Erica Slaughter, MS

Multiple sclerosis is a neurodegenerative disease in which the protective covering of nerves are eaten away by the immune system. However, a novel bioequivalent of dimethyl fumarate (Tecfidera) may soon be offering another treatment option for patients.

In November 2018, the US Food and Drug Administration (FDA) has granted tentative approval to Banner Life Sciences for its new drug application (NDA) for monomethyl fumarate (Bafiertam) delayed-release 95mg capsules, for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate is a novel bioequivalent of dimethyl fumarate (Tecfidera). According to the FDA, monomethyl fumarate met the required safety, efficacy, quality, and bioequivalence standards for approval.

Biogen, maker of Tecfidera, dismissed its lawsuit against Banner in September 2018, in which Biogen claimed that monomethyl fumarate would infringe on patents 7,320,999 and 8,399,514 related to Tecfidera. The FDA’s final approval of monomethyl fumarate is expected once Biogen’s current patent no. 7,619,001 for dimethyl fumarate expires on June 20, 2020.  

“We are very pleased with the FDA’s tentative approval and this important milestone brings us one step closer to providing another treatment option to patients living with relapsing-remitting multiple sclerosis,” Franck Rousseau, MD, CEO of Banner Life Sciences LLC, said in a 

. “In anticipation of final approval, we will establish our commercial vehicle, continue developing the clinical profile of monomethyl fumarate and refine our strategic positioning for this important drug.”

Monomethyl fumarate is a compound that can cross the blood-brain barrier. The precise mechanism of action has not yet been fully elucidated, but it is presumed to activate transcription factor known as the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway.

Tecfidera, the prodrug of monomethyl fumarate, is quickly converted from dimethyl fumarate into monomethyl fumarate in the body. Dimethyl fumarate has been shown in 2 separate studies to reduce the risk of relapse by 49% and 34%, and to reduce the number of relapses by 53% and 44%, compared to placebo.

The immunomodulatory properties of dimethyl fumarate have been demonstrated to alter the profile of the immune system by reducing the number of blood lymphocytes (particularly the pro-inflammatory subsets), and to block pro-inflammatory cytokine production.

“It’s similar but not completely the same as Tecfidera—it’s the same metabolite,” Douglas MacDougall, managing partner for MacDougall Biomedical Communications told 

®. “Monomethyl fumarate will compete with dimethyl fumarate as well as the other drugs that are currently FDA-approved for relapsing MS.  

The news of the FDA’s tentative approval for Banner Life Sciences’ NDA positions monomethyl fumarate to enter the market before any generic versions of dimethyl fumarate could be eligible to follow suit. At this time, nearly 30 companies have filed abbreviated NDAs to produce generic versions of Tecfidera, according to Rousseau, but none could bring them to the market sooner than September 2020.

MacDougall anticipates the launch of monomethyl fumarate on the market of available options for DMTs for RMS by early September 2020.

“We still have quite a bit of time to work out the positioning in the market. It could be July or it could be August, but most likely will be early September,” said MacDougall.

A key feature offered by monomethyl fumarate is its lower dose when compared to dimethyl fumarate. Whether a lower dose of a different application of this class of drug will result in fewer side effects is yet to be explored in a clinical trial.  

Articles

A novel bioequivalent of dimethyl fumarate (Tecfidera) may soon be offering another treatment option for patients with multiple sclerosis. 

Monomethyl Fumarate Challenges Multiple Sclerosis

Nonmyeloablative hematopoietic stem cell transplantation (HSCT) was associated with prolonged time to disease progression when compared to disease-modifying therapies (DMT) for patients with relapsing-remitting 

 (RRMS), according to results published in 

Journal of the American Medical Association (JAMA).

In a randomized controlled trial, participants who met inclusion criteria for the trial (N=110) were randomized into the HSCT group (n=55) and continuation of DMT group (n=55). There were no significant differences between the HSCT and DMT groups in terms of sex, age, baseline expanded disability status scale (EDSS) scores, number of gadolinium-enhancing lesions, T2-weighted lesion volume on MRI before randomization, number of prior DMTs, or type of prior DMT or immune treatments.

Participants in the DMT group received a DMT of higher efficacy or a different class than the therapy taken at the time of randomization (based on decision of their treating neurologist). For patients in the HSCT group, DMT use was discontinued, followed by variable washout periods before admission for HSCT.

Peripheral blood stem cells were collected 10 days after intravenous cyclophosphamide (2 g/m

) and 5 to 10 μg/kg per day of subcutaneous filgrastim beginning 5 days after cyclophosphamide. The immune ablative regimen was intravenous cyclophosphamide, 50 mg/kg per day on days −5 to day −2 before stem cell infusion (day 0) and rabbit antithymocyte globulin, .5 mg/kg on day −5, 1 mg/kg on day −4, and 1.5 mg/kg on days −3, −2, and −1. Blood products were irradiated, cytomegalovirus safe, and leukocyte depleted. Filgrastim (5-10 μg/kg per day) was started on day +4 and continued until engraftment.

