Multiple Sclerosis (MS) is a chronic neuron-inflammatory demyelinating disorder of the central nervous system (CNS) that predominantly affects young adults. Empirical evidence points toward an autoimmune pathogenesis, where myelin-specific CD4+ and CD8+ T cells are thought to play a central role by reacting against and destroying the myelin sheath. MS is characterized by areas of demyelinated plaques disseminated throughout the CNS with a predilection for optic nerves, spinal cord, periventricular white matter (WM), corpus callosum, and cortical and sub-cortical gray matter (GM). There are 4 types of MS: Relapsing Remitting (RRMS), Secondary Progressive (SPMS) Primary Progressive (PPMS) and Progressive relapsing (PRMS). The current Interferon treatment only works for RRMS and does not work for the progressive forms. In RRMS, one third of the patients does not respond to Interferon treatment and continue with the active disease. Moreover, all patients experience fatigue with Interferon treatment.

IB-MS: IB-MS is an oral drug, a small molecule which derived from botanical sources, which can also be made synthetically. IB-MS showed potential for reducing clinical signs of RRMS and Progressive form of MS. Preliminary 5 years observation study demonstrated an over 80% effectiveness for treating RRMS and progressive MS with no side effects in a variety of parameters of the disease, including reduction of fatigue, disability, frequency of relapsing, functional recovery, and reduction in number and size of new lesions. InnoBioscience have completed a 12 month Phase I/II clinical for patients with RRMS, showing significant reduction in fatigue score. InnoBioscience is currently conducting a Phase II human clinical trial for Progressive MS. Current 1 year interim data showed significant reduction in EDSS scale, improvement in the 9 hole pin test, and the 25 feet walk test.

Target Indication: Relapsing Remitting Multiple Sclerosis, Primary and Secondary form of Progressive Multiple Sclerosis

Route of Administration: Oral

Mechanism of Action:

• Activates the Wnt/β-catenin pathway --- increase in β-catenin, interacts with T-cell factor/lymphoid enhancer-binding factor (TCF/LEF).
• Activates the non-canonical Wnt pathways which regulate cell polarity, axonal growth, dendrite development, and synapse function.

Advantages of IB-MS:

• Non-invasive oral drug
• No side effects: Normal liver, kidney and metabolic functions. No death.
• Significantly reduce fatigue score
• Significantly reduce EDSS score
• Improve focal and physical functional capacity and coordination
• Works on Progressive MS
• Favors remyelinization, stimulates neurogenesis, reduces neuro-inflammation

Pre-Clinical in vivo Conclusion:

• IB–MS decreases significantly clinical scores in both models of EAE
• IB-MS significantly reduces IL-2, IFN-γ and inhibits T cell
• IB-MS was more effective than IFN-β itself
• Reduces neuro inflammation and protects against neuronal cell loss
• Reduces cell inflammatory infiltrate and demyelination in spinal cord
• Stimulates synapses function and stimulates neurogenesis

Results of 5 years Human Clinical Case Reports:

• IB-MS improve clinical symptoms, serological, MR inflammatory parameters.
• Complete safety and tolerability in all patients after 60 months of daily oral intake in mono therapy (7 cases) and combination with Interferon (3 cases). No side effects, Normal liver, kidney and metabolic functions.
• Only 10% of patients are experiencing relapses during the 60 months of treatment
• Early symptomatic synergistic effect on fatigue, antigravity displacement, strength and equilibrium when product is administered along with Interferon. (within 2 - 3 months)
• Partial, and in some cases significant functional recovery of sensitiveness and neuromotricity, observed between 24 and 30 months.
• Magnetic Resonance Imaging (MRI) at 4 month and 26 months showed no change in total number and no increase in size of demyelinating lesions in the brain white matter
• Highly significant reduction to normalizing of inflammatory activity of demyelinating lesions as measured by neuroimaging control between 14 and 24 months
• IB-MS can improve focal functionality, such as speech impairment (dysarthria) and vision, deglutition (severe neurologic dysphagia) and fine motricity (recovering writing, self eating and hygiene)

InnoBioscience has just completed a 12 months, randomized, comparative, double blind controlled phase I/II clinical trial, with 30 patients to evaluate the efficacy of IB-MS combined with Interferon in patients with RRMS. Data is published in BMC Neurology (2016) 16:77.

Background: IB-MS has shown to be anti-inflammatory, neuroprotective, and anti-fibrotic effects in animal models as well as clinical efficacy in different studies, including an anti-fatigue effect in autoimmune diseases such as rheumatoid arthritis. In multiple sclerosis (MS), fatigue is rated as one of the most common and disabling symptoms. In the present trial, we investigated the effect of IB-MS on relapse rate and fatigue in relapsing-remitting MS (RRMS) patients receiving interferon beta.

Methods: A randomised double-blind placebo-controlled trial assessed the effects of 170 mg of IB-MS tablet on relapse rate and fatigue using the Fatigue Severity Scores (FSS) over 12 months in RRMS patients receiving interferon. The Expanded Disability Status Scale (EDSS) score, inflammatory parameters and radiological findings were also investigated. Twenty-five patients were enrolled, and twenty-two patients were ultimately analysed and randomised to the active or placebo group.

