Biological Therapies in Multiple Sclerosis

Biological therapies, also known as biologics, have revolutionized the treatments of chronic inflammatory conditions such as MS (multiple sclerosis) which were previously thought incurable.

These therapies work by targeting specific immune cells or proteins in the body that are involved in the inflammatory process that damages the nervous system in MS.

Biologic Therapies for Multiple Sclerosis

Management of multiple sclerosis is a continuously advancing area in neuroscience where newer studies are being done to provide the best drug to control the disease progression and reduce morbidity and mortality.

Besides steroids, biological therapies are the mainstay of treatment for MS nowadays. Except for a few side effects, biological therapies are very targeted and associated with much fewer side effects compared to corticosteroids.

Biologics for MS: Interferons:

Beta interferons are some of the commonest drugs used in multiple sclerosis. They are used to alleviate the frequency as well as the duration of acute relapses however they can cause flu-like illness and marrow suppression and have particular indications for which they can be used.

1. Relapsing-remitting disease in which the patient can walk 100 meters unaided.
2. Secondary progressive disease in which the patient can walk 10 meters unaided.

Some of the commonly used brands of interferons are:

1. Interferon Beta 1A is available under the brands Avonex and Rebif
2. Interferon Beta 1B is available under the brands Betaseron and Extavia
3. PEG-Interferon Beta 1A is available under the brand name Plegridy.

 Dosage and administration:

Interferon beta therapies FDA approved for the treatment of relapsing-remitting multiple sclerosis

Side Effects:

Its side effects range from mild flu-like illness to severe body aches and bone marrow depression to severe transaminitis.

Biologics for MS: Glatiramer Acetate:

Trade name: Copaxone

The way that COPAXONE (Glatiramer Acetate) works is by acting as an immune decoy, which means that it misleads the antibodies in the body away from the myelin sheath.

By doing so, it helps to prevent damage to the myelin sheath, which can occur when the body’s immune system attacks it.

Dosage

Copaxone comes in two prefilled syringes of 20 mg and 40 mg per mL. 20mg dose is given subcutaneously each day or 40mg dose is given three times a week 48 hours apart. It is usually administered around the belly button, arms, and thighs.

Side Effects

Its side effects include site administration lipoatrophy, flu-like illness, headaches, nausea, and occasional diarrhea. Diplopia, chest tightness, opportunistic infections, vaginal candidiasis, and hepatitis can occur commonly.

Drug interactions are not studied in many trials for this drug.

Its use in pregnancy and lactation in humans is not studied yet however animal trials have shown no adverse effects.

Biologics for MS: Cladribine:

Cladribine is a synthetic purine analog that belongs to the class of anti-metabolite and anti-pyrimidine agents.

The discovery of cladribine’s potential as a treatment for multiple sclerosis (MS) came about incidentally when scientists observed that adenosine deaminase (ADA) deficiency caused the destruction of B-cell lymphocytes by leading to the accumulation of deoxynucleotides in the cells [Ref].

This discovery lead to the hypothesis that Cladribine could be used as a selective immune reconstitution therapy (SIRT) for MS.

Compared to other maintenance therapies for MS that result in long-term immunosuppression, cladribine acts as a short-term immunosuppressant.

It underwent several stages of regulatory approval before Merck-Serono released data from the Cladribine Tablets Treating MS Orally (CLARITY) trial in 2008, which demonstrated the drug’s effectiveness and safety for treating MS.

The following table summarizes the regulatory approval timeline for cladribine:

Mechanism of action of Cladribine:

Cladribine selectively disrupts T-cell (cell-targeting) and B-cell (humoral) immunity by mimicking severe immunodeficiency disorder.

When present in high concentrations within cells, it increases the expression of deoxycytidine kinase (DCK), ultimately resulting in lymphocyte apoptosis.

How to administer Cladribine:

Cladribine is an orally administered drug used for the treatment of multiple sclerosis. The FDA-approved dosing regimen involves the administration of 3.5 mg/kg of cladribine over the course of two years, with two treatment courses separated by a twelve-month interval.

During the first treatment course, the drug is given over four to five consecutive days in the first month, followed by an equivalent dose over four to five consecutive days in the second month.

The second treatment course of cladribine follows the same frequency and dosing schedule as the first and is administered twelve months later.

The recommended dosing for an adult of average body weight is estimated to be approximately 10 to 20 mg daily for 4 to 5 days.

However, prescribers must follow the manufacturer’s specific guidelines for weight-based dosing in accordance with the approved federal guidelines of the Risk Evaluation and Mitigation Strategies (REMS) program.

To ensure the safe remission of the disease without severe lymphopenia or other adverse events, patients receiving cladribine therapy must be monitored regularly. The table below summarizes the recommended monitoring schedule:

Side effects of Cladribine:

• Lymphopenia
• Headaches
• Herpetic infections
• Nasopharyngitis
• Alopecia
• Increased risk of malignancy.

Contraindications to Cladribine use:

• Hepatic cirrhosis
• CKD (chronic kidney disease)
• Active HIV
• Active Tuberculosis
• Concomitant use of immunosuppresants like Cyclophosphamide, Azathioprine

Biologics for MS: Fingolimod:

Fingolimod is a medication that modulates sphingosine 1-phosphate receptors and is indicated for the treatment of relapsing-remitting multiple sclerosis (MS).

It has also been studied for its potential to manage lung complications associated with COVID-19.

Mechanism of action:

Fingolimod is a medicine that is used to treat a type of multiple sclerosis called relapsing-remitting MS.

It works by binding to certain receptors in the body and preventing lymphocytes from leaving the lymph nodes.

This reduces the inflammation that causes MS symptoms. The exact way that fingolimod works is not completely understood, but it may also prevent lymphocytes from entering the central nervous system.

Absorption:

Fingolimod is slowly absorbed with a bioavailability of about 93%. It reaches its steady state concentration within 1 to 2 months.

Route of administration and elimination:

It is taken orally. Most of the drug is excreted via the kidneys as inactive metabolites. Only about 2.5% gets excreted in the feces.

Adverse effects:

• Hypotension
• Tachycardia
• Nausea
• Diarrhea
• Indigestion
• Cardiomyopathies

Drug interaction: 

Fingolimod can interact with other immunosuppressants leading to disturbance in half-life.

It is present in 0.25 mg or 0.5 mg pills.

Biologics for MS: Natalizumab:

Natalizumab is a monoclonal antibody that specifically targets alpha 4 integrin subunits, thereby inhibiting immune cell migration. It is indicated for the treatment of Crohn’s disease and multiple sclerosis.

Brand name: Tysabri

Mechanism of action:

This drug attaches to the α4 subunit of α4b1 and α4b7 integrins found on the surface of all leukocytes except neutrophils. It inhibits the adhesion of leukocytes to their counter-receptors that is mediated by α4.

Route of administration: Intravenous

Dosage: 150mg/15mL, 300 mg/15 mL

Adverse effects:

• Opportunistic infections
• Transaminitis
• Progressive multifocal leukoencephalopathy
• Headache
• Dizziness

Biologics for MS: Alemtuzumab:

Biologics for MS: Ocrelizumab:

Biologics for MS: Ofatumumab:

Biologics for MS: Dimethyl fumarate (Tecfidera):

Biologics for MS: Teriflunomide (Aubagio):

Biologics for MS: Siponimod:

Summary of Biologics for MS: