(Interferon beta-1b) was  launched in 2009. Ronbetal® is the first domestic recombinant human interferon beta-1b medication approved for treatment of multiple sclerosis.

History of drug development

Treatment of patients with multiple sclerosis with recombinant human interferon beta 1-b stops or slows down the disease progression, prevents early invalidity and allows to significantly improve quality of patients’ lives. The regular supply and delivery of these drugs to patients remain the top priority for state and society. Nowadays due to extremely expensive drugs of interferon beta 1-b this problem may be solved only if we develop and use in medical practice highly efficient domestic drugs that are more accessible. About 20-25,000 US dollars have been spent by the state yearly to treat a patient with multiple sclerosis.

Considering crucial social importance of such a drug BIOCAD started developing domestic biosimilar.

2004
It’s «Bioindustry Initiative» that accounts largely for development of complex technology of recombinant human interferon beta-1b. The initiative was announced by the US State department that granted $1,7 mln to develop it. BIOCAD had to invest equal sum of money to develop first domestic biosimilar and one of the first biosimilars of interferon-beta-1b in the world.

2005
The interferon beta-1b producent strain, technology of its cultivation and downstream process of recombinant protein purification were developed.

2006
Medical formulation of recombinant human interferon beta-1b (Ronbetal®) was developed. The comparative physical and chemical tests of Ronbetal® and Betaferon were conducted.

2007
Preliminary clinical trials of Ronbetal® compared to original drug Betaferon proved equivalence and identity of the 2 drugs. The protocol of registration clinical trial was developed by experts from I. M. Sechenov Moscow Medical Academy. The protocol was discussed and approved at the meeting, held in March 2007, by the leading experts in multiple sclerosis under the Professior Alexey Nikolaevich Boiko’s supervision.

Monthly report issued by «Bioindustry Initiative» covered the event. (http://www.biistate.net/docs/newsletter/BIINewsletterMay2007.pdf

2008
The regulatory approval was issued in early 2008 to conduct clinical trial, that was also covered by monthly report «Bioindustry Initiative» (http://biistate.net/wp/wp-content/uploads/2008/10/bii-newsletter-may2008-080527a.pdf)

Spring 2008 saw the start of registration clinical trial of Ronbetal®  in  patients with  multiple sclerosis in 4 leading Russian medical centers.
The trial that was controlled, randomized, open, multicenter, clinical and was held in groups, assessed the efficacy, safety and tolerability of Ronbetal®  l (BIOCAD CJSC, Russia) compared to Betaferon (Schering AG, Germany) in patients with multiple sclerosis and lasted for 13, 5 months in the following medical centers:

• Scientific center for neurology under RAMS (chief researcher – Professor I.A. Zavalishin)
• Moscow city center for multiple sclerosis under State Clinical Hospital №11 (chief researcher – Professor A.N. Boiko)
• Clinics for neurological diseases treatment under I. M. Sechenov Moscow Medical Academy (Roszdrav) (chief researcher – academician N.N. Yakhno)
• Moscow regional scientific and research clinical institute named after M.F. Vladimirsky) (chief researcher – Professor S.V. Kotov)

2009
BIOCAD arranged a meeting of leading experts in neurology who participated in clinical trials of Ronbetal®  – first domestic recombinant humban interferon-beta to treat multiple sclerosis– on February 18, 2009 in State clinical hospital №11.

There were Professor A.N. Boiko, MD,  Moscow city center for multiple sclerosis, State Clinical Hospital №11. Professor I.A. Zavalishin, MD,  (Scientific center for neurology under RAMS), academician N.N. Yakhno, MD,  (Clinics for neurological diseases treatment of I. M. Sechenov Moscow Medical Academy (Roszdrav)), Professor S.V. Kotov (Moscow regional scientific and research clinical institute named after M.F. Vladimirsky).

Medical director Ivanov R.A. presented a survey. He touched upon the latest news and prospects of scientific and research projects developed by BIOCAD, provided the results of phase I, preliminary results of phase II of clinical trials and told about phase III peculiarities. He presented the detailed program to launch Ronbetal®  on market and social projects underway.

The neurologists got particularly interested in successful preliminary results of registration trial that confirmed Ronbetal®   efficacy and adequate tolerability among patients. They also were interested in social project aimed to supply significant amount of patients, that were left behind federal and regional programs on privileged drug provision with Ronbetal®.

After the event finished the doctors had a chance to communicate informally, share their experience and expertise in multiple sclerosis treatment and to discuss with BIOCAD representatives upcoming plans and researches on the drug.

