The pain program COZY is being developed jointly with the Danish company Zyneyro. The goal is to develop an effective treatment for severe chronic nerve pain, a relatively common and often difficult-to-treat condition. The program consists of two projects – a peptide treatment and a gene therapy treatment (AAV), each of which builds upon a new principle for pain treatment, but which are both based on the same pain-relieving mechanism. In the peptide project, we are developing a synthetic molecule for short-term treatment and in the AAV project, we are developing a gene therapy for severely debilitating pain conditions with potentially lifelong effect.
About 20 percent of the world’s population suffers from some form of chronic pain. In the United States, between four and eight percent of the population is estimated to be affected by high impact chronic pain. Conventional treatment of severe pain consists primarily of anti-inflammatory drugs, antidepressants, antispasmodic drugs, and opioids (a group of substances with a morphine-like mechanism of action). 
The problem with these treatments is that they are not specifically developed to treat chronic pain. The pain relief that is achieved therefore often has a number of disabling side effects such as addiction problems, depression, anxiety, fatigue, impaired physical and mental ability. In the United States, an estimated 700,000 people have died due to opioid abuse in the past 20 years.
 Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016; CDC; Morbidity and Mortality Weekly Report Weekly / Vol. 67 / No. 36 September 14, 2018
CombiGene’s and Zyneyro’s pain program is being developed to offer effective pain relief without the side effects that today’s treatments often give rise to. This is possible thanks to Zyneyro’s researchers having identified a new biological mechanism of action, which forms the basis for the drug candidates.
The program consists of two drug candidates: a peptide treatment (short-term treatment) and a gene therapy treatment with potentially lifelong effect. The patient’s disease picture and possibly other factors will guide the choice of drug candidate.
In severe temporary pain conditions, the intention is to administer the peptide directly to the patient on one or more occasions to achieve effective pain relief.
In chronic pain conditions such as neuropathic pain, phantom pain and pain associated with various types of back injuries, which in conventional treatment require daily medication, pain relief can be achieved by treating the patient with an AAV vector that “instructs” the body to establish the pain-relieving mechanism itself. In this way, one can achieve long-term pain relief without daily medication. Since the AAV vector encodes the peptide, the mechanism of action and thus the expected effect are the same as in direct administration of the peptide.
The concept could potentially also offer an opportunity to check that a patient responds well to treatment with the peptide before proceeding with the more costly AAV treatment. By screening potential patients before a costly gene therapy treatment is initiated, it would be possible to increase the accuracy of the gene therapy treatment.
The peptide treatment is based on the molecule COZY01, which has shown good effects in various preclinical pain models. Further development will focus on carrying out as quickly and efficiently as possible the necessary preclinical studies to evaluate safety and toxicology, as well as producing clinical trial material with the aim of obtaining the approval of a regulatory authority to conduct the first human clinical trials with COZY01.
An independent evaluation of the potential of COZY01 as a future pain treatment is underway at the National Institute of Health (NIH) research institute in the US in a government-funded program (Preclinical Screening Platform for Pain, PSPP). COZY01 has undergone the first test level out of three and has been selected to move on to the next level where the substance will be tested in different pain models.
A prototype of the AAV vector that acts as a carrier of the genetic material in gene therapy has been developed by Zyneyro and tested in a preclinical pain model with very good and long-lasting effect. The upcoming work is focused on optimizing the genetic material to be included in the vector. AAV is the vector type that CombiGene has extensive experience of from our other projects. When the vector is optimized, preclinical studies follow to investigate and characterize distribution, protein expression, efficacy, and toxicology.
In parallel with the preclinical development, we will develop a process for the manufacturing of the selected vector for preclinical studies and for future clinical trials. Data from this work will form the basis for seeking permission to conduct a clinical trial in patients with severe chronic pain.
The program is based on discoveries regarding the role of an intracellular protein called PICK1 (protein that interacts with C-kinase 1) in modulating neuronal signal transmission via AMPA receptors in pain. Simply put, it can be described as PICK1 binds to and controls the localization and activation of receptors that participate in the transmission of pain signals between nerves in chronic pain. By blocking the interaction between PICK1 and receptor, you prevent a certain type of receptors from reaching the cell membrane and becoming activated, thereby inhibiting the pain signal.
(Sørensen AT, Rombach J, Gether U, Madsen KL. The Scaffold Protein PICK1 as a target in chronic pain. Cells. 2022;11(8):1255. )
The agreement with Zyneyro is a cooperation agreement that means that Zyneyro and CombiGene share the project’s costs and revenues equally. According to the agreement CombiGene paid Zyneyro an upfront of DKK 5 million in connection with the signing of the agreement. CombiGene has furthermore committed to pay an additional maximum of DKK 11.4 million in continued development support towards clinical Phase 1.