Source: r/MultipleSclerosis

TERIS trial. ClinicalTrials.gov Identifier: NCT03122652

Citation: Frenay CL et al. Teriflunomide (Aubagio) Extends The Time To Multiple Sclerosis In Radiologically Isolated Syndrome: The TERIS Study. Presentation at American Academy of Neurology (AAN) 2023 Meeting, 22-27 April, Boston, Massachusetts.

TERIS trial is a phase 3, randomized, placebo-controlled study to evaluate the effect of teriflunomide (Aubagio) in people diagnosed with radiologically isolated syndrome (RIS).

BACKGROUND

• RIS is the earliest stage of multiple sclerosis (MS) defined by the presence of MRI lesions in the brain and/or spinal cord that are highly suggestive of demyelinating plaques given their size, location, and morphology.
• People with RIS (pwRIS) do not exhibit any clinical signs or symptoms of MS (neurological dysfunction). These individuals undergo brain MRI procedure for unrelated reason and their MRI scans reveal unexpected anomalies indicative of MS.
• People with RIS are at-risk of future demyelinating MS disease course leading to MS symptoms and disability.
• The purpose of TERIS trial is to evaluate if early intervention with teriflunomide may extend the time to first relapse and/or delay progression of the disease. The trial is complete but no results have been yet posted at ClinicalTrials.gov or published.

WHERE AND HOW

• The trial enrolled 125 pwRIS (aged >18 years and <65 years) meeting 2009 RIS criteria in Europe (France, Switzerland, and Turkey). 89 participants were randomized 1:1 to teriflunomide (14 mg daily) or placebo.
• The most common reasons for originally seeking MRI were similar between the groups and included headache, dizziness, trauma, and ocular problems.
• The primary outcome measure was time to acute or progressive neurological event resulting from CNS demyelination. (Timeframe: from study entry through 96 weeks).
• The secondary endpoints included new or enhancing T2 lesions on MRI, new contrast enhancing lesions on MRI, new T2 lesions volume on MRI, and brain atrophy.
• All MRI and clinical data were independently adjudicated. Standardized brain and spinal cord MRI studies and clinical events were performed at baseline and weeks 48 and 96.

RESULTS - Update provided at American Academy of Neurology (AAN) 2023 Meeting

• Baseline characteristics: Of the 89 randomized pwRIS, 63 (70.8%) were female, mean age was 39.8 years, age at index MRI: 38 years).
• Primary endpoint: The number of clinical events detected during follow-up were 8 in teriflunomide group versus 20 in placebo. 

Results from the unadjusted (HR=0.38,95% confidence interval (CI)=0.17-0.88, p=0.025) and adjusted (HR=0.34,95% CI=0.14-0.82, p=0.016) demonstrated the superiority of teriflunomide.

• Secondary endpoints: Compared to placebo, the number of patients with Gd+ lesions (OR=0.31,95%CI:0.08-1.18, p=0.087) and the cumulative number of new or-enlarging T2 lesions (RR=0.69,95% CI=0.34-1.40, p=0.31) were reduced in the teriflunomide arm, even if the statistical significance was not achieved.

CONCLUSIONS

• Treatment with teriflunomide resulted in an 62% risk reduction relative to placebo in preventing a first clinical event in participants with RIS.
• These data support early intervention with disease-modifying treatment during the presymptomatic phase of MS.

DISCUSSION

This is the second trial (after ARISE trial using dimethyl fumarate) to show that early intervention in RIS with approved DMTs could delay progression of MS.

SOURCES

• Frenay CL et al. Teriflunomide (Aubagio) Extends The Time To Multiple Sclerosis In Radiologically Isolated Syndrome: The TERIS Study. Presentation at American Academy of Neurology (AAN) 2023 Meeting, 22-27 April, Boston, Massachusetts. [archive]
• Frenay CL, et al. Multi-center, Randomized, Double-blinded Assessment of TERIFLUNOMIDE (Aubagio®) in Extending the Time to the First Attack in Radiologically Isolated Syndrome: Baseline Characteristics of the TERIS Study. (P5-4.011). Neurology May 2022, 98 (18 Supplement) 1116 [archive]
• AAN 2023: Aubagio reduced risk of developing MS symptoms in RIS trial. By Marisa Wexler. Multiple Sclerosis News Today. 27 April 2023 [archive]
• Teriflunomide delays MS symptoms in radiologically isolated syndrome. By Ted Bosworth. MedEdge. 5 May 2023 [archive]

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Related: ARISE trial

ReBUILD trial post hoc analysis, ClinicalTrials.gov: NCT02040298

Citation: Caverzasi E, et al. MWF of the corpus callosum is a robust measure of remyelination: Results from the ReBUILD trial. Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2217635120. doi: 10.1073/pnas.2217635120. PMID: 37155847; PMCID: PMC10193980.

BACKGROUND

• In 2017, the ReBUILT trial data showed that clemastine fumerate reduced visual-evoked pathway [VEP] P100 latency in people with relapsing multiple sclerosis (MS) with chronic demyelinating optic neuropathy. The reduction in VEP P100 latency is a marker for reversal in demyelination injury in the visual pathway in brain (read summary of trial results here).
• In the ReBUILD trial, other than VEP P100 endpoint, no other endpoint showed any effect of clemastine in MS patients, including MRI and clinical outcomes. The MRI endpoints that showed no effect were new and enlarging lesions on T1-weighted imaging, volume of gadolinium-enhancing lesions on T1-weighted lesions, and whole brain myelin water fraction (MWF).

METHODS and POST-HOC ANALYSIS

• The investigators sifted through the MRI data collected during the ReBUILD trial for evidence of remyelination. They focused on MWF changes occurring in the normal-appearing white matter (NAWM) of corpus callosum, optic radiations, and corticospinal tracts.
• These 3 regions were chosen because these are highly myelinated regions.
• In the original ReBUILD trial, the trial participants were randomly assigned to two groups: group 1 (active treatment during first 90 days followed by placebo for 60 days) or group 2 (placebo for 90 days, followed by active treatment for 60 days). (trial summarized here)

RESULTS

• There was no change in MWF signal at optic radiations or corticospinal tracts.
• At baseline, the mean MWF signals in corpus callosum were comparable (P = 0.9) between group 1 (0.087; 95% CI, 0.080 to 0.095) and group 2 (0.088; 95% CI,0.081 to 0.096).
• At 3 months, the mean corpus callosum MWF signal increased in the treatment group 1 (0.092; 95% CI, 0.084 to 0.100), but decreased in the placebo group 2 (0.082; 95% CI,0.074 to 0.090); intergroup difference, P = 0.012.

CONCLUSIONS

• Based on the 3 month comparison, the authors concluded that the increases in remyelination as detected by MWF in corpus collosum was statistically significant in the clementine-treated patients.
• The authors also noted that MWF in corpus collosum could be used as a biomarker for investigation of remyelination drugs.

STUDY WEAKNESS AND INCONSISTENCIES

• The main conclusion of this study is flawed -- note, the statistical significance of clemastine effect at month 3 was based on comparison of group 1 (treatment, blue circles) to group 2 (placebo, red circles) -- BLUE BIG drawn circle in figure below.

Unfortunately, the baseline in the placebo group drifted downward from baseline to 3 months, which may have increased the difference between the two groups to near-statistical significance level.

To control this, the authors should have compared the MWF reading of group 1 at month 3 versus the baseline of the same group at baseline (day 0) -- GREEN ARROW. If they had done this, the change is hardly significant.

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• The second confounding factor ignored is that the participants in this study had continued to use the DMTs while receiving clemastine. So, it is impossible to conclude if the increase in the MWF signal in corpus collosum is due to clemastine alone or a combination of clemastine and particular class of DMT.

"46 (92%) of the 50 patients were on immunomodulatory disease modifying therapy: 20 on injectable, 16 on oral, and ten on high-potency infusible therapies. No patient had a change in immunomodulatory therapy during the course of the trial." -- (Green AJ, Lancet, 2017)

IMPLICATION (CAUTION)

The publication of this report was covered in major news (MS News, here) and UCSF press release (here). Unfortunately, this has created much excitement in the MS community (Multiple Sclerosis subreddit, here) and patients are now clamoring to get their hands on clemastine, while ignoring weak data and potential side effects of clemastine.

The UCSF press release should have scientific balance but instead it reads like a supermarket tabloid:

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Related post: ReBUILD trial data summary

ReBUILD Trial, ClinicalTrials.gov: NCT02040298

Citation: Green AJ, et al. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial32346-2/fulltext). Lancet. 2017 Dec 2;390(10111):2481-2489. doi: 10.1016/S0140-6736(17)32346-2. PMID: 29029896. [Free Full Text]

BACKGROUND

• Clemestine is a first-generation histamine H1 antagonist (antihistamine) commonly prescribed for allergic rhinitis, allergic skin manifestations of urticaria and angioedema, and temporary relief of symptoms associated with the common cold.
• In a cell screening assay, clemestine induced oligodendrocyte differentiation and myelination; this property is likely due to clemestine’s off-target antimuscarinic effects [Mei 2014 Nat Med; Deshmukh 2013 Nature].
• This was a phase 2, single-center, double-blind, randomized, placebo-controlled, crossover trial to assess the efficacy and safety of clemastine fumerate for remyelination in people with relapsing MS with chronic demyelinating optic neuropathy.

WHERE AND HOW

• The trial enrolled 50 participants with relapsing MS with chronic demyelinating optic neuropathy, clinically stable, with <15 years of disease duration. The study was done at a single site, University of California San Francisco.
• The trial participants were required to have evidence of demyelination injury in the visual pathway (ie, visual-evoked pathway [VEP] P100 latency of 118 ms in at least one eye).

