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A dowry to the seal the engagement
September 2010
by Jeffrey Bouley  |  Email the author


MARSEILLE, France—Privately-held Trophos SA, a clinical-stage pharmaceutical company, announced July 20 that it and Allschwil, Switzerland-based Actelion Ltd. have entered into an agreement whereby Actelion has, for roughly $12.8 million, obtained an exclusive option to acquire Trophos.
Trophos' lead compound olesoxime has completed enrollment into a Phase III study in amyotrophic lateral sclerosis (ALS), the orphan disease that is more colloquially known as Lou Gehrig's disease. This study is expected to report data by the end of 2011; at this time, Actelion may exercise the option for an acquisition price between $160 million and roughly $250 million in cash, contingent on different regulatory approvals and other clinical progress of Trophos' pipeline.
At the same time, the two companies also agreed on a research collaboration to allow Actelion access to Trophos' proprietary CNS assay technology and compound library. The technology mimics neuronal degeneration processes in the test tube and is used to screen chemical compounds for their ability to block these processes.  
"It's fair to say that olesoxime is a very major part of Actelion's interest, if not the key item on which hinges the decision to acquire, and the better the trial results are from late 2011, the more likely they will be to exercise the purchase option," says Damian Marron, Trophos' CEO. "But there is more to the situation than just that compound, because we also have the research collaboration in there as well and other compounds in our pipeline."
In addition, Trophos' platform technology, Plate RUNNER HD, may be an additional enticement, Marron notes. Previously known as the Flash Cytometer, Plate RUNNER HD is at the heart of Trophos' discovery platform, developed by Trophos scientists to fit a niche area need unmet by other technologies—midway between flow cytometry and electromicroscopy. It is reportedly unique in its capacity for counting live neurons—and now other cells and even small organisms like zebrafish—in high-throughput mode at very high definition.  
Although Marron notes that Trophos sells one or two Plate RUNNER HD systems a year to researchers, he isn't aware of any interest on Actelion's part to commercialize the platform, and he predicts that even if that did happen, it would be a highly sideline area of business at best for a merged Actelion and Trophos.
Trophos' efforts on the ALS front, though, are clearly of paramount concern for Actelion, with Simon Buckingham, president of global corporate and business development for the company, noting, "Trophos has done an excellent job to enroll more than 500 ALS patients into a well-designed pivotal study. Once study results are available, Actelion is ideally positioned to leverage these achievements with our proven global regulatory and marketing expertise in the area of orphan drugs."
Olesoxime is Trophos' lead compound of a proprietary mitochondrial pore modulator series, and preclinical studies have indicated that olesoxime may promote the function and survival of neurons and other cell types under disease-relevant stress conditions, through interactions with the mitochondrial permeability transition pore.
Phase I studies in healthy volunteers and Phase Ib studies in ALS patients demonstrated that olesoxime is well tolerated, according to Actelion and Trophos. These studies also helped to determine the dose regimen used in the pivotal Phase III study.
In addition to a pipeline of new molecular entities in development for the motor neuron diseases ALS and spinal muscular atrophy, of which olesoxime is just one candidate, Trophos is also developing a novel compound for cardiac ischemia-reperfusion injury.  
"Since its inception, Trophos has made significant progress in turning its key expertise in neurodegenerative disorders and orphan diseases into achievements that include advancing our lead compound olesoxime into late stage clinical development," Marron says. "The development of olesoxime has benefited from significant support from patient communities, clinical investigators and the European Union, including Trophos spearheading an EU- funded consortium dedicated to improving the treatment of ALS."  
Looking at the research collaboration that the two companies have agreed on in the interim period between the purchase option and the still-to-come olesoxime results, Actelion's chief scientific officer, Dr. Martine Clozel, says, "Trophos has a pioneering approach and proprietary expertise that has enabled the development of high-throughput screens using primary neurons as well as the ability to broadly profile more advanced compounds. This is of great value to Actelion as we have developed a large in-house compound library and significant expertise in the field of neurological disorders."  
Trophos publishes the identification and characterization of novel cardioprotective compound
  MARSEILLE, France—Trophos SA announced in late July that it had published important data on TRO40303, which will enter clinical development soon with the ultimate aim to reduce mortality and morbidity in myocardial infarction (MI) patients, and which is reportedly "the second most advanced cholesterol oxime to be discovered by Trophos. "  
The article, titled "TRO40303 (3,5-seco-4-nor-cholestan-5-one oxime-3-ol), a new cardioprotective compound, inhibits mitochondrial permeability transition," was published in the June issue of the Journal of Pharmacology And Experimental Therapeutics (JPET). The studies reported in the paper by Schaller, et al., demonstrate the potential for this compound to protect heart tissue from ischemia-reperfusion injury induced when treating MI.
"We are very pleased to publish this important work, which was conducted in collaboration with a distinguished international scientific network, in such a prestigious publication as JPET," says Rebecca Pruss, chief scientific officer at Trophos. "Cardiac reperfusion injury is a significant unmet medical need that contributes to long-term morbidity and progression to heart failure due to a MI. The role of mitochondrial permeability transition in cardiac reperfusion injury has recently been validated clinically. It is a tremendous clinical opportunity for the novel cholesterol oxime compounds discovered by Trophos that target this mechanism."  
Use of thrombolytics and balloon angioplasty to rapidly reperfuse heart tissue with oxygen following a MI has greatly reduced morbidity and mortality. Paradoxically, about 50 percent of the damage to heart tissue following MI is due to re-oxygenation leading to a burst of reactive oxygen species as energy production by mitochondria is reactivated. The mechanism of action of TRO40303 involves prevention of stress-induced mitochondrial permeability transition, a target implicated in cardiac reperfusion injury as well as neurodegenerative diseases and other pathologies.
The studies reported by Trophos and colleagues show that TRO40303 binds directly to the cholesterol site of the mitochondrial outer membrane protein, TSPO, which is highly expressed in heart and is associated to the mitochondrial permeability transition pore, allowing rapid uptake of TRO40303 into cardiac tissue. In vitro, TRO40303 reportedly improved oxidative stress-induced cardiomyocyte survival that was correlated with a reduction in reactive oxygen species production, slowed triggering of mitochondrial permeability transition and reduced cytoplasmic and mitochondrial calcium overload while also reducing the release of apoptotic factors, key events in cardiac reperfusion injury.
"We are particularly excited that there is increasing evidence that the mechanism of action of our cholesterol oxime family of mitochondrial pore modulator compounds will have tremendous commercial potential for chronic neurological and neurodegenerative disorders as well as non-neurologic conditions such as cardiac ischemia-reperfusion injury," says Damian Marron, Trophos' CEO. "There are around 1.6 million cardiac reperfusion procedures performed each year in the major markets and currently no available treatments to prevent ischemia-reperfusion injury. This fits perfectly with Trophos strategy of creating value by of targeting niche, high medical need markets."
Code: E091006



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