There are several ways for pharmaceuticals for treating multiple sclerosis (MS) to reach the market.
Novel pharmaceuticals cannot enter the US market without FDA approval, which typically requires evidence of safety and efficacy in human trials and large fees be submitted to the FDA and found to be adequate.
Pharmaceuticals already on the market, such as vitamin D, do not have to and may never have had do so, and the financial incentives to do so are relatively insignificant. Thus lack of approval of such drugs implies neither efficacy nor lack of efficacy.
In general, novel pharmaceuticals cannot enter a market without government approval; standards and political influences vary. Approved medication
The typical path to approval in the 21st century may include basic research leading to understanding of mechanisms of disease progression and prevention such as chemical pathways, or candidate medications that aid or interfere with such pathways, which may be tested in vitro or in an animal model. Later, three typically sequential phases of testing in humans are common. Promising results regarding safety, efficacy, and side effects are generally needed at each major phase of development.
Usually the regulatory agencies approve a multiple sclerosis medication for a specific clinical course. Treatments for RRMS (relapsing-remitting), SPMS (secondary progressive), or PPMS (primary progressive) are common. Sometimes they approve it for a subtype, like highly-active MS (HAMS, inside RRMS), rapidly-worsening MS (RWMS, inside PPMS), or "active SPMS" (previous progressive-relapsing)Novartis press release about the approval of a drug for SPMS
Approved for relapsing-remitting
, the approved drugs for relapsing-remitting multiple sclerosis (RRMS) are:
Two interferons: beta-1a and beta-1b (injections) Three generic immunomodulators: Glatiramer acetate (Copaxone, injection) Teriflunomide (Aubagio), Monomethyl fumarate itself and its two precursors, which alters the NRF2 (nuclear factor erythroid 2(NF-E2)-related factor 2) transcription factor: Dimethyl fumarate (Tecfidera), Diroximel fumarate (Vumerity),Matthew Dodson et al., Modulating NRF2 in Disease: Timing Is Everything, Annual Review of Pharmacology and Toxicology, Vol. 59, January 2019, Review in Advance first posted online on September 26, 2018, https://doi.org/10.1146/annurev-pharmtox-010818-021856 approved by the FDA in October 2019. Active principal monomethyl fumarate itself, (Bafiertam), approved in April 2020. Four S1P modulators: Fingolimod (Gilenya), an oral treatment and the first oral therapy approved for multiple sclerosis. Siponimod (Mayzent), oral. Approved in March 2019 for CIS, RRMS and SPMSFDA approves new oral drug to treat multiple sclerosis in the US, Press release, Novartis receives FDA approval for Mayzent (siponimod), the first oral drug to treat SPMS with active disease, Press Release, Ozanimod: oral. It was approved by the FDA in March 2020 with the trade name Zeposia Ponesimod (Ponvory) Five monoclonal antibodies: Alemtuzumab (Lemtrada, Campath). Natalizumab (Tysabri) Ocrelizumab (Ocrevus) which is also approved for primary progressive (PPMS) Ofatumumab (Kesimpta) is another anti-CD20 monoclonal antibody. Ublituximab (Briumvi) was approved for medical use in the United States in December 2022, with the name Briumvi, for relapsing forms, clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive.
There are reports comparing these treatments in front of each other. Restricting the research only to relapses, it seems that alemtuzumab is the most cost effective while anti-CD20 monoclonal antibodies (Rituxan, Ocrevus) have the better safety vs. efficacy profileStephen L. Hauser, Jonah R. Chan, Jorge R. Oksenberg, Multiple sclerosis: Prospects and promise, Annals of Neur. 16 August 2013,
Approved for special courses
The courses primary progressive (PPMS) and secondary progressive (SPMS) are normally treated apart from RRMS. Besides, the regulatory agencies treat sometimes apart the cases aSPMS (Active Secondary progressive), nSPMS(non-active SPMS), HAMS (highly active) and RPMS (rapidly progressive)
Primary progressive: Ocrelizumab and mitoxantrone are the only approved drugs for PPMS. The last with restrictions. Secondary progressive (SPMS, nSPMS, non-active SPMS): Ozanimod, cladribine and mitoxantrone are approved for SPMS. The last with restrictions. Though approved for SPMS its profile is considered dangerous and is not always risk worthy Cladribine was approved also for SPMS (secondary progressive) in Europe in 2017 and by FDA in April 2019FDA press release, April 2019 with the name Mavenclad. Active SPMS (aSPMS, formerly progressive-relapsing): In the US, the approval of cladribine includes active SPMS (aSPMS, SPMS with relapses) in its approval. Also siponimod, ofatumumab and Ublituximab are approved for this special course "active SPMS" Highly active MS (HAMS): As of 2020, cladribine is the only drug specifically approved for HAMS. Rapidly progressive MS (RPMS): For aggressive MS or rapidly progressive multiple sclerosis only mitoxantrone is approved
Withdrawn medication
daclizumab Finally, after some reported deaths, it has been withdrawn by the regulatory agencies that had it previously approved.