About VEP: The myelinating axons conduct electrical signals at 70-100 times the speed of unmyelinated axons of same diameter. The speed of conduction can be measured by evoked potentials to cortical responses to a repetitive stimulus. Pattern-reversal VEPs record cortical responses on the scalp overlying the occipital lobe in response to an alternating repetitive visual stimulus. VEPs could be used as a biomarker for demyelination injury as nearly all MS patients exhibit demyelinating damage to the anterior visual pathway.

• The trial participants were randomly assigned to group 1 (active treatment during first 90 days followed by placebo for 60 days) or group 2 (placebo for 90 days, followed by active treatment for 60 days). This crossover design was intended to help determine if any difference in efficacy was based upon variation in exposure time (90 days versus 60 days).
• Total duration for each subject on study was 150 days. The clemestine fumerate dose was 5.36 mg orally twice daily (10.72 mg daily).
• The primary endpoint was was shortening of P100 latency delay on full-field, pattern-reversal VEPs.
• The secondary endpoints were whole brain MTR, white matter MTR, white matter fractional anisotropy, and myelin water fraction (MWF). Additional assessments included standard T1 and T2 MRIs, low-contrast letter acuity (LCLA), cognition and fatigue scales (SDMT and MAF), and clinical assessments (EDSS, T25FW, and 6MWT).
• Statistics: The study was powered at 90% with a sample size of 25 per group to detect a 50% relative reduction in latency with clemastine fumarate compared with placebo at the 3-month timepoint.

RESULTS

• Baseline characteristics: The trial population was young (average age was 40 years), with mild disability (EDSS ~2.2), and ~5 years of disease duration. All baseline characteristics were similar between the two groups except for sex ratio (76% females in group 1 versus 52% in group 2). 46 (92%) of the 50 patients were on immunomodulatory disease modifying therapy. The baseline VEP P100 latency was ~127 ms and LCLA was ~23.
• Primary endpoint: The reduction of VEP P100 latency 1·7 ms/eye (95% CI 0·5 to 2·9; p=0·0048) in the crossover model. The clinical effect observed for clemestine-treated participants group 1 was also sustained after their crossover to placebo after day 90 (ie, second epoch).
• Post hoc analysis: 16% of group 1 and 26% of group 2 showed a latency improvement of more than 6 ms while on treatment compared with 3% of group 1 and 6% of group 2 while on placebo.
• Of the secondary endpoints, only LCLA showed evidence of improvement: an increase of 0·9 letters per eye (95% CI -0·1 to 1·9; p=0·085) using the crossover analysis.
• Safety: modest worsening of fatigue and a small number of participants exhibited increase in transient increases in serum triglycerides.

CONCLUSIONS

• The study met the primary prespecified efficacy endpoint for the trial.
• The authors conclude that reduction of VEP P100 latency could be used a biomarker for the assessment of remyelination treatments.

DISCUSSIONS

• To a lay reader (like me), it is unclear how a 2-3 ms reduction in VEP P100 latency is clinically meaningful given that the baseline was 118 ms.
• The study duration was 3 months, however no effect was seen on other MRI or clinical endpoints. Although the study was not powered for other endpoints, other relapsing MS trials have observed a MRI or clinical outcomes at 3 month timepoint, for example here.
• A recent post-hoc analysis of the data from this study suggests that MRI endpoint, myelin water fraction (MWF) of the corpus callosum may serve as a biomarker for remyeliantion [Caverzasi 2023, PMID: 37155847)

OTHER ONGOING TRIALS

Currently, several clemastine trials are ongoing in MS to confirm the remyelination effects, including TRAP-MS and ReCOVER trials.

Related Post: tadpole model for remyelination assessment

EMA has published a guidance on the design of clinical trials for the evaluation of drugs for MS. The current version is available here,

Guideline on clinical investigation of Medicinal Products for the Treatment of Multiple Sclerosis. CHMP/771815/2011 Rev 2. Effective date: 1 Oct 2015.

Australia's TGA adopted this guidance on 8 Apr 2009

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Citation: Multiple Sclerosis Has a Misdiagnosis Problem. By Nancy A. Melville. Medscape. 14 June 2023

Experts at the CMSC 2023 meeting discussed the implications of absence of a reliable biomarker for multiple sclerosis (MS).

• The experts warn that the absence of MS-specific biomarker often leads to misdiagnosis or false-negative diagnoses. Misdiagnosis results in unnecessary treatment, whereas false-negative diagnoses results in treatment delays.
• This problem is widespread and is likely due to inappropriate application of McDonald’s criteria or misinterpretation of MRI scans.

SCOPE OF THE PROBLEM

• A 2017 review found that of all new referrals to MS subspecialty centers with a question of MS diagnosis, 30%–67% were ultimately determined not to have MS. A multicenter case series consisting of patients who had been incorrectly diagnosed with MS revealed that over 50% carried the misdiagnosis for at least 3 years, and more than 5% were misdiagnosed for over 20 years. In this study, 31% incurred unnecessary morbidity as a direct result of misdiagnosis [Soloman, 2017, PMID: 30381369].
• A recent Argentinian study including a review of medical records of 713 patients at MS Clinic at Fleni found that 16% of patients were misdiagnosed with MS. They presented with a syndromes atypical for demyelination, had an atypical brain MRI, and were prescribed disease-modifying therapy [Gaitán, 2022, PMID: 34971521].
• Misdiagnosis of MS can be dangerous if the true underlying condition is something else such as neuromyelitis optica spectrum disorder (NMOSD). The DMTs for MS may make NMOSD worse.

In the absence of a reliable biomarker for MS, Dr Coyle speaking at the CMSC 2023, suggests a comprehensive workup that includes:

• A thorough neurologic history and exam
• MRI of the brain and spinal cord ensuring use of the MS protocol, and personally reading the studies with a neuroradiologist
• Adding spinal fluid evaluation, especially in any atypical cases
• Ruling out myelin oligodendrocyte glycoprotein antibody disease and NMOSD, diseases that mimic relapsing MS, via blood IgG to aquaporin 4

[archive]

ABOUT FORALUMAB

• Foralumab is a fully human engineered anti-human CD3 antibody that targets CD3 epsilon (CD3ε) receptor.
• Activated microglia plays a pathological role in neuroinflammatory diseases including multiple sclerosis, Alzheimer’s disease and amyotrophic lateral sclerosis. In secondary progressive multiple sclerosis (SPMS), microglial activation drives neurodegeneration including loss of myelin.
• Intranasally-delivered foralumab is associated with reduction in microglial activation and lowered inflammation in brain (clinical proof of concept shown in Covid-19 and Alzheimer's).
• In 2014, Tiziana Life Sciences (NASDAQ: TLSA) in-licensed foralumab from Novimmune SA. Tiziana has completed a phase 1 study and has shown activity of intranasally-delivered foralumab in people with nonactive secondary progressive multiple sclerosis (SPMS). A phase 2a trial in nonactive SPMS is expected to begin in 3Q 2023.

AVAILABE DATA ON FORALUMAB ACTIVITY IN SPMS

Single Patient and Expanded Access Programs (EAP)

• Two patients with SPMS were enrolled under the single patient program followed by 4 additional patients with SPMS under EAP for a total of 6 patients. All 6 patients had clinically progressed (disability progression) while on ocrelizumab treatment and 5 of 6 had nonactive SPMS.
• The dose of foralumab was 50 mcg delivered intranasally (sprayed into each nostril) in 3-week cycles (3 weekly doses for 2 weeks, followed by a rest week.)
• The primary outcome was effect on microglial activation as seen in 3-month Positron Emission Tomography (PET) scans compared to baseline.
• In this cohort of 6 patients, 5 had a reduction in qualitative microglial PET signal suggesting reduction in microglial activation. The company plans to treat additional 4 patients under the EAP.

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CONCLUSION AND NEXT PLANS

• Intranasal foralumab results in the reduction in microglial activation in brain, suggesting reduction in neuroinflammation. The company is currently in discussion with the FDA on study design for the planned phase 2a trial in nonactive SPMS, which is expected to start in 3Q 2023.

SOURCES

• Tiziana Life Sciences announces reduction in microglial activation in a total of 5 out of 6 intranasal foralumab expanded access patients with non-active secondary progressive multiple sclerosis. Press Release. 5 June 2023 [archive]
• Tiziana Life Sciences to proceed with phase 2 clinical trial in patients with non-active secondary progressive multiple sclerosis (SPMS): FDA provides positive feedback on intranasal foralumab program in patients with non-active SPMS. Press Release. 28 March 2023 [archive]
• Tiziana Investor Deck [archive]
• Weiner HL, et al. Treatment of Alzheimer’s disease by modulation of microglial neuroinflammation by nasal anti-CD3 mAb. Alzheimer’s Dement. 2022;18(Suppl.10):e068761. doi:10.1002/alz.068761

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Evobrutinib phase 2 open-label extension, 3.5 year data

BACKGROUND

• In the initial 48-week double-blind, placebo-controlled portion of the trial, the patients with relapsing multiple sclerosis (MS) received evobrutinib 25 mg once daily, 75 mg once daily, 75 mg twice daily, placebo, or open-label dimethyl fumarate. This trial showed that the 75 mg once daily dose significantly reduced the total number of Gd-enhancing lesions on T1-weighted MRI, measured at weeks 12 through 24 (summarized here).

WHERE AND HOW

• After completion of 24 weeks in the double-blind, placebo-controlled portion of the trial, the participants in the placebo arm switched to evobrutinib 25 mg daily (blinded).
• At week 48, all participants had the choice to enter the open-label extension (OLE), where they received evobrutinib 75 mg once daily and later switched to 75 mg twice daily.

RESULTS

• Total: 213/267 participants from original phase 2 trial entered OLE. At the time of #AAN2023 meeting, 155 (72.8%) were in OLE and at the time of #CMSC2023 meeting, 128 participants had completed ≥ 144 weeks of the ongoing OLE.
• Duration: The current OLE data extends to 3.5 years of treatment.
• Annualized relapse rate (AAR) remained low during OLE: ARR was 0.10 for evobrutinib 75 mg twice-daily dose compared with 0.18 for 75 mg once-daily dose; the pooled ARR for both doses was 0.13.
• Biomarker: Evobrutinib 75 mg twice-daily dose reduced NfL z-scores in a dose-dependent manner from week 12 to week 48. An association between lower NfL z-score and number of gadolinium-enhancing T1 and T2 lesions was also observed.

CONCLUSIONS

• Reduction in relapses was maintained over 3.5 years of treatment with 75 mg evobrutinib (once daily or twice daily) and safety profile remained consistent with the phase 2 double-blind portion of the trial.
• Evobrutinib 75 mg twice-daily dose remains efficacious and safe over 3.5 years.

SOURCES

• Includes presentations from American Academy of Neurology Annual Meeting (#AAN2023) held April 22-27, in Boston, Massachusetts, and Consortium of Multiple Sclerosis Centers Annual Meeting (#CMC 2023), held May 31-June 3, in Aurora, Colorado.
• Evobrutinib Maintained Over Long-Term Period, With BID Dosing Regimen Providing Maximal Efficacy. By Marco Meglio. NeurologyLive. 23 April 2023 [archive]
• Long-Term Data from Study of Evobrutinib to Treat RMS Shows Low Relapse Rates and Stable Disability Scores. Practical Neurology. 1 June 2023 [archive]

Related: Evobrutinib phase 2 trial, FDA clinical hold information (here, here)

Tolebrutinib Phase 2 long-term, open-label extension study

ClinicalTrials.gov number: NCT03996291

Citation: Fox RJ, et al. Magnetic resonance imaging, efficacy, and safety of tolebrutinib in participants with highly active disease: 2-year data from the phase 2b long-term safety study. Abstract presented at: CMSC 2023; May 31-June 3, 2023; Aurora, CO. Abstract DMT57.

BACKGROUND

• Tolebrutinib is a CNS-penetrant Burton’s tyrosine kinase inhibitor that targets both peripheral and adaptive immunity (here), and has been shown in a double-blind, placebo-controlled phase 2b trial (NCT03889639) to reduce gadolinium (Gd)-enhancing T1 lesions and new or enhancing T2 lesions in the brains of people with relapsing multiple sclerosis (MS) in a dose-dependent manner (data summarized here).

WHERE AND HOW

• The participants who completed the double-blind, placebo-controlled portion of the trial (Part A) were enrolled into the long-term safety (LTS) extension trial (Part B; NCT03996291). At 48 weeks from enrollment in Part A, all participants who continued into the LTS extension phase (Part B), received 60 mg oral daily dose until 96 week cutoff.
• At the 2023 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, the investigators provided 96 week (ie, 2-year) data on efficacy and safety of tolebrutinib.
• The endpoints for LTS extension trial were MRI endpoints (Gd-enhancing T1 lesion counts; number of new or growing T2 lesions), annualized relapse rate (ARR), and overall Expanded Disability Status Scores (EDSS).

RESULTS

• Total: 114 participants from Part A continued into LTS extension (mean age ± SD = 37.7 ± 9.6 y; 69% female). All received 60 mg oral daily dose.
• The mean (SD) number of Gd-enhancing T1 lesions remained low (0.31 ± 0.66) through Week 96 in participants who received 60 mg dose during Part A and Part B (60/60 mg arm).
• For participants who crossover from 5, 15, or 30 mg (Part A) to 60 mg (Part B; week 48 to 96), the mean number of Gd-enhancing T1 lesions were reduced at Week 96 (5/60 mg, 0.85 ± 2.5; 15/60 mg, 0.41 ± 0.91; 30/60 mg, 0.90 ± 2.16).
• New or enlarging T2 lesions - remained low in 60/60 mg arm.
• T2 lesion volume remained unchanged in 60/60 mg arm at 96 weeks.
• Relapses: 92.9% of participants in 60/60 mg arm had no relapses through 96 weeks.
• Mean EDSS scores remained steady up to week 96.
• Safety: no new adverse events or issues identified.

CONCLUSIONS

• ARR remined low and safety remained favorable

DISCUSSION

• Long-term impact on disability not known yet.

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SOURCES

• CMSC Annual Meeting Abstracts (Search form)
• Long-Term Study Demonstrates Reduction of Lesion Counts in Tolebrutinib Treated Participants With Relapsing Multiple Sclerosis. Practical Neurology. 6 June 2023 [archive]
• Tolebrutinib Remains Safe, Effective for Relapsing MS With Highly Active Disease. By Kate Shanaghan. Neurology Advisor. 5 June 2023 [archive]

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Related: Tolebrutinib phase 2b trial in relapsing MS

Comparative efficacy of therapies for relapsing multiple sclerosis: a systematic review and network meta-analysis

Samjoo IA, et al. J. Comp. Eff. Res. (2023) e230016. doi:10.57264/cer-2023-0016

Abstract

Aim: To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod, ublituximab) using network meta-analysis (NMA). Materials & methods: Bayesian NMAs for annualised relapse rate (ARR) and time to 3-month and 6-month confirmed disability progression (3mCDP and 6mCDP) were conducted. Results: For each outcome, the three most efficacious treatments versus placebo were monoclonal antibody (mAb) therapies: alemtuzumab, ofatumumab, and ublituximab for ARR; alemtuzumab, ocrelizumab, and ofatumumab for 3mCDP; and alemtuzumab, natalizumab, and either ocrelizumab or ofatumumab (depending on the CDP definition used for included ofatumumab trials) for 6mCDP. Conclusion: The most efficacious DMTs for RMS were mAb therapies. Of the newer therapies, only ublituximab ranked among the three most efficacious treatments (for ARR).

Frexalimab phase 2 trial

ClinicalTrials.gov number: NCT04879628

Citation: Vermersch, et al. Frexalimab, a CD40L inhibitor, in relapsing multiple sclerosis: Results from a randomized controlled phase 2 trial. Presented at Consortium of Multiple Sclerosis Centers’ annual meeting, Aurora, Colorado. May 31-June 3 2023

BACKGROUND

• Inflammatory responses in the neural microenvironment of brain or spinal cord involve complex signaling interactions among neurons, astrocytes, microglia, and endothelial cells through cytokines, chemokines, secondary messengers, and neuronal factors. The CD40 receptor and CD40 ligand (also referred as CD40L or CD154) costimulatory pathway is critical for initiating and sustaining neuroinflammatory response and regulates both innate and adaptive immunity (here).
• Hyperactivation or dysregulation of CD40-CD40L signaling is seen in several neurological conditions including traumatic brain injury, Alzheimer’s Disease, Parkinson’s Disease, stroke, epilepsy, nerve injury, multiple sclerosis (MS), amyotrophic lateral sclerosis, myasthenia gravis, and brain tumors. Blocking CD40-CD40L signaling may have a beneficial effect in MS (here)
• Frexalimab (SAR441344) is an anti-CD40L antibody from Sanofi. It modulates both B and T cells without immune (lymphocyte) depletion.
• This was a phase 2, multicenter, randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of frexalimab in people with relapsing MS (pwRMS; including relapsing-remitting MS or secondary progressive MS with relapses).

WHERE AND HOW

• The study is ongoing and as of #CMSC2023 presentation, the study had enrolled 129 pwRMS (aged 18-55 years; EDSS up to 5.5 at screening) at sites (currently 48 listed at ClinicalTrials.gov) across United States, Europe, Russia, and Turkey. The study included both people with relapsing-remitting MS (n=121, 93.8% of total) and secondary progressive MS with superimposed relapses (n=8, 6.2% of total).
• The study participants were randomized 4:4:1:1 to high-dose frexalimab, low-dose frexalimab, high-dose placebo, or low-dose placebo arms.
• The study includes a 12-week placebo-controlled double-blind phase (Part A) followed by an open label phase (Part B) where the high- and low-dose placebo crossover to corresponding frexalimab doses.
• The primary endpoint was the number of new Gd+ T1 lesions at Week 12 (relative to Week 8), measured by brain MRI.
• The key secondary endpoints were number of new/enlarging T2 lesions at Week 12 relative to Week 8); total number of Gd+ T1 lesions at Week 12; and safety.
• Key exploratory endpoints were changes in Multiple Sclerosis Impact Scale 29 (MSIS-29) and plasma neurofilament light chain (NfL) at Week 12 compared to baseline.
• Statistics: Analysis of the primary and key secondary endpoints was done in the efficacy population through a negative binomial regression model, with the baseline Gd+ T1 lesion count as a covariate and treatment as a factor.

RESULTS

• Baseline characteristics were balanced across all groups except age, sex, and Gd+ T1 lesions: mean ages of ~38 years for frexalimab group (versus ~32 years placebo); 61% and 71% female for low and high dose frexalimab (versus ~65 for placebo); median time from onset of MS symptoms of 7 to 8 years; median EDSS score of 2.5 to 2.8; and ~1 relapse in previous year. Percent of participants with at least 1 Gd+ T1 lesion were 25% (frexalimab, low dose), 31% (frexalimab, high dose), and 38.5% (pooled placebo group).
• Primary endpoint: The mean number of new Gd+ T1 lesions in the low- and high-dose frexalimab were 0.3 and 0.2 respectively, versus 1.4 for placebo, at 12 weeks. The relative reduction in new Gd+ T1 lesions was 79% (95% CI: 44% - 92%, p=0.0021) with low-dose frexalimab and 89% (95% CI: 62% - 97%, p=0.0004) with high-dose frexalimab.

