Earlier this week, Sweden-based Isofol Medical confirmed a definitive license agreement with Endo Ventures, a subsidiary of Endo International for the registration and commercialization of arfolitixorin on an exclusive basis in Canada.

With the consent of Isofol, Endo Ventures has designated Paladin Labs Inc., an operating company of Endo, to be responsible for seeking regulatory approval for arfolitixorin in Canada and after receipt of such approval, to be responsible for the commercialization of arfolitixorin in Canada, including distribution, marketing, medical affairs, pricing and reimbursement activities. Isofol may receive up to US $ 23.05 million (SEK 205 million**) as upfront, development, regulatory, and sales-based milestone payments. In addition, Isofol will receive tiered royalties on net sales in solid double-digit figures.

The license agreement is focused on the registration and commercialization of arfolitixorin as first-line treatment for metastatic colorectal cancer (mCRC) patients in Canada. Isofol will be responsible for supplying the drug to Endo and will retain all international development rights.

“This licensing agreement between Isofol and Endo is a strong validation of the potential for arfolitixorin to address the large unmet medical need for patients treated for CRC,”  nted Ulf Jungnelius, M.D, the Chief Executive Officer of Isofol.

“The collaboration will allow Canadian patients access to arfolitixorin upon receipt of the requisite regulatory approval, advancing the treatment regimens of difficult to treat cancers and also demonstrates our commitment to advance the quality of cancer care worldwide. Endo, through Paladin, has a very successful track record of commercializing innovative pharmaceutical products in Canada and our collaboration with them will be an invaluable component of our strategy to ensure global access to arfolitixorin,” Jungnelius added.

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“Arfolitixorin is an important addition to our portfolio of innovative oncology therapies,” said Livio Di Francesco, Vice President and General Manager of Paladin.

“Colorectal cancer is the third most common cancer affecting nearly 27 thousand Canadians annually**. Paladin is dedicated to bringing new treatment options to Canadians, such as arfolitixorin, which could potentially provide an additional therapeutic option to patients undergoing chemotherapy treatment for metastatic colorectal cancer,” Di Franco explained.

Isofol’s drug candidate arfolitixorin is being evaluated in the ongoing global Phase III AGENT study, as a first-line treatment for mCRC. The study is currently being conducted in the U.S., Canada, Europe, Australia and Japan in over 90 clinics that are open worldwide.

Clinical development
Isofol will remain as global sponsor of the AGENT study and Endo will be responsible for registrational filing and pursuing potential regulatory approval. Paladin will, as the Market Authorization holder, be responsible for the commercialization of arfolitixorin in Canada. Furthermore, Isofol will receive solid double-digit tiered royalty rates on future net sales applicable for the deal.

Earlier this year, researchers at Isofol presented an update on the extension study portion of the ISO-CC-005 Phase I/IIa study. New data following 16-weeks of treatment and beyond shows best Overall Response Rate (ORR) of 55% in 31 patients. The results are in line with the targeted readout in the ongoing global Phase III study, AGENT (NCT03750786).[1]

The new data comes from the two safety extension cohorts of 31 evaluable patients who have been followed and evaluated with CT-scans after 16 weeks or longer, to analyze the exploratory endpoint best ORR – defined as the percentage of patients whose disease decreased more than 30% and/or disappears after treatment – which is the primary endpoint in the AGENT-study. Out of the 31 patients, 17 were treated with an ARFOX regimen***, which is the experimental regimen in the ongoing AGENT-study. A best ORR of 59% was observed in the ARFOX regimen group versus 50% in the ARFIRI regimen*** group, despite a high frequency of right-sided tumor location and BRAF mutation, both being poor prognostic factors for a response. In total, the data resulted in a best ORR of 55 %.

“We are excited to see continued signals of safety and efficacy on the extension cohorts of the Phase I/IIa study of arfolitixorin in mCRC. An improvement of approximately 10-15% over standard of care chemotherapy, which is typically in the 40-45% range in a non-selected population (all-comers), provides strong validation for the ongoing AGENT-study. We are confident that the data generated with arfolitixorin support its potential as a new treatment option for people with mCRC, an indication with a great unmet need,” commented Roger Tell, M.D., Ph.D., Chief Medical Officer at Isofol.

The ISO-CC-005 Phase I/IIa study was completed in January 2020 and included totally 105 patients between dose-finding cohorts (62 patients) and two safety extension cohorts (43 patients). The extension phases include a similar target population, as in the AGENT-study in the first-line setting, to evaluate safety and efficacy at eight weeks on the selected dose regimen of arfolitixorin (120 mg/m2). After the eight weeks of the main study, the investigators could decide to either terminate the patient’s participation or continue treatment and evaluate patients beyond eight weeks.

* The amount given in SEK is subject to the exchange rate
** Canadian Cancer Society Statistical data per province. Online. Last accessed on November 2, 2020
*** arfolitixorin and 5-fluorouracil (5-FU) + oxaliplatin
**** arfolitixorin and 5-fluorouracil (5-FU) + irinotecan

Clinical trials
A Study to Compare the Efficacy of Arfolitixorin Versus Leucovorin in Combination With 5 Fluorouracil, Oxaliplatin, and Bevacizumab in Patients With Advanced Colorectal Cancer (AGENT) – NCT03750786
An Extended Feasibility Phase I/II Study of Methylenetetrahydrofolate (Arfolitixorin) and Pemetrexed Single Agent, Given as Neoadjuvant Treatment in Patients With Resectable Rectal Cancer – NCT01397305
Investigation of [6R] 5,10-methylenetetrahydrofolate (Arfolitixorin) as Rescue Therapy for Osteosarcoma Patients Treated With HDMTX – NCT01987102
PK/PD Investigation of Modufolin (Arfolitixorin) in Plasma, Tumor and Adjacent Mucosa Adjacent Mucosa in Patients With Colon Cancer – NCT01681472
Modelle 001, TS-inhibition in Colorectal Liver Metastases Comparing Arfolitixorin and Calciumfolinate – NCT04126655
Study Evaluating ECG Effects, Safety, Tolerability and Pharmacokinetics of Single Doses of Modufolin (Arfolitixorin) in Healthy Volunteers Tetrahydrofolate in Healthy Male Volunteers – NCT03203564
Modufolin (Arfolitixorin) in Combination With 5-Fluorouracil Alone or Together With Oxaliplatin or Irinotecan in Colorectal Cancer – NCT02244632

[1] Taflin H, Odin E, Carlsson G, Tell R, Gustavsson B, Wettergren Y. Plasma deoxyuridine as a surrogate marker for toxicity and early clinical response in patients with metastatic colorectal cancer after 5-FU-based therapy in combination with arfolitixorin. Cancer Chemother Pharmacol. 2020 Oct 24. doi: 10.1007/s00280-020-04173-2. Epub ahead of print. PMID: 33099678.

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