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Non-approved treatments used for MS disease modification

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The U.S. Food and Drug Administration (FDA) provides regulations, guidelines and evaluation to assure that drugs, and vaccines and other biological products and medical devices intended for human use are safe and effective. The FDA has approved a number of medications for the treatment of relapsing forms of MS.  Individual response to these FDA-approved MS disease-modifying therapies (DMTs) is variable, and each DMT has contraindications, side effects and risks that restrict their use for some people. 

Over the past few decades, several medications that have FDA approval for diagnoses other than MS have been prescribed by doctors for the treatment of MS — also called “off-label” use.  For each of these medications there is some, but often limited, clinical trial evidence of efficacy.

Cellcept (mycophonolate mofetil)

Cellcept is an immunosuppressant taken by mouth twice daily.  It works by blocking an enzyme that is needed for certain white blood cells, specifically B- and T-cells to carry out an immune system attack.
  • Cellcept is FDA-approved for preventing rejection in patients receiving organ transplants.
  • It is used "off-label" to treat lupus, certain types of skin diseases, other immune system-related diseases, including MS.
CellCept has been studied as a monotherapy (use of a single drug to treat a disease or condition) and also in combination with other DMTs such as interferon-beta medications. The results suggest that Cellcept may reduce the annual number of MS relapses, limit new areas of central nervous system (CNS) damage and may slow disease worsening.

Side effects and risks include increased risk of infection (including opportunistic infections such as progressive multifocal leukoencephalopathy – PML), nausea, diarrhea, stomach pain, weakness, dizziness, difficulty sleeping, increased risk of skin cancer and lymphoma, stomach ulcers and bleeding, elevation in liver enzymes, yellowing of the skin (jaundice), can cause fetal death or malformations.

Cladribine

Cladribine is in a class of medications known as purine analogs. It works by stopping or slowing the growth of certain types of cells.
  • Cladribine is FDA-approved to treat hairy cell leukemia, which is a cancer of a certain type of white blood cell.
An oral formulation of cladribine has been evaluated in two phase 3 trials in MS.
  1. In a trial of people with relapsing-remitting MS, participants were randomized to receive one of two doses of cladribine or placebo. Both doses of the medications significantly reduced the rate of relapses, disease progression and disease activity as measure on MRI.
  2. In a trial involving people with clinically-isolated syndrome (CIS), participants were randomized to receive one of two doses of cladribine or placebo. Compared with placebo, both doses of cladribine significantly delayed the occurrence of new disease activity (and therefore the diagnosis of MS).
The medication was approved in 2010 in Russia and Australia but denied approval in Europe and the United States because of safety concerns.

In a large-scale study that analyzed the results of the phase 3 trials of all of the approved MS DMTs and of cladribine, no evidence was found of an increased cancer risk for cladribine. Based on these data, Merck has submitted a letter of intent to the European Medicines Agency (EMA) to apply for marketing authorization in Europe.

The most common side effect with cladribine is lymphocytopenia — an abnormally low level of a certain type of white blood cell in the body, which can increase a person’s risk of infections. In the clinical trials, different types of cancer were identified in the groups receiving cladribine.  This medication is known to cause fetal damage or death.

Cytoxan (cyclophosphamide)

Cytoxan is an immunosuppressant medication that is given intravenously or orally. It works by binding to cell DNA and thereby interferes with cell division and replication.
 
  • Cytoxan is FDA-approved for the treatment of various types of cancers.
  • It is used "off-label" to treat a number of autoimmune conditions such as Wegener’s granulomatosis, myasthenia gravis, lupus, rheumatoid arthritis and MS.
 
Several clinical trials in people with MS demonstrated a reduction in relapses, fewer new areas of CNS inflammation and a variable effect on disease worsening.
 
Side effects and risks include nausea, vomiting, hair thinning/loss, low white blood cell count, risk of infections, risk of cancers, infertility, inflammation of the bladder with bleeding, and fetal abnormalities.

