Multiple sclerosis drug pipeline

Since a theoretical model of the disease is hypothesized, until a drug appears that interferes with one of its pathways, several phases must be completed. First an animal model of the pathway to be studied must be developed, and the possible drugs that will be tried to interfere with it must be tried out. After that, three phases of human testing begin, and if everything works as expected, finally the drug will reach the status of approved by the regulatory agencies.

Approved medication

As of 2016, there are 10 active principles approved for RRMS and one for SPMS. Currently there is nothing approved for PPMS.

The approved drugs for RRMS are: Two interferons (interferon beta-1a and interferon beta-1b), glatiramer acetate, mitoxantrone, teriflunomide,^[1] dimethyl fumarate,^[2] one S1P modulator (fingolimod) and finally three monoclonal antibodies (natalizumab, alemtuzumab^[3] and since May 2016 daclizumab^[4][5]).

Only one of them, Mitoxantrone, has been approved for Secondary Progressive MS (SPMS) and for the special course of PPMS "rapidly progressive multiple sclerosis".^[6] There is no disease-modifying treatment for normal Primary Progressive (PPMS), but currently several new drugs are being tried out in clinical trials.

Cleared for review and fast track

When a company considers that there is enough information from clinical trial to fill an application, they submit to the regulatory agencies a request for approval. When the agency considers that the request is worthy to be evaluated they grant the state "under review" to the drug. Some regulatory agencies have special workflows for drugs that cover something uncovered, like the FDA fast track.

• Cladribine (under development by Merck Serono; anticipated brand name: Movectro) is an antineoplastic oral drug with immunosuppressive effects. It is already currently used as an intravenous infusion to treat hairy cell leukemia (leukemic reticuloendotheliosis). An oral version of cladribine is in phase III.^[7] The completion of the phase III program took place in early 2009 meeting its main endpoint with 58% relative reduction in annualized relapse rates with respect to placebo.^[8] Formal submission to European EMEA took place in middle 2009. In January 2010, researchers published in NEJM significant results of cladribine use in reducing relapsing course of multiple sclerosis.^[9] This drug was expected to be in the market in 2011 for use in multiple sclerosis patients.,^[10][11] but in 2011 the company decided to stop selling the tablets in Russia and Australia though it was already approved in this countries.^[12] Nevertheless, it seems that approval process continued in Europe and the EMEA has accepted a review process^[13]
• Ocrelizumab (proposed trade name Ocrevus), Anti-CD20 humanized monoclonal antibody, whose mechanism of action targets B-Cells, like Rituximab, currently having passed a phase III trial.^[14] As of 2016 the drug has completed already a phase III trial showing NEDA (No Evidence of Disease Activity) status achievement.^[15] Cleared for review in FDA and EMEA since 30/6/16 for relapsing and primary progressive MS.^[16]
• 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^[17] In March 2016 Ibudilast was designated a FDA fast track candidate for progressive MS^[18]

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 (EMEA) 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 2 years per patient.

• Angioplasty for chronic cerebrospinal venous insufficiency (the so-called Zamboni liberation procedure), currently in phase III.^[19] The treatment uses an inflatable balloon (instead of stenting) to open narrowed blood vessels in hopes of improving blood flow, based on the hypothesis that a compromised blood drainage system can debilitate the blood–brain barrier.^[20]
• Tovaxin (injectable) A vaccine against self T-Cells, which consist of attenuated autoreactive T cells. It is developed by Opexa Therapeutics, (previously known as PharmaFrontiers), and finished a phase IIb September 2008,^[21] failing its primary target though in March 2008 was still performing good.^[22] After several financial troubles, a phase III trial has been granted in 2011^[23]
• Siponimod, (BAF312) is a sphingosine-1-phosphate receptor modulator for oral use for MS. A phase III trial should run from Dec 2012 to Dec 2016.^[24]
• Masitinib, anticancer drug that blocks cell replication and immune responses^[25]
• MD1003 based on a highly concentrated dosis Biotin has also passed a phase III trial for progressive MS^[26]

Phase II

Phase II studies are performed on mid-sized groups of patients (20 to 300) and are designed to assess whether a drug may work 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.

