IK01400: non-opioid preclinical drug candidate for pain treatment

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1 IK01400: non-opioid preclinical drug candidate for pain treatment Introduction Bio-Link presents a valuable licensing opportunity for the development of novel nonopioid drug candidates to manage acute and chronic pain. InterK Peptide Therapeutics Ltd (InterK) is a cancer drug discovery company focused on selective activators of Lck kinase, a member of the Src family of kinases which are intracellular signaling molecules that regulate a diverse range of cell functions. The InterK drug discovery program has led to the fortuitous discovery of peptide candidates with in vivo efficacy in reducing pain after oral, intraperitoneal and intrathecal administration. Lead pain candidates IK01400 and its D-isomer IKD01400 are both potent in vitro inhibitors of PKG-1α, with IC50 values under 10nM. PKG-1α mediates pain by increasing the release of neurotransmitters in dorsal root ganglia upon pain receptor (nociceptor) activation 1. As a result, the IK01400 leads block the sensation of pain after nerve injury and peripheral nerve stimulation, offering a complementary mechanism of action for the treatment of post-operative, neuropathic and inflammatory pain. InterK has generated extensive preclinical data demonstrating in vivo efficacy and non-toxicity of the lead candidates in two important pain models. Oral administration of IKD01400 in an inflammatory pain model, and intrathecal administration of IK01400 in a neuropathic pain model, both kill pain with equal or better efficacy than morphine. InterK s lead compounds have potential to be developed as an alternative to opioid drugs, reducing the associated risk of abuse, addiction, morbidity and mortality. As pain management lies outside InterK s core focus, the company seeks to out-license the IK01400 pain program. Companies interested to diversify or enrich their drug development pipeline with a promising, non-opioid drug candidate for pain management, are invited to evaluate InterK s program and IK01400 candidates as a potential in-licensing opportunity. Pain background and market opportunity Pain is categorized in two classes, acute and chronic, based on its duration. Nociception associated with acute pain arises from tissue damage, which can occur after injury or surgery. Chronic pain can be classified as inflammatory or neuropathic. Inflammatory pain is associated with the inflammation process that ensues after tissue damage, while neuropathic pain can emerge from damage or dysfunction of the peripheral or central nervous system. Chronic pain is often the result of a combination of inflammatory and neuropathic pain. The following metrics indicate a significant unmet medical need and a large market opportunity for non-opioid drugs that can effectively treat patients suffering pain: Opioid crisis in the US Opioids are the current mainstay for post-operative pain, despite their side effects including respiratory depression, insomnia, memory deficits, nausea, and addiction. Opioid abuse is of particular concern in the US, where 215 million opioid prescriptions were dispensed in 2016 and where 2.5 million adults are addicted to opioids, resulting in over 20,000 deaths annually. 1

2 The global pain management therapeutics market is estimated to be worth over $83 billion by 2024, with a CAGR of 3.5%. About one third of the market is comprised of opioid drugs. Globally 230 million surgeries are performed annually, in which up to 75% of the patients suffer from moderate to extreme acute post-operative pain 2 and more than 50% report inadequate pain relief. The post-operative pain market is estimated to be $6.2 billion in the US alone. Chronic pain reportedly arises in 10% to 50% of the patients undergoing surgery 3. Over 100 million adults in the USA suffer from chronic pain and the annual economic losses due to chronic pain is estimated to be around $600 million, a number that is steadily increasing with an ageing population 4. An estimated 7% to 10% of the general population experience chronic pain with neuropathic characteristics. 75% of patients treated for neuropathic pain report no significant pain relief. For those that do benefit the pain is only partly reduced (by about 50%) 5. The healthcare and disability-related costs due to neuropathic pain is substantial, estimated at almost $40 billion annually in the US alone 6. The anticonvulsant Pregabalin (LYRICA, Pfizer) is one of the leading products in the neuropathic pain market yielding a global revenue of $5 billion in 2016, despite having various CNS side-effects. In several countries, generic competitors are eroding LYRICA s blockbuster status. Preclinical in vivo efficacy inflammatory pain model i. Oral administration The analgesic efficacy of IKD01400 was tested against the current standard of care (morphine) in an inflammatory pain model where the left hindpaws of mice are injected with Complete Freund s Adjuvant (CFA) and consequently develop inflammation. Differences in weight-bearing across treated and untreated paws were assessed using the Linton Incapacitance tester. IKD01400 and morphine were given orally at approximately 200 and 10 mg/kg, respectively, Figure 1. Vehicle (water, n=6) Morphine (240 ug, n=6) IKD01400 (4800 ug, n=6) Figure 1. Incapacitance (analgesic effect) of IKD01400 and morphine in an inflammatory pain model. Weight-bearing was assessed after CFA injection for left and right paws at the times indicated. Error bars are standard errors. 2

