MARSEILLE, France—Privately-held Trophos SA, aclinical-stage pharmaceutical company, announced July 20 that it and Allschwil,Switzerland-based Actelion Ltd. have entered into an agreement whereby Actelionhas, for roughly $12.8 million, obtained an exclusive option to acquireTrophos.
Trophos' lead compound olesoxime has completed enrollmentinto a Phase III study in amyotrophic lateral sclerosis (ALS), the orphandisease that is more colloquially known as Lou Gehrig's disease. This study isexpected to report data by the end of 2011; at this time, Actelion may exercisethe option for an acquisition price between $160 million and roughly $250million in cash, contingent on different regulatory approvals and otherclinical progress of Trophos' pipeline.
At the same time, the two companies also agreed on aresearch collaboration to allow Actelion access to Trophos' proprietary CNSassay technology and compound library. The technology mimics neuronaldegeneration processes in the test tube and is used to screen chemicalcompounds for their ability to block these processes.
"It's fair to say that olesoxime is a very major part ofActelion's interest, if not the key item on which hinges the decision toacquire, and the better the trial results are from late 2011, the more likelythey will be to exercise the purchase option," says Damian Marron, Trophos'CEO. "But there is more to the situation than just that compound, because wealso have the research collaboration in there as well and other compounds inour pipeline."
In addition, Trophos' platform technology, Plate RUNNER HD,may be an additional enticement, Marron notes. Previously known as the FlashCytometer, Plate RUNNER HD is at the heart of Trophos' discovery platform,developed by Trophos scientists to fit a niche area need unmet by othertechnologies—midway between flow cytometry and electromicroscopy. It isreportedly unique in its capacity for counting live neurons—and now other cellsand even small organisms like zebrafish—in high-throughput mode at very highdefinition.
Although Marron notes that Trophos sells one or two PlateRUNNER HD systems a year to researchers, he isn't aware of any interest onActelion's part to commercialize the platform, and he predicts that even ifthat did happen, it would be a highly sideline area of business at best for amerged Actelion and Trophos.
Trophos' efforts on the ALS front, though, are clearly ofparamount concern for Actelion, with Simon Buckingham, president of globalcorporate and business development for the company, noting, "Trophos has donean excellent job to enroll more than 500 ALS patients into a well-designedpivotal study. Once study results are available, Actelion is ideally positionedto leverage these achievements with our proven global regulatory and marketingexpertise in the area of orphan drugs."
Olesoxime is Trophos' lead compound of a proprietarymitochondrial pore modulator series, and preclinical studies have indicatedthat olesoxime may promote the function and survival of neurons and other celltypes under disease-relevant stress conditions, through interactions with themitochondrial permeability transition pore.
Phase I studies in healthy volunteers and Phase Ib studiesin ALS patients demonstrated that olesoxime is well tolerated, according toActelion and Trophos. These studies also helped to determine the dose regimenused in the pivotal Phase III study.
In addition to a pipeline of new molecular entities indevelopment for the motor neuron diseases ALS and spinal muscular atrophy, ofwhich olesoxime is just one candidate, Trophos is also developing a novelcompound for cardiac ischemia-reperfusion injury.
"Since its inception, Trophos has made significant progressin turning its key expertise in neurodegenerative disorders and orphan diseasesinto achievements that include advancing our lead compound olesoxime into latestage clinical development," Marron says. "The development of olesoxime hasbenefited from significant support from patient communities, clinicalinvestigators and the European Union, including Trophos spearheading anEU-funded consortium dedicated to improving the treatment of ALS."
Looking at the research collaboration that the two companieshave agreed on in the interim period between the purchase option and thestill-to-come olesoxime results, Actelion's chief scientific officer, Dr. MartineClozel, says, "Trophos has a pioneering approach and proprietary expertise thathas enabled the development of high-throughput screens using primary neurons aswell as the ability to broadly profile more advanced compounds. This is ofgreat value to Actelion as we have developed a large in-house compound libraryand significant expertise in the field of neurological disorders."
Trophos publishes the identification and characterizationof novel cardioprotective compound
MARSEILLE, France—Trophos SA announced in late July that ithad published important data on TRO40303, which will enter clinical developmentsoon with the ultimate aim to reduce mortality and morbidity in myocardialinfarction (MI) patients, and which is reportedly "the second most advancedcholesterol 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 Juneissue of the Journal of Pharmacology And Experimental Therapeutics (JPET). The studies reported in the paper bySchaller, et al., demonstrate thepotential for this compound to protect heart tissue from ischemia-reperfusioninjury induced when treating MI.
"We are very pleased to publish this important work, whichwas conducted in collaboration with a distinguished international scientificnetwork, in such a prestigious publication as JPET," says Rebecca Pruss, chiefscientific officer at Trophos. "Cardiac reperfusion injury is a significantunmet medical need that contributes to long-term morbidity and progression toheart failure due to a MI. The role of mitochondrial permeability transition incardiac reperfusion injury has recently been validated clinically. It is a tremendousclinical opportunity for the novel cholesterol oxime compounds discovered byTrophos that target this mechanism."
Use of thrombolytics and balloon angioplasty to rapidlyreperfuse heart tissue with oxygen following a MI has greatly reduced morbidityand mortality. Paradoxically, about 50 percent of the damage to heart tissuefollowing MI is due to re-oxygenation leading to a burst of reactive oxygenspecies as energy production by mitochondria is reactivated. The mechanism ofaction of TRO40303 involves prevention of stress-induced mitochondrialpermeability transition, a target implicated in cardiac reperfusion injury aswell as neurodegenerative diseases and other pathologies.
The studies reported by Trophos and colleagues show thatTRO40303 binds directly to the cholesterol site of the mitochondrial outermembrane protein, TSPO, which is highly expressed in heart and is associated tothe mitochondrial permeability transition pore, allowing rapid uptake ofTRO40303 into cardiac tissue. In vitro,TRO40303 reportedly improved oxidative stress-induced cardiomyocyte survivalthat was correlated with a reduction in reactive oxygen species production,slowed triggering of mitochondrial permeability transition and reducedcytoplasmic and mitochondrial calcium overload while also reducing the releaseof apoptotic factors, key events in cardiac reperfusion injury.
"We are particularly excited that there is increasing evidence that themechanism of action of our cholesterol oxime family of mitochondrial poremodulator compounds will have tremendous commercial potential for chronicneurological and neurodegenerative disorders as well as non-neurologicconditions such as cardiac ischemia-reperfusion injury," says Damian Marron,Trophos' CEO. "There are around 1.6 million cardiac reperfusion proceduresperformed each year in the major markets and currently no available treatmentsto prevent ischemia-reperfusion injury. This fits perfectly with Trophosstrategy of creating value by of targeting niche, high medical need markets."