The surprising discovery that sensory nerves play a role in glucose regulation besides being target for signal substances that control pain and inflammation in year 2000 led Dorte X. Gram to propose the hypothesis that type 2 diabetes is an inflammatory disorder and should be treated as such.
Several exploratory studies – all conducted by Dorte X. Gram when she worked at Novo Nordisk A/S in Denmark – led to the understanding that the ‘capsaicin-receptor’ (chili-receptor, VR1 or TRPV1) was involved.
TRPV1 is found on sensory nerves and is associated with the regulation of inflammation, pain-sensation as well as energy expenditure.
European Journal of Neuroscience, Volume 25, Issue 1, pages 213–223, January 2007 In 1999, Dorte X. Gram’s first experimental study in diabetic rats most surprisingly revealed a very dramatic effect on the control of hyperglycemia following the systemic administration of capsaicin (sensory desensitization). This led to a change of focus during the PhD studies to exploring the role of sensory nerves in experiemental diabetes.
Great colleagues and collaborators at Novo Nordisk as well as externally (Richard D. Carr, Carolyn F. Deacon, Bo Ahrén, Anton Scheurink, Wolfgang Langhans, Arpad Szallasi, Istvan Nagy and Ove Svendsen) contributed heavily to the experiments, discussions, interpretation and publication of results, and challenged the hypothesis
– No invention is made alone but requires a collection of great brains!
In 2003, the hypothesis was presented in Dorte X. Gram’s PhD thesis, Capsaicin-sensitive nerves in experimental diabetes, to the ‘dream-team’ of opponents: Henning Beck-Nielsen, Jens Juul Holst and Mads Krogsgaard Thomsen.
In 2004, a use-patent application, Method of selectively inhibiting the activity of the capsaicin receptor in obesity or in obesity-related diseases or disorders, was filed.
In 2008, Novo Nordisk A/S made a strategic decision to focus on injectable peptide-based drugs. As a consequence, all patents and projects in the oral anti-diabetic category were spun out and Dorte X. Gram via her own company was able to purchase the 2004 patent application.
In 2011, a use-patent giving the exclusive right to use TRPV1 antagonists for the treatment of obesity was granted in the US and in 2013, this was followed by the granting of use-patents giving the exclusive right to use TRPV1 antagonists for the treatment of diabetes (in US and Europe, issued 2013). (Download patents as PDF / US7879866B2 / US8455504B2 / EP1771162B1).
In 2014, PILA PHARMA was established and the granted use-patents were transferred to PILA PHARMA with the aim of combining the use-patents with a clinical ready TRPV1 clinical development candidate with a good safety profile. A search for suitable candidates was initiated.
In January 2015, ALMI Invest, Sweden, joined as first investors in PILA PHARMA and financed a preclinical screen of suitable clinical ready TRPV1 antagonist development candidates with the aim of selecting the best for inlicensing or acquisition for further development as anti-diabetic agent.
In August 2015, ALMI Företagspartner awarded PILA PHARMA an Innovation loan to finance the asset transfer of the selected lead candidate and the preparation for clinical trials.
In March 2016, PILA PHARMA acquired a TRPV1 antagonist asset from Ario Pharma Ltd (Cambridge, U.K.). The acquired asset includes the clinical ready and safe development candidate XEN-D0501, patents, know-how, and data.
In June 2016, PILA PHARMA completed an emission of new shares to private investors and ALMI Invest and has thus secured the necessary financing for the conduct of the first clinical trial of XEN-D0501 in type 2 diabetic patients (to investigate the safety and tolerability).
In February 2017, PILA PHARMA received the regulatory green-light to conduct a single-dose safety trial of XEN-D0501 in type 2 diabetic patients in Denmark with Professor Henning Beck-Nielsen as principal investigator.
In March 2017, PILA PHARMA completed a fully-subscribed issue of new shares permitting the company to further consolidate its internal organisation, to plan for the next clinical efficacy trial and to – earlier than originally planned – initiate internal research activities with the aim of strengthening the company’s IP-portfolio, carry out further asset exploration and to evaluate new licensing opportunities.