Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Interferon beta-1b is a cytokine used for the treatment of relapsing-remitting multiple sclerosis (RRMS) and secondary-progressive forms of multiple sclerosis (SPMS). It is commercialized as Betaseron® (by Bayer) and as Extavia® (by Novartis).1,2 The US Food and Drug Administration (FDA) approved Betaseron in 19931 and Extavia in 2009.3
The use of Betaseron or Extavia is indicated for patients after a first MS attack. In clinically isolated syndrome (CIS), a single event occurs, and even though demyelination appears to be present, these patients frequently do not fit into the criteria supporting an MS diagnosis. This is the earliest clinical presentation of MS.4 Treating patients with Betaseron or Extavia can decrease the probability of the patients progressing into clinical definite multiple sclerosis (CDMS).5 Interferon beta-1b cytokine can reduce the frequency of attacks in RRMS patients while also reducing the number of brain lesions.1,2,5
The recommended dose is 0.25 mg administered subcutaneously every other day after a 6-week titration period. This protein is commercialized in vials for single use as a lyophilized powder for further reconstitution.1,2
Mechanism of Action
The mechanism of action of interferon beta-1b in MS is not known.2 Studies show that this protein presents a similar profile as interferon beta-1a, reducing neuron inflammation by regulating anti-inflammatory molecules, controlling the passage of pro-inflammatory molecules through the blood-brain barrier (BBB), and stimulating nerve growth factor synthesis.6,7
The use of interferons in MS therapy can lead to a significant reduction of relapses.5 There is, however, a percentage of patients who do not respond to interferon beta-1b administration. Patients may present genetic factors contributing to the inefficacy of the therapy, but a subset of these patients produces interferon beta neutralizing antibodies after treatment initializes.8
Interferon beta-1b presents subtle amino acid differences when compared to the naturally produced interferon-beta. These differences render the protein less biologically active. As higher doses of interferon beta-1b are necessary to induce a therapeutic effect, the chances of patients developing neutralizing antibodies then become significant.8 Other patients may not show any improvement during treatment; this may occur with RRMS patients who show a fast progression of the disease.9
Research on interferon beta-1b suggests that early treatment is beneficial for MS patients but that there is no correlation between its administration and a reduction in progression of disability.10
Warnings, Precautions, and Adverse Reactions
Interferon beta-1b can induce side effects such as changes in white and red blood cell count, seizures, headache, insomnia, hypertension, abdominal pain, myalgia, incoordination, and hepatic injury.1,2
Flu-like symptoms can also occur, as well as depression and suicide ideation.1,2 Reactions at the site of injection, including necrosis, typically occur in the first 4 months after administration.1
Efficacy in Clinical Trials
The clinical efficacy of interferon beta-1b has been assessed in different randomized, multicenter, double-blind, placebo-controlled studies involving patients with RRMS, SPMS, and CIS.1,2
Firstly, the beneficial effects of interferon beta 1-b were shown through a double-blinded, placebo-controlled study. Low (1.6 million international units (MIU)) and high (8 MIU) doses of interferon beta-1b were administered subcutaneously every other day.11
Results showed a lower relapse rate in the higher dose-treated group compared to the group of patients treated with a lower dose and to the placebo group. This trial was also the first to use magnetic resonance imaging (MRI) for evidencing MS lesions. Fifty-two patients were tested using MRI, which revealed that those individuals treated with higher protein doses presented a median reduction of 80% on MRI active scans.11 An extension of the trial for 3 years pointed to a disability decrease in comparison to the placebo-treated group.
Two long-term follow-up studies (16- and 21-years) relied on cognitive outcome measures by using symbol digit modality task (SDMT), paced auditory serial addition test (PASAT), and California verbal learning test II (CVLT-II). A reduction of 5.6% in the mortality rate of patients was observed as being the lowest in the group with the 8 MIU-administered dose.12-14 The 21-year trial (EVIDENCE) showed a decrease of 46.8% in long-term mortality when compared to the placebo group.14
Two multicenter, double-blind and randomized placebo-controlled studies allowed evaluation of the efficacy of interferon beta-1b in SPMS patients. Time to progression in the baseline Kurtzke expanded disability status scale (EDSS) was longer when compared to the placebo group, Similar to what was observed for the pivotal trial, a statistically significant reduction in the incidence of relapses was observed.1
In patients showing a single demyelinating event and MS lesions in the brain, interferon beta-1b led to a reduction in new active brain lesions. Additionally, the development of a second attack was delayed for patients included in the interferon beta-1b-treated group.1
1. Betaseron. Package insert. Bayer HealthCare Pharmaceuticals; 1993. Updated April 2016. Accessed June 13, 2021.
2. Extavia. Package insert. Novartis Pharmaceuticals Corporation; 1993. Updated July 2009. Accessed June 13, 2021.
3. Biologic License Application (BLA): 125290. US Food and Drug Administration. Accessed May 4, 2021.
4. Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol. 2005;4(5):281-288. doi:10.1016/S1474-4422(05)70071-5
5. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-1517. doi:10.1016/S0140-6736(08)61620-7
6. Walther EU, Hohlfeld R. Multiple sclerosis: side effects of interferon beta therapy and their management. Neurology. 1999;53(8):1622-1627. doi:10.1212/wnl.53.8.1622
7. Kieseier BC. The mechanism of action of interferon-β in relapsing multiple sclerosis. CNS Drugs. 2011;25(6):491-502. doi:10.2165/11591110-000000000-00000
8. Jakimovski D, Kolb C, Ramanathan M, et al. Interferon β for multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(11):a032003. doi:10.1101/cshperspect.a032003
9. Boster A, Edan G, Frohman E, et al. Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician. Lancet Neurol. 2008;7(2):173-183. doi:10.1016/S1474-4422(08)70020-6
10. Shirani A, Zhao Y, Karim ME, et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA. 2012;308(3):247-256. doi:10.1001/jama.2012.7625
11. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology. 1993;43(4):655-661. doi:10.1212/wnl.43.4.655
12. Ebers G, Reder A, Traboulsee A, et al. Long-term follow-up of the original interferon-β1b trial in multiple sclerosis: design and lessons from a 16-year observational study. Clin Ther. 2009;31(8):1724-1736. doi:10.1016/j.clinthera.2009.08.003
13. Reder A, Ebers G, Traboulsee A, et al. Cross-sectional study assessing long-term safety of interferon-β-1b for relapsing-remitting MS. Neurology. 2010;74(23):1877-1885. doi:10.1212/WNL.0b013e3181e240d014.
14. Panitch H, Goodin D, Francis G, et al. Randomized, comparative study of interferon β-1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;9(10):1496-1506. doi:10.1212/01.wnl.0000034080.43681.da
Reviewed by Kyle Habet, MD, on 7/1/2021.