• 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.^[27]
• Estradiol and estrogen receptors(ER): Both have been shown to be antiinflammatory and neuroprotective in a variety of neurological disease models and now is known that they work also in presence of inflammation^[28][29]
• Inosine: Inosine is a compound that has shown interesting preliminary results in phases I and II clinical trials.^[30][31] Two different mechanisms of action have been proposed. First, it produces uric acid after ingestion,^[32] which is a natural antioxidant;^[33] second, it has been shown to induce axonal rewiring in laboratory animals with stroke,^[34] and spinal cord injury.^[35] However it can cause health problems in a long-term treatment,^[36] mainly kidney stones.^[37] It seems that its mechanism of action is peroxynitrite inactivation^[38] Other reports point to an immune modulation^[39]
• Ofatumumab, other anti-CD20 monoclonal antibody, also in phase II for MS, and phase III for others autoimmune diseases
• 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.^[40] Earlier studies in the secondary-progressive stage of MS have failed to shown reversal of neurological symptoms.
• Amiselimod, S1P modulator^[41]

Phase I and animal models

Phase I and medicaments used in animal models would make a huge list. Here only some of them with special interest are listed.

• GIFT15 is a treatment which suppresses the immune system, and has been successfully used in the treatment of mice. The immune system attacks the central nervous system in Multiple Sclerosis patients. Specifically a "granulocyte-macrophage colony–stimulating factor (GM-CSF) and interleukin-15 (IL-15) 'fusokine]' (GIFT15) exerts immune suppression via aberrant signaling through the IL-15 receptor on lymphomyeloid cells. We show here that ex vivo GIFT15 treatment of mouse splenocytes generates suppressive regulatory cells of B cell ontogeny (hereafter called GIFT15 Breg cells)."^[42][43][44]

• Bosentan, endothelin-1 antagonist, has been proposed to lower the ET1 levels, which are involved in brain hypoperfusion^[45]

Research into progressive variants

Progressive variants are more difficult to treat than the Relapsing-Remitting course. Normally research for PPMS and SPMS goes together, being more difficult to treat PPMS. Therefore, we present here the research on SPMS with a mention to PPMS when applicable

Relapsing-Onset variants (RO), even when they turn into progressive, have proved easier to treat than Progressive-Onset variants. Though difficult to treat, Secondary progressive and progressive-relapsing are easier to treat than PPMS. Only Mitoxantrone has been approved for them, but most of the previous pipeline drugs have been or will be tried on it at some point. At this moment several therapies are under research:

• Cyclophosphamide (trade name Revimmune) is currently in Phase III for secondary progressive MS.^[46] It was also studied for RRMS but the company does not pursue actively this path. After a 2006 study for refractory cases it showed good behaviour^[47] Later, a 2007 open label study found it equivalent to Mitoxantrone^[48] and in 2008 evidence appeared that it can reverse disability.^[49]
• Simvastatin, a cholesterol-lowering statin, Simvastatin (Zocor), has shown good results in progressive variants^[50] This has shown brain atrophy reduction in secondary progressive MS.^[51] This drug is under research for PPMS and SPMS.
• Tcelna is currently under active research by Opexa, showing promising results.^[52]

Some PPMS patients with a special biomarker (Immunoglobulin M oligoclonal bands) have been shown to respond to standard RRMS medications, though there is only preliminary evidence waiting to be confirmed^[53]