The primary endpoint, defined as an increase in disease progression (EDSS score increase of ≥1) of at least 1 point on 2 evaluations 6 months apart after at least 1 year of treatment, occurred in 3 patients in the HSCT group and 34 patients in the DMT group, with a median follow-up of 2 years. The proportion of patients in the HSCT group with disease progression was 1.92% (95% confidence interval [CI], .27%-12.9%) at 1 year and 2 years, 5.19% (95% CI, 1.26%- 20.1%) at 3 years, and 9.71% (95% CI, 3%-28.8%) at 4 and 5 years.

The proportion of patients in the DMT group with disease progression was 24.5% (95% CI, 14.7%-39.1%) at 1 year, 54.5% (95% CI, 40.7%-69.4%) at 2 years, 62.5% (95% CI,48.3%- 76.7%) at 3 years, 71.2% (95% CI, 56.8%-84.2%) at 4 years, and 75.3% (95% CI, 60.4%-87.8%) at 5 years.

Mean EDSS score decreased (improved) in the HSCT group, from a pre-HSCT score of 3.38 to 2.36 at 1 year (mean change, −1.02 points), while the mean EDSS score increased (worsened) in the DMT group, from 3.31 to 3.98 at 1 year (mean change, +.67 points). The difference between the HSCT group and DMT group in the change in EDSS scores from baseline to 1 year was −1.7 (95% CI, −2.03 to −1.29; 

Notably, there was significant improvement in EDSS scores, NRS scores, and T2-weighted lesion volume percentages in the 31 patients who crossed over from the DMT group to receive HCST, suggesting that current definitions of progression for RRMS may not accurately assess irreversible disease progression for all patients.

Investigators noted this study was limited by its small sample size and the limited ability to collect follow-up data for patients receiving DMT and to assess longer-term secondary outcomes due to a study design that allowed patients in the DMT group in whom that treatment failed to cross over to receive HSCT.

HSCT is designed to eliminate autoreactive lymphocytes and “reboot” the immune system in a non-inflammatory environment. In an observational study of long-term disability outcomes of patients with relapsing and progressive forms of MS, researchers found that nearly half of these patients were free of neurological progression 5 years after receiving autologous HSCT

. Better outcomes were associated with younger age, relapsing form of MS, fewer prior immunotherapies, and lower EDSS score at baseline.

“We think what happens in HSCT is that the immune response is exposed to myelin in the absence of the danger signal,” Richard K. Burt, MD, principle investigator and chief, division of immunotherapy at Northwestern University's Feinberg School of Medicine in Chicago, Illinois, said in an interview with the National MS Society. “What we’re doing is stopping inflammation you need to treat when the disease in its inflammatory stage.”

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis

 Journal of the American Medical Association (JAMA).

[1] Muraro PA, Pasquini M, Atkins HL, et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. 

. 2017;74(4):459-469. doi:10.1001/jamaneurol.2016.5867

For patients in the HSCT group, disease-modifying therapies use was discontinued, followed by variable washout periods before admission for HSCT.
 

 Greater Benefits for Relapsing-Remitting MS Found with HSCT Therapy

Elevated acrolein levels may be a future diagnostic tool for multiple sclerosis (MS), according to a study published in 

In both urine and serum in patients with multiple sclerosis, acrolein levels were significantly elevated compared to healthy controls.

In an MS and experimental autoimmune encephalomyelitis (EAE) animal model, acrolein levels were also significantly elevated and inflicted damage to myelin, axolemma, and mitochondria—both directly and indirectly.

Systemic acrolein levels were determined through the quantification of 3-hydroxypropyl mercapturic acid (3-HPMA). Mean 3-HPMA levels were significantly elevated in the urine of 40 patients with MS (1.094 ± .212 μg/mg creatinine) relative to healthy controls (.570 ± .082 μg/mg creatinine, 

Results obtained in patient serum specimens corresponded with results obtained from urine analyses for both the MS group (.065 ± .009 μg/g protein) and the control group (.036 ± .004 μg/g protein), in which MS patients demonstrated a significant elevation compared to control (

Investigators noted that they feel these elevations represent augmented levels of immunological/inflammatory activity that preceded motor deficits in the animal model of MS. The possibility exists that elevation of a 3-HPMA could be used as a diagnostic and/or monitoring tool to associate and predict the emergence of MS symptoms.

“What we have so far is very preliminary,” David H. Mattson, MD, PhD, professor of neurology and director of the Neuroimmunology/Multiple Sclerosis (MS) Program at the Indiana University (IU) School of Medicine, told 

®. “We saw elevated acrolein in patients with MS that the controls did not have.”

