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May 15, 2013 (Vol. 33, No. 10)

Softening the Blow from FOLFOX Treatment

PledPharma’s Modified Form of Mangafodipir Shown to Reduce Side Effects of Chemotherapy

  • Click Image To Enlarge +
    PledOx is a stabilized form of mangafodipir, an MRI contrast agent.

    Just as serendipity wrought the discoveries that Viagra did wonders for sexual dysfunction in men, and Dramamine treated travel sickness better than allergies, so too did it cause a seven-year-old Swedish drug developer to reposition the MRI contrast agent mangafodipir, a PyridoxyL EthylDiamine (PLED)-derivative, into a drug candidate for colorectal cancer patients undergoing chemotherapy.

    PledPharma launched the multicenter Phase IIb PLIANT trial, intended to evaluate whether pretreatment with a stabilized form of mangafodipir, PledOx™ (calmangafodipir or PP-095), can reduce the severe side effects caused by the chemo agent FOLFOX in patients treated for metastatic colorectal cancer.

    The study’s first patient was enrolled in February at Uppsala Academic Hospital, one of four centers in Sweden and the U.S. where 9–12 patients are to be selected for the dose-escalation phase, set to run four to five months. Afterward, a total of 126 patients from at least 28 centers in Europe and the U.S. will be randomized for either PledOx in two different doses or placebo in the same manner. That randomized phase is expected to start in the second half of this year, and expected to be completed in the first half of 2014.

    “Our focus is on colorectal cancer, and protecting against the side effects of chemotherapy. But we would like to develop this more, to be used for the other chemotherapy agents for other cancers, and maybe also radiation,” PledPharma CEO Jacques Näsström told GEN.

    Using a SEK 500,000 (about $79,000) Vinnova grant awarded last year, PledPharma has performed some preclinical studies on PledOx and chemotherapies involved with non-small-cell lung cancer.

    PLIANT was launched soon after a study published in Translational Oncology showed that PledOx had a substantial and statistically significantly better protective effect on blood-forming bone marrow than mangafodipir, when used as an adjunct to treatment with the chemo drug oxaliplatin. PledOx replaces most of the manganese in mangafodipir with calcium, preventing the severe side effects associated with chemo treatment by eliminating the hazard of manganese-induced brain accumulation.

    Research suggesting a role for mangafodipir in chemo dates back two decades, when PledPharma founder Jan Olof G. Karlsson, Ph.D., assistant professor of pharmacology with the faculty of medicine at the University of Linköping, was asked by Nycomed to elucidate a potential side effect of the then-new contrast agent for magnetic resonance imaging in the liver: When injected too rapidly, patients’ faces appeared to blush bright red.

    Dr. Karlsson and colleagues carried out cardiovascular studies showing that mangafodipir could protect the heart against the cardiotoxic effects around anthracycline chemo drugs that were used for treating many types of cancer, but which damaged the DNA in cancer cells, causing them to die. The mangafodipir had dismutated superoxide, preventing the nitric oxide within cells from forming highly toxic peroxynitrate.

    Nycomed and Dr. Karlsson hoped to develop mangafodipir against the cardiotoxic side effects of anthracycline during breast cancer, only to see those plans waylaid by a series of mergers. Meanwhile, a team of French researchers in 2006 showed that mangafodipir protected against chemotherapy-induced myelosuppression in mice.

    A year later, PledPharma was spun out of Linköping University based on the research of Dr. Karlsson, the company’s co-founder and senior scientist. The fledgling company followed up with studies of mangafodipir’s effect in chemo patients—first via a case study, then a clinical trial.

    “A young man in the case study Googled and found out about mangafodipir, and he said, ‘Well, I want to try this.’ We had the history from the cardioprotective area. Some of Dr. Karlsson’s earlier work actually showed that this compound can also protect against ischemia of the heart muscles,” Näsström recalled. “That’s the history of how we actually wound up in the cardioprotective area and the oncology field.”

    The patient had Crohn’s disease and terminal colorectal cancer, the world’s third most common cancer with more than 1.2 million new cases worldwide each year, according to the World Cancer Research Fund. Colorectal cancer requires treatment through several cycles of chemotherapy drugs, FOLFOX, or other oxaliplatin-induced combinations. Side effects associated with treatment include sensory nerve damage, loss of white blood cells, inflammation or ulceration in the mouth, and loss of blood platelets. Less than half of colorectal cancer patients undergo therapy as intended.

    “It’s more by serendipity that we ended up in colorectal cancer, but colorectal cancer is one of the big three cancers. It’s not a bad choice. It was not our decision to start with. It’s more that this young man, when it was tested, it worked out, so that’s where we ended up,” Näsström said.

    Hence PledPharma’s positioning of PledOx as its lead drug candidate. PledOx is a lowMEM (low molecular enzyme mimetic) mimicking the endogenous enzyme Manganese Super Oxide Dismutase (MnSOD), the body’s key protection against oxidative stress caused by overproduction of harmful oxygen/nitrogen molecules, such as during chemotherapy.

    With an estimated price per dose of $2,000, compared to $5,000 for FOLFOX per cycle (dose and a complete treatment regimen, which is usually 8–12 cycles, one every second week), Näsström acknowledges PledOx pre-treatment will be somewhat costlier for patients. However, PledPharma is counting on patients to find benefit in better quality of life and in the potential for prolonged life expectancy.

    PledPharma sees potential to use PLED-derivative compounds against several diseases, and stake a presence in a global market for supportive cancer treatment estimated by Datamonitor at $10.3 billion. The company’s pipeline includes a PLED-derivative (PP-099) being evaluated in a small (just one center), investigator-initiated Phase IIa safety trial against reperfusion injuries that may appear in treatment of patients with acute myocardial infarction treated with coronary angioplasty.

    Nineteen of 20 patients have been enrolled in the study, and PledPharma hopes to present results later this year. Until now, PLED-derivatives have shown a protective effect in preclinical studies against reperfusion injuries.

    “I would say we’re putting more than 95% of our resources on the PledOx, and the PP-099 trial is a much smaller trial,” Näsström said.

    PledPharma’s business goal is to develop its clinical programs through Phase IIb, then license them out to partners for up-front, milestone, and royalty payments. The company is in the process of selecting an advisor for commercializing PledOx, who will oversee more structured talks with potential partners beyond their initial conversations with Näsström.

  • PledPharma

    Location: Grev Turegatan 11 C
    114 46 Stockholm, Sweden

    Phone: +46 8 679 72 10

    Website: www.pledpharma.se/en

    Principal: Jacques Näsström, CEO
    Michaela Johansson, CFO

    Number of Employees: 6

    Focus: PledPharma is developing PledOx for prevention of severe chemotherapy-induced side effects. The firm is also evaluating opportunities for PLED substances in other diseases related to oxidative stress.


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