Other possible treatments under research

• Antimicrobial agents against Chlamydophila pneumoniae: MS patients are more likely to have detectable levels of Chlamydophila pneumoniae DNA in their cerebrospinal fluid, compared to other patients with neurological diseases; however these findings are insufficient to establish an etiologic relation.^[54] Anecdotal reports of the use of antimicrobial agents against Chlamydophila pneumoniae are favorable, but only one double-blind placebo-controlled trial has been published, in which the number of patients studied was too small (four in each arm of the trial) to reach statistical significance in the primary outcome measure (volume of gadolinium-enhancing lesions, as viewed on MRI).^[55]
• Antioxidants, available as supplements, are reported to reduce the blood–brain barrier permeability.^[56] Related to this, MS patients have been reported to have low levels of uric acid, which is a natural antioxidant,^[57] and has been observed that raising uric acid levels protects against blood–brain barrier destruction (through peroxynitrite scavenging ).^[58] Peroxynitrite has been correlated with the axons degeneration and its removal can protect neurons from further damage after an attack. They can also remove other reactive oxygen species^[59] It is also known that uric acid levels decrease during the course of the disease^[60]
• Bilirubin has been found to have immunomodulatory properties, apart from the already known antioxidant properties, and is a possible future treatment.^[61]
• Use of drugs to suppress myelin-reactive effector memory T cells by blocking voltage-gated Kv1.3 channels in these cells.^{[62][63][64][65][66]}
• Hydralazine Due to its ability to damage myelin nerve sheaths, acrolein may be a factor in the development of multiple sclerosis. The antihypertensive drug hydralazine, a known scavenger of acrolein, was found to reduce myelin damage and significantly improve behavioral outcomes in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis).^[67]
• Helminthic therapy: A study showed a negative association between multiple sclerosis and infection with intestinal parasites, such as hookworm indicating that parasites may protect against multiple sclerosis.^[68][69] Helminth therapy involves ingesting helminth eggs by the names of Trichuris suis, which are non parasitic worms. This is done in hopes that the body will redirect the immune response away from attacking the myelin, which produce lesions, and target the helminths. The study by Dr Fleming shows this is affective in reducing the extent of lesions seen through MRI’s taken before and after the study.^[70]
• BCG vaccine: The common, live, attenuated vaccine against tuberculosis, has substantially reduced recurrence of symptoms in multiple sclerosis patients.^[71] The frequency of new enhancing lesions as detected by Gd-enhanced MRI was reduced by more than half in 12 patients, comparing the six-month run-in phase to the six-month post BCG phase of the experiment. Persistence at subsequent MR scan was reduced from 18 to 1 lesion, and evolution to black holes was reduced from 28 to 6 lesions.^[72] The conventional explanation of such protection is that parasites (including bacteria) modulate the sensitivity of the immune system. BCG appears safe as a treatment for multiple sclerosis.^[71][73]

• Low dose naltrexone is also known as LDN. Naltrexone, a pure opiate antagonist, licensed by the FDA for the treatment of alcohol and opioid addictions, is currently being studied at a lower dosage for MS patients. A small, short-duration clinical trial^[74] with MS patients was recently conducted at the University of California, San Francisco. In October 2007 data was presented at the European Congress of MS in Prague regarding safety findings of a pilot study of low dose naltrexone therapy in multiple sclerosis by neurological researchers in Milan, Italy.^[75] However, no compelling efficacy results for LDN in MS therapy have been published. LDN is currently available to MS patients in the USA by off-label prescription.
• Minocycline: the antibiotic minocycline has shown an effect on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in MS patients over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment relapse rate in patients in the study prior to treatment, no relapses occurred between months 6 and 24. The only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Clinical and MRI outcomes in this study were supported by systemic immunological changes and call for further investigation of minocycline in MS.^[76][77][78]
• Pixantrone: pixantrone (BBR2778) is an analogue of mitoxantrone devoid of toxic effects on cardiac tissue. It is as potent as mitoxantrone in animal models of MS; however results of human trials had not been published in 2007.^[79]
• Plasmapheresis. Pattern II MS lesions have been reported to respond to plasmapheresis,^[80] which points to something pathogenic into the blood serum, and the percentaje reported of pattern II is very close to the 47% reported in Kir4.1 MS cases,^[81] turning Kir4.1 patients into candidates for plasma exchange.
• Prolactin:In 2007 it was published that the hormone prolactin can ease the effects of demyelination in animal models of MS.^[82] This effect of prolactin may be the reason why pregnancy tends to reduce the effects of multiple sclerosis in women.^[83]
• Statins: a family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS.^[84] However, there is no evidence that statins are beneficial in the treatment of human MS patients, and concerns exist that, if ever shown to be effective, the high doses needed would prevent long-term use due to the potential for liver damage and muscle-wasting disease. One of them, Atorvastatin, has been tried in combination with several approved treatments, though with little success. Other, Simvastatin (Zocor) has shown good results in progressive variants^[85]
• Testosterone has been studied for its potential benefits in men with Multiple Sclerosis, but the results are preliminary.^[86]
• Vitamin D: a 2004 study found that women who took vitamin D supplements were 40% less likely to develop MS than women who did not take supplements. However, this study does not provide enough data to conclude that vitamin D has a beneficial influence on ongoing MS. Furthermore, it could not distinguish between a beneficial effect of vitamin D and that of multivitamin supplements including vitamin E and various B vitamins, which may also exert a protective effect.^[87] A new study in the same sense was published in 2013^[88]
• Omega-3 fatty acid: A study found that Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis^[89]

Combined therapies

Several combinations of drugs have been tested. Some of them are couples of approved drugs. Other tests try one approved drug with one experimental substance. Finally, at some point there could appear some trials testing couples of non-approved drugs.

