Pain Program Overview


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Pain Program Overview

  1. 1. Benitec’s ddRNAiChronic Pain Opportunity Non-Confidential Presentation Benitec Ltd 1
  2. 2. This presentation contains forward looking statements that involve risks and uncertainties. Althoughwe believe that the expectations reflected in the forward looking statements are reasonable at this time,Benitec can give no assurance that these expectations will prove to be correct. Actual resultscould differ materially from those anticipated. Reasons may include risks associated with drugdevelopment and manufacture, risks inherent in the regulatory processes, delays in clinical trials, risksassociated with patent protection, future capital needs or other general risks or factors. Benitec Ltd 2
  3. 3. Table of Contents ddRNAi Technology Investment Thesis 4 Benitec Corporate Overview 5 Overview of the ddRNAi Technology 7 Cancer Pain Market Overview 9 The ddRNAi Neuropathic Pain Target 13 Preclinical Cancer Pain Data 15 KOL Reaction to Cancer Pain Product 17 Additional Indications for the Lead ddRNAi Product 20 Cancer Pain Product Development Plan 22 Investment Opportunity Summary 24 Contact Information 25 Benitec Ltd 3
  4. 4. ddRNAi TechnologyInvestment Thesis  DNA-directed RNA interference (ddRNAi) is a novel technology platform capable of achieving long-term targeted gene silencing.  Benitec’s pain product utilizes the ddRNAi technology to treat neuropathic pain in patients suffering from cancer and to overcome morphine tolerance in chronic pain sufferers.  Currently available treatments for cancer pain are largely opioids that do not effectively treat neuropathic pain, creating significant need for a product with a novel mechanism of action.  An accelerated approval pathway is expected for the lead product given the high-risk patient population.  Interviewed Key Opinion Leaders have uniformly expressed enthusiasm for the product based on its novel mechanism of action and potential for long-term pain inhibition. Benitec Ltd 4
  5. 5. Benitec Corporate Overview Based in Sydney, Australia, Benitec is a biopharmaceutical company developing a novel DNA-directed RNA interference (ddRNAi) platform for therapeutic use. The company Business Overview is listed on the Australian stock exchange (ASX: BLT) with a market cap of ~AU$25M and AU$7M cash at hand. The novel, proprietary ddRNAi platform is currently being developed across multiple Business Strategy therapeutic areas where there is a significant unmet need including oncology, neuropathic pain, and hepatitis. The lead product in development internally at Benitec is targeted to terminal patients with cancer for the treatment of neuropathic pain and has the potential for Product Strategy commercialization other painful conditions. Benitec also has in-house programs in lung cancer and hepatitis B, and a partnered program in hepatitis C. Benitec has a robust patent portfolio protecting their platform technology across the Intellectual Property major pharmaceutical markets with patent coverage extending through 2030. Benitec has a strong management team with deep scientific and clinical resources Management Team and extensive experience with the commercialization of biological intellectual property. Benitec Ltd 5
  6. 6. Benitec Senior Leadership TeamBenitec’s management team has demonstrated experience and expertise in developing and licensing noveltherapeutic technology. CEO CFO, Company Secretary Peter French, PhD Greg West Cell and molecular biologist with an MBA in Chartered Accountant, Director and audit Technology Management. Founder of stem cell committee chairman of ITC Ltd, IDP storage company Cryosite Ltd, launched six Education Pty Ltd, Education Australia Ltd, new probiotic-based products with Probiomics. and Sydney International Film School Pty Ltd. Board of Directors Peter Francis LLB Grad Dip Mel Bridges BAppSc FAICD John Chiplin PhD Iain Ross BSc ChD (Intellectual Property) Non- Non-executive Director Non-executive Director Non-executive Director executive Chairman More than 30 years experience His most recent accomplishment Over 30 years experience in the Partner at Francis Abourizk in the global biotechnology and was the corporate reengineering international life sciences sector. Lightowlers (FAL), a legal healthcare industry. During this of Arana Therapeutics, a world Following a career with Sandoz, specialist in the areas of period, he founded and leading Antibody developer, Fisons, Hoffman La Roche, and intellectual property and licensing managed successful which resulted in the acquisition Celltech he has undertaken and and provides legal advice to a diagnostics, biotechnology and of the company by Cephalon for had input to a number of large number of corporations and medical device businesses. a significant premium to market. company turnarounds and research bodies. start‐ups Benitec Ltd 6
