New research has shown that the protein – called Votucalis – provided pain and itch relief in research involving mice.
The findings from Durham and Newcastle Universities, in collaboration with pharmaceutical company Akari Therapeutics Plc, could lead to a replacement for traditional painkillers, for example opioids, that can be ineffective, can have serious side-effects and can be addictive.
The research is published in the journal Frontiers in Pharmacology.
Votucalis is derived from the saliva of ticks – in this case the brown-ear tick Rhipicephalus appendiculatus – who secrete the protein into their host when feeding so the host is unaware that they have been bitten.
Votucalis is a biologic drug that works by binding histamine, produced in the body, with high-affinity and thereby prevents histamine activating its four cell surface receptors resulting in reduced itch or chronic pain responses.
Study co-author Dr. Paul Chazot, in the Department of Biosciences, Durham University, UK, said: “Persistent or chronic pain is a huge global health challenge, which affects over 20 percent of the population.
“It is the single biggest reason that people in the UK visit their doctor and it is recognized as a priority disease by the World Health Organization.
“The National Institute for Health and Care Excellence (NICE) has recommended that current opioid and gabapentinoid pain medications should not be prescribed to patients newly diagnosed with chronic pain, apart from cancer sufferers, so there is an urgent need to develop a new, long-lasting medication that is both effective and safe to use.
“Our study is the first to show evidence of the anti-itch and pain relief potential of Votucalis, which is very exciting. We could be on the brink of discovering a viable alternative to opioid and gabapentinoid drugs.”
Unlike opioids—which are morphine-based—the research shows that Votucalis does not enter the brain, which means it is not addictive and less likely to cause side-effects. It can be manufactured in large amounts using recombinant methods.
Study co-author Dr. Ilona Obara, began the research with Dr. Chazot while at Durham and continued the work after moving to the School of Pharmacy, Newcastle University, UK.
Dr. Obara said: “It is amazing that a protein found in the saliva of this tiny creature could prevent chronic pain and itching in people.
“These are conditions that bring a huge amount of misery, and current medication displays limited efficacy, and can also often be detrimental to patients.
“Votucalis has already been tested in humans with other conditions, including conjunctivitis, without major side-effects, so the potential for this to be developed into a drug to tackle chronic pain and itching is definitely there.”
The researchers say the next step towards clinical testing is to develop a delivery system to effectively administer the drug at the site of itch and pain.
Votucalis is a pipeline drug for Akari Therapeutics Plc (UK), and Drs Chazot and Obara are co-authors on its patent for neuropathic and inflammatory pain.
Mr Clive Richardson, Chief Executive Officer of Akari Therapeutics Plc (UK), said: “We are delighted to be working with Drs Chazot and Obara on the pipeline drug Votucalis.
The exciting new data in pain and itch supports the potential that the unique mode of action of Votucalis, inhibiting all four histamine receptors, opens exciting therapeutic opportunities in pain management and dermatology.”
Akari Therapeutics Adds Histamine Inhibitor Votucalis to Pipeline to treat Neuropathic Pain and Dermatological Disease
Building on the positive clinical and safety data from its lead drug nomacopan, Akari is developing a second related therapeutic candidate (votucalis) focusing on new clinical targets. Votucalis captures histamine and thereby has the unique potential to prevent activation of all four histamine G-protein coupled receptors (GPCRs) which can induce diverse pathophysiological processes, including chronic pain, itch and inflammation.
Akari Therapeutics, Plc (Nasdaq: AKTX), a late-stage biopharmaceutical company focused on innovative therapeutics to treat orphan autoimmune and inflammatory diseases where complement (C5) and/or leukotriene (LTB4) systems are implicated, today announced that it is developing a second clinical candidate, votucalis, which specifically inhibits histamine.
