ThykamineTM is an active lead drug candidate with excellent safety and efficacy profiles confirmed in several pre-clinical and clinical studies targeting inflammation.
Devonian has completed a phase 2 clinical trial in mild-to-moderate atopic dermatitis using Thykamine™ in a cream formulation. The Phase 2 trial was a double‐blind, randomized, placebo‐controlled trial designed to evaluate the efficacy and safety of Thykamine™ cream monotherapy (0.05%, 0.1% and 0.25%) compared to placebo in skin clearance as assessed by the Investigator Global Assessment (IGA) in adult patients with mild-to-moderate atopic dermatitis. Efficacy and safety were assessed every week over a four-week dosing treatment (twice-a-day). A total of 162 patients, spread over several sites in Canada, were recruited for this study.
Compared to placebo, Thykamine™ at 0.1% demonstrated significant improvement of the primary endpoint, i.e. skin clearance (IGA) at all measured timelines (week 1: p = 0.006; week 2: p < 0.001; week 3: p < 0.001; Week 4: p=0.002) resulting in demonstrating a fast onset of the therapeutic effect.
IGA success rates at week 4 were 6.7% for placebo (vehicle cream), 19.0% for Thykamine™ cream 0.05% (p=0.053 vs placebo), 30.8% Thykamine™ cream 0.10% (p=0.014 vs placebo) and 12.1% for Thykamine™ cream 0.25% (p=0.461 vs placebo). Success rate over placebo of Thykamine™ cream 0.1% was not only reached at week 4 but also at week 3 (p = 0.04), resulting in a fast onset of the therapeutic effect. As such, Thykamine™ cream 0.10% has been retained for Phase 3 trials.
In addition, Thykamine™ achieved statistically significant differences, compared to placebo, in its key secondary efficacy endpoints, i.e. BSA, pruritis, POEM and Quality of Life measurement.
Thykamine™ was shown to be safe and well tolerated during the study.
The Corporation conducted a phase 2a clinical trial in Germany. This was a 2-week, exploratory randomized, double-blind, parallel-group, dose-ranging, placebo-controlled study investigating the safety and tolerability of Thykamine™ administered as a rectal enema in patients with active mild-to-moderate ulcerative colitis. The efficacy was also investigated through the modified Mayo score and the measure of different biomarkers of inflammation.
The primary objective of the study was met. Administration of 250 mg, 500 mg and 1000 mg doses of Thykamine™ rectal enema once daily was safe and well tolerated in subjects with active mild-to-moderate distal ulcerative colitis. There was a statistically significant (p<0.05) reduction in the mean change from baseline in the rectal bleeding sub-score of the modified Mayo score, a cardinal symptom/sign of ulcerative colitis, for the Thykamine™ – 250 mg dose compared to placebo at Endpoint/Day 14.
Among the biomarkers, there was a statistically significant reductions in the fecal lactoferrin (FL) levels, a biomarker with high specificity and sensitivity to detect intestinal inflammation, in serum Transforming Growth Factor-beta (TGF-b) and serum M-30 apoptosome.
The objective evidence of activity as per the biomarkers’ reductions and the clinical assessment’s results of the clinical study together have demonstrated the biological activity of Thykamine™ rectal enema in patients with active mild-to-moderate distal ulcerative colitis within a very short treatment duration.
HAND AND FOOT SYNDROME ASSOCIATD TO CHEMOTHERAPY
Hand-and-foot syndrome (HFS), also known as palmoplantar erythrodysesthesia or acral erythema, is a well-documented adverse effect of numerous chemotherapeutic agents 1,2,3,4,5. The prevalent characteristic manifestations include erythema, dysesthesia, pain, cracking, and desquamation. The most common causes are pegylated liposomal doxorubicin (PLD), capecitabine and 5-fluorouracil (FU), cytarabine, and docetaxel. Newer targeted multikinase inhibitors (MKIs) such as sorafenib, sunitinib, axitinib, pazopanib, regorafenib, and vemurafenib also cause a reaction involving the hands and feet. HFS incidence varies with causative agent. PLD and capecitabine have the highest reported HFS incidence at 40% to 50% and at 50% to 60%, respectively. The MKIs sorafenib and sunitinib cause HFS in 10% to 28% and in 10% to 62% of patients, respectively. In addition, certain chemotherapeutic combinations can increase the risk of HFS. The risk of developing HFS appears to be dose dependent. Drug formulations that prolong serum drug levels or that concentrate drug at affected sites have higher rates. Withdrawal or dose reduction of the implicated drug usually gives rise to amelioration of the symptoms.
