NIR Research and Product Company Kiev, Ukraine (стр. 1 )

NIR Research and Product Company

Kiev, Ukraine

BIPEXUM®

KIEV-2003

TABLE OF CONTENTS

INTRODUCTION.................................................................................................................................................... 3

RESULTS OF CLINICAL TRIALS OF THE DRUG BIPEXUMâ BASED ON ACADEMY OF MEDICAL SCIENCES OF UKRAINE’S PRACTICAL RESEARCH CENTRE OF ENDOVASCULAR NEURORADIOSURGERY....................... 4

1. Investigational Mission and Rationale........................................................................................................ 4

2. Test Method..................................................................................................................................................... 5

3. Patients’ Clinical Characteristic.................................................................................................................... 5

4. Investigational Methods................................................................................................................................ 5

5. Results of Bipexum’sâ Clinical Use in Neurooncology............................................................................. 5

6. Clinical Assay to Measure Bipexum’sâ Clinical Efficacy........................................................................ 7

7. Conclusion...................................................................................................................................................... 10

BIPEXUM® INJECTION POST-LICENSE USE. BACKGROUND USE OF BIPEXUM® IN NEUROONCOLOGY 12

USE OF THE DRUG BIPEXUM® IN TREATING BRAIN AND SPINAL CORD METASTASES........ 17

ASPECTS OF TREATING MALIGNANT LYMPHOMAS............................................................................ 18

Bipexum®: Medical Instructions......................................................................................................................... 21

INTRODUCTION

Bipexumâ, a drug of biological descent, contains the optimal set of free amino acids, native peptides and products of the controlled proteolysis of the bovine embryo brain proteins.

Experimental studies of the way Bipexumâ effects metastatic processes were done by the Academy of Sciences of Ukraine’s Institute of Experimental Pathology, Oncology and Radiology.

This suggested the following Conclusions:

1. Bipexumâ has apparent anticancer activity in the experiment using different modes of administration at widely scattered doses (45 to 200 mg/kg): around 90 % inhibited tumour growth in two tumour strains (breast adenocarcinoma – 88.5 %, Guerin’s carcinoma – 89.7 %); over 80 % inhibited tumour growth in two strains (sarcoma – 85.9 %, Pliss' lymphosarcoma – 83.5 %). Modelled leukemic processes showed life expectancy to extend by 95 %.

The above effect has been observed along with great per cent of animals’ primary recovery.

As tested by sub-capsular method, II and III gliomas display signalled Bipexumâ susceptibility.

Bipexumâ has evident anticancer action vis-a-vis metastatic processes that are fully (100 %) suppressed.

Bipexumâ safety studies in line with applicable requirements demonstrated that neither the drug’s ‘acute’ nor ‘chronic’ action promotes any manifesting clinical variations.

The total body of observational findings suggests that the drug has neither skin-resorption nor toxic-when-inhaled action. It has no cumulative carcinogenicity. Bipexum’sâ formulation method assumes it to have neither embryolethal nor mutagenic properties.

Given subtle interspecies difference in indices of toxic response, as well as the value of species sensitivity factor, Bipexumâ has no apparent species sensitivity, so the experimental data can be extrapolated to humans.

RESULTS OF CLINICAL TRIALS OF THE DRUG BIPEXUMâ BASED ON ACADEMY OF MEDICAL SCIENCES OF UKRAINE’S PRACTICAL RESEARCH CENTRE OF ENDOVASCULAR NEURORADIOSURGERY

1. Investigational Mission and Rationale

As proved by the up-to-date knowledge gained from treating glial brain cancers, mere surgical intervention can not be expected to be a way to prolonged and sustainable remission. Life expectancy of patients that had nothing but operations makes an average of 6 to 9 months.

Given the above, finding ways to enhance clinical performance in curing brain cancers gains earnest priority. As cancer neurosurgeons have it, the most feasible method is to give the said patients combined therapy involving surgical intervention followed up with antiblastic chemotherapy, beamed radiation exposure along with immunostimulation, hyperglycemia and other adjuvant methods.

