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TO INVESTIGATE THE EFFICACY OF ORAL LAT8881
FOR THE TREATMENT OF NEUROPATHIC PAIN

TRIAL SITE LOCATIONS IN AUSTRALIA: MELBOURNE, SYDNEY, BRISBANE AND NEWCASTLE

CLINICAL TRIAL LAT-NP-001 IS NOW UNDERWAY

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Developing proprietary Lateral Compounds

AND OTHER PAINFUL INDICATIONS

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FOR NEUROPATHIC PAIN

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Lateral Pharma Pty Ltd Is a privately-owned biotechnology company that commenced operations in May 2015 to repurpose LAT8881, a Phase 2 orally-available compound with extensive toxicology and human safety data, into new high potential indications.

LAT8881 was originally developed for obesity, based on extensive animal model data in mice, rats and pigs. Lateral Pharma has focused on repurposing LAT8881 for treatments of neuropathic pain, osteoarthritis and other chronic painful diseases. Results to date demonstrate:

  • LAT8881 has an established excellent safety profile in animals and humans, with no adverse CNS or other side effects commonly seen with established pain drugs
  • LAT8881 has a novel mechanism of action distinct from other pain drugs
  • LAT8881 has oral efficacy in several animal models of neuropathic and osteoarthiritis pain comparable to existing approved drugs
  • LAT8881 is active following local and systemic injection and oral delivery
  • Multiple back-up and follow on compounds have been identified with a similar Mode of Action

A Proof of Concept phase 2 human clinical trial using LAT8881 to treat pain caused by post herpetic neuralgia and diabetic neuropathy commenced in March 2019

Human Clinical Trials

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LAT8881 is a small 16 amino acid peptide modelled on the C-terminus segment of human growth hormone (hGH).

LAT8881 has been shown to have an excellent preclinical and clinical safety profile, with none of the side effects associated with hGH, such as raised IGF-1 levels or insulin resistance, and has no involvement with the growth hormone receptor.

Phase IIa – Neuropathic Pain

A Phase IIa Proof of Concept study LAT-NP-001 is currently underway using twice daily delivery of of 30mg of LAT8881 by capsule for the treatment of the painful symptoms of post herpetic neuralgia and diabetic neuropathy. Lateral Pharma is looking for efficacy at least comparable to Gabapentanoids and clinical safety comparable to prior clinical studies with LAT8881.

LAT-NP-001 started in March 2019 at four Australian sites: Melbourne, Sydney, Brisbane and Newcastle, while two UK sites are to commence upon regulatory approval by July 2019.

The clinical trial protocol was developed by Lateral’s in-house team, with input from the clinical advisory board and experienced clinicians including Prof Paul Rolan, Prof Ralf Baron, Prof Tony Pickering and Prof Andy Rice

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Past Clinical Trials

A Phase IIb study was conducted (capsule formulation) for 12 weeks (METAOD005). The patients were clinically obese males, and females of non-child bearing potential.

  • LAT8881 was well tolerated over the dose range; there were no changes of clinical significance in vital signs, safety laboratory tests or ECGs during the study.
  • This study demonstrated that daily oral administration of LAT8881 was safe and well tolerated.

The OPTIONS Study was a Phase IIb, randomised, double-blind, placebo-controlled, multicentre, parallel-group study to assess the efficacy, safety, and tolerability of 24 weeks of treatment with different doses of LAT8881 tablets for weight loss in obese adults (METAOD006). A total of 413 subjects contributed to the primary analysis.

The results of the OPTIONS study did not meet its primary clinical endpoint and the project was terminated by Metabolic in February 2007.

At the end of 2001 the first Phase IIa study was completed (METAOD002). This was a double-blind placebo-controlled 4 ´ 4 Latin Square design study in which 24 healthy clinically obese males participated.

  • LAT8881 was well tolerated over the dose range: there were no study drug-related withdrawals, serious AEs, clinically significant AEs, or changes of clinical significance in vital signs, safety laboratory tests, or ECGs during the study.
  • No significant changes in glucose or insulin-like growth factor 1 (IGF-1) levels were observed following LAT8881 treatment compared with placebo.

A second double-blind placebo-controlled 4 x 4 Latin Square design Phase IIa study was conducted using single oral doses to evaluate safety, tolerability and pharmacodynamic endpoints in healthy, clinically obese males (METAOD003).

  • LAT8881 was well tolerated over the oral dose range: there were no study drug-related withdrawals or serious AEs, clinically significant AEs, or changes of clinical significance in vital signs, safety laboratory tests or ECGs during the study.
  • No significant differences in IGF-1 values were evident for any of the doses compared to placebo.