The pathogenesis of HFS is poorly understood. It has been proposed that the predilection of HFS for the palms and soles may be a result of an accumulation of drug in the eccrine ducts in these areas2,5. The Reactive Oxygen Species-Mediated Inflammation (ROS) and Apoptosis has been identified to be a crucial factor in the development of HFS 6,7,8. These ROS induced the release on chemokines and inflammatory cytokines from keratinocytes which induce apoptosis of these cells as well as positive chemotaxis in blood vessels6.
Development Stage: Devonian is currently developing a specific formulation which would include Thykamine™ as the main active ingredient. The company expect to conduct a phase 2 Proof of Concept clinical study during 2022-23.
RADIODERMATITIS ASSOCIATED TO RADIOTHERAPY
Radiodermatitis (radiation dermatitis) is a signiﬁcant side effect of ionizing radiation delivered to the skin during cancer treatment as well as a result of nuclear attacks and disasters. Radiodermatitis have been classified into three levels; grade 1 (mild erythema), grade 2 (dry desquamation), and grade 3 (severe moist desquamation).
International data indicate that 50% of patients diagnosed with cancer will receive some form of radiation therapy. Radiodermatitis concerns around 95% of all cancer patients receiving radiation therapy9. It is particularly problematic in cancers of the breast, perineum, and head and neck region. These radiation skin reactions result in a myriad of complications, including delays or interruption in treatment, diminished aesthetic appeal, and reduced quality of life.
Development Stage: Devonian is currently developing a specific formulation which would include Thykamine™ as the main active ingredient. It is expected that the company will conduct a phase 2, proof of concept, study in 2022-23.
- Kwakman JM, Elshot YS, Punt CJA, and Koopman M. Management of cytotoxic chemotherapy-induced hand-foot syndrome. Oncology Reviews; volume 14:442, 57-73, 2020.
- Nikolaou V, Syrigos K and Saif MW. Incidence and implications of chemotherapy related hand-foot syndrome. Expert Opinion on Drug Safety, Vol. 15, No. 12, 1625–1633, 2016
- Nagore E, Insa A and Sanmartín O. Antineoplastic Therapy–Induced Palmar Plantar Erythrodysesthesia (‘Hand-Foot’) Syndrome : Incidence, Recognition and Management. Am J Clin Dermatol 2000 Jul-Aug; 1 (4): 225-234.
- Son H-S, Lee WY, Lee W-S, Yun SH, and Chun H-K. Compliance and Effective Management of the Hand-Foot Syndrome in Colon Cancer Patients Receiving Capecitabine as Adjuvant Chemotherapy. Yonsei Med J 50(6): 796-802, 2009.
- Miller KK, Gorcey L, and McLellan BN. Chemotherapy-induced hand-foot syndrome and nail changes: A review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol,Vol 71, Number 4, 787-794, 2014.
- Yokomichi N, Nagasawa T, Coler-Reilly A, Suzuki H et al. Pathogenesis of Hand-Foot Syndrome induced by PEG-modified liposomal Doxorubicin. Human Cell volume 26, 8–18, 2013.
- Patzelt a, Zastrow L, Darvin ME, et al. Detection of free radical formation in human skin upon systemic application of chemotherapeutics. J of Clinical Oncology, vol 31.15_suppl.e20689, 2013.
- Hu X, Dong M, Liang X, Liu Z and Li Q. Reactive Oxygen Species-Mediated Inflammation and Apoptosis in Hand-Foot Syndrome Induced by PEGylated Liposomal Doxorubicin. International Journal of Nanomedicine, 16 471–480, 2021.
- Singh M., Alavi A., Wong R., Akita S. Radiodermatitis: A Review of Our Current Understanding. Am J Clin Dermatol 17:277–292, 2016.