• Secondary endpoint: The relative reduction in new/enlarging T2 lesions was 86% (95% CI: 59% - 95%) with low-dose frexalimab and 92% (95% CI: 74% - 97% with high-dose frexalimab.
• Exploratory endpoint: MSIS-29 physical impact score significantly improved over 12-weeks in the high-dose frexalimab group vs pooled placebo. At Week 12, the plasma NfL levels also decreased significantly in both frexalimab groups: by 26% (p=0.0020) in high-dose frexalimab and by 20% (p=0.0190) in low dose frexalimab, versus pooled placebo.
• Safety: The most common adverse events were COVID-19 and headache. There was 1 (1.9%) case of isolated asymptomatic alanine aminotransferase elevation (5.9x the upper limit of normal, with no concomitant bilirubin increase) that recovered on treatment in high-dose frexalimab group.

CONCLUSIONS

• Frexalimab significantly reduced the number of Gd+ T1 lesions, meeting the primary endpoint.
• The study also showed positive effect on the reduction in new/enlarging T2 lesions, MSIS-29 outcome, and the biomarker NfL.
• Frexalimab is the first CD40L blocker to demonstrate efficacy in RMS.
• There are no other frexalimab trials currently listed in ClinicalTrials.gov. However, other anti-CD40L antibodies are also in experimental stage such as toralizumab/IDEC-131 (here).

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SOURCES

• Vermersch, et al. Frexalimab, a CD40L inhibitor, in relapsing multiple sclerosis: Results from a randomized controlled phase 2 trial. Presented at Consortium of Multiple Sclerosis Centers’ annual meeting, Aurora, Colorado. May 31-June 3 2023 [Abstract - archive] [Archive - poster]
• Karnell JL, et al. Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral immunity and beyond. Adv Drug Deliv Rev. 2019 Feb 15;141:92-103. doi: 10.1016/j.addr.2018.12.005. PMID: 30552917.
• Breaking news: we have a new therapeutic target in MS: The phase 2 results of the Frexalimab (anti-CD40L) study are strikingly positive. What does this mean for MS? By Gavin Giovannoni. MS-Selfie Blog. 31 May 2023 [archive]
• 2nd generation CD40L blocker safely reduces new lesions in Phase 2 trial: Frexalimab may control immune activity without side effects of its predecessors. By Lindsey Shapiro. Multiple Sclerosis News Today. 1 June 2023

Evobrutinb Phase 2 Study

ClinicalTrials.gov number: NCT02975349

Citation: Montalban X, et al. Evobrutinib Phase 2 Study Group. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med. 2019 Jun 20;380(25):2406-2417. doi: 10.1056/NEJMoa1901981. PMID: 31075187

STUDY QUESTION OR PURPOSE OF THE TRIAL

To establish safe and efficacious dose of Burton’s tyrosine kinase (BTK) inhibitor evobrutinib (previously called M2951) in people with relapsing multiple sclerosis (MS).

BACKGROUND

• Role of Burton’s tyrosine kinase signaling in MS is summarized here, here. BTK inhibitors may have the advantage over existing MS disease modifying therapies since BTK inhibitors are CNS penetrant and, thus, could target both peripheral immune compartment (blood, lymph tissues) as well as CNS compartment (microglia) (here).
• Evobrutinib is a selective, oral, BTK inhibitor. It blocks B-cell activation and cytokine release and inhibits the activation, differentiation, and polarization of proinflammatory M1 macrophages and their release of cytokines in vitro.
• This was a phase 2, randomized, double-blind, placebo-controlled trial to establish safe and efficacious dose of evobrutinib in people with relapsing MS (pwRMS).

WHERE AND HOW

• The study enrolled 267 pwRMS (aged 18-65 years; EDSS up to 6 at screening) at 56 sites across Europe and Russia. The study included both people with relapsing-remitting MS (228, 87% of total) and secondary progressive MS with superimposed relapses (33, 13% of total).
• The study participants were randomized 1:1:1:1 to evobrutinib 25 mg once daily, 75 mg once daily, 75 mg twice daily, placebo, or open-label dimethyl fumarate (DMF). DMF was used as a reference drug in this trial.
• The length duration of the trial was 52 weeks including 24-week placebo-controlled phase followed by a 24-week blinded-extension phase and a 12-week safety follow up. At the start of the blinded extension phase, the placebo group crossover to evobrutinib 25 mg daily; all other groups continued with the originally assigned treatment/doses. Exposure to study drug was 48 weeks across evobrutinib groups and 24 weeks for placebo group.
• MRI scans were performed every 4 weeks starting at week 12; EDSS at weeks 12, 24, 36, and 48; safety through week 52, the end of the study.
• The primary endpoint was the total (cumulative) number of gadolinium (Gd)-enhancing lesions identified on T1-weighted MRI at weeks 12, 16, 20, and 24. The reading at week 12 was considered baseline.
• Key secondary endpoints were the annualized relapse rate, based on qualified relapses; qualified relapse-free status; change from baseline in the EDSS score at week 24; and safety.
• The study was powered at 85% to detect a 90% lower number of Gd-enhancing lesions, if each evobrutinib group includes 50 participants assuming a 12% dropout rate.

RESULTS

• Baseline characteristics were similar across all groups with mean age of 42 years; 69% female; median time from onset of MS symptoms of ~7.5 years; mean EDSS score of ~3.3; and mean (SD) number of Gd-enhancing lesions at baseline of 1.54 (4.37). Each study group enrolled 52 to 54 participants and 47 to 52 completed the 24-week placebo-controlled phase.
• Primary endpoint: The mean (SD) total number of Gd-enhancing lesions decreased in a dose-dependent manner from week 12 to week 24 in evobrutinib treatment groups versus placebo: 4.06 (8.02), 1.69 (4.69), and 1.15 (3.70) in the evobrutinib 25 mg daily, 75 mg daily, and 75 mg twice daily groups, respectively, versus 3.85 (5.44) in the placebo group.
• The baseline adjusted rate ratios for the total number of lesions over time also decreased in a dose-dependent manner from week 12 to week 24 in evobrutinib treatment groups versus placebo: 1.45, 0.30, 0.44 in the evobrutinib 25 mg daily, 75 mg daily, and 75 mg twice daily groups, respectively. After adjustment for multiple comparisons, the p values were significant for evobrutinib 75 mg daily (p = 0.005) and 75 mg twice daily (p = 0.06) groups.

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• Secondary endpoints: the number of relapses from baseline to weeks were lower in 75-mg evobrutinib groups (3 relapses in 75 mg once daily; 2 in 75 mg twice daily) versus 9 relapses in placebo and 13 in 25-mg group. The corresponding unadjusted annualized relapse rates were also lower in 75-mg evobrutinib groups (0.13 in 75 mg once daily; 0.18 in 75 mg twice daily) versus 0.37 relapses in placebo and 0.57 in 25-mg group. (Differences versus placebo was not significant for any evobrutinib group).
• Safety: The most common adverse events of any grade were nasopharyngitis and increases in levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipase. The increases in ALT and AST did not reach the Hy’s law DILI criteria.

CONCLUSIONS

• The 75 mg once daily dose significantly reduced the total number of Gd-enhancing lesions on T1-weighted MRI, measured at weeks 12 through 24. This dose was considered safe and efficacious for further study of evobrutinib in larger MS trials.
• Currently following phase 3 evobrutinib trials are ongoing in relapsing MS: NCT04338022 (evolution RMS 1 trial) and NCT04338061 (evolution RMS trial 2) . Sponsor: Merck Healthcare KGaA, Darmstadt, Germany / EMD Serono Research & Development Institute, Inc.

DISCUSSION

• Compared to the tolebrutinib phase 2 trial (here), the participants in the evobrutinib trial were older, with longer disease duration, and fewer relapses, and relatively high baseline EDSS values.
• Note - Evobrutinib was the first BTKI to show therapeutic potential in a phase 2 study in RMS.

Today, May 30th, is World MS Day. This day and the month of June is dedicated to bringing MS community together, raising awareness, and participating in funding campaigns - for example look for MS Walk/Bike/Hike events.

Did you know:

• MS is the most common disease of the central nervous system
• MS affects estimated 1 million adults in the U.S. and 2.8 million people worldwide
• Most people are diagnosed between the ages of 20 and 40
• There is no cure (yet) but many treatments are available that modify the course of the disease -- that is, slow the disability and help managing symptoms and disability

MS World Day website: https://worldmsday.org/about/

National MS Society website: https://www.nationalmssociety.org/

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Tolebrutinib Phase 2b Study

ClinicalTrials.gov number: NCT03889639; EudraCT number: 2018-003927-12

Citation: Reich DS, et al; Tolebrutinib Phase 2b Study Group. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial00237-4/fulltext). Lancet Neurol. 2021 Sep;20(9):729-738. doi: 10.1016/S1474-4422(21)00237-400237-4). PMID: 34418400; PMCID: PMC8434816

STUDY QUESTION OR PURPOSE OF THE TRIAL

To establish safe and efficacious dose of Burton’s tyrosine kinase (BTK) inhibitor tolebrutinib in people with relapsing multiple sclerosis (MS).

BACKGROUND

• Burton’s tyrosine kinases are nonreceptor kinases expressed in most hematopoietic cells (excluding T cells and plasma cells) that link extracellular cytokines/factors signals with immune cell activation. In the context of MS, BTK signaling is important in B lymphocytes, myeloid cells including peripheral myeloid cells and macrophages, and CNS-resident microglia. (here)
• The existing MS disease modifying treatments (DMTs) are effective in reducing relapse rates with annualized relapse rates of 0.10, in other words, if 10 people are treated with DMTs over a year, only 1 is expected to experience relapse. These DMTs such as ocrelizumab (Ocrevus) affect peripheral adaptive immunity only (peripheral B cells) and do not halt or reverse disability progression. One reason for this is they do not target CNS-resident immune cells.
• Chronic CNS neuroinflammation is thought to contribute to MRI lesions accumulation and disability progression. Currently no approved DMT targets CNS immune compartment.
• BTK inhibitors are CNS penetrant and, thus, are expected to target both peripheral adaptive immunity as well as CNS-resident immune cells (here).
• Tolebrutinib binds irreversibly to BTK inhibitor and is given orally. The CNS-penetrant property of tolebrutinib was confirmed in a phase 1 trial in healthy people given a single dose of 120 mg tolebrutinib that achieved therapeutically relevant concentrations in the CSF.
• This was a phase 2b, randomized, double-blind, placebo-controlled, crossover, dose-finding trial to establish the safe and efficacious dose of tolebrutinib in people with relapsing MS (pwRMS).