Votucalis originates from the same research program as nomacopan and it shares a similar unique mode of action – specifically capturing and tightly binding to small highly potent ligands such as C5 plus LTB4 (nomacopan) or histamine (votucalis). By inhibiting the host immune response, ticks can feed for extensive periods without damage from an inflammatory response, benefiting from circa 300 million years of evolutionary development. The inhibition of the histamine pathway affords Akari the potential to target a range of new diseases, separate from those of nomacopan.
Dr Ilona Obara (Newcastle University, UK; Senior Lecturer of pain pharmacology, council member of European Histamine Research Society EHRS) said, “Votucalis is a unique centrally sparing natural product-based drug which captures histamine within a high-affinity internal binding site. In our studies we used a pre-clinical model of neuropathic pain and observed that selective targeting of peripheral histamine by votucalis resulted in highly effective inhibition of mechanical hypersensitivity. It is very exciting to see that votucalis may represent a novel and safe therapeutic strategy for chronic neuropathic pain and other conditions such as atopic dermatitis and psoriasis, where raised endogenous histamine is a known mediator.”
Dr Paul Chazot (FBPhS University of Durham, UK; Chair of NC-IUPHAR subcommittee for histamine pharmacology, past-President of EHRS) said, “Chronic pain has been recently recognised by the WHO as a priority disease area lacking in effective and safe therapeutics. The majority of therapeutic issues are associated with side effects of current medications acting on the brain. In addition, the current opioid crisis in the U.S. and Europe, and recent shifts in national policies for chronic pain management prescriptions necessitates the need for a new way to treat chronic pain. The natural product drug, votucalis offers this potential based on its unique mode of action, the work we have done and the known role of histamine and its receptors in chronic peripheral pain mechanisms.”
Votucalis, which is related to nomacopan, has a different mechanism of action and by specifically inhibiting histamine opens a new range of clinical targets. Like complement and LTB4 (inhibited by nomacopan), histamine is part of the innate immune response and is dysregulated in many diseases.
Inhibiting histamine is a well-established treatment route with drugs targeting individual histamine receptors primarily H1R and H2R. By contrast, votucalis has the unique potential to inhibit all 4 histamine-dependent GPCRS (H1R, H2R, H3R, and H4R) by sequestering histamine within the body of the protein thereby preventing histamine binding to its receptors. A further desirable feature of votucalis, is that due to its size (21kDa) votucalis does not enter the central nervous system or brain and thus acts peripherally and is centrally sparing and is hence less likely to cause side effects or drug dependencies.
New preclinical data using a mouse model of neuropathic pain shows votucalis blocks chronic neuropathic pain symptoms. In addition, data from an itch model demonstrated a potential for votucalis to treat atopic dermatitis and attendant chronic pruritis. In both cases local subcutaneous administration of votucalis was more effective than systemic administration – requiring a far lower dose and lasting for longer than systemic treatment.
Akari is continuing their work with Dr Paul Chazot and Dr Ilona Obara focused on progressing votucalis into the clinic around two targets both based on local administration. These are for treatment of neuropathic pain, and for dermatological conditions associated with inflammation and itch – especially diseases where H4R may have a role in disease pathology, given there are currently no marketed anti H4R drugs.
Votucalis has been GMP manufactured and following ongoing evaluation and safety studies, proof of principle Phase II trials in 2022 under an IND would enable this project to be potentially partnered in neuropathic pain and further developed as part of the Akari dermatological franchise.
Dr Miles Nunn, Chief Scientific Officer of Akari Therapeutics said, “The further development of votucalis affords Akari the potential to expand our pipeline and target a range of new diseases. The planned work will allow us to evaluate the clinical route forward for votucalis which potentially provides a new means to ameliorate neuropathic pain and treat dermatological diseases where more than one histamine activated GPCR contributes to disease pathology.”
More information: Ibrahim Alrashdi et al, Votucalis, a Novel Centrally Sparing Histamine-Binding Protein, Attenuates Histaminergic Itch and Neuropathic Pain in Mice, Frontiers in Pharmacology (2022). DOI: 10.3389/fphar.2022.846683