3 L:R weight distribution Our in vivo data in inflammatory pain models demonstrate a similar incapacitance effect (feeling of pain) between IKD01400 and morphine after oral administration. To exclude the possibility that measured pain relief was due to paw paralysis, grip-strength was determined for all mice at various time points, Figure 2. There was no significant difference between vehicle control and IKD As the mice were alert at all time points, the increased grip strength seen for morphine-treated mice was due to the side effects of morphine, i.e. hyperactivity. Vehicle (water, n=6) Morphine (240 ug, n=6) IKD01400 (4800 ug, n=6) ii. Figure 2. Assessment of grip strength in CFA animal models after oral administration of IKD01400, morphine or vehicle control. The dotted line represents the average baseline scores for pain-free animals before CFA injection. Error bars are standard errors. Intraperitoneal administration Additional in vivo data in CFA animal models suggest that IK01400 has a more potent analgesic effect than morphine after intraperitoneal (i.p.) administration. To determine a potential dose/response effect for IK01400, data were pooled for experiments performed on three different dates. The data suggest that higher doses of intraperitoneally administered IK01400 are more effective than lower doses. Furthermore, morphine appears more effective during the first 30 minutes after injection but less effective than the higher dose of IK01400 during the second hour of testing, Incapacitance Figure IK01400 (200ug, n = 8) IK01400 (100ug, n = 4) Morphine (240 ug, n = 9) Time Time (mins) Figure 3. Incapacitance (analgesic effect) of intraperitoneally administered IK01400 and morphine in an inflammatory pain model. Data pooled from 3 separate experiments. 3

4 von Frey Threshold The in vivo data from the inflammatory pain model (Figures 1-3) indicate that IKD01400 and IK01400 have comparable in vivo efficacy to morphine. IKD01400 was given orally at a relatively high dose to mitigate against the risk of digestive degradation; lower doses were not investigated. However, after i.p. administration, IK01400 demonstrated 16 times higher potency on a molar basis compared to morphine. Precisely, a 100ug (45 nmol) dose of IK01400 had the same analgesic effect as a 240ug (746 nmol) dose of morphine, Table 1. Table 1: Dosage and molarity of IKD01400 and IK01400administration in CFA mouse model Route of administration MW Dose Vol. Av. weight g/mol mg mg/kg mm nmol ul kg Molar ratio Morphine:IK Morphine Oral/i.p n/a IK01400 i.p IK01400 i.p IKD01400 Oral Preclinical in vivo efficacy neuropathic pain model IK01400 was also tested in a model of neuropathic pain, in which rats are surgically injured through partial nerve ligation at the sciatic nerve in the left hindpaw. Mechanical allodynia (pain due to a stimulus that does not usually provoke pain) was assessed using the von Frey nociceptive test, a well-established, objective and quantitative assay where von Frey hairs are applied to a rat s paw causing a paw withdrawal response. In control animals, the paw withdrawal response is almost instantaneous; in a rat under analgesia, withdrawal is only observed as the von Frey threshold (force applied) increases, Figure Time (mins) Figure 4. The analgesic effect of 5.4 μg IK01400 (2.4 nmol) and 3.0 μg morphine (10 nmol) injected intrathecally in a neuropathic pain model. The higher the von Frey threshold, the greater the stimulus required for the rat to respond, indicating a greater analgesic effect. Both IK01400 and morphine demonstrate an analgesia effect at the first 15 minutes; at 90 minutes the effect is almost identical and remains stable up to 3 hours. In the neuropathic pain model, IK01400 had analgesic efficacy comparable to that of morphine, despite being administered intrathecally at a molar dose 4 times lower (2.4 nmol IK01400 vs 10 nmol morphine). In addition, the analgesic effect of IK01400 lasted as long as that of morphine (3 hours), despite its shorter half-life compared to morphine (<0.5h vs <2h for morphine). 4

5 Overall, the preclinical in vivo data demonstrate a time course of pain relief for the IK01400 candidates that could potentially support their use alone, or in combination with morphine, for effective and sustained analgesia in inflammatory and neuropathic pain. Nonclinical biodistribution and toxicity studies Toxicity studies demonstrate that intravenous administration of IK01400 was well tolerated in rats up to 20 mg/kg, though some temporary adverse reactions were noted at doses of 15 and 20 mg/kg. IKD01400 effectively killed pain and had no observed toxicity after oral administration of a relatively high dose of about 200 mg/kg in the mouse. Neglecting the potential efficacy of lower doses (yet to be investigated), an equivalent oral dose in an average 70 kg human would be about 15 grams, which may approach the feasibility range for daily dosage. As a further indication of non-toxicity, the IK01400 leads had no effect on body weight of rats, or any haematology or pathology parameters at all doses tested. Biodistribution data in mice indicate that oral and intravenous administration of the IK01400 peptides accumulate in all major organs including the liver, kidney and gut, with peptide clearance occurring through several mechanisms including the renal and biliary systems. An example of biodistribution data is shown in Figure 5, indicating renal clearance as major disposal route at 4 hours post administration. Figure 5. In vivo PET-CT images of IK14820 distribution 4hrs post administration. Accumulation of the peptide in the bladder suggests renal clearance of the peptide. Following oral administration of 1mg of Cu 64 -labelled IK01400 and IKD01400 in mice, PET-CT scans show mean percentage injected dose per gram (%ID/g) in the blood around 0.05% for both peptides. IK01400 s %ID/g value remains almost unchanged between the 4 th and 20 th hour post administration, while the D-isomer, IKD01400, presents a non-significant increase of %ID/g value at the 20 th hour after administration (Figure 6A). At 20 hours post oral administration of only 1mg, accumulation of IK01400 and IKD01400 is detectable in tissues frequently associated with pain, including bone, skin, and muscle (Figure 6B). The observed oral efficacy despite relatively low retention in pain-associated tissues, suggests significant potency of the IK compounds that may enable efficacious transdermal delivery for skin surface, inflammatory and joint pain. 5

6 % ID/g % ID/g O r g a n s Percentage ID/g A PEPTIDE RETENTION Blood Samples IN BLOOD B IK IKD01400 D Hours 20 Hours % ID /g Percentage ID/g B lo o d s a m p le s 1.5 B r a in IK PEPTIDE RETENTION Organs IN ORGANS AT 20 HOURS % ID /g IK L iv e r B lo o d 4 H S p le e n K id n e y s T is s u e H e a rt B lo o d 2 0 H L u n g s T h y m u s IK IKD IK IKD01400 T ib ia S k in M u s c le IK IK IK IK D IK IK D T is s u e Figure 6. Retention of Cu 64 -labelled IK01400 and IKD01400 administered orally in mice. A) In blood at 4 and 20 hours post administration; B) In brain, liver, spleen, kidneys, heart, lung, thymus, tibia, skin and muscle at 20 hours post administration. Clinical development strategy Having demonstrated potent in vivo analgesic effects of the IK01400 compounds via various routes of administration, InterK s pain program is well positioned for lead optimization prior to commencement of repeat-dose toxicity studies. The overall clinical development strategy aims to develop the IK01400 lead candidate as a novel, non-opioid analgesic for post-operative, neuropathic and inflammatory pain. After completion of lead optimization, formal preclinical ADME and toxicology studies must be conducted to enable filing of an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). A positive evaluation by the FDA will allow initiation of clinical trials in humans. Based on pain drug development programs conducted by other companies, a Phase 1 clinical trial typically requires between 30 to 80 subjects. For a Phase 2 proof-of-concept study, between 60 to 200 patients will be required. Phase 3 trials in pain usually involve more than 1000 patients and require significant financial resources. Demonstration of Phase 2 proof of concept in a human clinical study would add significant value and likely substantiate a commercial partnership with a major pharmaceutical company for further clinical and commercial development. Intellectual property InterK owns all intellectual property associated with its drug development programs, including a number of patent families covering compositions of matter and methods of use for therapeutic agents. InterK s pain management program offers maximum patent life in major markets worldwide through provisional patent application(s) covering method of use for the IK01400 lead peptides. 6

7 InterK Peptide Therapeutics InterK is based in Sydney, Australia, and is a privately owned, virtual biotechnology company developing immune-boosting peptide drug candidates for a range of therapeutic indications, including cancer and chronic infections. The Company s focus is on the discovery of selective activators of Lck kinase, a member of the Src family of kinases which are non-receptor membrane-bound signaling molecules that regulate a diverse range of cell functions. Lck modulates immune function, specifically T-cell activation. In support of this work, InterK was awarded two federally-funded Australian Research Council (ARC) Linkage Grants with the Lowy Cancer Research Centre and the Australian Institute for Bioengineering and Nanotechnology. While screening its peptides for modulation of kinase activity, InterK discovered a set of peptides with analgesic properties, including IKD As therapeutic applications for pain lies outside InterK s corporate development plan, InterK is seeking external development partnerships for the IKD01400 peptides. Commercial Opportunity Bio-Link Australia is a specialist business development consultancy that works with Australian and international biotech companies and biomedical research institutions to facilitate commercialisation of innovative biotechnologies. Bio-Link has been engaged by InterK to secure a licensing and commercial development partner for the remaining preclinical and clinical development of the selected lead IK01400 candidate. Companies are invited to express their interest by contacting Christopher Boyer at Bio-Link. Christopher Boyer, Executive Director 108 South Parade, Blackburn VIC 3130 Australia Tel c.boyer@bio-link.com References 1. Sung et al. (2017) Pain. 158(5): Katz et al. (2017) Curr Med Res Opin. 33: Gan et al. (2014) Curr Med Res Opin. 30: Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington: The National Academies Press (2011) 5. Nightingale (2012) Nat Rev Drug Discov. 11(2): Gilron (2012) Neuropathic Pain. Mechanisms, Diagnosis and Treatment. Ed. Simpson, McArthur & Dworkin 7