  7. 7. Benitec’s NovelRNA Interference TechnologyBenitec’s ddRNAi technology platform utilizes a self-inactivating lentiviral vector to express shRNA moleculeswhich silence a targeted gene of interest. ddRNAi Mechanism of Action ddRNAi Mechanism of ActionBenitec technology  The ddRNAi-based product consists of a third-generation ddRNAi DNA construct vesicular stomatitis virus G (VSV-G) pseudotyped self- inactivating lentiviral vector containing a novel gene construct.  The construct expresses a short hairpin RNA (shRNA) molecule intended to silence the selected gene of interest.  The expressed shRNA integrates into the host’s native RNAi process where it is separated into single strands and binds to the target mRNA. – This results in cleavage of the target RNA and silencing of the gene of interest. Sources: Zou W et al., Intrathecal Lentiviral-Mediated RNA Interference Targeting PKCγ Attenuates Chronic Constriction Injury–Induced Neuropathic Pain in Rats. Human Gene Therapy. 22:465–475 (April 2011) Benitec Ltd 7
  8. 8. ddRNAi Technology ForCancer Pain TreatmentUtilizing the ddRNAi platform, Benitec has developed their gene silencing technology for the treatment of painin terminal cancer patients. The ddRNAi Platform Technology A ddRNAi Construct for Treating Cancer Pain  Benitec’s novel ddRNAi technology allows for long-term gene silencing. Brain  The technology can be targeted to silence a specific Spinal Cord gene or multiple selected genes. Intrathecal injection of + ddRNAi DNA construct  Unlike current treatments for pain, this product is long- lasting and has the potential to cause only minimal side effects.  The ddRNAi product is injected intrathecally into the spinal canal where it transfects the PKCγ-containing Benitec Technology interneurons. ddRNAi DNA construct Source: Benitec Ltd 8
  9. 9. Cancer-Associated Pain MarketThe global incidence of cancer is expected to experience a slow and steady rise driven by population growthand increasing lifespan. More than half of all cancer patients experience some form of pain. Cancer Pain Incidence and Prevalence Global Incidence of Cancer-Associated Pain Among Cancer Patients  There are approximately 11.7 million people in the US with cancer.  Among newly diagnosed cancer patients, 38% experience pain. 65%  About 74% of cancer patients with advanced disease Experience experience some form of pain, with estimates ranging as Cancer-Related Pain high as 82%.  Among the cancer patient population who experience pain, 30% suffer from breakthrough pain, an acute and oftentimes extremely painful flair of pain that “breaks Approximately 65% of all cancer through” chronic pain analgesia. patients experience painSources: Cowen Therapeutic Categories Outlook – Pain Management, March 20, 2011; Hearn J, Higginson IJ. Cancer Pain epidemiology: a systematic review. In Bruera ED, Portenoy RK, eds. Cancer PainAssessment and Management. UK: Cambridge University Press; 2003; Vuorenin E. Pain as an early symptom in cancer. Clin J Pain 9(4):272-8, 1993; Ger LP et al., The prevalence and severity of cancer pain: astudy of newly diagnosed cancer patients in Taiwan. J Pain Symptom Manage 15(5):285-93, 1998; Datamonitor. Cancer Pain. December 2009; US National Cancer Institutes Surveillance Epidemiology and End Results (SEER) database. 2007. Benitec Ltd 9