The registration clinical trial of Ronbetal® was finished in May 2009.

All  researches who conducted trial signed the report on results of clinical trial which recommended and  approved Ronbetal® as means of treatment in medicine. Signed report about clinical trial of Ronbetal®.

The cost of Ronbetal preparation will be much lower than that of its foreign analogue Betaferon®. This would allow to reduce significantly spending money from the governmental budget for pharmaceutical supply for patients with multiple sclerosis.

The state registration procedures  to prove quality, efficiency and safety of the  Ronbetal® (recombinant human interferon beta-1b) finished in early September 2009. The registration certificate was issued by the Federal Service on Surveillance in Healthcare and Social Development (Roszdravnadzor) on September 17, 2009.

The company-distributor R-Pharm won the state auction for supply of interferon beta-1b medications under “7 nosologies program” from March till December 2010.
Ronbetal® was one of those medications to be supplied according to the action results.

2010
BIOCAD has started post-registration clinical trial: 120 patients in 7 research centers participate in it.

The protocol for surveillance during clinical studies over 2 years to monitor over 300 patients to be treated with Ronbetal®, has been worked out and approved.

The first supplies of the drug was made in February under “7 nosologies program” from March till December 2010.

Follow the link below for the registration certificate http://biocad.ru/files/RU_Ronbetal.pdf

PRESCRIBING INFORMATION RONBETAL®
Trade name:  Ronbetal®
International nonproprietary (generic) name:  interferon beta-1b
Pharmaceutical form: solution for subcutaneous injection

Contains:
1 ml of solution contains:
active substance:  human recombinant interferon beta-1b - 8  million international units (IU) (0.25 mg) or 16  million IU (0.5 mg).
excipients: mannitol, dextran, edetate disodium,
polysorbate 80, sodium acetate trihydrate, acetic acid, water for injection.

Description
Transparent, colorless or yellowish liquid.

Pharmacotherapeutic group: cytokine.
Medication for treatment of  multiple sclerosis.
ATX code: L03AB08

Pharmacological  properties 
Recombinant interferon beta-1b is manufactured by bacterial fermentation of Escherichia coli that bear a genetically engineered plasmid containing the gene for human interferon beta 1-b, which altered in a way that substitutes serine for the cysteine residue found at position 17. Interferon beta-1b has 165 amino acids and a approximate molecular weight of 18,500 daltons. 
Pharmacodynamics
Interferons (IFNs) are a family of naturally occurring proteins, produced by eukaryotic cells in response to viral infection and other biologic agents. Interferon beta-1b receptor binding induces the expression of proteins that are responsible for the pleiotropic bioactivities of interferon beta-1b (including neopterin, β2-microglobulin, MxA protein, and IL-10). Immunomodulatory effects of interferon beta-1b include the enhancement of suppressor T cell activity, reduction of pro-inflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system. It is not known if these effects play an important role in the observed clinical activity of interferon beta-1b in multiple sclerosis (MS).
Pharmacokinetics
Because serum concentrations of interferon beta-1b are low or not detectable following subcutaneous administration of 0.25 mg or less, pharmacokinetic information in patients with MS receiving the recommended dose of interferon beta-1b is not available. Following single and multiple daily subcutaneous administrations of 0.5 mg interferon beta-1b, serum interferon beta-1b concentrations were generally below 100 IU/ml. Peak serum interferon beta-1b concentrations occurred between one to eight hours, with a mean peak serum interferon concentration of 40 IU/ml. Bioavailability, based on a total dose of 0.5 mg interferon bata-1b given as two subcutaneous injections at different sites, was approximately 50%. After intravenous administration of interferon beta-1b,  serum clearance and half-life values were 30 mL/min•kg-1 and 5 kg respectively. Three-times-a-week intravenous dosing resulted in no accumulation of interferon beta-1b in sera of patients. Pharmacokinetic parameters after single and multiple intravenous doses of interferon beta-1b were comparable.
Following every other day subcutaneous administration of 0.25 mg interferon beta-1b, biologic response marker levels (neopterin, β2 - microglobulin, MxA protein, and the immunosuppressive cytokine, IL-10) increased significantly above baseline six-twelve hours after the first interferon beta-1b dose. Biologic response marker levels peaked between 40 and 124 hours and remained elevated above baseline throughout the seven-day (168-hour) study. The relationship between serum interferon beta-1b levels or induced biologic response marker levels and the clinical effects of interferon beta-1b in multiple sclerosis is unknown.