Results: Patients treated with IB-MS showed a significant reduction in their FSS score as compared to the placebo, equivalent to a 44 % reduction at 12 months. No statistically significant differences were observed for relapse rate, EDSS or inflammatory parameters, with a trend in reducing new lesions among the IB-MS group. One patient in the IB-MS group presented with a mild and transient skin rash, which was alleviated with anti-histamine treatment for three weeks.

Conclusion: IB-MS was well tolerated in patients and no changes in clinical parameters were observed. IB-MS significantly reduces fatigue in patients with RRMS receiving interferon beta in comparison to placebo and only interferon beta treatment.

IB-MS showed potential for reducing clinical signs of Progressive form of MS. Preliminary 4 years compassionate observation have demonstrated over 80% effectiveness for treating progressive MS with no side effects in a variety of parameters of the disease, including reduction of fatigue, disability, frequency of relapsing, functional recovery, reduction in number and size of new lesions.

Innobioscience is currently conducting a 2 year, Phase II clinical trial involving 80 patients. This is a randomized, comparative, double blind controlled clinical trial to evaluate the efficacy, safety and tolerability of IB-MS versus placebo in patients with primary and secondary progressive forms of MS. Estimated Completion Date: End of 2017

The purpose of this study is to compare the efficacy and safety of 140 mg IB-MS administered twice a day orally versus a placebo as a modifying treatment of the disease in patients with the progressive forms of Multiple Sclerosis (MS).

Primary Outcome Measure:

• The principal outcome is to determine the efficacy, of IB-MS in retarding the progression of brain atrophy in patients with progressive forms of MS, as measured by MR quantified by the percentage of change in volume size utilizing SIENA.

Secondary Outcome Measures:

• Delay in the disability capacity progression through the Expanded Disability Status Scale (EDSS) at 24 months compared to the baseline.
• Delay in cognitive impairment by means Paced Auditory Serial Addition Test (PASAT) at 24 months compared to the baseline.
• Quality of life Multiple Sclerosis Impact Scale (MSIS 29) through parameters reported by the patients at 24 months compared to the baseline.
• Tolerability of IB-MS as measured by Treatment Satisfaction Questionnaire for Medication (TSQM) at 24 months.
• Number of new lesions T2 by MR at 24 months compared to the baseline.
• New hypointense lesions in T1 by MR at 24 months compared to the baseline.
• Delay in the retinal thinning measured by Optical Coherence Tomography (OCT) at 24 months compared to the baseline.
• Safety of IB-MS at 24 months through the record of adverse effects in daily symptoms and programmed interviews.
• Delay in the disability capacity progression through the Multiple Sclerosis Functional Composite (MSFC) at 24 months compared to the baseline.
• Delay in cognitive impairment by means of Symbol Digit Modalities Test (SDMT) at 24 months compared to the baseline.
• Evaluate mood disorders by means of Beck scale at 24 months compared to the baseline.
• Evaluate fatigue by Krupp scale reported by the patients at 24 months compared to the baseline.
• Number of new gadolinium enhancement lesions in T1 by MR at 24 months compared to the baseline.
• Change in visual field at 24 months compared to the baseline.
• Volume of size in T2 by MR at 24 months compared to the baseline.

Other Outcome Measure:

• Determination of Th1, Th2, Th17 and Treg lymphocyte sub-populations.
• Determination of cytokines IFNgama, TNFalpha, IL2, IL17alpha and TGFbeta.

Key Patent and IP Rights:

1. US Patent Number 8,084,495: Composition of labdane diterpenes extracted from andrographis paniculata, useful for the treatment of autoimmune diseases, and alzheimer disease by activation for PPR-gamma receptors
2. US Patent Number 9,060,994: Combination therapy with Interferon and Andrographolide in multiple sclerosis.
3. PCT Serial No Filed. US62/026,801: Pharmaceutical compositions for treating the secondary progressive and primary progressive forms of multiple sclerosis

Key Publication:

1. Journal of Pharmacology and Experimental Therapies. Vol 312, No.1 Jan 2005. Andrographolides interferes with T cell activation and reduces EAE in the mouse
2. British Journal of Pharmacology. 2005 Mar;144(5):680-6. Andrographolide interferes with binding of nuclear factor-kappaB to DNA in HL-60-derived neutrophilic cells.
3. Planta Med. 2005 May;71(5):429-34. Andrographolide inhibits IFN-gamma and IL-2 cytokine production and protects against cell apoptosis.
4. Journal of Pharmacology and Experimental Therapies: Vol. 318 No.1 2006. Inhibition of NFkB enhances the capacity of immature dendritic cells to induce Antigen specific tolerance in EAE
5. Eur J Pharmacol. 2009 Jan 14;602(2-3):413-21. doi: 10.1016/j.ejphar.2008.11.011. Epub 2008 Nov 13. Andrographolide reduces IL-2 production in T-cells by interfering with NFAT and MAPK activation.
6. BMC Neurology (2016) 16:77. Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pilot study