A third Phase IIa study was conducted to assess the safety of multiple daily oral dosing of LAT8881(METAOD004).

  • LAT8881 was well tolerated over the oral dose range: there were no study drug-related withdrawals or serious AEs, clinically significant AEs, or changes of clinical significance in vital signs, safety laboratory tests or ECGs during the study.

A Phase I study was conducted in 2001 (METAOD001). LAT8881 was administered intravenously to 14 healthy male volunteers.

  • LAT8881 was well tolerated over the dose range.
  • There were no clinically significant adverse events (AEs); or significant abnormalities in vital signs, safety laboratory tests or electrocardiograms (ECGs) during the study.

Safety

The safety and toxicity of LAT8881 has been evaluated using conventional acute and chronic repeat-dose studies in animals. Toxicology data from rodents and primates indicated no significant safety signals attributable to LAT8881 up to doses of 100mg/kg/day for 6 months following oral delivery in rats and 50mg/kg/day for 9 months in cynomolgous monkeys.

In the six (6) human clinical trials involving 925 patients conducted at Medeval, Manchester, UK and seventeen (17) major Australian hospitals and medical centres between 2001 and 2007 with 694 patients dosed with LAT8881 it has been shown that LAT8881 is safe and well tolerated in humans.

This safety and tolerability record of LAT8881 was further validated in July 2014 by the receipt of a self-affirmed GRAS (Generally Recognized as Safe) status recognition to enter the U.S. market as a food additive. The peptide had received in June 2012, GRAS status in the USA conditional on the publication of safety related data in peer-reviewed scientific journals. Two such scientific papers detailing these safety aspects are available for downloading here.

GRAS status allows LAT8881 to be sold as a component in conventional and functional foods, drinks and dietary supplements in the USA at the daily level of up to 1 mg per person.

Drug Development Program

  • Neuropathic Pain
  • Osteoarthritis
  • Mechanism of Action (MOA)
  • Backup Program

Lateral Pharma is repurposing LAT8881 for treatment of neuropathic pain, osteoarthritis and other painful chronic diseases.  Lateral has worked with external CROs and collaborators using different approaches to investigate analgesic properties of LAT8881 and other backup LAT peptides:

  • Prof David Spanswick at Pacific Discovery Services (PDS)/Neurosolutions and Charles River Labs have been key collaborators for the pain studies in the following model systems :
  • Ex vivo spinal cord slice model (DRG) preparations from rats subject to chronic nerve constriction (Chung model) directly monitoring neuronal activity with electrophysiology
  • In vivo behavioural models of pain monitoring mechanical or thermal hyperalgesia or other pain responses mostly conducted by Pacific Discovery Services (PDS):
    • Chung model of chronic nerve constriction injury – studies conducted by PDS
    • Chemotherapy-induced neuropathic pain model – two studies, one conducted by PDS and one by Charles River Laboratories
    • Streptozotocin Diabetic neuropathy – one study conducted by PDS
    • Reserpine model of fibromyalgia – one study conducted by PDS
    • Post operative surgical pain – one study conducted by PDS
    • Models of osteoarthritis, (1) Intra-articular Collagenase – one study conducted by Prof Kwon of Daegu Catholic University Medical Center and (2) Mono-iodo acetate – two studies, one conducted by PDS and one by Charles River Laboratories

Lateral has obtained positive results with IA delivery of LAT8881 in the rabbit collagenase model of OA

    • LAT8881 alone was as effective as Hyaluronic acid (HA)
    • LAT8881 plus HA resulted in additive effects on lameness and joint architecture
    • Published by Kwon et al in Ann Clin Lab Sci 2015

Charles River Labs have completed a model of OA in the rat in which joint pathology is induced by local injection of mono-iodoacetate (MIA)

    • LAT8881 given orally improved weight bearing on affected limb in rats at 3 and 21 days after disease induction

PDS also confirmed efficacy of oral LAT8881 in their MIA model

    • LAT8881 at 5mg/kg given orally improved weight bearing in rats on the affected limb at 14 days

Conclusion LAT8881 has effects on the painful symptoms in some models of OA and may also improve the repair of damaged joint tissue

Lateral Pharma has been conducting an extensive program of work with various external contract research laboratories and academic collaborators to understand how LAT8881 achieves its analgesic effects in neuropathic pain (both its Mode of Action & Mechanism of Action).

