Marco Meglio

Interim analysis from an open-label extension of patients with relapsing forms of multiple sclerosis (RMS) enrolled in the DAYBREAK study (NCT02576717) showed an association between ozanimod (Zeposia; Bristol Myers Squibb) and low annualized relapse rate (ARR) and low counts of new or enlarging T2 and gadolinium-enhancing (GdE) lesions over time.

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, senior author Bruce Cree, clinical research director, UCSF Multiple Sclerosis Center, and professor of clinical neurology, USCF Weill Institute for Neurosciences, and colleagues aimed to characterize the long-term safety and efficacy of ozanimod in patients with RMS in this ongoing open-label extension trial.

At Months 24 and 36, 79% and 75% of participants, respectively, were relapse free. A cohort of 2492 participants with a mean ozanimod exposure of 35.4 months (range, 0.03–50.2) revealed an adjusted ARR of 0.112 (95% CI, 0.093–0.135).

Participants within the trial were eligible if they had completed any phase 1, 2, or 3 trial of ozanimod previously. Investigators calculated number of new/enlarging T2 and GdE magnetic resonance imaging (MRI) brain lesions for the subset of patients who entered the open-label extension from an active-controlled phase 3 trial.

Regardless of parent-trial treatment group mean number of new/enlarging T2 lesions per scan at 24 hours was similar (range, 1.57–1.90), as well as the mean number of GdE lesions at month 24 (range, 0.2–0.4). Confirmed disability progression (CDP) was observed in 10.8% and 8.6% of participants at 3- and 6-months, respectively.

READ MORE: Disability, Economic Burden Greater in MS Patients With High Levels of Fatigue

Available data on safety measures from 2039 participants showed that 81.8% of the population had a treatment-emergent adverse event (TEAE). Additionally, 9.5% of patients had a serious TEAE (SAE) and 56 (2.2%) discontinued due to a TEAE. Researchers also noted that similar rates of TEAEs and SAEs occurred when assessed by the parent-trial treatment group.

Nasopharyngitis (17.9%), headache (14%), upper respiratory tract infection (9.9%), and lymphopenia (9.6%) were among the most common TEAEs observed within the extension period. There were no serious opportunistic infections and exposure-adjusted incidence rates of TEAEs and SAEs decreased over time.

Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator was 

 for the treatment of adults with RMS, including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS in March.

The approval of ozanimod was based off data from the phase 3 SUNBEAM (NCT02294058) and RADIANCE part B (NCT01628393) trials that included more than 2600 adults. The randomized, active-controlled studies compared ozanimod to interferon beta-1a (IFNß1a; Avonex) on the primary end point of ARR.

Bristol Myers Squibb announced the commercial launch and 

 in June, making it the first and only S1P on the market that required no first dose observation.

1. Selmaj K, Steinman L, Comi G, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1–3 trials. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0217.

2. U.S. Food and Drug Administration Approves Bristol Myers Squibb’s ZEPOSIA® (ozanimod), a New Oral Treatment for Relapsing Forms of Multiple Sclerosis [news release]. Briston Myers Squibb Company. March 26, 2020. finance.yahoo.com/news/u-food-drug-administration-approves-103000096.html

3. Bristol Myers Squibb Announces Commercial Launch and Availability of ZEPOSIA® (ozanimod), a New Oral Treatment for Relapsing Forms of Multiple Sclerosis [news release]. Princeton, NJ; Published June 1, 2020. Accessed June 8, 2020. news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-announces-commercial-launch-and-availabil

Articles

Along with being generally well tolerated, ozanimod was able to help most patients become relapse free without disability progression.

Ozanimod Shows Long-Term Safety, Efficacy in Open-Label Extension

Cassava Sciences announced that its lead drug candidate, sumifilam, significantly improved a panel of validated Alzheimer disease (AD) biomarkers in patients with a clinical diagnosis of AD in a phase 2b study, something that no drug has shown the ability to do to date.

Patients with AD administered sumifilam in the randomized, placebo-controlled, double-blind, multicenter clinical study (

showed improvements in tests of episodic and spatial working memory compared with patients on placebo. Additionally, improvements in cognition correlated most strongly with decreases in phosphorylated tau (P-tau181), of which an 8% to 11% reduction was recorded versus placebo.

“Filamin-binding molecules are new to Alzheimer research and may represent an important advance if these data can be replicated in larger studies,” Jeffrey Cummings, MD, ScD, founding director, Cleveland Clinic Lou Ruvo Center for Brain Health, and Chambers Professor of Brain Science, University of Nevada–Las Vegas, said in a statement.

 “I am pleased to see early evidence of disease-modifying effects in patients with this investigational drug. The data appear to represent a step forward toward urgently needed treatments for Alzheimer disease.”