  10. 10. Current Treatments for Cancer PainOpioids are the first line of therapy for cancer pain, but their efficacy is often insufficient and their side effectscan be severe.  Opioids are the most commonly used therapy for pain, EU Palliative Care Perspective Treatment Algorithm for Severe but they are generally not helpful for neuropathic pain. Cancer Pain  Commonly used opioids include: Adjuvant: Opioid NSAID Opioid Antidepressant – Morphine, hydrocodone, oxycodone, codeine, and Combination Anticonvulsant fentanyl Inadequate response  Opioids are often associated with side effects that include: – Constipation, confusion, insomnia, delirium, anxiety, Change to a Change to a Change to a nausea, vomiting, sleep apnea, and interference with different drug drug of a different route of gonadotropins of the same different class administration class  Even with the addition of adjuvant treatments such as anti-convulsants, KOLs stated that the majority of Inadequate response patients do not have their neuropathic pain significantly relieved. Try other options from above groups. Also consider spinal administration of local anesthetics, alpha-2 agonists, nerve blocks, and spinal cord stimulation. “It could be argued that we shorten lives of many patients by giving them increasing doses of strong opioids.” —Palliative Care SpecialistSources: Datamonitor. Cancer Pain. December 2009; Results of nine KOL interviews conducted by Campbell Alliance in July and August 2011. Benitec Ltd 10
  11. 11. Unmet Needs in Cancer PainA significant need exists for a therapy capable of treating the complex neuropathic pain often experienced bycancer patients. Unmet Needs in Cancer Pain  Neuropathic pain was universally regarded by KOLs as the most difficult type of pain to treat with currently available therapies. “There’s always some issue related to their opioids. There’s always something in terms of side effects.”  A reduction in the many side effects caused by opioids —Palliative Care Specialist was stated by many KOLs to be the greatest unmet need.  The worsening of sleep apnea and interference with gonadotropins are major concerns associated with the “We have a lot of drugs available, but unfortunately even high-dosage opioids used for cancer pain. when you combine three or four drugs there is a group of patients that you can only marginally help.” —Palliative Care SpecialistSource: Results of nine KOL interviews conducted by Campbell Alliance in July and August 2011. Benitec Ltd 11
  12. 12. Cancer PainMarket OpportunityThe cancer pain ddRNAi product may be used in up to 65% of cancer patients receiving invasive paintherapy, and significant potential exists to expand into the larger cancer pain patient population. Patient Population Potentially Treated with ddRNAi Technology for Cancer Pain 80 Cancer Pain Patients (Thousands) Number of Refractory Terminal 70 60 50 40 30 20 10 0 ddRNAi Product Other Invasive ProductsSource: Results of nine KOL interviews conducted by Campbell Alliance in July and August 2011; Campbell Alliance analysis. Benitec Ltd 12
  13. 13. ddRNAi Neuropathic Pain TargetBenitec has identified PKCγ as a unique target to address the unmet need in cancer pain. PKCγ has beenshown to play a major role in the transmission of neuropathic pain. PKCγ in Pain Transmission  The PKC superfamily consists of a set of enzymes that phosphorylate serine and threonine amino acids. The PKC enzymes are involved in cellular processes ranging from proliferation to memory.  PKCγ is a member of the PKC superfamily found mostly in the brain and spinal cord. PKCγ has PKCγ Localization been implicated in the transmission of neuropathic pain. Brain  Activation of PKCγ in the spinal cord is involved in persistent pain states, especially in neuropathic pain after nerve injury. Spinal Cord  The restricted spinal cord location of the PKCγ-containing interneurons allows a selective inhibitor to inhibit nerve injury-induced neuropathic pain without the side effects of nonselective PKC inhibitors.  Additional gene targets can be incorporated into the DNA construct to allow for more robust pain inhibition. – Additional identified targets include D-Amino acid oxidase (DAO) and nerve growth factors.Sources: Zou W et al., Intrathecal Lentiviral-Mediated RNA Interference Targeting PKCγ Attenuates Chronic Constriction Injury–Induced Neuropathic Pain in Rats. Human Gene Therapy. 22:465–475 (April2011). Mellor H and Parker PJ, The extended protein kinase C superfamily. Biochem J. 1998 Jun 1;332 ( Pt 2):281-92. Benitec Ltd 13