To come up with agents and methods to combat malignant brain neoplasms is one of primary neurooncological missions. Research to accomplish these ends builds on the most signal achievements in natural sciences, in the first place, molecular biology, biochemistry and pharmacology, and incorporates strengthening efforts related to eliminating and inhibiting proliferation of tumour cells by influencing its various metabolic fates (alkylating agents, antimetabolites, vegetable drugs, enzymes, etc.). Presently, drugs belonging to the said groups provide a basis for the state-of-the-art pharmacotherapy combating malignant neoplasms.

Over the last few years, regulators of proliferative processes, inter alia, those neoplastically transformed, have gained prominence in treating cancers. These are hormone-like drugs, growth factors, interferons, paraoncotropics, differentiation inducers, mutagenic signal transmittance blockers having different mechanisms of action. Immunomodulators have special reputation as oncostatics. Domestically-made drugs such as Propesumâ proved themselves in oncotherapy.

As proved experimentally, Bipexumâ is a low-toxic drug having biological activity that signals specific stimulation of protective and adaptational mechanisms in organs and systems by influencing the macrophagic system.

Based on experimental results, however administered, Bipexumâ also has overt anticancer activity (80 % to 90 % inhibited tumour growth) at widely ranging doses (45 mg/kg to 200 mg/kg). The said effects are observed together with attaining large percentage of primary recovery in animals.

Bipexum’sâ cell and molecular mechanisms of action have been studied to demonstrate that, as tested by the sub-capsular method, II-III gliomas display sharply signalled susceptibility to the drug by betraying greatly damaged cancer. Histologically, ‘cured’ gliomas show widely ranging cytotoxic transformations and disorganised microarchitectonics of the glioma’s tissue.

The first phase findings of clinical study showed that Bipexumâ is well tolerated and, not occasionally, improves habitus.

2. Test Method

Open investigation has been conducted by treating 74 patients having brain cancers. Fifteen of these were given therapy by the neurosurgical division in the employ of the I. I. Mechnikov Dnepropetrovsk Oblast Clinical Hospital. Results of the said investigation were used to optimise getting to the meaning of the obtained data. The patients received inpatient therapy. The control group of 40 patients with brain cancers was given either chemotherapy or radiation therapy.

3. Patients’ Clinical Characteristic

a) subjective data.

Complaints of general weakness, sleepiness, headache, nausea.

b) objective data.

Diagnosis was made based on clinical findings, CAT, MR-scanning, cerebral angiography and echoencephalography.

4. Investigational Methods

The effort was put forth using the following investigational methods:

1. clinical assays: complete blood count and urine test, liver function tests, total protein, protein fractions, sulphhydryl groups, blood electrolytes, hematocrit, sugar, creatinine, immunologic indices;

2. using clinical instrumentation: computerised axial angiography performed on everybody concerned once two months;

3. mathematical methods employed to process laboratory test findings.

5. Results of Bipexum’sâ Clinical Use in Neurooncology

Bipexumâ was administered to combat histologically proved neuroectodermal (glial) brain II-III cancers as identified by the international histological C. N.S. cancer classification. They largely consisted of anaplastic astrocytomas (51 %) and histoblastomas (33 %). Once in a while, cancer-metastasised anaplastic oligodendrogliomas and medulloblastomas were diagnosed.

Bipexumâ has been administered to 74 patients with brain cancers, the figure that was made of 28 women and 46 men at 4 to 64 years of age. Most patients were given multimodality therapy involving surgical removal of cancer and Bipexumâ cure along with chemotherapy (57 individuals) with drugs broteofin, chlofiden and belustin. Given deep-seatedness and no hypertension syndrome betrayed, 17 patients received no operative therapy. Also gamma telemetry was performed on 33 patients.

Two millilitres of Bipexumâ were administered intramuscularly starting from 5-7 days after surgical intervention. The total dose was 20 ml. Administrations were intermitted every 24 hours.

Therapeutic effectiveness was assayed based on how life expectancy extended, as well as what was found out by scanning the dynamics of the clinical presentation of the disease, neuroophtalmological monitoring (normalised picture of vessels of the fundus of eye), MR-scanning, CAT (further growth not signalled) and echoencephalography.

The investigational effort showed that condition of the control group receiving no Bipexumâ naturally deteriorated in the course of radiation and chemotherapy that appeared in increasingly aggravated obnubilation, poor appetite, nausea, vomiting, general weakness.

Habitus was fairly good and moderately impaired. As receiving the drug therapy, patients showed no aggravated condition.

After Bipexumâ therapy, based on CAT and MR-scanning, brain edema and dislocation syndrome got relieved, appetite was invigorated and motor performance came into view.

One female patient was prevented from being given the drug therapy because of post-operative complications and eventual death.

Five patients relapsed 3 months after performing the operation for sub-total cancer removal.

Example 1.

Patient Y. having case history No. 958/98 was admitted to the Centre complaining of headache, nausea, vomiting. Investigations, inter alia, angiography, CAT, MR-scanning, were carried out to display large cancer in the left temporal region (II-III anaplastic astrocytoma). Post-operatively, he received Bipexumâ and broteofin. Relapse occurred in 3 months. The similar outcome was the case with another 3 patients. Given this, the said two drugs were not administered in combination any more.

Example 2.

Patient P. having case history Nos. 404/97 and 3074/98 was admitted to the Centre complaining of epileptic episode and headache. Investigations were carried out to display cancer in the left frontal lobe invading median structures (II-III anaplastic astrocytoma). Post-operatively (operation for sub-total removal of cancer), he received Bipexumâ and chlofiden. Thenceforth, no signs of positive tumour growth were observable. Other patients relapsed in 6 to 10 months.

6. Clinical Assay to Measure Bipexum’sâ Clinical Efficacy

The way Bipexumâ therapy influenced the status of blood profile factors in brain cancer patients was studied to display marked alterations neither in haemoglobin, number of erythrocytes / leukocytes nor ESR (table 1).

Table 1

The Way Bipexumâ Therapy Influences the Status of Blood Profile Factors in Brain Cancer Patients

No.	Factors	Before Therapy, М±m	After Therapy, М±m	Р	Control Group, М±m	Р
1	Haemoglobin, g/l	142.55 ± 2.48	140.95 ±2.05	>0.05	135.8 + 2.96	>0.05
2	Erythrocytes, 1012g/l	4.21 ±0.07	4.19 + 0.09	>0.05	4.02 ±0.15	>0.05
3	Leukocytes, 109g/l	7.37 ± 0.57	6.62 ± 0.33	>0.05	3.52 ±0.21	<0.05
4	Lymphocytes, %	26.35 ± 3.20	23.35 ±1.67	>0.05	19.71 ±2.43	>0.05
5	ESR, mm/hr	15.0 ±1.84	12.45± 1.6	>0.05	10.2 ±1.32	>0.05

Stability of these factors can prove Bipexumâ having no ghost effect on haemopoietic processes. After Bipexumâ therapy, complete urine test factors did not go beyond normal values.

Table 2

The Way Bipexumâ Therapy Influences the Status of Biochemical Plasma Indices in Brain Cancer Patients

No.	Indices	Before Therapy, М±m	After Therapy, М±m	Р	Control Group, М±m	Р
1	Hematocrit, %	44.2±1.04	43.5±1.05	>0.05	42.5±0.94	>0.05
2	Potassium, mmol/l	3.81±0.1	3.69±0.09	>0.05	3.49±0.07	>0.05
3	Sodium, mmol/l	138.42±0.83	138.37±0.82	>0.05	136.71±0.68	>0.05
4	Sugar, mmol/l	5.71 ±0.17	5.71 ±0.22	>0.05	5.54±0.33	>0.05
5	Creatine, mmol/l	96.41±4.38	94.90±3.87	>0.05	101.23±3.49	>0.05
6	Non-protein nitrogen, mmol/l	17.7±0.91	18.6±1.15	>0.05	18.8±1.06	>0.05

The control group given chemotherapy and radiation therapy without Bipexumâ showed statistically confident decrease in blood leukocytes, as well as somewhat reduced haemoglobin, erythrocytes, lymphocytes and ESR.