The phase 2b study funded by the National Institutes of Health (NIH) included 64 patients with mild to moderate AD, age 50 to 85, who were randomized 1:1:1 to 50- or 100-mg oral sumifilam or matching placebo twice daily for 28 days.

Sumifilam is a small molecule drug that restores the normal shape and function of altered filamin A (FLNA), a scaffolding protein. Upon conclusion of the trial, both active treatment doses showed statistically significant (

 <.05) improvements in biomarkers of disease pathology, neurodegeneration, and neuroinflammation compared with placebo.

READ MORE: The Key Role of Biomarkers in Alzheimer Disease Research

Core markers of AD pathology including total-tau decreased by 15% and 18% for patients in the 50- and 100-mg groups, respectively (all 

 <.01). P-tau decreased by 8% for patients in the 50-mg group and 11% in the 100-mg group (all 

) increased by 17% and 14% in the 50- and 100-mg groups, respectively (all 

Elevated cerebrospinal fluid (CSF) levels of neurogranin (ng) and neurofilament light chain (NfL), which indicate neurodegeneration, decreased by 36% and 28% in the 50-mg group, respectively, and by 43% and 34% in patients in the 100-mg group, respectively.

Proinflammatory IL-6 (interleukin 6), produced in response to tissue stress and injury, decreased by 10% in the 50-mg group and 11% in the 100-mg group (all 

Investigators also noted that patients in the 50-mg group had decreased levels of YKL-40 by 10% (

 <.01). Those in the 100-mg group saw similar results, with decreases of 12% (

 <.01). sTREM2, a neuroinflammation biomarker, decreased by 43% and 46% in the 50- and 100-mg groups, respectively (all 

Cognition, which was assessed via the Cambridge Neuropsychological Test Automated Battery (CANTAB) at baseline and day 28, showed directional improvements on tests of episodic memory and spatial memory in patients treated with sumifilam compared with placebo, with an effect size of 46% to 17%.

Furthermore, episodic memory improved by –5.7 and –4.3 for patients with AD in the 50- and 100-mg groups, respectively, compared to –1.5 for patients in the placebo group. Spatial memory also improved by –1.6 for patients with AD in the 50-mg group and –3.3 for patients in the 100-mg group compared with –0.4 in the placebo group. 

The investigators noted that improvements in cognition correlated most strongly (statistical R2 = 0.5) with decreases in cerebrospinal fluid P-tau181, with decreases of 8% to 11% recorded in the treatment groups compared with placebo.

findings observed in this study are consistent with prior clinical and preclinical results (

he drug was deemed both safe and tolerable, with no treatment-related discontinuations recorded. 

There is currently an ongoing long-term, open-label study of sumifilam 100-mg twice-daily for 12 months. The study is currently at 50% enrollment, with a target enrollment of approximately 100 patients with mild to moderate AD.

"Other than a few drugs to help ease the decline, there’s really nothing out there to treat people with Alzheimer," Remi Barbier, chairman, president and chief executive officer, Cassava Sciences, said in a statement.

 "The improvement on multiple biomarkers in this clinical study is a first and offers hope that sumifilam has potential to become a transformative treatment for people with Alzheimer disease."

Notably, Cassava initially reported disappointing topline results from the phase 2b study in May of this year

 after an initial bioanalysis showed highly "anomalous data" that included major swings in levels of biomarkers observed in patients in the placebo group. Deemed invalid, a new bioanalysis of the full results was undertaken and is reported herein.

1. Cassava Sciences announces final results of a phase 2b clinical study of sumifilam in patients with Alzheimer disease. News release. Cassava Sciences. September 14, 2020. Accessed September 16, 2020. 

https://www.globenewswire.com/news-release/2020/09/14/2092861/0/en/Cassava-Sciences-Announces-Final-Results-of-a-Phase-2b-Clinical-Study-of-Sumifilam-in-Patients-with-Alzheimer-s-Disease.html

2. Top-line results from a phase 2b study of PTI-125 in Alzheimer’s disease does not meet primary endpoint. Cassava Sciences. May 15, 2020. Accessed September 16, 2020. 

https://www.cassavasciences.com/news-releases/news-release-details/top-line-results-phase-2b-study-pti-125-alzheimers-disease-does 

The results point to the potential for sumifilam to become a transformative treatment for patients with Alzheimer disease.

Sumifilam Improves Multiple Alzheimer Disease Biomarkers in Phase 2b Study

Data from the open-label extension and a substudy of the SAkuraSky (NCT02028884) and SAkuraStar (NCT02073279) trials revealed that patients with neuromyelitis optica spectrum disorder (NMOSD), whether they were treatment-naïve or not, had a reduced risk of relapse with treatment of satralizumab (Enspryng; Genentech).

, September 12–16, 2020, and assessed protocol-defined relapse (PDR) in patients with NMOSD who were assigned to satralizumab.