Phase III Phase III programs consist of studies on large patient groups (300 to 3,000 or more) and are aimed at being the definitive assessment of how effective and safe a test drug will be. It is the last stage of drug development and is followed by a submission to the appropriate regulatory agencies (e.g., European Medicines Agency (EMA) for the European Union, the Food and Drug Administration (FDA) for the United States, Therapeutic Goods Administration (TGA) for Australia, etc.) to obtain approval for marketing. Treatment in MS Phase III studies is usually two years per patient. In July 2021, the FDA gave the go-ahead for an investigational new drug application (IND) for the phase 3 ENSURE program, which will evaluate IMU-838 in patients with relapsing-remitting multiple sclerosis (RRMS). Immunic also announced that a separate IND application for the supportive phase 2 CALLIPER trial of IMU-838 in patients with progressive multiple sclerosis has been cleared as well. The ENSURE program consists of two identical, double-blind, twin phase 3 trials, titled ENSURE-1 and ENSURE-2, designed to evaluate the efficacy, safety, and tolerability of IMU-838 in a 30-mg daily dose versus placebo in patients with RRMS. Approximately 1050 adult patients with active RRMS are expected to be enrolled in the studies and will be evaluated on time to first relapse as the primary end point. Both trials will run concurrently, with dosing of the first patient expected in the second half of 2021.2Hoffman, M. (2021). Pipeline update: Status of clinical development for multiple sclerosis. Neurology Livehttps://doi.org/10.1093/ajhp/zxad247
masitinib, anticancer drug that blocks cell replication and immune responses, It targets the innate immune system (mast cells and microglia) and has shown efficacy in the progressive courses. The appropriate pathway to put forward masitinib through the regulatory agencies, for the treatment of progressive forms of multiple sclerosis, is under studyAB Science Press release evobrutinib is a selective oral Bruton's tyrosine kinase (BTK) inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo. In phase III.Press release The results in phase III are much below expectations and the drug failed.Ludwig Burger: Merck KGaA suffers major blow as MS drug fails in late-stage trials. In: Reuters. 6 Decemvber 2023 tolebrutinib, in phase III but currently on hold.Sanofi press release Expected FDA submission on 2024Sanofi press release simvastatin, a cholesterol-lowering statin, has shown good results in progressive variants. This has shown brain atrophy reduction in secondary progressive MS. This drug is under research for PPMS and SPMS in phase III.
Phase II
Phase II studies are performed on mid-sized groups of patients (20 to 300) and are designed to assess whether a drug works in the targeted disease area, as well as to continue earlier safety assessments obtained in healthy volunteers. Treatment in MS phase II studies is with 4–12 months usually shorter than in phase III studies.
amiselimod, S1P modulator amiloride (Midamor) - Midamor is a sodium channel blocker. It can stop sodium from entering the nerve cells, which in turn reduces the release of calcium. Therefore, Midamor could have a neuroprotective function in MS patients ATL1102 (under development by Teva and Antisense therapeutics) is a second-generation antisense inhibitor of CD49d, a subunit of VLA-4 (Very Late Antigen-4). Results of a Phase IIa have been reported. CDP323 (under development by UCB S.A. and Biogen) is a compound for oral intake acting against α4-integrin, i.e., it has the same mechanism of action as natalizumab. Phase II investigations started in 2007.clinicaltrial.gov CDP323 Phase II Study. Retrieved on 25 November 2007. clemastine fumarate, also known as meclastin, is an antihistamine and anticholinergic drug. Between Jan 1, 2014, and April 11, 2015, it performed well in a Phase II clinical trial estradiol, estriol, and estrogen receptors(ER): Estrogens have been shown to be anti-inflammatory and neuroprotective in a variety of neurological disease models and it is known that they work also in presence of inflammation. Research in this area has focused on the efficacy of estriol as a treatment to reduce symptoms of relapse-remitting multiple sclerosis in non-pregnant women. ibudilast: A phase II trial shows that Ibudilast does not reduce lesion rate, but prevents them to turn into black holes. They classify its action as class III evidence of delay on disease activity In March 2016 Ibudilast was designated a FDA fast track candidate for progressive MS. Anyway as of 2020 is still on phase II. inosine: Inosine is a compound that has shown interesting preliminary results in Phase I and II clinical trials. Two different mechanisms of action have been proposed. First, it produces uric acid after ingestion, which is a natural antioxidant; second, it has been shown to induce axonal rewiring in laboratory animals with stroke, and spinal cord injury. However it can cause health problems in a long-term treatment, mainly kidney stones. It seems that its mechanism of action is peroxynitrite inactivation Other reports point to an immune modulation Stem cell transplantation was found feasible in a Phase I/II study in 21 patients with relapsing-remitting MS not responsive to interferon beta. It involves collecting some of the patient's own peripheral blood stem cells, giving low-intensity chemotherapy to eliminate auto-reactive lymphocytes, and then reinfusing the stem cells. Earlier studies in the secondary-progressive stage of MS have failed to show reversal of neurological symptoms. temelimab or Geneuro GNbAC1 - Monoclonal antibody against the viral The HERV-W envelope glycoprotein, which is supposed to be somehow pathogenic. It has passed a Phase IIb and a high dosis safety profile studyGeNeuro Announces Positive Results from Temelimab (GNbAC1) Phase 1 High-dose Clinical Trial, Press Release, In Phase IIbANGEL-MS Phase 2b extension study confirms and extends the neuroprotective effects of temelimab in MS, Press release, fluoxetine (Prozac) riluzole (Rilutek)MS society o Canada, press release https://mssociety.ca/research-news/treatments-in-development/amiloride-fluoxetine-riluzole orelabrutinibBiogen press release and fenebrutinib
Phase I and animal models Phase I and medicaments used in animal models include, but are not limited to: