Prof. Charles Wambebe PhD, President/Founder, International Biomedical Research Institute, Abuja, Nigeria. To be presented at:

Transcription

1 Medical Products: From Plants to the Market in Africa Prof. Charles Wambebe PhD, President/Founder, International Biomedical Research Institute, Abuja, Nigeria. To be presented at: SARIMA 2016, Durban, South Africa May 2016

2 Outline Introduction Sickle Cell Disease (SCD) Malaria. Road to commercialization. Key issues.

3 Introduction Partnerships between academia and business community are few, weak and just emerging. Regulatory structures needed to provide regulatory leadership for drug development lack requisite trained personnel, infrastructure and consistent funding. Transforming innovations to products is challenging. Mentoring in concept development and funding by investment community is challenging.

4 Introduction Issues : Intellectual Property Rights Taking business risks. Pilot scale production. Developing concepts and Validating the concepts through business incubators are crucial to move from lab to market.

5 Research Questions Where are the needs in the society within your field of expertise? What are the gaps in treatment of diseases? Choosing priorities. Resources-human, facilities, infrastructure, finances.

6 Sickle Cell Disorder Prevalence 2% (SCD), 25% (carriers) Palliative management Over 10 million patients in Africa. Mortality : 95% in rural areas before 5 years of age. Morbidity: over 50% loss in school attendance.

7 SCD Management Hydroxyurea: toxic (leukemia, hair loss, infertility), only about 50% response, generally inaccessible in Africa, close clinical lab monitoring needed. Generally, only palliative management in Africa. Gap: No effective, safe, affordable and accessible medicine for SCD in sub-saharan Africa.

8 Sickle Cell Disorder Response: Research and develop effective, safe and affordable and accessible medicine for management of sickle cell disorder from African Indigenous Medical Knowledge (AIMK).

9 Study model Reverse pharmacology: Ethnomedical survey (late Rev P.O.Ogunyale) Clinical observational study. Toxicity assessment Safety profile Efficacy evaluation IPR Clinical trials

10 Chemistry of Niprisan Phytochemical : ethanol/water extract of Piper guineense seeds, Pterocarpus osun stem, Eugenia caryopyllus fruit and sorghum bicolor leaves. Bio-guided fractionation. The total extract more bio-active than the pure compounds.

11 Safety profile The highest dose used in the animal studies, which failed to elicit toxic symptoms is about 500 times higher than the effective clinical dose. This wide gap between the clinically effective dose and the toxic dose (high therapeutic index) provides a strong ethical basis to evaluate NIPRISAN in humans without compromising on the safety and well being of the trial participants.

12 In vitro anti-sickling effect of Niprisan 0.05 mg/ml induced 50% inhibition of erythrocyte sickling. As for the kinetics of polymerization, addition of 0.05 microg/ml caused a six-fold prolongation of the delay time prior to deoxy-hb S polymerization when compared with that of untreated Hb S samples. The solubility of deoxy-hb S significantly increased by Niprisan.

13 improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions. Brit J Haematol 122: , Shows striking dose-dependent decrease in sickled cells over time

14 In vitro effects of Niprisan Incubation of RBC suspensions with Niprisan did not dehydrate RBCs, cause haemolysis, increase the amount of denatured Hb, nor form met-hb. Ref: Iyamu et al; British J of Haematology 2002; 118 (1),

15 Efficacy profile NIPRISAN reversed sickled red blood cells and protected them from being sickled when exposed to low oxygen tension thus providing scientific evidence for its therapeutic use. NIPRISAN dose-dependently delayed polymer formation of haemoglobin S, which demonstrates additional evidence for the clinical use of NIPRISAN.

16 NIPRISAN : In Vivo Data

17 Efficacy of Niprisan The efficacy studies indicate that NIPRISAN improved oxygenation of these animals and protected them from death in a dose dependent manner when they were exposed to low oxygen tension. Since SCD patients can die from acute chest syndrome without warning, it is significant that NIPRISAN prevents such sudden deaths in animals, thereby providing a scientific basis to use NIPRISAN as a prophylactic medicine.

18 Effect of NIPRISAN on trapping of sickle cells in mouse lung Hypoxic, control Hypoxic, with Niprisan (0.5mg/mg) E. W. Iyamu, E. A. Turner, T. Asakura. Niprisan (Nix-0699) improves the survival rates of transgenic sickle cell mice under acute severe hypoxic conditions. Br. J. Haematol. 122: , 2003.

19 Standardization of Niprisan Specifications: foreign matter; loss on drying; total ash; and water extractable matter, using the methods prescribed by the WHO (1998) for quality control of medicinal plant materials. Results suggest the existence of one variety of E. caryophyllata; but two varieties of S. bicolor and trona, differing in loss on drying; and two varieties of P. guineense and P. osun, differing in both total ash and water extractable matter. Ref: Obodozie et al, J. of Med Plants Research 3(4), , 2009

20 Kinetics of Niprisan The single oral dose pharmacokinetics of paracetamol was studied alone and after coadministration with Niprisan in rats. Paracetamol concentrations were measured in rat plasma using UV-spectrophotometer and the data were fitted into an open two-compartment pharmacokinetic model using the computer program (STATIS Version 3.0). Results indicated no significant difference in the absorption of paracetamol between study and control groups but a significant reduction (p<0.05) at some sampling time as the dose of NIPRISAN was increased double-fold.

21 Kinetics of Niprisan The pharmacokinetic parameters showed only 1.51 and 7.19% reduction in AUC0 α and Cmax respectively for paracetamol (20 mg/kg) + NIPRISAN (500 mg/kg). Conclusion: Gastric presence of NIPRISAN did not significantly reduce the absorption of paracetamol in rats. Ref: Adzu et al, 2001: European Journal of Drug Metabolism and Pharmacokinetics 2001; 26 (3),

22 Formulation of Niprisan Formulation studies-dosage (efficacy studies), standardization, pharmaceutical technical processes. Pilot scale production. Committee on business concept, business management, business options, etc. Partnership with private sector

23 Patenting of Niprisan According to Article 27 of Trade Related Aspects of Intellectual Property Rights (TRIPS) Agreement, patents can be granted in all fields of technology vis-a -vis processes and products. Although article 27.3(b) of TRIPS allows the exclusion of plants and animals from patentability, article 27.1 contains universally accepted criteria for patentability viz; novelty, non-obviousness and applicability or utility.

24 Patenting of Niprisan Thus, the caveat that natural substances do not qualify for patentability applies directly to plants, animals and microorganisms, whereas the technical processes applied to develop a product with a potential for future commercialization for specific public use can be patented. The patenting of NIPRISAN in the USA was undertaken under this premise. Subsequently, through UNDP grant, Niprisan was patented in 46 countries.

25 Clinical trials Protocol development Ethical approval Regulatory clearance Study sites Investigators Selection criteria Efficacy criteria Statistics, etc.

26 Clinical trial of Niprisan Objective: To assess tolerability and efficacy of Niprisan in SCD patients. Method: Randomized, placebo-controlled, crossover clinical trial. Inclusion criteria: 3 episodes of painful or vaso-occlusive crises per year were randomized to 1 or 2 study groups.

27 Clinical trial IIB Clinical trials I and IIA. Group A took Niprisan for 6 months before crossover to placebo for another 6 months. One month washout period. Group B took placebo for 6 months then crossed over to Niprisan for 6 months. 100 SCD patients recruited; 84 completed the study.

28 Clinical trial of Niprisan Main outcome measures were the incidence of crises; the occurrence of painful episodes; certain clinical, haematological and biochemical measures; patients' daily self-assessment of health, hospitalization, blood transfusion, absenteeism from school.

29 Clinical trial Results: One oral dose of 12 mg/kg Niprisan daily significantly reduced the frequency of sickle cell crises, bone pain, and hospital admission (P < 0.05). The mean number of crises per person per month was 0.05 in patients who received Niprisan initially, compared with 0.11 per person per month after the crossover to placebo.

30 Clinical trial of Niprisan Patients generally rated their health as better and reported less sickness and school absenteeism with Niprisan than with placebo. No adverse effect reported. Conclusion: Niprisan was efficacious in the prophylactic management of patients with sickle cell disease. Ref: Wambebe et al; Current Therapeutic Research 2001: 62 (1),

31 Phase II Trial of Niprisan in Sickle Cell Disease Percent of Baseline Value Controls,% Niprisan,% 0 Crises Pain Rep. Sch. Abs. Hgb Control / 6 months Treated / 6 months C. Wambebe, E. A. Bamgboye, B. O. Badru, et al. Double-blind, placebo-controlled, randomised, cross-over, clinical trial of NIPRISAN in patients with Sickle Cell Disorder. Curr. Ther. Res. 62: 26-34, 2001.