Indications
Ronbetal® is indicated for:
• Treatment of relapsing remitting multiple sclerosis to reduce the frequency and severity of clinical exacerbations .
• Treatment of secondary progressive multiple sclerosis to decrease rate of disease progression.

Contraindications:
• Hypersensitivity to recombinant interferon beta1-b or any other components of formulation.
• Hepatic failure.
• Severe depression and/or previous suicidal ideation. 
• Epilepsy.
• Pregnancy.

Precautions
Ronbetal® should be administered with caution for patients who had anamnesis of depression or seizures and patients who receive anticonvulsants. Also Ronbetal® should be administered with caution for patients with heart failure III-IV according to NYHA classification and for patients with cardiomyopathy. Exercise caution in patients with bone marrow pathology, anemia, thrombocytopenia. Safety and efficacy in pediatric patients have not been established.  

Dosing and administration
The recommended dose of Ronbetal® is 8 million IU injected subcutaneously every other day. Generally, patients should be started at 2 million IU  (25%) subcutaneously every other day, and increased over a six week period to 8 million IU (100%) every other day.

Table 1. Schedule for Dose Titration

Stability and Storage
Ronbetal® should be stored refrigerated between 2-8°C (36-46°F). DO NOT FREEZE.

How supplied
Ronbetal® is supplied as a sterile solution in vials with 1.0 ml/8 million IU per vial. One carton package contains 1 or 3 PVC blisters with 5 or 10 vials .
The package with vials is additionally supplied with:
- a single-use sterile 1.0 ml insulin syringes with 26G x 12mm needles 5, 10, 15 or 30 per package, respectively.
- a single-use sterile 30G x13 mm needles 5,10, 15 or 30 per package, respectively;
- a single-use sterile 29G x 8 mm needles 5,10, 15 or 30 per package, respectively;
- alcohol prep pads 10, 20, 30 or 60 per package, respectively.

Ronbetal® can also be supplied as a sterile solution in prefilled syringes with 0.5 ml/8 million IU per syringe. One carton package contains 1, 5 or 15 syringes in a PVC blister. 
One package with prefilled syringes is additionally supplied  with 1, 5 or 15 alcohol prep pads per package, respectively.

Special instructions
Ronbetal® is intended for use under the guidance and supervision of a physician. It is recommended that physicians or qualified medical personnel train patients in the proper technique for self-administering subcutaneous injections. Patients should be advised to rotate sites for subcutaneous injections. Concurrent use of analgesics and/or antipyretics may help ameliorate flu-like symptoms on treatment days. Ronbetal®  should be visually inspected for particulate matter and discoloration prior to administration.

Ronbetal Side Effects & Drug Interactions
During clinical studies of Ronbetal®  following side effects were revealed:
General reactions: Flu-like syndrome, fever, chills.
Injection site reactions: Injection site reaction, pain.
Cardiovascular system: Hypertension.
Blood and lymphatic system: Anemia, lymphopenia.
Metabolic, Alimentary abnormalities: Increase of thyrotropin, fourfold increase of hepatic enzymes.  
Neurological system: Anxiety.
Locomotor system: Myalgia.
Skin: Maculopapular rash.

The safety profiles for Ronbetal ® and original interferon beta-1b  were similar.
In all studies, the most serious adverse reactions with interferon beta-1b were depression, suicidal ideation and injection site necrosis. The incidence of depression of any severity was approximately 30% in both interferon beta-1b -treated patients and placebo-treated patients. Anaphylaxis and other allergic reactions have been reported in patients using interferon beta-1b. The most commonly reported adverse reactions were lymphopenia (lymphocytes < 1500/mm³), injection site reaction, asthenia, flu-like symptom complex, headache, and pain. The most frequently reported adverse reactions resulting in clinical intervention (e.g., discontinuation of interferon beta-1b, adjustment in dosage, or the need for concomitant medication to treat an adverse  reaction symptom) were depression, flu-like symptom complex, injection site reactions, leucopenia, increased liver enzymes, asthenia, hypertonia, and myasthenia.
The data described below reflect exposure to interferon beta-1b  in the four placebo controlled trials of 1407 patients with MS treated with 0.25 mg or 0.16 mg/m², including 1261 exposed for greater than one year. The population encompassed an age range from 18-65 years. Sixty-four percent (64%) of the patients were female. The percentages of Caucasian, Black, Asian, and Hispanic patients were 94.8%, 3.5%, 0.1%, and 0.7%, respectively.
The safety profiles for interferon beta-1b -treated patients with SPMS and RRMS were similar. Clinical experience with interferon beta-1b  in other populations (patients with cancer, HIV positive patients, etc.) provides additional data regarding adverse reactions; however, experience in non-MS populations may not be fully applicable to the MS population.
Table 2 enumerates adverse events and laboratory abnormalities that occurred among all patients treated with 0.25 mg or 0.16 mg/m² interferon beta-1b every other day for periods of up to three years in the four placebo controlled trials (Study 1-4) at an incidence that was at least 2.0% more than that observed in the placebo patients (System Organ Class, MedDRA v. 8.0).