Lateral is currently conducting external research projects at Evotec to identify the molecular target for LAT peptides (France & Germany), Pacific Discovery Services to characterise their biological effects in nerve slices and animal models (Australia/UK) and Metrion to investigate effects on cell lines expressing candidate ion channels (UK). Electrophysiology conclusions from research projects are:

  • LAT8881 when dosed to animals or when applied directly to spinal cord slice DRG preparations from chronic nerve constriction models has an inhibitory effect on pain signal transmission
  • LAT8881 reduced post-synaptic excitation following stimulation of dorsal root afferents within 8 minutes
    • The effect was reversible on wash out
    • GH had no effect
  • LAT8881 reduced wind-up and spontaneous activity of spinal cord dorsal horn neurons
  • Effects consistent with an ultimate effect on ion channels

LAT8881 is our lead compound and has entered clinical development for the treatment of neuropathic pain. We have identified several other orally active peptides derived from LAT8881 that could have cost of goods or formulation advantages over LAT8881. We have also identified other compounds derived from different proteins with activity in spinal cord slice assays which provide additional IP. Once the LAT8881 target is identified we aim to perform HTS to identify new peptide and non-peptide leads as potential follow on compounds.

The potential for enhanced tissue repair suggested by the Mesenchymal Stem Cell differentiation and rabbit OA studies presents a potential additional opportunity for development of a treatment for Osteoarthritis.

Newly filed patents around backup compounds also provide the potential for Lateral Pharma to revisit the treatment of obesity.

Neuropathic Pain

  • Potential Utility of LAT8881 in Neuropathic Pain
  • Potential Utility of LAT8881 in Osteoarthritis
  • Target Osteoarthritis Market
  • References

Chronic neuropathic pain remains a clinical area with high unmet need due to several factors. Including a relative lack of investment in new pain drugs by biotech and pharma; Clinical failures/delays due to safety issues in humans (anti-NGF) or failure to demonstrate efficacy in trials with the overall lower success rate for pain drugs transitioning from Phase 1 to Approval of 2% compared to average for all drugs of 9.6%; and  the highly publicized safety and misuse concerns with opioids and more recently with gabapentinoids.

The extent of the opioid and gabapentinoid crises is outlined by the following statistics:

  • 80% of heroin users report misusing prescription opioids prior to heroin (NIH, 2019)
  • 11.1 million Americans are estimated to have past-year misuse/abuse of prescription opioids (FDA, 2019)
  • 130+ people a day die from opioid-related drug overdoses in the U.S. (NIH, 2019)
  • The total “economic burden” of prescription opioid misuse alone in the US is estimated to be USD$78.5 Billion in healthcare, law enforcement and lost productivity (NIH, 2017)
  • In 2017, 47,600 Americans died because of opioid overdose (Centers for Disease Control and Prevention, 2018)
  • In UK  from 2006-2016 prescriptions of gabapentin have risen fivefold, from 1 million to 6.5 million, while those for pregabalin, have risen tenfold (Waters, 2017)
  • GABA drugs are also being prescribed for pain they’re not actually licensed to treat, such as arthritis or lower back pain (Waters, 2017)
  • gabapentin and pregabalin use in non-neuropathic pain disorders indicates they are less effective than several other licensed non-opioid analgesics (Morrison, Sandilands & Webb, 2017)
  • There is a significant illicit market for these controlled drugs, which are known to ‘potentiate’ or enhance the effects of opioids (Peckham, Ananickal & Sclar,  2018)

 

Figure 1 U.S drug overdose deaths involving any opioid, 1999-2017 (Center for Disease Control and Prevention, 2018)National drug overdose deaths

The Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act – October 2018 is aimed at addressing the opioid overdose epidemic in the United States. It includes provisions to educate the population about addiction medicine, standardize the delivery of addiction medicine and cover addiction medicine in a way that facilitates the delivery of coordinated and comprehensive treatment. It also outlines the need for a safe, effective, non-addictive treatments to manage chronic pain (FDA, 2019).

Policy change in the U.S. raises the possibility of collaborative research studies with the NIH through the HEAL initiative, and FDA expedited pathways. Lateral could pursue:

  • various partnerships and collaboration opportunities with the NIH
  • NIH grant opportunities
  • Breakthrough Therapy Designation with the FDA
  • FDA Accelerated Approval
  • FDA Fast Track
  • FDA Priority Review

In 2015 our collaborator published:

Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model – Kwon and Park (2015)

In 2010 Dr Kwon and co-workers published a paper in the Journal of Korean Medical Science (2010; 25: 776-780) titled “Additive Effects of Intra-articular Injection of Growth Hormone and Hyaluronic Acid in Rabbit Model of Collagenase-induced Osteoarthritis”. In that study the co-injection of intra-articular HA and human Growth Hormone (hGH) was more effective than HA alone in the osteoarthritis model in terms of duration and severity of lameness, lower macroscopic scores of cartilage damage and histopathological scores of cartilage damage.  In that study HA alone proved to be more effective than control (saline) on the same measures.