  14. 14. Key Opinion Leader Validation of theNeuropathic Pain TargetKOLs reacted favorably to the mechanism of action because of the strong connection between PKCγ andneuropathic pain. PKCγ Target for Silencing  There was a very positive reception of PKCγ as a target for the treatment of pain. “Noting the mechanism of neuropathic pain and the cascade of evidence associated with the activation of kinases, this  KOLs familiar with the role of PKCγ in neuropathic pain product seems to be good, especially in neuropathic pain expressed strong optimism regarding the potential to but also in opioid tolerance.” alleviate neuropathic pain by silencing PKCγ —Palliative Care Specialist expression.  It was noted that PKCγ makes a lot of sense for preventing allodynia, defined as pain due to a stimulus which does not normally provoke pain, which is a common problem in patients with sever cancer pain. “The type of cancer pain with nerve compression is the hardest to treat, I would guess PKCγ would be  KOLs also saw potential for the target to help with better…PKCγ is involved in the development of allodynia, opioid tolerance due to the relevant biochemical so blocking it makes sense” cascade being similar to that of neuropathic pain. —KOL in Pain ResearchSource: Results of nine KOL interviews conducted by Campbell Alliance in July and August 2011. Benitec Ltd 14
  15. 15. ddRNAi Cancer Pain ProductPreclinical StudiesPreclinical studies have been conducted to determine the efficacy of PKCγ-targeted ddRNAi on paininhibition. Study Design  Lentiviral vectors encoding a specially designed shRNA against the PKCγ gene (shPKCγ) were introduced into neurons and spinal cord of rats via intrathecal catheter.  Pain threshold testing was performed using tests for mechanical and thermal pain. – Mechanical pain was assessed by measuring paw mechanical withdrawal thresholds (PMWT) in response to pressure from an electronic von Frey anesthesiometer (N=8). – Thermal pain was assessed by measuring the paw withdrawal thermal latency (PWTL) upon application of a heat source aimed at the mid-plantar area (N=8). Sources: Zou W et al., Intrathecal Lentiviral-Mediated RNA Interference Targeting PKCγ Attenuates Chronic Constriction Injury–Induced Neuropathic Pain in Rats. Human Gene Therapy. 22:465–475 (April 2011). Accessed October 2011. Benitec Ltd 15
  16. 16. ddRNAi Cancer Pain Product Preclinical Studies—Results These preliminary animal studies demonstrate the ability of PKCγ-targeted ddRNAi to achieve pain inhibition for at least six weeks post injection. PKCγ-Mediated Pain Inhibition in Rats Results Mechanical Withdrawal Threshold (g) A Sham Saline Control Vector  Animals showed a significant increase in pain shPKCγ1 (10μl) threshold to mechanical (A) and thermal (B) shPKCγ2 (10μl) shPKCγ1 (5μl) stimulation. shPKCγ2 (5μl) Efficacy  The increase in pain threshold was dose-dependent and lasted for the duration of monitoring. Time after intrathecal delivery (days) B Sham Paw Withdrawal Latency (sec) Saline Control Vector  No toxicity was observed in any animals for six shPKCγ1 (10μl) shPKCγ2 (10μl) weeks following injection of vectors. shPKCγ1 (5μl) Toxicity shPKCγ2 (5μl) – Rats had normal appearance, levels of activity, and feeding patterns.Sources: Zou W et al., Intrathecal Lentiviral-Mediated RNA Interference Targeting PKCγ Attenuates ChronicConstriction Injury–Induced Neuropathic Pain in Rats. Human Gene Therapy. 22:465–475 (April 2011) Time after intrathecal delivery (days) *p<0.05 vs. sham or saline group Benitec Ltd 16
  17. 17. Key Opinion Leader Assessment ofthe ddRNAi Cancer Pain Product Overall Product Perception Overall Opinion of the ddRNAi Product Average: 6.4  KOLs consistently viewed the product favorably due to its 7 unique mechanism of action and potential for minimal toxicity. 6 5  No other current pipeline products were viewed with 4 consistent optimism and a product with a new mechanism 3 of action was said to be sorely needed. 2 1 0 US KOL EU KOL n = 5 out of 9 Potential to Fulfill Unmet Needs Question: On a scale of 1 to 7 (1=Very low, 7=Very high) how would you rate this product based on the product profile?  The potential for the product to treat neuropathic pain “No one med is overwhelmingly efficacious for neuropathic was seen as especially beneficial, as current treatments pain. In studies it’s about 30% of the time that you’re going to are severely lacking for this type of pain. target that pain effectively. It’s usually polypharmacy, which also is a challenge.” —Palliative Care Specialist  The product may be particularly useful for patients with “This product sounds exciting, if you can turn off the protein significant opioid tolerance for whom adjuvants are that is being produced that is turning the cell on or basically ineffective. sensitizing it, you know it has so much more potential, not only for cancer pain but other types of neuropathic pain, even for opioid-induced hyperalgesia.” —KOL in Pain ResearchSource: Results of nine KOL interviews conducted by Campbell Alliance in July and August 2011. Benitec Ltd 17