As of 2016, there are 10 active principles approved which are: Two interferons (interferon beta-1a and interferon beta-1b), glatiramer acetate, mitoxantrone, fingolimod, teriflunomide,^[1] dimethyl fumarate^[2] and finally three monoclonal antibodies (natalizumab, alemtuzumab^[3] and since May 2016 daclizumab^[4][5])

Combination of approved drugs

• Mitoxantrone & Copaxone: A recent study in the United Kingdom revealed interesting results when using a combination of mitoxantrone and copaxone. In an open-label study of 27 patients with RRMS, the results suggested a rapid and sustained suppression of relapses. A three-year controlled study of 60 patients is now being launched at 10 centres across the UK.^[90] In another clinical trial, glatiramer acetate (Copaxone) has been combined with Mitoxantrone in such a way that every course of Mitoxantrone is followed by GA treatment. It has yielded promising results twice, in a consistent way.^[91][92]
• Tysabri & Copaxone This combination has been found to be safe and well tolerated after six months.^[93]
• Mitoxantrone & beta-interferon: This combination has worked in some cases but not in others^[94]
• Avonex & Copaxone: Currently in phase III, with good results published^[95]
• Interferon beta 1a & Tysabri: Dangerous but effective.^[96] Linked with PML, but is remarkable that Natalizumab alone is also linked with it.
• Natalizumab and Fingolimod. No formal research has been done, but some problems have been reported.^[97]
• Interferon beta 1a & Glatimer acetate: No additional benefits found^[98]
• Alemtuzumab & Copaxone: A combination trial of Alemtuzumab with glatiramer acetate (Copaxone) is being considered, and is expected to work synergistically.^[99]
• Laquinimod & Fampridine, with good results, subject to patent where applicable^[100]

Approved and experimental drugs combined

• Copaxone & Minocycline. Good results^[101]
• Avonex & Atorvastatin: Avonex (beta-1a) has also been combined with Atorvastatin in a clinical trial showing that is safe in its conditions,^[102] even though high-dose statins are expected to produce liver problems and muscle-wasting disease over the long-term.^[103] Other clinical trials have found problems combining IFN beta with Atorvastatin^[104]
• Betaseron & Atorvastatin: Betaseron (beta-1b) has also been combined with Atorvastatin with good safety results but poor performance. The combined treatment did not have any beneficial effects on RRMS compared to IFNB-1b monotherapy.^[105]
• Cyclophosphamide & Beta-interferon has been tried on IFNbeta-unresponsive patients with success, but it is still under study.^[106]
• Avonex & Inosine: Avonex (interferon beta-1a) was combined with Inosine. Available data suggests that this combination is safe and well tolerated, though with no improvements respect interferon beta alone.^[107][108] Recently the lack of additional benefits respect Avonex have been confirmed, and it has been reported that 2gr/day should be considered as the maximum safe dosage.^[109]
• Avonex & Lipoic Acid: Lipoic Acid is another common antioxidant^[110]

Summary table

Summarizing in a table which combinations have been tried:

Biomarkers for the expected response

Beta-interferons are contraindicated in cases of anti-AQP4 or anti-MOG seropositivity. Interferon injections can induce neutralising antibodies against them, turning the medication ineffective. IFN-β 1b is more immunogenic than IFN-β 1a, and the subcutaneous administration has a higher risk than the intramuscular administration^[112] Both interferons should induce MxA mRNA, being its absence a negative indicator^[113]

For Glatimer Acetate, the biomarkers for response are interleukins. IL-27 is a biomarker for response, and IL-18 and IL-4 are also possible good biomarkers^[114][115]

The best predictive biomarker for Mitoxantrone available is the number of relapses in separate areas within the past 24 months before treatment.^[116]

Natalizumab can also induce neutralising antibodies 4 to 6 months after treatment initiation. Fetuin-A (alpha-2-HS-glycoprotein) and circulating CD49 expression are emerging biomarkers for the therapeutic efficacy of natalizumab^[112]

References

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