Dr Kwon was asked to collaborate on a similarly designed study to evaluate the effect of LAT8881 in the University Medical Center’s model.

In commenting on his study findings Dr Kwon MD, PhD said “These results are exciting because they provide early stage evidence in a rabbit model that LAT8881 may help to repair OA damaged tissue.  LAT8881 appears to have retained the same beneficial effects as hGH in our rabbit model of collagenase-induced OA.” This evidence gives Lateral Pharma increased confidence that LAT8881 can be further developed to become an effective treatment for OA in both humans and companion animals.

Potential Utility of LAT8881 in Osteoarthritis This encouraging in-vivo efficacy data when combined with the highly favourable safety profile of LAT8881, proven in formal pre-clinical toxicology studies and six human clinical trials, provides strong rationale for use of the peptide to treat OA.

LAT8881 could offer further advantages in that it can be dosed in multiple forms including oral, transdermal, injection and intra-articular.

The potential uses outlined above target support in conditions, trauma and injuries with very large markets and where there are limited or no adequate treatment options.

For instance in the case of Osteoarthritis, this is the most common joint disease with 12.1% of US adults showing symptoms in the knee and obesity being associated with a 3.5 fold prevalence of OA in US adults between 60-64 years of age. (Medtrack database).

The majority of treatments only address the pain associated with OA. Across the seven major markets of the U.S, France, Germany, Italy, Spain, the U.K and Japan the osteoarthritis market was worth $3.25B in 2014 and expected to grow at a Compound Annual Growth Rate of 17.8%  to reach $10.49B by 2024 (GlobalData, 2016)

Centers for Disease Control and Prevention. (2018). “National Drug Overdose Deaths Number      Among All Ages, by Gender, 1999-2017.” National Institute of Health. Retrieved on the           13th of May 2019 from https://www.drugabuse.gov/related-topics/trends-statistics/overdose   death-rates

 

Gottlieb, S. (2018). “Statement by FDA Commissioner Scott Gottlieb, M.D., on the agency’s           ongoing work to forcefully address the opioid crisis.” U.S. Food & Drug Administration        (FDA). Retrieved on the 13th of May 2019 from https://www.fda.gov/news-events/press      announcements/statement-fda-commissioner-scott-gottlieb-md-agencys-ongoing-work         forcefully-address-opioid-crisis

 

Morrison, E.E., Sandilands, E.A., & Webb, D.J. (2017). “Gabapentin and pregabalin: do the benefits outweigh the harms?” J R Coll Physicians Edinb, 47(4), 310-313. doi:10.4997/JRCPE.2017.402

 

National Instutute on Drug Abuse. (2019). “Opioid Overdose Crisis.” National Institute of Health.  Retrieved on the 13th of May 2019 from https://www.drugabuse.gov/drugs abuse/opioids/opioid-overdose-crisis

 

Peckham, A.M., Ananickal, M.J., & Sclar, D.A. (2018). “Gabapentin use, abuse, and the US opioid epidemic: the case for reclassification as a controlled substance and the need for     pharmacovigilance.” Risk Manag Healthc Policy, 11, 109-116. doi:10.2147/RMHP.S168504

 

Thomas, D., & Wessel, D. (2018). “Volume II: Pain and Addiction Therapeutics.” The State of         Innovation in Highly Prevalent Chronic Diseases. Biotechnology Innovation Organization. Retrieved on the 13th May 2019 from https://www.bio.org/sites/default/files/BIO_HPCP_Series-Pain_Addiction_2018-02-08.pdf

 

Waters, J. (2017). “The crippling toll of the new Valium that’s ruining the lives of MILLIONS: Rapid            rise in prescriptions for GABA drugs is worrying experts.” Daily Mail Australia. Retrieved on 13 May 2019 from https://www.dailymail.co.uk/health/article-5102355/Crippling-toll-new     valium-ruining-lives-MILLIONS.html

The Team Behind LAT8881:

Peter Francis
Chairman/Director
David Kenley
CEO
Dr. Gavin Shepherd
Director
Barry Pang
Director
Nima Alavi
Director
David Williamson
CFO
John Pang
Operations and Projects Manager
Nicky Wallis
Clinical Project Manager & VP Operations
Colin Hannah
Director

Contact

Lateral Pharma Pty Ltd is an Australian registered private company,

ABN 40 605 241 665

14/114 William Street

Melbourne VIC 3000

Australia

E: info@lateral-pharma.com

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