The first of the 2 presentations used data from both the SAkura studies and their open-label extension periods. Among a cohort of 179 patients, patients originally randomized to satralizumab (n = 105) showed a 51% lower risk of investigator-reported PDR compared to those originally randomized to placebo (n = 74; hazard risk [HR], 0.49; 95% CI, 0.31–0.79; 

Led by Benjamin Greenberg, MD, pediatric neurologist, University of Texas Southwestern Medical Center, the study also showed that the risk reduction was more pronounced in aquaporin-4-IgG seropositive (AQP4-IgG+) patients with NMOSD (66% risk reduction; HR, 0.34; 95% CI, 0.19–0.62; 

There were no patients in the satralizumab group that withdrew during the open-label extension due to a relapse compared to 4 patients who were originally randomized to placebo. Additionally, the safety findings noted in the open-label extension were consistent to those found in the double-blind period.

Satralizumab, a humanized, monoclonal recycling antibody that targets the interleukin-6 receptor, was also observed in a subgroup of 6 treatment-naïve, AQP4-IgG+ patients with NMOSD enrolled in SAkuraStar after their first attack. After their incident attack, treatment-naïve AQP4-IgG+ patients randomized to placebo (n = 2) experienced a relapse earlier than those randomized to satralizumab (n = 4). All patients fully recovered to pre-relapse Expanded Disability Status Scale (EDSS) score at the end of the trial period.

In total, 1 patient who received placebo experienced a PDR on study Day 21, and 2 of the 4 satralizumab patients experienced a relapse as well. The patient on placebo who experienced a PDR had a 1.5-point increase in EDSS score and was able to fully recover to pre-relapse EDSS score. As for the 2 on satralizumab, the first patient experienced a PDR on Day 214, with a 1-point increase in EDSS, and the second patient experienced a relapse (not meeting PDR criteria) on Day 458, with a 0.5-point increase in EDSS score. Both patients were able to fully recover to pre-relapse EDSS score. Investigators noted that interpretation of the study is limited due to the small sample size.

 for the treatment of adult patients with AQP4-IgG antibody positive NMOSD in August, becoming the third targeted treatment along with Alexion’s eculizumab (Soliris) and Viela Bio’s inebilizumab (Uplizna) for this population and the first eligible for at-home administration.

, which combined included more than 170 patients who were randomly assigned to received satralizumab 120 mg or placebo. In SAkuraSky, patients added treatment to baseline immunosuppressive therapy.

In SAkuraStar, 30% of patients treated with 

 experienced relapse compared with 50% of those who received placebo (HR 0.45; 95% CI, 0.23—0.89; 

 Among those who were AQP4-IgG antibody positive, a 74% reduction in relapse risk was observed. In the overall satralizumab-treated population, 76.1% and 72.1% were relapse-free at 48 and 96 weeks, respectively, compared with 61.9% and 51.2% with placebo. Data from the AQP4-IgG seropositive subgroup showed that 82.9% and 76.5% were relapse-free at 48 and 96 weeks compared with 55.4% and 41.1% with placebo, respectively.

In total, 92% (n = 58) of those in the satralizumab group experienced an adverse event compared with 75% (n = 24) of the placebo group. Serious AEs were similar between groups; only 1 event led to study drug discontinuation in the treatment group.

In SAkuraSky, the overall population saw a 62% reduction in the risk of relapse (HR 0.38, 95% CI, 0.16-0.88; 

 =.0184), while the group of AQP4-IgG seropositive patients experienced a 79% reduction in relapse risk (HR 0.21, 95% CI, 0.06-0.75; 

 Results showed 88.9% and 77.6% of patients in the total population were relapse-free at 48 and 96 weeks, respectively, compared with 66% and 58.7% of patients in the placebo group. Among AQP4-IgG seropositive patients, 91.5% treated with satralizumab were relapse-free at 48 and 96 weeks compared with 59.9% and 53.3% of patients in the placebo group. The most common AEs observed were upper respiratory tract infection, nasopharyngitis, and headache.

1. Greenberg B, Bennett J, De Seze J, et al. Efficacy of satralizumab in neuromyelitis optica spectrum disorder (NMOSD): results from open-label extension periods of SAkuraSky and SAkuraStar. Presented at MDS Virtual Congress; September 12–16, 2020. Abstract P0711

2. Palace J, Bennett J, Stokmaier D, Von Budingen H, Klingelschmitt G, Traboulsee A. Satralizumab in first incident treatment-naïve AQP4-IgG seropositive NMOSD patients enrolled to SAkuraStar: a case series. Presented at MDS Virtual Congress; September 12–16, 2020. Abstract P0754.