Table 2 Adverse Reactions and Laboratory Abnormalities

Injection Site Reactions
In four controlled clinical trials, injection site reactions occurred in 78% of patients receiving interferon beta-1b with injection site necrosis in 4%. Injection site inflammation (42%), injection site pain (16%), injection site hypersensitivity (4%), injection site necrosis (4%), injection site mass (2%), injection site edema (2%) and non-specific reactions were significantly associated with interferon beta-1b treatment. The incidence of injection site reactions tended to decrease over time. Approximately 69% of patients experienced the event during the first three months of treatment, compared to approximately 40% at the end of the studies.

Flu-Like Symptom Complex
The rate of flu-like symptom complex was approximately 57% in the four controlled clinical trials. The incidence decreased over time, with only 10% of patients reporting flu-like symptom complex at the end of the studies. For patients who experienced a flu-like symptom complex in Study 1, the median duration was 7.5 days.

Laboratory Abnormalities
In the four clinical trials, leukopenia was reported in 18% and 6% [of patients in interferon beta-1b- and placebo-treated groups, respectively. No patients were withdrawn or dose reduced for neutropena in Study 1. Three percent (3%) of patients in Studies 2 and 3 experienced leukopenia and were dose-reduced. Other abnormalities included increase of SGPT to greater than five times baseline value (12%), and increase of SGOT to greater than five times baseline value (4%). In Study 1, two patients were dose reduced for increased hepatic enzymes; one continued on treatment and one was ultimately withdrawn. In Studies 2 and 3, 1.5% of interferon beta-1b  patients were dose-reduced or interrupted treatment for increased hepatic enzymes. In Study 4, 1.7% of patients were withdrawn from treatment due to increased hepatic enzymes, two of them after a dose reduction. In Studies 1-4, nine (0.6%) patients were withdrawn from treatment with interferon beta-1b for any laboratory abnormality, including four (0.3%) patients following dose reduction. 

Menstrual Irregularities
In the four clinical trials, 97 (12%) of the 783 pre-menopausal females treated with interferon beta-1b  and 79 (15%) of the 528 pre-menopausal females treated with placebo reported menstrual disorders. One event was reported as severe, all other reports were mild to moderate severity. No patients withdrew from the studies due to menstrual irregularities.

Postmarketing interferon beta-1b Experience
The following adverse events have been observed during postmarketing experience with interferon beta-1b and are classified within body system categories:
Blood and lymphatic system disorders: Anemia, Thrombocytopenia.
Endocrine disorders: Hypothyroidism, Hyperthyroidism, Thyroid dysfunction.
Metabolism and nutrition disorders: Hypocalciemia, Hyperuricemia, Triglyceride increased, Anorexia, Weight decrease.
Psychiatric disorders: Confusion, Depersonalization, Emotional lability.
Nervous system disorders: Ataxia, Convulsion, Paresthesia, Psychotic symptoms.
Cardiac disorders: Cardiomyopathy.
Vascular disorders: Deep vein thrombosis, Pulmonary embolism.
Respiratory, thoracic and mediastinal disorders: Bronchospasm, Pneumonia.
Gastrointestinal disorders: Pancreatitis.
Vomiting Hepatobiliary disorders: Hepatitis, Gamma GT increased.
Skin and subcutaneous tissue disorders: Pruritis, Skin discoloration, Urticaria.
Renal and urinary disorders: Urinary tract infection, Urosepsis.
General disorders and administration site conditions: Fatal capillary leak syndrome.
*The administration of cytokines to patients with a pre-existing monoclonal gammopathy has been associated with the development of this syndrome.

Drug Abuse And Dependence
No evidence or experience suggests that abuse or dependence occurs with interferon beta-1b therapy; however, the risk of dependence has not been systematically evaluated.

Drug interactions
Patients on interferon beta-1b therapy tolerated corticosteroids given for treatment of multiple sclerosis exacerbations well. Interferon therapy can inhibit hepatic cytochrome P450 activity and medications that have this metabolism pattern should be administered with caution (anticonvulsants). Exercise caution with combining interferons and medications that have an impact on blood coagulation. 

