furthermore, previous data showed that motor function (as measured by the MFM32 scale) improved by at least 3 points from baseline in 71% of patients aged 2–11 years and 42% of patients aged 12–25 years (referring to all patients who completed assessments during visits up to Month 12) [6]. Currently, Roche has multiple clinical trials of risdiplam ongoing or planned, covering SMA patients from presymptomatic neonates to those up to 60 years of age, and also including previously treated patients.

Neuromyelitis Optica Spectrum Disorders (NMOSD)

NMOSD is a rare, lifelong, disabling autoimmune disease of the central nervous system that damages the optic nerves and spinal cord, leading to blindness, muscle weakness, and paralysis [7, 8]. Currently, there are no approved treatments for NMOSD.

Satralizumab is a humanized IgG2 neutralizing monoclonal antibody targeting the human interleukin-6 (IL-6) receptor, representing a novel mechanism of action [9], which can selectively inhibit the inflammatory effects of IL-6. IL-6 is a protein produced by immune cells in the body and plays a key role in inflammation in patients with neuromyelitis optica spectrum disorder (NMOSD), potentially triggering unpredictable severe relapses [10].

Roche presented data from the pivotal Phase III SakuraSky study (combination therapy) and SAkuraStar study (monotherapy) of satralizumab at the AAN. Data from the SakuraSky study demonstrated that satralizumab, when added to baseline therapy (immunosuppressants and/or corticosteroids), reduced the risk of relapse by 62% compared with placebo plus baseline therapy in patients with neuromyelitis optica spectrum disorder (NMOSD), including both aquaporin-4 immunoglobulin G (AQP4-IgG)–positive and –negative patients. Subgroup analysis showed that satralizumab plus baseline therapy (immunosuppressants and/or corticosteroids) reduced the risk of relapse by 79% compared with placebo in AQP4-IgG–seropositive patients. The SAkuraStar study compared satralizumab monotherapy with placebo and met its primary endpoint; the data will be disclosed at subsequent scientific meetings.

Based on the positive data from these two pivotal studies, satralizumab, either in combination or as monotherapy, effectively treats a broad population of patients with neuromyelitis optica spectrum disorder (NMOSD), including adolescents aged 12 years and older.

Huntington's Disease (HD)

Huntington’s disease (HD) is a devastating, rare hereditary neurodegenerative disorder that causes neuronal death in the brain, severely impairing patients’ daily functioning, including motor and cognitive abilities. There is an urgent unmet need for novel therapies for HD. Although existing medications can alleviate multiple HD-related symptoms, no current drug can modify the disease course or provide a cure.

RG6042 (previously known as Ionis HTT-Rx) is an antisense oligonucleotide (ASO) that effectively reduces mutant huntingtin protein (HTT), the specific toxic protein that is the root cause of Huntington’s disease (HD). RG6042 is the first drug in this therapeutic class to enter pivotal studies and has been designated as an orphan drug for the treatment of HD patients by both the U.S. FDA and the European EMA, holding promise to become the first disease-modifying therapy in this disease area.

During the AAN conference, Roche reported data from pharmacokinetic/pharmacodynamic (PK/PD) modeling studies supporting dose selection for RG6042, including 9-month preliminary data from an extension study of the ongoing Phase I/IIa RG6042 trial. Based on these findings, Roche amended the study protocol in March this year to evaluate the potential benefits of RG6042 administered every 2 months or every 4 months compared with placebo. Data from the initial Phase I/IIa trial of RG6042 were published in the May issue of The New England Journal of Medicine. Additionally, Roche presented the following HD-related reports at the conference: 1. Feasibility of using a smartphone app to collect novel digital biomarkers for assessing patients’ cognitive and motor symptom levels; 2. Correlation between clinically meaningful changes in the composite Unified Huntington’s Disease Rating Scale (cUHDRS) scores and patients’ functional status.

Alzheimer's Disease (AD)

Roche is committed to continuously improving the diagnosis and treatment of Alzheimer’s disease (AD) and striving to transform the lives of patients suffering from the disease, as well as their families and caregivers. Roche is currently continuing its Phase III GRADUATE trials of gantenerumab, along with the DIAN-TU study focusing on familial AD. Meanwhile, two Phase II studies of investigational anti-tau molecules have been initiated, including the Phase II TAURIEL trial targeting patients with AD (from prodromal to mild stages).

According to the data and safety results from the open-label extension studies of gantenerumab (SCarletRoAD and Marguerite RoAD) presented by Roche at the AAN, patients with Alzheimer’s disease (AD), with or without ARIA-E, showed sustained and substantial reduction in brain amyloid.

In March this year, Roche announced the termination of two pivotal Phase III studies of another investigational Alzheimer’s disease (AD) drug, crenezumab. At the conference, Roche stated that it would continue to study crenezumab within the Alzheimer’s Prevention Initiative (API), which enrolls individuals carrying autosomal dominant mutations and thus at risk for familial AD (fAD). Meanwhile, Roche is also continuing to explore new diagnostic approaches for AD (such as cerebrospinal fluid-based tests and plasma-based tests) and disease monitoring strategies.

In addition, Roche also shared data on several other drugs in the neurology field at AAN. New analysis results from Ocrevus® (ocrelizumab) for the treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) indicate that higher doses of Ocrevus^®Exposure levels and lower B-cell counts are critical for controlling disability progression; early treatment with Ocrevus® can reduce the risk of permanent disability progression. Meanwhile, results from the Phase Ib/II study of RG6206, an investigational anti-myostatin adnectin for Duchenne Muscular Dystrophy (DMD), confirmed its safety profile, with no drug-related safety issues leading to study withdrawal observed during the 72-week treatment period.

References:

1. Spinal Muscular Atrophy UK. What is spinal muscular atrophy?Available from: http://www.smasupportuk.org.uk/what-is-spinal-muscular-atrophy.Accessed March 2019.

2. Cure SMA. About SMA. 2018. Available from: http://www.curesma.org/sma/about-sma/.Accessed March 2019.

3. Ratni H et al. Discovery of risdiplam, a selective survivalmotor neuron-2 (SMN2) gene splicing modifier for the treatment of spinalmuscular atrophy (SMA). J Med Chem. 2018;61:6501-17.

4. Baranello G et al.FIREFISH Part 1: 1-Year Results on MotorFunction in Babies with Type 1 SMA. S25.003. Presented at 71st American Academyof Neurology Annual Meeting, Philadelphia, Pennsylvania, 4-10 May 2019.

5. Servais L et al. FIREFISH Part 1: Survival, Ventilation andSwallowing Ability in Babies with Type 1 SMA Receiving Risdiplam (RG7916).S25.008. Presented at 71st American Academy of Neurology Annual Meeting,Philadelphia, Pennsylvania, 4-10 May 2019.

6. Mercuri E. Update from SUNFISH Part 1: Safety, Tolerability andPK/PD from the Dose-Finding Study, Including Exploratory Efficacy Data inPatients with Type 2 or 3 Spinal Muscular Atrophy (SMA) Treated with Risdiplam(RG7916). S25.007. Presented at 71st American Academy of Neurology AnnualMeeting, Philadelphia, Pennsylvania, 4-10 May 2019.

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8. Papadopoulos MC, Bennett JL, Verkman AS. Nat Rev Neurol2014;10:493-506.

9. Reichert JM. MAbs 2017;9:167-81.

10.Garbers C, Heink S, Korn T, Rose-JohnS. Nat Rev Drug Discov 2018;17:395-412.

(The original text has been abridged)