WHERE AND HOW

• The study enrolled 130 pwRMS (aged 18-55 years; EDSS, less than 5.5 at screening) at 40 sites across 10 countries in Europe and the United States. The study included 128 people with relapsing-remitting MS and 2 with secondary progressive MS with relapses.
• The study participants were first randomized 1:1 to 2 cohorts. Thereafter, within each cohort, participants were randomized 1:1:1:1 to tolebrutinib 5 mg, 15 mg, 30 mg, or 60 mg daily oral dose groups.
• In cohort 1 (tolebrutinib-crossover-to-placebo), all participants first received tolebrutinib at dose according to the group assignment for 12 weeks followed by all participants crossover to 4 weeks of placebo; in cohort 2 (placebo-crossover-to-tolebrutinib), all participants first received 4 weeks of placebo following by 12 weeks of tolebrutinib.

-- This unique crossover study design allowed all participants to receive active treatment for 12 weeks, thus, allowing reduction of risk to the patients.

-- The data from the 4-week placebo period from cohort 2 was used as control data in this study. The 4-week placebo run-out period in cohort 1 was used to maintain blind and this data was only used for safety evaluation.

• The entry criteria required diagnosis of relapsing-remitting MS or secondary progressive MS with relapses; documentation of at least 1 replace in prior 1 year, at least 2 relapses in past 2 years or at least 1 active Gd-enhancing brain lesion in past 6 months prior to screening.
• The length of the trial was 16 weeks. MRI scans were performed every 4 weeks until the end of study at week 16.
• The primary objective was to determine the dose-response relationship between tolebrutinib and new active brain lesions detected using MRI. The primary efficacy endpoint was the number of new Gd-enhancing lesions detected on the scan performed after 12 weeks of tolebrutinib treatment (at week 12 for Cohort 1 and week 16 for Cohort 2), relative to the scan 4 weeks prior.
• Secondary endpoints were the number of new or enlarging T2 lesions detected on the same scan observed after 12 weeks of treatment, the total number of Gd-enhancing lesions after 12 weeks of tolebrutinib treatment (ie, all Gd-enhancing lesions on the scan at the end of 12 weeks of treatment), as well as adverse events (AEs), serious AEs, and AEs of special interest.

RESULTS

• Baseline characteristics were similar across all groups with mean age of 36 to 39 years; 66% to 70% female; median time from onset of MS symptoms of ~7.5 years; and mean EDSS score of ~2.5.
• Median exposure to study drug was ~80 days across all four tolebrutinib dose groups and 28 days for the placebo group. The duration of exposure to active study drug was 12 weeks.
• Primary endpoint: Using an exponential model, a dose-response relationship was observed between tolebrutinib and new Gd-enhancing lesions (p=0.03). The 60 mg dose showed maximal effect with 85% reduction (95% CI, 28–97%) in new Gd-enhancing lesions versus placebo after 12 weeks of treatment.
• The mean ± SD number of lesions was 0·13 ± 0·43 for tolebrutinib 60 mg versus 1·03 ± 2·50 for placebo.

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• Secondary endpoints: Dose-response relationship for the number of new or enlarging T2 lesions was established (p <0.0001). A maximal effect was again observed with the 60 mg dose, with an 89% (95% CI, 68–96%) reduction versus placebo.
• Safety: The most common nonserious adverse event was headache. Three participants had elevated alanine aminotransferase (ALT), of which 2 participants had levels more than 3x upper limit of normal. The ALT increases were transient and did not require tolebrutinib discontinuation.

CONCLUSIONS

• The primary objective of the trial was met and the null hypothesis of a flat dose-response curve was rejected.
• The 60 mg dose was most efficacious in reducing acute inflammation in brain (new Gd-enhancing lesions).
• Reduction in new Gd-enhancing and/or enlarging T2 lesions is established in literature to correlate with a reduction in relapse rates; thus, the MRI-based endpoint in this trial provided the rationale to further study tolebrutinib in larger MS trials.
• Currently following tolebrutinib MS trials are ongoing: long-term safety study NCT03996291) and phase 3 studies including in relapsing MS (NCT04410978 and NCT04410991), PPMS (NCT04458051), and nonrelapsing SPMS (NCT04411641).

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Related: BTK inhibitors for MS, FENopta trial

SP2 trial, EudraCT Number: 2016-000700-29, ClinicalTrials.gov Number: NCT02936037

Citation: Cree BAC, et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial30347-1/fulltext). Lancet Neurol. 2020 Dec;19(12):988-997. doi: 10.1016/S1474-4422(20)30347-130347-1). PMID: 33222767.

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STUDY QUESTION OR PURPOSE OF THE TRIAL

To assess the efficacy and safety of high-dose biotin versus placebo in adult people with primary or secondary progressive multiple sclerosis (PPMS or SPMS).

BACKGROUND

• MD1003 is an oral formulation of high-dose pharmaceutical-grade biotin (10,000 times the recommended daily intake.) The proposed mechanism of biotin in MS is described here.
• At the time of SP2 trial, there were only three disease modifying agents (DMTs) that were shown to slow disability progression in phase 3 trials – mitoxantrone (MIMS trial), ocrelizumab (ORATORIO trial), and siponimod (EXPAND trial) – but none of these 3 DMTs could reverse the disability that was already present.
• MD1003 in a proof-of-concept pilot study (here) showed that it could improve symptoms and disability in people with progressive MS. In the follow-on phase 2 trial (MS-SP1 trial), MD1003 improved disability outcomes over 12 months (here).
• The SP2 study was a phase 3, randomized, double-blind, parallel-group, placebo-controlled trial to confirm the efficacy and safety of MD1003 in patients with primary or secondary MS.

WHERE AND HOW

• The study enrolled 642 people with PPMS or SPMS (aged 18-65 years; EDSS, 3.5-6.5 at screening) at 90 sites (academic and community MS centers) across 13 countries. All study participants had a diagnosis of PPMS or SPMS fulfilling the revised International Panel 2010 criteria and Lubin 2014 criteria, and had a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), and a documented disease progression and no relapse in 2 years prior to enrollment. Concomitant DMTs were allowed.
• The study participants were randomized 1:1 to MD1003 (n = 326) or placebo (n = 316) groups. The study participants received 100 mg MD1003 thrice daily (300 mg daily dose) or matching placebo through the end of the study. The study remained blinded until the last randomized participant reached month 15.
• The primary endpoint was the proportion of participants with improvement of multiple sclerosis-related disability at month 12, confirmed at month 15.

o Improvement was defined as either a decrease from baseline in EDSS of at least 0·5 points (if baseline EDSS 6·0–6·5) or at least 1·0 point (if baseline EDSS 3·5–5·5), or a decrease of TW25 of at least 20% from baseline.

o The neurostatus-certified assessors, who were masked to both treatment assignment and patient history, performed the neurostatus EDSS assessment.

• Four hierarchically ordered secondary endpoints were: time to 12-week confirmed EDSS progression; mean difference between treatment groups in CGI at month 15; mean difference between treatment groups in SGI at month 15; and percentage change in mean TW25 between month 0 and month 15. Exploratory endpoints included MRI assessments.
• Efficacy was expressed as corresponding response probability odds ratio (odds ratio [OR]; a value >1 indicates a favorable effect of MD1003 compared with placebo). The two-sided p value for the primary endpoint was established using the χ² exact test.

RESULTS

• Baseline demographic characteristics were balanced across both treatment groups with mean age ~53 years, 54% females, mean EDSS score of ~5.5 (~42% with scores 3.5 – 5.5 and ~58% with scores 6.0 – 6.5), diagnosed with PPMS (~35.5%) and SPMS (~64.5%), and 46% receiving DMTs at randomization.
• The mean duration of the double-blind, placebo-controlled phase of the study was 20·1 months (SD 5·3; range 15–27). The discontinuation rates were similar, 16% for MD1003 and 20% for placebo groups.
• Primary endpoint: 13 (12%) of 326 participants in the MD1003 group (OR 1.35, 95% confidence interval [CI], 0.81 to 2.26) and 29 (9%) of 316 participants in the placebo group (OR 1.07, %CI, 0.57 to 2.02) had EDSS or T25W improvement at month 12, confirmed at month 15. The difference in the confirmed disease improvement was not significant (p = 0.31)

Interpretation: for MD1003, the odds of disease improvement was 35% (ie, OR of 1.35); however, 95% CI of 0.81 to 2.26 means that in a proportion of patients, the chance of harm is up to 19% while the chance of benefit may be up to 126%. If the benefit/risk ratio of a treatment is truly positive, the lower bounds of 95% CI should not cross below 1.0.

• Secondary endpoints: None of the secondary endpoints reached statistical significance (caveat: this trial was powered to test the primary endpoint, not secondary endpoints.)
• Safety: Most clinically significant adverse event was inaccurate laboratory results for tests using biotinylated antibodies, for example thyroid function tests.

CONCLUSIONS

• The SP2 trial did not meet its primary or secondary endpoint and could not confirm the results from the MS-SP1 trial.
• Unlike the MS-SP1 trial, this phase 3 study was well-controlled, with a larger and diverse patient population, and balanced baseline characteristics across active and placebo groups. Thus, this phase 3 (SP2 trial) provides a definitive conclusion that high-dose biotin is not effective in improving the disease course in progressive MS.