Warnings
Depression and Suicide
Interferon beta-1b should be used with caution in patients with depression, a condition that is common in people with multiple sclerosis. Depression and suicide have been reported to occur with increased frequency in patients receiving interferon compounds, including interferon beta-1b. Patients treated with interferon beta-1b  should be advised to report immediately any symptoms of depression and/or suicidal ideation to their prescribing physicians. If a patient develops depression, cessation of interferon beta-1b should be considered.
Injection Site Necrosis
Injection site necrosis (ISN) has been reported in 4% of patients in controlled clinical trials. Typically, injection site necrosis occurs within the first four months of therapy, although post-marketing reports have been received of ISN occurring over one year after initiation of therapy. Necrosis may occur at a single or multiple injection sites. The necrotic lesions are typically three cm or less in diameter, but larger areas have been reported. Generally the necrosis has extended only to subcutaneous fat. However, there are also reports of necrosis extending to and including fascia overlying muscle. In some lesions where biopsy results are available, vasculitis has been reported. For some lesions debridement and, infrequently, skin grafting have been required.
As with any open lesion, it is important to avoid infection and, if it occurs, to treat the infection. Time to healing was varied depending on the severity of the necrosis at the time treatment was begun. In most cases healing was associated with scarring.
Some patients have experienced healing of necrotic skin lesions while interferon beta-1b therapy continued; others have not. Whether to discontinue therapy following a single site of necrosis is dependent on the extent of necrosis. For patients who continue therapy with interferon beta-1b  after injection site necrosis has occurred, interferon beta-1b  should not be administered into the affected area until it is fully healed. If multiple lesions occur, therapy should be discontinued until healing occurs.
Patient understanding and use of aseptic self-injection techniques and procedures should be periodically reevaluated, particularly if injection site necrosis has occurred.

Anaphylaxis
Anaphylaxis has been reported as a rare complication of interferon beta-1b use. Other allergic reactions have included dyspnea, bronchospasm, tongue edema, skin rash and urticaia.

Laboratory Tests
In addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete blood and differential white blood cell counts, platelet counts and blood chemistries, including liver function tests, are recommended at regular intervals (one, three, and six months) following introduction of interferon beta-1b therapy, and then periodically thereafter in the absence of clinical symptoms. Thyroid function tests are recommended every six months in patients with a history of thyroid dysfunction or as clinically indicated. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis: Interferon beta-1b has not been tested for its carcinogenic potential in animals.
Mutagenesis: interferon beta-1b was not mutagenic when assayed for genotoxicity in the Ames bacterial test in the presence or absence of metabolic activation. Interferon beta-1b was not mutagenic to human peripheral blood lymphocytes in vitro, in the presence or absence of metabolic inactivation. Interferon beta-1b treatment of mouse BALBc-3T3 cells did not result in increased transformation frequency in an in vitro model of tumor transformation.

Impairment of fertility: Studies in normally cycling, female rhesus monkeys at doses up to 0.33 mg/kg/day (32 times the recommended human dose based on body surface area, body surface dose based on 70 kg female) had no apparent adverse effects on either menstrual cycle duration or associated hormonal profiles (progesterone and estradiol) when administered over three consecutive menstrual cycles. The validity of extrapolating doses used in animal studies to human doses is not known. Effects of interferon beta-1b  on normally cycling human females are not known.

Pregnancy-Teratogenic effects
Pregnancy Category C: Interferon beta-1b was not teratogenic at doses up to 0.42 mg/kg/day when given to pregnant female rhesus monkeys on gestation days 20 to 70. However, a dose related abortifacient activity was observed in these monkeys when Interferon beta-1b was administered at doses ranging from 0.028 mg/kg/day to 0.42 mg/kg/day (2.8 to 40 times the recommended human dose based on body surface area comparison). The validity of extrapolating doses used in animal studies to human doses is not known. Lower doses were not studied in monkeys. Spontaneous abortions while on treatment were reported in patients (n=4) who participated in the interferon beta-1b  RRMS clinical trial. Interferon beta-1b  given to rhesus monkeys on gestation days 20 to 70 did not cause teratogenic effects; however, it is not known if teratogenic effects exist in humans. There are no adequate and well-controlled studies in pregnant women. If the patient becomes pregnant or plans to become pregnant while taking interferon beta-1b, the patient should be apprised of the potential hazard to the fetus and it should be recommended that the patient discontinue therapy.

Pediatric Use
Safety and efficacy in pediatric patients have not been established.

Follow the link below for more information about Ronbetal® www.ronbetal.ru