microrna Therapeutics Heading Towards the Clinic

Transcription

1 GENReports: Market & Tech Analysis microrna Therapeutics Heading Towards the Clinic > Enal Razvi, Ph.D. Biotechnology Analyst, Managing Director SELECTBIO US

2 Topic Introduction and Scope The focus of this GEN Market & Tech Analysis Report is to frame the translation of micrornas from research towards therapeutics Currently, there are two segments of the microrna research marketplace that are translating towards the clinic mir Signatures as Biomarkers with Utility in Diagnostics Development Modulating mirs Therapeutically as a Means to Modulate Disease The challenge in the translation of micrornas from research towards therapeutic utilization is that a given microrna is known to modulate the expression of several genetic elements Therefore, the up/down regulation of a given microrna is expected to broadly affect several genes in vivo In spite of this challenge, there is a movement of specific microrna species towards the clinic and in this report we analyze this landscape

3 30,000 25,000 Latest Version is v20.0, released in June 2013 with 24,521 entries 20,000 15,000 10,000 The Growth of Content in the mir Base Database has been a Driver for the identification and Validation of microrna Signatures Associated with Disease Driver for: microrna Signatures as Biomarkers Associations have been discovered Driver for: micrornas as Therapeutics to modulate targets in vivo Modulations with therapeutic value have been discovered 5,000 Dec 2002 Jan 2003 April 2003 May 2003 July 2003 July 2003 Sept 2003 Nov 2003 Jan 2004 April 2004 July 2004 Sept 2004 Dec 2004 April 2005 June 2005 Oct 2005 Feb 2006 May 2006 July 2006 Oct 2006 Feb 2007 May 2007 Aug 2007 Dec 2007 April 2008 Sept 2008 March 2009 Sept 2009 April 2010 Aug 2010 April 2011 Nov 2011 Aug 2012 June GENReports: Market & 9.0 Tech 9.1Analysis, Produced by 13.0 Enal 14.0Razvi, Ph.D

4 micrornas of Therapeutic Significance Currently The following micrornas are being targeted for therapeutic purposes currently: mir 21 Found to be up regulated in many solid tumors Being addressed as a mir to down regulate for various solid tumors mir 34 Found to have tumor suppressor properties Some have referred to it as a master tumor suppressor Ongoing phase I clinical trial focuses on mir 34 modulation in liver cancer mir 122 Imperative for Hepatitis C Virus (HCV) infection Down regulation of mir 122 blocks productive HCV infection and subsequent Hepatocellular Carcinoma (HCC) mir 33 Involved in cholesterol biosynthesis Preclinical in vivo data suggests

5 mir-21 Extensive interest in mir 21 centered around its role in maintaining solid tumors by way of blocking the programmed cell death pathway in vivo Various classes of solid tumors have mir 21 associated with them as shown in the following slides publications on associations of specific micrornas with different cancer classes [mir 21 illustrated with arrow] Regulus Therapeutics has programs modulating mir 21 in HCC and Renal Fibrosis

6 Breast Cancer Time Axis

7 Glioblastoma Time Axis

8 Colon Cancer Time Axis

9 Metastasis Time Axis

10 mir-34 mir 34 is down regulated in many cancers Solid tumors Hematological (liquid) tumors Therefore it is believed to be a tumor suppressor mir in vivo some reports have referred to it as a master tumor suppressor given that its associated with many different cancer classes Mirna Therapeutics, Inc. is focused on restoring loss of function of mir 34 via a mimic delivered in vivo using nanoparticle based delivery approach Restoration of loss of function of this tumor suppressor Modulate gene functionality of cancer genes addressed by this mir The company has begun a phase I clinical trial focusing on mir 34 based therapy in unresectable primary liver cancer or metastatic cancer with liver involvement

11 mir-122 This microrna has received by far the most attention vis à vis its therapeutic potential The source of the interest is driven by the fact that Hepatitis C Virus (HCV) requires in its life cycle cell derived mir 122 Cell lines with low levels of endogenous mir 122 are refractory to HCV infection Up regulation of mir 122 via transfection makes these cell lines permissive to HCV infection Furthermore, HCV infection is a prelude to HCC and therefore a strategy of mir 122 down regulation via a therapeutic strategy is devised to therapeuticallytarget HCV infection and down stream HCC event

12 mir-122 Therapeutic Targeting Regulus Therapeutics mir 122 targeting for HCV Santaris Pharma A/S Phase 2a trial of Miravirsen (blocks mir 122 via LNA antisense molecule) completed Enrollment completed for combination therapy with other anti HCV anti virals First mir Modulator to Move into Clinical Trials, albeit for an Infectious Disease

13 mir-3157 InteRNA Technologies B.V. has been focusing on several oncology programs and has disclosed that mir 3157 is their target for the B raf/melanoma space Their lead compound is a mimic of mir 3157

14 Beyond Cancer to Cardiovascular Disease Although the majority of the interest and drive for mirs as biomarkers has been in the oncology space, this is not exclusively the case as mirs associated with cardiovascular disease are translating from research towards the clinic miragen Therapeutics is focused on the therapeutic targeting of mirs associated with cardiovascular disease All programs in preclinical stages Disease classes addressed are presented in the table below mir Targeted mir 208 mir 15/ 195 mir 145 mir 29 mir 92 mir 378 mir 206 Disease Class Addressed Heart Failure Post Myocardial Infarction Vascular Disease Fibrosis Peripheral Artery Disease Cardiometabolic Disease Neuromuscular Disease

15 Therapeutic Targeting of micrornas is Moving Forward Towards the Clinic Even Though Majority of Efforts are in Biomarker/Diagnostics Development using mir Signatures, Therapeutic Modulation of mirs in vivo Remains an Attractive Clinic Space and there are now reports of specific mirs targeted by therapeutics in defined clinical [disease] spaces most notably cancer In summary, we reaffirm our position that as the microrna space becomes populated with associations with disease, these associations can be leveraged in biomarker based assays for LDTs/Dx, but also for Rx development In Summary