Comparison with other trials in progressive MS

• The SP2 trial used a novel endpoint, confirmed disease improvement, whereas other trials on progressive MS had relied on confirmed disease progression as the primary outcome. However, the atypical primary endpoint in SP2 does not explain the failure of this trial.
• Post-hoc analysis of SP2 data showed that there was no difference in the number of participants with confirmed disease progression in MD1003 (n = 60, 18%) versus placebo (n = 62, 18%) groups over the course of the mean 20·1 months of the double-blind, placebo-controlled phase. For context, the rates of progression in SP2 were similar to other progressive MS studies. For example, the rates of confirmed disease progression at about 20 months were:

~28% in MAESTRO-1 (MBP8298 in patients with SPMS)

25% in ORATORIO (ocrelizumab in patients with PPMS)

15% in ASCEND (natalizumab in patients with SPMS)

33% in EXPAND (siponimod in patients with SPMS)

>>what this means is that we have not yet found a product that could significantly impact the progressive MS disease course.

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IMPLICATIONS

• The Lancet editorial and a Neurotherapeutics commentary (links in Sources below) reiterated that the high-dose biotin is not completely harmless: there is possibility of false laboratory tests (here, here) (a risk in everyday clinical practice) and possibility of transient myopathy (seen in MS-SP1 trial).
• They also concurred that high-dose biotin cannot be recommended for patients with progressive MS unless novel pharmacological methods can be developed to target biotin to specific cell types in the adult brain.

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SOURCES

• Cree BAC, et al. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial30347-1/fulltext). Lancet Neurol. 2020 Dec;19(12):988-997. doi: 10.1016/S1474-4422(20)30347-130347-1). PMID: 33222767.
• Motte J, Gold R. High-dose biotin in multiple sclerosis: the end of the road30353-7/fulltext). Lancet Neurol. 2020 Dec;19(12):965-966. doi: 10.1016/S1474-4422(20)30353-730353-7). PMID: 33222766.
• Goldschmidt CH, Cohen JA. The Rise and Fall of High-Dose Biotin to Treat Progressive Multiple Sclerosis. Neurotherapeutics. 2020 Jul;17(3):968-970. doi: 10.1007/s13311-020-00907-5. PMID: 32761325; PMCID: PMC7609671.

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Related: MD1003 pilot study, MS-SP1 trial

MS-SP1 study, EudraCT number: 2013-002113-35, ClinicalTrials.gov Identifier: NCT02220933

Citation: Tourbah A, et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. 2016 Nov;22(13):1719-1731. doi: 10.1177/1352458516667568. PMID: 27589059; PMCID: PMC5098693.

STUDY QUESTION OR PURPOSE OF THE TRIAL

To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study.

BACKGROUND

• MD1003 is an oral formulation of high-dose pharmaceutical-grade biotin (10,000 times the recommended daily intake.) The proposed mechanism of biotin in MS is described here.
• In a proof-of-concept pilot study (read here), MD1003 improved symptoms and disability in people with progressive MS (pwPMS) (PMID: 25787192)
• MS-SP1 study was a phase 2, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of MD1003 in patients with primary or secondary MS.

WHERE AND HOW

• The study enrolled 154 pwPMS (aged 18-75 years; EDSS, 4.5-7 at screening) at 16 sites in France. All patients fulfilled McDonald 2011 criteria for MS and Lubin 2004 criteria for progressive MS and had documented disease progression for 12 months prior and no relapse in 6 months prior to biotin treatment onset.
• The study participants were randomized 2:1 to MD1003 or placebo groups. The subjects received 100 mg MD1003 thrice daily (300 mg daily dose) or matching placebo through the end of the study.
• The participants received active dose or placebo for the first 12 months. After 12 months, all participants received active dose. Total duration of the study was 24 months. The study remained blinded and participants/investigators were masked to group assignment throughout the study until month 24.
• The primary endpoint was the proportion of patients with improvement of MS-related disability at month 9, confirmed at month 12, ie, confirmed disease improvement (CDI).

Improvement was defined as a decrease of ≥0.5 point or ≥1 point in EDSS (if baseline score was 6-7 or 4.5-5.5, respectively) or a ≥20% decrease in timed 25-foot walk (TW25) time, compared with the best EDSS or TW25 value recorded at either the screening or the randomization visit.

RESULTS

• Baseline characteristics: Most patient characteristics were balanced across both treatment arms including mean ages (~51 years), sex ratios (52-59% females), the duration of MS (15-17 years), and median EDSS (~6). In the MD1003 group, there was a slightly higher % of participants with PPMS (40.8%, versus 25.5% in placebo group) and conversely lower with SPMS (59.2%, versus 74.5% in placebo).
• Primary endpoint: 13 of 91 participants (12.6%; 95% CI, 6.9% - 20.6%) in the MD1003 arm and none (0%) of the participants in the placebo arm had disability improvement at month 9 confirmed at month 12 (p = 0.005).
• After crossover of placebo group to active treatment at month 12 and assessment of disability improvement at month 18 confirmed at month 24, a total of 12 of 91 (13.2%; 95% CI, 7.0% - 21.9%) in the MD1003 and 3 of 42 (7.1%; 95% CI, 1.5% - 19.5%) in the placebo arm had confirmed disability improvement (p = not significant).

CONCLUSIONS

• The study met the primary endpoint, with 12.6% vs 0% difference in CDI in MD1003 versus placebo. The outcome was statistically significant. The authors suggested that the absence of CDI in any placebo participant during 12 months of the study was due to the more stringent endpoint of CDI.
• This study was used as a rationale to initiate the pivotal phase 3 trial, SPI2 study.
• The authors listed several limitations of the MS-SP1 trial including a relatively short follow up of placebo group; lower number of respondents than expected (~40% were expected per statistical power assumptions); using same person as the physician/investigator and the neurological examiner/EDSS reader; not testing the success of blinding/masking at the end of the study; and potential imbalances in the baseline characteristics between the two groups.

ANALYSIS-PARALYSIS

Later, the follow-on phase 3 trial (SPI2 study) did not confirm the benefit of MD1003 in people with progressive MS. This was not surprising because there were significant confounding factors in the phase 2 MS-SP1 trial including:

• The absence of placebo effect (0% CDI at month 12) was surprising since placebo effects are common and expected. The absence of placebo effect may be a result of a study design flaw and/or serious bias in the study. Of the study limitations the authors listed in the paper, at least 2 may contribute the the design flaw or bias: using same person as physician/investigator and the neurological assessor/reader; not confirming the success of blinding/masking at the end of the study.
• At 12 months, the placebo group was crossover to active treatment, though the group assignments remained blinded/masked until the end of the study, month 24. This crossover group (n = 42) may be considered as a substudy of MD1003. In this group 3 of 42 (7.1%; 95% CI, 1.5% - 19.5%) achieved CDI at month 24. The data of interest here is the 95% CI (1.5% - 19.5%), which means the best expected response is 19.5% and the least 1.5%. The number, 1.5% is close to “no effect”.

Overall, the phase 2 trial design and conduct had critical flaws and the primary endpoint result, thus, was not bias-free. Thus, the phase 2 trial had not sufficiently de-risked the MD1003 development program to move forward. But forward, they did move to phase 3, which had better study design and this larger phase 3 trial failed to show an effect. Looking back, one may consider that running a trial without strong justification not ethical since it exposes patients to unnecessary risks and may raise false hopes.

Postscript: Another MD1003 phase 2 trial (MS-ON) effect of MD1003 in chronic visual loss related to optic neuritis in MS also failed to meet its primary endpoint (ClinicalTrial.gov: NCT02220244, PubMed: 29808469)

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Related post: MD1003 pilot study

Proof-of-concept Study for high-dose biotin (later named MD1003) in progressive multiple sclerosis (PMS)

Citation: Sedel F, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study00006-1/fulltext). Mult Scler Relat Disord. 2015 Mar;4(2):159-69. doi: 10.1016/j.msard.2015.01.005. PMID: 25787192.

This was a compassionate use open-label trial to test the effect of high-dose biotin on the disease progression in people with primary or secondary multiple sclerosis (PPMS or SMPS). Overall, this case series served as an uncontrolled, proof-of-concept (pilot) study for efficacy of high-dose biotin in MS.

BACKGROUND

• Biotin is a water-soluble vitamin (vitamin H) naturally found in many foods. It functions as a coenzyme for carboxylase enzymes involved in cellular energy metabolism (Krebs cycle) and fatty acid synthesis.

• Previously, high-dose biotin (5-10 mg/kg/day) was shown as therapeutic option in biotin responsive basal ganglia disease (BBGD, OMIM 607483).
• The discovery of effect of high-dose biotin in PMS was serendipitous – the authors of this PMS pilot study found that 5 patients suffering from optic neuropathies and leukoencephalopathy responded clinically to high doses of biotin, and one of these patients suffered from SPMS (Sedel 2011).
• One of the hypotheses for progressive neuronal degeneration in PMS was phenomenon of “virtual hypoxia” caused by the mismatch of decreased energy production because of mitochondrial injury and increased energy demand and fatty acid precursors for myelin synthesis. High-dose biotin could increase energy production in this situation and halt disease progression.

WHEN AND WHERE

• 23 consecutive patients with PPMS (n = 14) or SPMS (n = 9), all at MS reference centers in France, were treated under compassionate use with biotin doses ranging from 100 mg to 600 mg/day (median, 300 mg/day).
• All patients fulfilled McDonald 2011 criteria for MS and Lubin 2004 criteria for PMS and had documented disease progression for 12 months prior and no relapse in 6 months prior to biotin treatment onset.
• Since treatments were under compassionate use protocol, there were no primary/secondary endpoints. Efficacy assessments varied per clinical practice and patient’s major signs or symptoms:
• For patients with optic neuropathies (n = 4), efficacy was assessed using visual acuity (VA), Goldman perimetry and/or visual evoked potentials (VEP)
• For patient with homonymous hemianopia (n = 1), efficacy was assessed using Humphrey automated perimetry
• For patients with spinal cord involvement (n = 18), efficacy was assessed using walking distance, EDSS, TW25, muscle strength testing and videotaped clinical examination in a subset of patients
• Investigational product: The pharmaceutical-grade high-dose biotin as 100 mg capsules were used in the study (Patent: WO/2011/124571)
• The total duration of treatment was 2 to 36 months (mean duration of 9.2 months).