Mattson added a more longitudinal study is needed in order to see if they can reproduce the idea that people with MS have elevated levels of acrolein compared to controls. Most importantly, investigators need find out whether the acrolein levels go up during an attack and back down during periods of remission, whether they go up over time with disability, or whether people with higher levels have—on average&mdash;worse disability.

“Does this acrolein correlate with attacks?” asked Mattson. “It’s indirect evidence, but still more suggestive that it’s a factor that might be causing some of the damage in MS.”

Although whether acrolein correlates with disease activity is a big “what if,” Mattson noted that it would be helpful since MRI scans are all that is currently available to monitor disease activity, which cannot be performed every week or even every month.

Blood tests that check for elevated acrolein levels in correlation with an exacerbation would be helpful for monitoring the disease since new lesions don’t always have a symptom attached to them. If the acrolein levels are going up, there could be a reason to think that there’s an attack about to happen, or that would help confirm an attack if there is clinical uncertainty.  

If the correlation between acrolein levels and MS activity is confirmed, acrolein may also serve as a therapeutic target for pharmacological intervention and treatment evaluation for a novel anti-acrolein therapy strategy in management of MS.

“If it turns out that acrolein is elevated during attacks, and then we think it’s causing part of the damage in attacks, the next question is whether the drugs will reduce the levels, and whether that’s helpful for the MS,” said Mattson.

Systemic Acrolein Elevations in Mice With Experimental Autoimmune Encephalomyelitis and Patients With Multiple Sclerosis

Acrolein levels were significantly elevated in urine and serum in patients with multiple sclerosis compared to healthy controls.

Elevated Acrolein Levels May Be a Future Diagnostic Tool in Multiple Sclerosis

Efficacy of ocrelizumab, a humanized anti-CD20 monoclonal antibody, was found to be superior to or comparable with 14 other disease-modifying therapies (DMTs) currently approved by the European Medicines Agency (EMA) forrelapsing 

 (RMS) in 7 network meta analyses (NMAs). Ocrelizumab also demonstrated a similar safety profile to each of the DMTs in the analysis.  

A systematic literature review was conducted in MEDLINE, Embase, the Cochrane Library, trial registers, relevant conferences websites, and health technology assessment agency websites by researchers at York Health Economics Consortium and Quantics Biostatistics. A total of 33 randomized controlled trials (RCTs) met the eligibility criteria of a trial duration of at least 12 weeks and evaluation of suitable interventions for a subject base in which at least 75% of patients had RMS. Key efficacy outcome variables of interest were the 12-week confirmed disability progression (12-week confirmed disability progression [CDP]) and annualized relapse rate (ARR).

The key safety outcomes of interest were severe adverse events (SAEs) and discontinuation of treatment due to an adverse events (AEs). Outcomes were analyzed using standard Bayesian approaches, as described in the NICE Decision Support Unit Technical Support Document (DSU TSD) 2. Two sensitivity analyses were conducted to evaluate the assumptions of the base-case NMA for each outcome.

Heterogeneity and inconsistency assessments were also conducted for base-case NMAs. Surface under the cumulative ranking curve (SUCRA) values were used to demonstrate the efficacy and safety profile of each treatment for the 2 key efficacy outcomes (12-week CDP and ARR) and 2 key safety outcomes (SAEs and discontinuation due to AEs).

Investigators found that ocrelizumab was more effective in reducing the risk of 12-week CDP compared to 10 other treatments, including placebo, with no evidence to suggest that any other treatment was more effective than Ocrelizumab. Analysis of the second key efficacy outcome showed that ocrelizumab was also found to be more effective in reducing ARR than 12 other treatments. There were no differences in SAEs or discontinuation due to AEs between ocrelizumab and other DMTs studied.

Ocrelizumab demonstrated a consistently high probability of ranking the most effective or tolerable treatment across all 4 outcomes when probabilities of the 2 key efficacy outcomes were plotted with the 2 key safety outcomes.

Limitations of using NMAs included the lack of RCTs that were statistically powered to analyze safety, and that SAEs and AEs were only recorded during trial periods. Short-term (12 week) results obtained from the RCTs may not be relevant for long-term outcomes.

The researchers concluded that “in the absence of head-to-head trials against other DMTs for the treatment of patients with RMS, this NMA provides important evidence on the relative efficacy and safety of ocrelizumab compared with other approved treatments for RMS. This evidence suggests that ocrelizumab has an efficacy superior to or comparable with all other current approved DMTs across all endpoints analyzed as well as a similar safety profile, indicating that it offers a complete and valuable package for the treatment of patients with RMS.”

Systematic review and network meta-analysis comparing ocrelizumab with other treatments for relapsing multiple sclerosis

Multiple Sclerosis and Related Disorders. 

Ocrelizumab demonstrated superiority to or comparability with 14 other disease-modifying therapies currently approved by the European Medicines Agency.  