Research Impact


Healing chronic wounds with Nexagon

12 December 2014


CoDa Therapeutics was founded to develop NexagonTM, a topically applied antisense gel that stimulates and accelerates wound healing. The company has raised $42 million in finance and completed good manufacturing practice manufacture and toxicity testing. Clinical trials for various indications are under way.

Most acute wounds heal without issue. However, this process may be compromised by factors such as poor blood circulation and conditions such as diabetes, leaving hard-to-heal chronic wounds or ulcers. Unfortunately, a significant proportion of these chronic wounds and leg ulcers - which are becoming more prevalent as the population ages and diabetes rates increase - fail to respond to conventional treatment. When that happens, and in the absence of any effective alternative therapeutic agents, there is often no choice but to amputate the affected lower limb.

Now, though, the results of research conducted at UCL offer new hope for the effective treatment of these wounds and ulcers. In 1994, Professsor David Becker (UCL Cell & Developmental Biology) and Professor Colin Green (now at the University of Auckland) found that the gap junction protein Connexin43 (Cx43) plays an important role in the wound healing process and hypothesised that its down-regulation would accelerate that process.

When Professor Becker's theory proved correct, he and his colleagues began working on the development of Nexagon, a topically applied antisense gel that down-regulates Cx43 protein production, accelerating the healing of acute wounds, and reducing inflammation and scar formation. One of the most important features of the Nexagon technology, moreover, is its capacity to kick-start healing in chronic wounds, a clinical need that has so far not been met.

Turning their attention specifically to the notoriously slow wound healing in diabetic patients, the research team went on to demonstrate abnormal up-regulation of Cx43 at the edge of wounds in the streptozotocin-diabetic rat model. By reducing the Cx43 expression using Nexagon, they were able to restore healing rates to normal or better. Subsequent preclinical studies of biopsy samples from a wide variety of human chronic wound samples also showed a striking over-expression of Cx43 protein, reconfirming Professor Becker's theory about the role of Cx43 in healing.

Following Wellcome Trust (Catalyst Biomedica) seed funding support for proof of concept studies with Nexagon, Professors Becker and Green founded CoDa Therapeutics (NZ) Ltd in 2003 and then CoDa Therapeutics, Inc., based in San Diego CA, in 2006. The company now employs 11 Biotech team members in New Zealand and around seven staff at the San Diego site.

For its beneficial effects to be realised in patients, however, Nexagon needs to go through the lengthy process of clinical trialling. In 2006, CoDa Therapeutics raised $23m in series A financing to complete good manufacturing practice (GMP) manufacture and toxicity testing. Clinical trials with Nexagon were started in 2008. Phase 1 safety trials were successfully completed for both skin and eye indications and Phase 2 trials for these indications are ongoing.

Nexagon has also shown positive results in Phase 2a and 2b clinical trials for venous leg ulcers. The Phase 2a trial showed that venous leg ulcers treated with Nexagon healed five times faster than those treated conventionally. Indeed, 31% healed completely within four weeks, compared to just 6% of those treated with the current standard treatment. One study participant, who had suffered from debilitating leg ulcers for three years, described this trial as "the answer to my prayers".

In 2012 CoDa raised series B funding of about $38 million, some of which has been used to support a Phase 2 double-blind randomised vehicle-controlled clinical trial for subjects with diabetic foot ulcers, which ran between 2012 and 2014. An efficacy and safety double-blinded study of Nexagon for Persistent Corneal Epithelial Defects - which frequently result in loss of eyesight - started in 2011 and is due for completion in 2014.

An investigational drug such as Nexagen may occasionally be used outside of a clinical trial to treat a patient with a serious or immediately life-threatening disease or condition who has no comparable or satisfactory alternative treatment options. In 2008, CoDa Therapeutics were given approval for this type of 'compassionate use' of Nexagon on an amputee patient with a below-the-knee wound that had not healed for 18 months. The patient was scheduled for amputation above the knee, but just two treatments with Nexagon triggered healing and saved his leg from further amputation.

Nexagon has also saved the eyes of over a dozen people New Zealand, where regulatory authorities granted compassionate use approval for treatment of persistent epithelial defects following corneal burns.