BioWorld International Correspondent

BioXell SpA could earn up to $150 million in milestone payments from Merck & Co. Inc., which has gained exclusive commercialization rights to BioXell's preclinical TREM (Triggering Receptors Expressed on Myeloid Cells) programs.

It also is pocketing an undisclosed up-front fee, and it could earn royalties on both therapeutic and diagnostic products. More than one-third of the total potential milestones on offer - $55.5 million - are tied to the most advanced program, in sepsis.

Merck, of Whitehouse Station, N.J., will be responsible for development and commercialization. It also is funding ongoing research at Milan, Italy-based BioXell.

BioXell gained the TREM biology platform when it was spun out of Basel, Switzerland-based F. Hoffmann-La Roche Ltd. in January 2002. Marco Colonna, a member of BioXell's scientific advisory board, reported the first TREM receptor, TREM-1, in 2000. The protein plays a role in amplifying inflammatory responses and is expressed on the surface of myeloid cells such as monocytes.

TREM-2 appears to play a role in regulating osteoclasts, which are responsible for bone formation, and microglial cells in the central nervous system. Individuals with Nasu-Hakula, a rare genetic condition in which patients develop bone cysts and progressive dementia during their 30s, have mutations either in TREM-2 or in a gene encoding an associated adaptor protein DAP-12. BioXell also is studying TREM-4 and TREM-5. A gene originally designated TREM-3 was subsequently identified as a pseudogene.

The decision to partner the entire program at such an early juncture was motivated by two factors.

"The bigger piece is we have a very strong development focus on urology," said Alex Martin, chief business officer at BioXell. The company's lead candidate, a vitamin D3 analogue called BXL-628, is either undergoing or is about to enter Phase II trials in four urological or gynecological indications.

"In urological disease, we will move programs as far as we can; that could be ultimately as far as approval," Martin said.

The particular characteristics of BioXell's first TREM-related indication added further weight to the decision. "Sepsis is a challenging field - especially for a biotechnology company. There are many drugs which have failed in sepsis," BioXell CEO Francesco Sinigaglia said. Part of the problem is identifying the underlying cause. "The challenge is to be able to stratify the population and identify the patients who will be susceptible to your treatment," Sinigaglia said.

Data already have been published indicating that TREM-1 expression is up-regulated during septic shock caused by bacteria and fungi, but not during aseptic shock. That finding will form the basis of a diagnostic that will differentiate the two patient groups.

BioXell also has developed a preclinical drug candidate for treating microbial sepsis, a recombinant protein comprising the extracellular domain of the TREM-1 receptor fused to the Fc portion of human immunoglobulin. The rationale simply is to dampen the excessive inflammation by mopping up whatever signaling molecule is responsible for triggering the effects associated with TREM-1.

"The ligand has not yet been identified. This is part of our current research," Sinigaglia said. The therapeutic approach already has been shown to work in a mouse model of sepsis.