32 Pilot scale production of Niprisan Through a grant from UNDP, with technical partnership of UNIDO, a multi-purpose pilot scale extraction facility was established at NIPRD. Drug manufacturing unit (NIPCO) established at NIPRD. The facility was inspected and approved by the Pharmacists Council of Nigeria (site) (check list obtained). NAFDAC inspected and approved NIPCO for GMP production of essential medicines in accordance with cgmp (check list obtained).

33 cgmp This includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable labs. This formal system of controls at a pharmaceutical company, if adequately put into practice, helps to prevent instances of contamination, mix-ups, deviations, failures, and errors. This assures that drug products meet their quality standards.

34 Licensing to Xechem (USA) The negotiations on granting the company the exclusive license for the production and global marketing of NIPRISAN involved the NIPRD, the Federal Ministry of Health and the potential investor; XECHEM International Inc., (XECHEM). Eventually, the decision was made to grant XECHEM the license with a provision of 7.5% of total sales as royalties, and a good faith payment. Due to internal conflicts within Xechem Inc, the license was withdrawn. The new licensee is May & Baker.

35 LICENSING Of NIPRISAN TO XECHEM In July 2002, Nigerian Government granted XECHEM Inc. an exclusive license for the manufacture, global sale and marketing of NIPRISAN NIPRISAN was registered in Nigeria with NAFDAC in March 2006

36 Commercial production of Niprisan: c-gmp by Xechem (USA) Based on the License, Xechem established the manufacturing facility at Abuja, Nigeria for the commercial production of Niprisan for global marketing. Pharmacists Council of Nigeria inspected the site for cgmp compliance (systems that assure proper design, monitoring, and control of manufacturing processes and facilities).

37 Technology transfer to Xechem (USA) A ceremony to mark this remarkable event, the first of its kind in Africa involving the transfer of medicine fully developed in Africa, by African scientists, to the Western world, took place on July 18, The President of the Federal Republic of Nigeria, Olusegun Obasanjo, personally launched NIPRISAN after it had been registered by NAFDAC.

38 Technology transfer The uniqueness of the NIPRISAN case is that the project was initiated and executed by African scientists working in Africa at a time when international provisions for benefit sharing regarding commercial products derived from indigenous medical knowledge were unavailable. Ref: Wambebe, Charles (2006): Guest Editorial: Innovation and Discovery, vol. 18 (1) pp1-4.

39 Malaria Prevalence Gap-Drug resistance Response: research and development of new effective medicines.

40 Safety Profile Mice Rats. Monkeys.

41 Efficacy Profile Mice. Monkeys. Human volunteers.

42 Percentage Cure Curative Effect of AM1 on Plasmodium falciparum Malaria in Human Subjects AM1 16 mg/kg p.o * P < , Paired t- test n = * n = 16

43 Road to commercialization Commercial milestones: Adequate funding lab facilities, pilot facility, NIPCO, clinic. Regulatory approval in Nigeria; Patenting in USA and other countries. Securing US-based commercial pharmaceutical partner Xechem.

44 Road to commercialization Robust pre-clinical data. Demonstrating clinical efficacy and safety : beyond gold standard. Being accorded orphan drug status by the US Food and Drug Administration and European Medicine Evaluation Agency. Striking important relationships with domestic and international groups.

45 Key Issues Key issues: Establishment of benefit-sharing agreements (MoU). Patenting in Nigeria, USA, and 44 other countries. Fostering partnerships with established research institutions. Sound pre-clinical data (WHO Good Lab Practice) Improving standardization and quality control.

46 Key issues Ensuring financial and managerial due diligence. Recruiting entrepreneurial leaders capable of holding dual scientific and business responsibilities. Country-level supporting policies and conditions are also important. Funding from Federal Government of Nigeria, UNDP, Japanese Government. Sickle Cell Comprehensive Center, Nashville, USA for collaboration (clinical). Children Hospital of Philadelphia, USA for collaboration (pre-clinical studies).

47 Benefits The establishment of a drug manufacturing facility at Abuja by XECHEM created jobs for Nigerians, built capacity, generated wealth for the economy and promoted the development of other herbal medicines based on indigenous medical knowledge.

48 ACKNOWLEDGEMENTS UNDP, Governments of Nigeria and Japan for generous funding for R&D studies. WIPO for guidance on IPR and licensing issues. Late Rev P.O. Ogunyale for entrusting me with the original recipe for Niprisan. SARIMA for sponsorship to this conference.

49 Acknowledgements The Almighty God for blessing the works of my hands. THANK YOU.