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Orellanine – a first-in-class drug candidate
Oncorena is developing a potentially curative therapy for advanced kidney cancer based on orellanine, a toxin from the Cortinarius family of mushrooms. Accidental intake of such mushrooms are well known to cause an acute renal failure, but no other toxic effects in other organs.
Pioneering preclinical research findings by the founders of Oncorena have shown that orellanine has a powerful killing effect on human metastatic kidney cancer in different experimental set ups. This discovery has ignited efforts to develop orellanine into a first-in-class drug that potentially may revolutionize the treatment of advanced kidney cancer.
Orellanine will initially be examined in patients with advanced kidney cancer already on dialysis. These patients have no remaining kidney function but are in great need for treatment of the metastatic disease and they may have a therapeutic anti-tumor benefit of orellanine. If the expected superior benefits are confirmed in these patients, then the next step may be to expand into patients with advanced kidney cancer with remaining kidney function. This patient population would benefit from “kidney-saving” strategies that are currently being developed.
Advanced kidney cancer is rarely cured. Orellanine addresses a major unmet medical need:
Powerful anti-cancer effect
Orellanine has been shown in several experimental preclinical studies on advanced (metastatic) human kidney cancer to exert powerful anti-tumor effects, suggesting that orellanine may provide markedly improved clinical benefits for patients with advanced kidney cancer compared with current treatment options.
Selectivity and specificity to kidney cancer cells
Orellanine, given intravenously into the bloodstream, is actively and selectively pumped into the kidney cancer cells. Preclinical studies have shown a very specific uptake essentially only in the kidneys and the specific action of orellanine will hopefully translate into a favorable adverse event profile.
Clinical precedence established
Humans have already been exposed to orellanine through accidental ingestion of mushrooms from the Cortinarius family containing this nephrotoxin. The clinical effects are well known, and no other clinical toxicity has been detected apart from the consequences of kidney failure, (i.e., uremic symptoms and signs), source: Hedman et al. BMC Nephrology volume 18, Article number: 121 (2017). Epidemiological studies have shown that the long-term prognosis for patients poisoned by orellanine is comparable to other patients on active uremic care. This clinical experience provides a major advantage and reduces development risk.
Unique mechanism of action
Orellanine kills kidney cancer cells through a completely different mode of action than the available treatment options. It is killing kidney cancer cells by oxidative stress induction and weakens the intracellular defense mechanism by decreasing the synthesis of oxidative stress-protecting enzymes leading to perturbation of the mitochondria function and as a result induction of apoptosis and cell death.
Clinical program — Phase I-II clinical study
Oncorena has completed all preclinical studies and the next step is to demonstrate safety and tolerability, as well as anti-tumor activity of orellanine in advanced kidney cancer patients in a Phase I-II clinical study.
The clinical Phase I-II trial protocol has been developed in collaboration with Karolinska Hospital in Stockholm, Sweden, external clinical oncology advisors and a CRO (Contract Research Organization).
Oncorena has received regulatory approval by the Swedish Medical Products Agency to start the first clinical trial of orellanine in patients with metastatic renal cancer at Centre for Clinical Cancer Studies at the Karolinska University Hospital in Stockholm, Sweden. The study will subsequently be expanded to other countries.
“The biggest challenge in advanced renal cell carcinoma is that most patients cannot be cured with current medical therapy. Developing treatments that induce disease remission and eventually lead to cure is the highest priority for these patients.”
David F. McDermott, MD, professor, Harvard Medical School
Quick facts about orellanine
Orellanine is expected to have positive effect on the two most common forms of kidney cancer: Clear-Cell Carcinoma and Papillary Renal Carcinoma. About 90 % of kidney cancer patients are affected by these types of cancer
Orellanine is a nephrotoxin found in Cortinarius family of mushrooms
Orellanine will be given as an intravenous infusion with the goal to provide superior long-term survival benefit compared to current treatments
Orellanine may have a very favorable adverse event profile
Orellanine is synthetically produced
Orellanine demonstrates an excellent three-year stability and process is scalable to commercial production
Orellanine has no direct competition
Orellanine targets an orphan drug indication
Scientific Articles on Orellanine from PubMed (links)
Orellanine specifically targets renal clear cell carcinoma
Buvall et al. Oncotargets, 2017
Long-term clinical outcome for patients poisoned by the fungal nephrotoxin orellanine
Hedman et al. BMC Nephrology, 2017