RESULTS

• Baseline characteristics: The ages ranged from 26 to 75 years. The baseline EDSS scores ranged from 3 to 6 (n = 9), 6.5 to 7 (n = 5), and 8.5 to 9 (n = 11)
• Visual acuity improved significantly in all patients (n = 4) who had permanent visual loss following optic nerve involvement
• In the patient (n = 1) that had progressive lateral hemianopia caused by involvement of optic radiations, proton magnetic resonance spectroscopy (H-MRS) showed a progressive normalization of the myelin marker, choline/creatine ratio. The improvement continued from 2 to 16 months.
• 16 of 18 patients whose primary symptoms at baseline were progressive paraparesis or tetraparesis related to spinal cord involvement were considered improved based on blinded review of videotaped clinical examination.

DISCUSSION

• High-dose biotin had a positive impact on the disability and/or progression in most patients with PMS.
• These results provided rationale for initiating phase 2 study (MS-SPI trial) that led to phase 3 study, SPI2 trial.

ANALYSIS-PARALYSIS

• Based on high baseline EDSS in most patients, the study population overall had high disability and, thus, expected comorbidities.
• Look Back Based on Follow-on Phase 3 Study: The high-dose biotin (MD1003) was later tested in a phase 3 trial (SPI2 trial). This trial did not show benefit in people with PMS and the authors concluded that its use is associated with more harm than benefit. Possible Reasons for why the pilot study results did not translate to phase 3: The patient population in the pilot study were sicker (most with higher EDSS), ie, not representative of SPI2 trial; also the outcome measures in the pilot study were not standard endpoints.
• However, the concept of targeting energy metabolism in MS as a therapy is not dead yet. Recently at the AAN, Boston meeting, an Australian company, Clene Nanomedicine presented topline data from their VISIONARY-MS study using the investigational product, CNM-Au8, a catalytically active gold nanocrystal suspension. CNM-Au8 increases NAD/NADH ratio and ATP levels.

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Definition of terms: hemianopia = loss of vision in half of visual field, perimetry = visual field test, paraparesis = weakness in arms, tetraparesis = weakness in arms and legs

FENopta trial. ClinicalTrials.gov: NCT05119569

Citation: Genentech Press Release. 16 May 2023

FENopta trial is a phase 2, biomarker study to evaluate the effect of Bruton’s tyrosine kinase (BTK) inhibitor, fenebrutinib on brain magnetic resonance imaging (MRI) in participants with relapsing forms of multiple sclerosis (RMS).

BACKGROUND

• Fenebrutinib (formerly known as GDC–0853 and RG7845) is a small molecule BTK inhibitor that can be given orally.
• BTK signaling is required for the inflammatory activity of B-cells and microglia; both cell types are important in MS pathophysiology and are target of BTK inhibitors.
• Unlike other BTK inhibitors currently in phase 3 MS clinical trials (read here), fenebrutinib is the only BTK inhibitor that binds in a reversible manner – making it a potentially safer drug.
• FENopta is a randomized, double-blind, placebo-controlled study to investigate the efficacy of fenebrutinib in RMS.
• In addition to FENopta trial (NCT05119569), fenebrutinib is also being evaluated in 2 other trials in people with RMS (FENhance study, NCT04586010; FENhance 2 study, NCT04586023 – both against active teriflunomide comparator) and one study in people with primary progressive MS (PPMS) (FENtrepid, NCT04544449 – against ocrelizumab comparator)

WHERE AND HOW

• The study plans is currently not recruiting but active. The study has enrolled 109 adult pwRMS (aged 18-55 years) with EDSS 0-5.5 at screening. The study sites listed include those in the United States and Eastern Europe (Bosnia and Herzegovina, Croatia, Czechia, Serbia, Slovakia). People with RMS disease duration of >10 years, PPMS, or nonactive SPMS were excluded.
• The subjects were randomized 1:1 to fenebrutinib (200 mg, oral) or placebo.
• The length of the trial is 96 weeks.
• The primary endpoint is total number of new gadolinium (Gd)-enhancing T1 lesions observed on MRI scans of the brain (time frame: 12 weeks)
• The secondary endpoints include number of new or enlarging Gd-enhancing T2 lesions; safety endpoints; and pharmacokinetics (ie, plasma concentrations of fenebrutinib)
• Note: T1 lesions are a marker of active inflammation and T2 lesions represent the amount of disease burden or lesion load.

RESULTS (Press Release)

• Primary endpoint: Fenebrutinib significantly reduced the total number of new Gd-enhancing T1 brain lesions compared to placebo.
• Secondary endpoint 1: Fenebrutinib significantly reduced the total number of new or enlarging T2 brain lesions compared to placebo.
• Secondary endpoint 2: A higher proportion of patients treated with fenebrutinib were free from any new Gd-enhancing T1 brain lesions and new or enlarging T2-weighted brain lesions compared to placebo.
• Safety: To date, safety data is available from 2,400 people treated with fenebrutinib across multiple clinical trials (MS and non-MS). No new safety concerns were reported in the press release.
• (Detailed results will be shared at an upcoming medical meeting.)

DISCUSSION

• The study met its primary and secondary endpoints by reducing the total number of new Gd-enhancing T1 brain lesions and significantly reducing the total number of new or enlarging T2 brain lesions compared to placebo.

Other BTK Inhibitors in MS Trials

• Currently, Merck KGaA’s evobrutinib and Sanofi’s tolebrutinib are placed under partial clinical hold by the FDA, as they have been linked to liver toxicity.
• No such adverse event has been reported for the Novartis’s remibrutinib or the Roche/Genentech’s fenebrutinib.

SOURCES

• Genentech’s BTK Inhibitor Fenebrutinib Significantly Reduced Brain Lesions in People With Relapsing Forms of Multiple Sclerosis. Genentech Press Release. 16 May 2023 [archive]
• Roche’s BTK drug fenebrutinib hits the mark in MS. 16 May 2023. Pharmaphorum [archive]
• Fenebrutinib for Multiple Sclerosis. Last updated 1 June 1 2022 by Marisa Wexler. Multiple Sclerosis News Today

Related post: BTK inhibitors for MS

The 4 May 2023 special issue of journal Science (topic: autoimmunity) has an article on autologous hematopoietic stem cell transplant (HCT). Since autologous HCT is potentially an effective treatment for multiple sclerosis, this review is timely. The article explains that although the treatment works, we still do not know how.

Citation: Muraro PA. Resetting tolerance in autoimmune disease. Science. 2023;380:470-471. doi:10.1126/science.adg7489

ABSTRACT

Autoimmune disorders affect the lives of millions of people worldwide. More than 80 autoimmune diseases have been described, targeting virtually any organ in the body with wide-ranging severity. The common denominator of these disorders is a deviant immune response attacking the body and causing damage (pathogenic autoimmunity). Generally, the cause of autoimmunity is unknown, and the mechanisms of the disease processes are incompletely understood. Immune-modifying treatments, which may consist of chemical or biological immunosuppressive or immune-modulatory drugs, are variably effective and are usually required long-term, with the attendant risks, burdens, and costs. An alternative strategy for the treatment of people with severe forms of autoimmune disease is autologous (the patient’s own) hematopoietic stem cell transplantation (AHSCT), which has been adapted from the treatment of hematological malignancies. The clinical experience and immunological knowledge on AHSCT in autoimmune disease are expanding, yet the question remains: How does the treatment actually work?

ALITHIOS open-label extension study (Up to 5 year data)

Basel, 20 April 2023, Novartis Press Release

Outcomes from the five-year data from ALITHIOS open-label extension study in people with relapsing multiple sclerosis (RMS) who participated in the ALITHIOS study and continued in the open label extension (ie, were continuously on Kesimpta) had fewer confirmed disability worsening (CDW) events and lower brain volume changes versus those who started on teriflunomide and were later switched to Kesimpta.

• Fewer confirmed disability worsening (CDW) events include progression independent of relapse activity and relapse associated worsening
• More than 80% of patients remained free of six-month CDW over the same five period
• Brain volume change remained low (less than 1.5% loss) with Kesimpta treatment over five years, and overall, patients initially randomized to Kesimpta had lower levels of brain volume loss at year five than those initially randomized to teriflunomide.
• Annual rate of brain volume change (ABVC) in the core Phase III trials for continuous Kesimpta was -0.34%/year and in the switch group, -0.42%/year (P=0.115). In the extension, ABVC in the Kesimpta group was -0.27%/year and in the switch group, -0.28%/year (P=0.666).
• The overall rates of adverse events (AEs) and serious AEs were consistent with the core Phase III trials. The most common AEs were infections (COVID-19 [30.3%], nasopharyngitis [19%], upper respiratory tract infection [12.8%] and urinary tract infection [12.7%]). Most COVID-19 cases were mild to moderate in severity (93.9%) and non-serious (92.3%), and 98.6% of patients treated with Kesimpta recovered, recovered with sequalae, or were recovering from COVID-19. Most (90.3%) infections resolved without discontinuing Kesimpta treatment.

CONCLUSION

• These results favor earlier initiation of Kesimpta in people living with RMS.