  18. 18. Potential Lead Indication for theddRNAi Pain ProductKOLs saw terminal cancer patients as an ideal lead indication for the ddRNAi product due to the level ofnovelty of the product and the length of trials required for an indication in this patient segment. Terminal Cancer Patients  KOLs see strong potential for the ddRNAi cancer pain product to be used in terminal patients suffering from all types of cancer. “Terminal cancer patients are a good group to target…it’s a group that the FDA will allow you to go after relatively easily.” —KOL in Pain Research  Tumor types with a high degree of neuropathic pain were noted to include pancreatic, lung, breast, ovarian, and head & neck.  KOLs expect the ddRNAi cancer pain product to be “Virtually all cancer patients at some time in their disease experience neuropathic pain. It’s more common in terminal used before other invasive therapies such as nerve patients…performance and pain are intertwined, this blocks, opioid catheters, and spinal cord stimulation. may make a huge impact on life expectancy.” —Palliative Care SpecialistSource: Results of nine KOL interviews conducted by Campbell Alliance in July and August 2011. Benitec Ltd 18
  19. 19. Potential Product Adoption inCancer PainKOLs anticipate physician adoption to be initially concentrated on patients with tumor types that either areassociated with neuropathic pain or have a high number of terminal patients. Number of Tumor Type Rationale Annual Deaths (US & EU) “Any kind of tumor may produce neuropathic pain because High prevalence, chronic neuropathic Breast 86,000 of the growth of the mass.” pain common following surgery —Palliative Care Specialist High prevalence, likely to metastasize Lung 290,000 near neural structures Severe pain with high degree of Pancreatic 82,000 neuropathic qualities, difficult to treat Complications with nerves, significant “I would use this in patients with neuropathic pain and in Cervical 9,000 patients who are receiving increasing doses of opioids, just visceral pain High degree of pain with complex pain to minimize the escalation of opioids. So not only Head and Neck 17,000 neuropathic pain in my opinion.” symptoms —Palliative Care Specialist High degree of neuropathic pain Lymphoma 45,000 common with paraspinal involvement Colon High prevalence 108,000 “I would definitely use this. It’s something I could offer easily High prevalence, likely to cause bone and for some of these patients that are so severe this would Prostate 74,000 metastases that are difficult to treat be easier and less severe than some of the neurolytic High degree of difficult to treat pain, blocks…any tumor type with spinal metastasis would Ovarian 34,000 likely to receive intrathecal pumps be a good candidate.” —Palliative Care Specialist Esophageal High degree of pain 32,000Source: Results of nine KOL interviews conducted by Campbell Alliance in July and August 2011. American Cancer Society. Cancer Facts and Figures 2011. Available at Accessed August 2011. Benitec Ltd 19
  20. 20. Potential Additional Indications forthe ddRNAi Pain ProductKOLs anticipate the ddRNAi product to have use treating pain in all types of cancer patients as well aspatients suffering from conditions such as diabetic neuropathy, postherpetic neuralgia, and HIV/AIDS. Additional Indications  Following the initial indication of terminal cancer pain, physicians indicated the product could fill a significant unmet need in non-terminal patients also suffering from cancer-related pain, especially those whose pain is “Patients having chemotherapy can have an activation of opioid refractory. herpes. It’s devastating, it changes their life more than cancer. There is no treatment that is effective so I’m sure  Approval in non-terminal cancer patients may drive the the patients would be willing to try this. They have use of the product in the medical oncology setting. neuropathic pain; it’s very bad.” —Palliative Care Specialist  There is also a high unmet medical need in treating patients for post-herpetic neuralgia (shingles), and this patient segment is often also treated by palliative care physicians. Physicians interviewed indicated that “HIV patients often have neuropathic pain, and it can be this indication would be a logical next step in the product chronic pain. This product has the potential to reduce pain life cycle. for a long period of time, and the patient is taking drugs day in and day out for their condition.”  KOLs noted that the ddRNAi product also has potential —Palliative Care Specialist to meet significant unmet needs in patients with pain caused by diabetic neuropathy, chemotherapy- induced neuropathy, and HIV/AIDs.Source: Results of nine KOL interviews conducted by Campbell Alliance in July and August 2011. Benitec Ltd 20
  21. 21. Potential Additional Indications forthe ddRNAi Pain ProductRecent research has shown that silencing of the PKCg gene also significantly reduces morphine tolerance ina pre-clinical pain model. Addressing Morphine Tolerance  Morphine is among the most prescribed opioid pain relievers for severe chronic pain.  Morphine tolerance is a major clinical hurdle due to the progressive decline of dose potency occurring after a few weeks of treatment.  Tolerance is countered by administration of increasing dosage, increasing the side effects of morphine therapy, or selecting another pain suppressant in opioid rotation trails.  Research demonstrated successful reduction of morphine tolerance using the same ddRNAi construct that is shown to be effective in overcoming neuropathic pain.  These finding broaden the areas of application of the technology Benitec is developing, increasing morphine treatment efficiency in a large of chronic pain patients besides those suffering from cancer related neuropathic pain. Source: Z. Song et al, THE JOURNAL OF GENE MEDICINE Vol 12, pages 873–880, 2010 Benitec Ltd 21
  22. 22. Clinical Trial Plan for the ddRNAiCancer Pain ProductA phase I/II study of the ddRNAi-based product is planned in terminal cancer patients with intractable painand a quick timeline to approval is expected. Study Overview Randomised double blind phase I/II study of ascending single doses of intrathecally administered ddRNAi-based product in terminal cancer patients experiencing cancer-associated pain Patient Population Objectives Study Design  Patients who have  Determine the acute safety profile of the  The study will include three dosing intractable pain due to an ddRNAi-based product when administered arms with each dose given to n = 4 underlying malignancy (or intrathecally in a single dose patients and 1 control patient other terminal illness)  Determine the efficacy (chemo-sensitizing)  Dose 1 (low dose)  Life expectancy < 6 months effects of the ddRNAi-based product when  Dose 2 (medium dose) administered three days prior to each cycle of standard chemotherapy (repeat single  Dose 3 (high dose) doses) Benitec Ltd 22
  23. 23. ddRNAi Cancer Pain ProductDevelopment Plan and Timeline ddRNAi Cancer Pain Product Clinical Development Timeline 2011 2012 2013 2014 2015 Proof of concept in pre-clinicalPreclinical model of painStudies(anti-humanPKCγ construct) Toxicology studies Phase I/II Trial (cancer patients IND Preparation and Submission with intractable pain)Phase I/IIClinical Additional Planned Studies:Studies  Toxicology and biodistribution studies  Large Phase II and III studies in cancer patients  Other indications** Other indications include: diabetic neuropathy, postherpetic neuralgia, and HIV/AIDS Benitec Ltd 23
  24. 24. Investment Opportunity Summary ddRNAi Product Asset Summary Large Market Opportunity Favorable KOL Response High Revenue Potential in Oncology and Additional Strong Support From KOLs for the Unique MOA Indications Additional Indications Potential for Accelerated Timeline Potential use in Diabetic Neuropathy, Postherpetic Neuralgia, Short-term Trials are Anticipated in Initial Indications and HIV/AIDS Unmet Medical Need Extensive IP Estate Large, Unmet Need for Treatment of Cancer Pain Patent Coverage Through 2030 Benitec Ltd 24
  25. 25. Contact InformationTo respond to this introduction to the ddRNAi opportunity, please contact: Dr. Peter French, Ph.D., M.B.A. CEO Benitec Ltd. Phone: +61 (0)412 457 595 E-mail: or Ben Bonifant Senior Vice President Campbell Alliance Phone: (919) 844-7100 x7176 E-mail: Benitec Ltd 25