Imuran (Azathioprine)

Imuran is an oral immunosuppressant drug that targets activation, proliferation, and differentiation of both T and B lymphocytes. 
  • Imuran is FDA-approved for use in combination with other medications to prevent organ rejection after kidney transplant and also for the treatment of active rheumatoid arthritis. It is used outside of FDA approval for conditions such as Crohns disease, ulcerative colitis, lupus, autoimmune hepatitis, neuromyelitis optica, myasthenia gravis and MS.
Imuran has been used in MS for over 30 years. Several clinical trials of Imuran as a monotherapy (use of a single drug to treat a disease or condition) and in combinations with other DMTs have demonstrated an effect on relapse reduction, new CNS inflammation and disease worsening.  Imuran is approved in parts of Europe for use in MS, but not in the US at this time.

Side effects and risks include abdominal pain, severe nausea, vomiting, loss of appetite, mouth sores/ulcers, increased risk of infection, hair loss, change in hair color and texture, risk of malignancies and blood abnormalities, and fetal abnormalities

Minocycline

  • Minocyline is an oral tetracycline antibiotic that is FDA-approved for the treatment of a number of different types of bacterial infection.
  • Minocycline is used "off-label" as a treatment for rheumatoid arthritis. Minocycline has also been studied in conditions such as osteoporosis, schizophrenia, cystic fibrosis and MS.
Minocycline has been studied in MS in combination with interferon beta-1a (Rebif) and in combination with glatiramer acetate (Copaxone) to determine whether adding minocycline to these DMTs provides added benefit.
  • Interferon beta-1a plus minocycline was found to be no more effective than interferon beta-1a plus placebo in time to first relapse, annualized relapse rate, number of new or enlarging T2 lesions on MRI, or change in brain volume.
  • Minocyline plus glatiramer acetate was found to be safe and well-tolerated, and reduced the number of T1 gadolinium-enhanced lesions, the total number of new and enlarging T2 lesions, and the total T2 burden of disease compared to minocycline plus placebo.
Side effects and risks include gastrointestinal problems, liver damage, mild to severe skin conditions, respiratory problems, kidney toxicity, muscle and joint pain, blood cell abnormalities, CNS disorders, and potential for fetal abnormalities

Rituxan (rituximab)

Rituxan is a monoclonal antibody (a protein made in the laboratory) that targets a specific protein on the surface of B-lymphocytes. B-lymphocytes are white blood cells that are known to cause inflammation and damage in MS. 
Rituxan is given by intravenous (into a vein) infusion. The first dose is given in two intravenous infusions that are separated by two weeks. This dosing regimen is then repeated every six months.
  • Rituxan is FDA-approved for the treatment of several other conditions including some cancers, rheumatoid arthritis and certain types of vasculitis (inflammation of the blood vessels).
  • In addition, it has been used “off-label” to treat several immune-mediated conditions, including neuromyelitis optica, Sjogrens syndrome and MS.
Several clinical trials have demonstrated that Rituxan is effective in reducing clinical relapses and limiting new inflammation in the CNS. It may also limit progression (worsening) of MS.
Side effects and risks include infusion reactions (symptoms that occur during or soon after an infusion), infections (including opportunistic infections such as PML), allergic reactions, headache, fatigue and anemia. Rituxan should be used with caution in pregnancy.

Statins

  • Statins are oral medications that are FDA-approved to lower cholesterol.
  • They have been used outside of FDA approval to treat conditions such as rheumatoid arthritis and are being tested in a variety of conditions such as cancer and MS.
Statins are being studied in MS because they are known to modulate the immune system and to help support the growth, health and protection of nerve cells.
  • They have been studied in combination with beta-interferon medications in relapsing MS, as a treatment for people with a first episode of neurologic dysfunction (clinically-isolated syndrome), and as a treatment for secondary-progressive MS (SPMS). Statins were not found to have a benefit as an add-on to beta-interferon medication or to reduce disease activity in people with relapsing MS or CIS.
  • One statin – simvastatin – was found to significantly reduce the annualized rate of brain atrophy compared to placebo in SPMS. Simvastatin was also found to be safe and well-tolerated.
Side effects and risks include headache, difficulty sleeping, flushing of the skin, muscle aches, inflammation and potentially severe muscle and kidney damage, weakness, drowsiness, nausea and vomiting, abdominal cramping or pain, bloating or gas, diarrhea, constipation, rash, and fetal abnormalities.
 

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