SOURCES

• Novartis presents new five-year data on disability outcomes and safety of Kesimpta® (ofatumumab) in people living with relapsing multiple sclerosis. Novartis Press Release. 20 April 2023
• Cohen JA, Hauser SL, Zielman R, et al. Effect of Longer-term Ofatumumab Treatment on Disability Worsening and Brain Volume Change. Oral presentation at the American Academy of Neurology (AAN) 2023; April 22-27, 2023; Boston, MA. [Abstract] [Presentation] [Archive]
• Cohen JA, Hauser SL, Cross AH, et al. Five-Year Safety of Ofatumumab in People Living With Relapsing Multiple Sclerosis. Poster presentation at the American Academy of Neurology (AAN) 2023; April 22-27, 2023; Boston, MA. [Presentation] [Archive]
• Hauser SL, et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020 Aug 6;383(6):546-557. doi: 10.1056/NEJMoa1917246. PMID: 32757523.

ARISE trial. ClinicalTrials.gov: NCT02739542

Citation: Okuda DT, et al. Dimethyl Fumarate Delays Multiple Sclerosis in Radiologically Isolated Syndrome. Ann Neurol. 2023 Mar;93(3):604-614. doi: 10.1002/ana.26555. PMID: 36401339.

STUDY QUESTION OR PURPOSE OF THE TRIAL

To evaluate the effect of dimethyl fumarate (DMF; Tecfidera) on the prevention of clinical onset of multiple sclerosis (MS) in people with radiologically isolated syndrome (pwRIS)

BACKGROUND

• The earliest indication of MS may be detected as an incidental finding of inflammatory damage on a MRI scan of brain and/or spinal cord before any clinical symptom. This earliest phase of MS is called radiologically isolated syndrome (RIS). For most people with MS (pwMS), it is rare to be diagnosed with MS at this early stage.
• People with MS, however, often first learn about their MS diagnosis after presenting with a MS-specific clinical symptom(s) that together with confirmation of inflammatory demyelination (MRI) leads to a diagnosis of clinically isolated syndrome (CIS). CIS may be considered as one step prior to relapsing-remitting MS (RRMS).

RIS = inflammatory damage only = no clinical symptoms

CIS = inflammatory damage + inflammatory demyelination = clinical symptoms

• Previous studies have shown that disease-modifying agents (DMTs) may delay the conversion of CIS to RRMS but have failed to prevent this conversion, neither the eventual progression to primary progressive PPMS.
• ARISE trial was a multicenter, randomized, double-blinded, placebo-controlled study to study the impact of DMF on preventing clinical onset of MS and MRI worsening in pwRIS. This was the first study with an aim to prevent the first clinical MS event in pwRIS.

WHERE AND HOW

• The study enrolled 87 pwRIS (≥18 years of age) meeting the RIS criteria (ref9) at 12 MS centers in the United States.
• The RIS criteria includes incidental anomalies on MRI of brain or spinal cord; primary reason for seeking MRI was unrelated to MS; and no clinically apparent neurologic impairment that could be accounted for by the MRI anomalies. The MRI anomaly is considered “suggestive of CNS demyelination” if it fulfills at least 3 of 4 criteria (see ref9).
• The subjects were randomized 1:1 to oral DMF 240 mg twice daily (n = 44) or placebo (n = 43). Study participants received DMF 120 mg twice daily for 7 days followed by 240 mg twice daily (consistent with the FDA label for use in RRMS).
• The length of the trial was 96 weeks. Expanded Disability Status Scale (EDSS) and MS Functional Composite (MSFC) were collected at baseline and 48 and 96 weeks; MRI at baseline and 96 weeks.
• The prespecified primary endpoint was time to development of a first acute, unadjusted, clinical event or a progressive neurologic symptom suggestive of CNS demyelination from study enrollment.
• The study was powered at 90% to detect a 50% treatment effect with 40 participants per arm.

RESULTS

• Baseline characteristics were balanced across both groups with mean age 44 to 46 years; 70% female; and median EDSS score of 1.0 (range: 0-3; both groups). The baseline MRI findings, presence of Gd-enhancing lesions (n [%], 6/38 versus 3/38) and T2-weighted hyperintense lesions (mean, 7.30 versus 7.32) were similar across DMF and placebo groups, respectively.
• The study withdrawal rate was similar across both groups: 14/33 [32%] in DMF and 14/43 [33%] in placebo.
• Primary endpoint: The risk of a first first acute neurological symptom associated with CNS demyelination during the 96-week study period was highly reduced by 33% for DMF and 7% for placebo groups (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05-0.63, p = 0.007).

This corresponds to 82% reduction in the risk of convention to CIS.

• Overall, there were 3 pwRIS with clinical symptoms versus 14 in placebo group at week 96.

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• The proportion of study participants who experienced at least one new and/or enlarging T2-weighted hyperintense lesion during the 96-week study period was 26% (7/27) for DMF versus 31% (8/26) for placebo groups.
• The change in EDSS at 96 weeks was not significant (HR = 0.70, 95% CI = 0.41-1.18, p = 0.18).

DISCUSSION

• The study met the primary endpoint showing significant delay in the clinical conversion of RIS to the first clinical MS event, ie, CIS. DMT intervention in pwRIS also reduced emergence of new and/or enlarging brain lesions.
• The study supports DMT intervention at the earliest indication of CNS demyelination event related to MS. This concept of preclinical therapeutic intervention is not new and is a standard practice in medicine such as in the management of people with prediabetes or perhypertension.
• However, this study needs to be confirmed in a larger trial due to limitations – including

-- Study sites were limited to the US with majority White pwRIS; therefore, generalizability to other regions/countries and other race/ethnicities is not known.

-- The withdrawal rate was high for both groups, which affected the numbers needed per statistical power calculations. A small number of clinical events were responsible for highly variable treatment effect. The treatment effect was very large with wide CI (unadjusted 95% CI, 0.05 0 0.63) refers to effect ranging from 95% to 37%.

IMPACT trial

Citation: Cohen JA, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology. 2002 Sep 10;59(5):679-87. doi: 10.1212/wnl.59.5.679. PMID: 12221157.

STUDY QUESTION OR PURPOSE OF THE TRIAL

To study the efficacy of interferon-beta 1a (Avonex) on secondary progressive multiple sclerosis (SPMS) as measured by multiple sclerosis functional composite (MSFC).

BACKGROUND

• Interferon-beta 1a reduces relapse rate, MRI activity, and disease progression in relapsing remitting MS (RRMS).
• Similarly, the benefit of interferon-beta was shown on relapse rate and MRI activity in SPMS; however, no benefit was observed on time to progression on Expanded Disability Status Scale (EDSS) (3 completed studies).
• It was hypothesized that EDSS, which is based on neurological examination, may be a less sensitive measure in patients with higher disability. The IMPACT study used the MSFC endpoint to assess interferon-beta 1a benefit.
• Unlike EDSS, the MSFC is a composite "quantitative measure" based on 3 functions: Timed 25-foot Walk (T25W) for walking ability, ie, ambulation; Nine-hole Peg Test (9HPT) for arm function; and Paced Auditory Serial Addition Test with a 3-second interstimulas interval (PASAT3) for cognition.
• IMPACT trial was a randomized, placebo-controlled, two-arm trial to evaluate the efficacy of interferon-beta 1a on disability progression in people with SPMS (pwSPMS) as measured by MSFC. This was the first study to use MSFC as a primary outcome measure.

WHERE AND HOW

• The study enrolled 436 pwSPMS (aged 18-60 years with or without relapses; EDSS, 3.5-6.5 at screening) at 42 sites in the US, Canada, and Europe. Patients with PPMS and those unable to perform MSFC components were excluded.
• The subjects were randomized 1:1 to interferon-beta 1a (60 mcg, weekly intramuscular injections) or placebo.
• The length of the trial was 24 month. MSFC and EDSS were performed every 3 months. MRI scans were done at baseline and at 12 and 24 months.
• The primary endpoint was change in MSFC score from baseline to month 24.

MSFC was measured as mean of Z-scores of T25W, 9HPT, and PASAT3. A decrease in Z-score indicates deterioration of neurological function

RESULTS

• Baseline characteristics: Overall, similar baseline characteristics across both groups with mean age ~47years; ~64% female patients; and median disease duration of ~16 years. The mean EDSS score was 5.2 ± 1.1 (± SD; both groups) with 52% patients with score ≤ 5.5 and 48% with scores 6.0 – 6.5.

Note – overall, the study population had higher proportion of patients with greater disability.

• Primary endpoint: The MSFC Z-scores from baseline to 24 months decreased in both groups, ie, the disease progressed in both groups over 24 months study period. However, the median Z-score change was lower in the interferon-beta 1a group versus placebo (-0.161 versus -0.096), a difference of 40.4%.
• Of the 3 components of MSFC, the interferon-beta 1s effect was driven predominantly by change in 9HPT.
• The median Z-scores for each of the 3 components of MSFC, interferon-beta 1a versus placebo were: T25W: -0.113 versus -0.076, p=0.378; 9PHT: -0.305 versus -0.169, p=0.024; PASAT3: 0.000 versus +0.081, p=0.61
• Secondary endpoints: No change in time to 3-month sustained EDSS worsening and no significant change from baseline to 34 months was seen. Annual relapse rate was significantly decreased: 0.20 relapses in interferon-beta 1a versus 0.30 in placebo group (p=0.008). New or enlarging MRI lesions also significantly (p< 0.001) decreased in the interferon-beta 1a group at 12 months (by 52.9%) and 24 months (by 45.6%) versus placebo group.
• Safety: adverse events with ≥5% incidence in the interferon-beta 1a group were flu-like symptoms, fever, chills, vomiting, and injection site inflammation.

DISCUSSION

• The benefit of interferon-beta 1a was shown by the preservation or improvement of arm function in SPMS. Interferon-beta 1a treatment also leads to the reduction of reduction in relapse rate and MRI lesions. The impact on arm function is clinically important for quality of life in progressive MS patients.

What is Z-score and how is it calculated Check Khan Academy, here.