3. FDA approves Genentech’s Enspryng for neuromyelitis optica spectrum disorder. News release. Genentech. August 14, 2020. Accessed September 15, 2020. 

https://www.businesswire.com/news/home/20200814005501/en/ADDING-MULTIMEDIA%C2%A0FDA-Approves-Genentech%E2%80%99s-Enspryng-Neuromyelitis-Optica

4. Traboulsee A, Greenberg BM, Bennett JL, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomized, double-blind, multicentre, placebo-controlled phase 3 trial. 

. 2020;19(5):402&shy;-412. doi: 10.1016/S1474-4422(20)30078-8

5. Yamamura T, Kleiter I, Fujihara K, et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. 

 2019; 381:2114-2124. doi:10.1056/NEJMoa1901747

Two posters presented at MDS 2020 confirm satralizumab’s ability to reduce protocol-defined relapse including in patients with treatment-naïve NMOSD. 

Satralizumab Reduces Risk of Relapse, Including in Treatment-Naïve NMOSD

Results from a placebo-controlled, double-blind, randomized 3-way crossover study demonstrated that THN102 (Theranexus), a combination of modafinil and low-dose flecainide, was well tolerated and significant improved excessive daytime sleepiness (EDS) in patients with Parkinson disease (PD).

The study included 75 subjects (mean age, 63.5 years [±9.35]; male participants, n = 50; Epworth sleepiness scale [ESS] score, 16.2 [±2]) in the safety population and was presented at the 2020 

, September 12–16, 2020, by lead investigator Jean-Christophe Corvol, MD, PhD, Parkinson disease specialist, Pitié Salpêtrière Hospital and the Brain Institute, and colleagues.

Patients were treated with THN102 in 2 dosing groups: 200-mg modafinil/2-mg flecainide (THN102-200/2), and 200-mg modafinil/18-mg flecainide (THN102-200/18), or placebo for 2 weeks each separated by a 1- to 2-week wash-out period. The efficacy population, which included 72 subjects, showed no significant treatment period interaction while those treated with THN102-200/2 significantly improved sleepiness compared to placebo (THN102-200/2: least square-mean [LS-mean], –3.84 [±0.5]; placebo: LS-mean, –2.44 [±0.5]; 

Corvol and colleagues noted that THN102-200/18 also improved ESS but did not reach statistical significance (LS-mean, –3.18 [±0.5]; 

Overall, there was no treatment-related serious adverse events (TEAEs) reported, but there were 6 patients, 3 from each treatment group, that discontinued due to AEs. Headache, nausea, and nasopharyngitis, all of which were found in the THN102-200/18 group were among the most frequent AEs observed and occurred in 4, 3, and 3, patients respectively.

READ MORE: Amantadine Shows Treatment Durability for Reducing OFF Time in Parkinson Disease

The proportion of patients no longer presenting EDS for the duration of treatment was considerably higher with THN102-200/2 than in the placebo group (27.5% vs 16.2;

 = .05). Investigators noted that the other exploratory efficacy parameters used in the trial did not show a difference between THN102 and the placebo.

Theranexus originally announced the success of the phase 2 trial in March, at which time Corvol noted that “the symptom addressed by THN102—excessive daytime sleepiness in Parkinson’s disease—affects around 40% of patients. It is particularly debilitating and represents 1 of the primary risk factors for accidents, with considerable medical and economic consequences. There is currently no approved treatment to mitigate these major impacts. The positive results achieved with THN102 in this trial are a tremendous step forward in treating this debilitating symptom.”

The patient population all had ESS score of 14 or higher and Hoehn and Yahr scale score ≤4. Investigators of the study used treatment tolerance as the primary end point, with secondary end points that evaluated sleepiness, vigilance, and cognition.

Investigators noted that THN102’s success in improving excessive daytime sleepiness warrants future clinical trials.

1. Corvol JC, Klostermann F, Kovacs N, et al. THN 102, an association of modafinil and low dose flecainide, in the treatment of excessive daytime sleepiness associated with Parkinson disease: a double-blind, placebo controlled study. Presented at MDS Virtual Congress; September 12–16. Abstract LBA 3

2. Theranexus announces the success of its phase 2 trial for THN 102 in Parkinson’s patients. News release. Lyon, France: Theranexus. March 31, 2020. Accessed September 16, 2020. 

https://www.actusnews.com/en/THERANEXUS/pr/2020/03/31/theranexus-announces-the-success-of-its-phase-ii-trial-for-thn102-in-parkinson_s-patients

The investigational drug consistently increased the proportion of patients no longer suffering from daytime sleepiness during treatment.

Author | Marco Meglio

Articles

Ozanimod Shows Long-Term Safety, Efficacy in Open-Label Extension

Sumifilam Improves Multiple Alzheimer Disease Biomarkers in Phase 2b Study

Satralizumab Reduces Risk of Relapse, Including in Treatment-Naïve NMOSD

THN102 Is Safe, Improves Excessive Daytime Sleepiness in Parkinson Disease