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While details are scant, the five-year collaboration will pair C4's targeted protein degradation approach with Calico's focus on diseases of aging. Privately held C4 otherwise is aiming to bring its first Degronomid candidate into the clinic in 2018.




Two of the more mystery-shrouded new players in the biopharmaceutical sector – C4 Therapeutics Inc. and Calico Life Sciences LLC – are teaming up to join the former's targeted protein degradation approach with the latter's focus on treating "diseases of aging." Presumably, big bucks are part of the five-year collaboration between the two privately held firms, but no one is saying.

Announced March 23, C4, whose backers in a $73.5m Series A last year included Roche and Novartis AG[See Deal], and Calico, a Google-financed startup, will collaborate to discover, develop and commercialize therapies that treat diseases associated with aging. Calico lists cancer among aging-related diseases, but C4 President and Chief Scientific Officer Andrew Phillips told Scrip not to assume cancer will be a focus of this partnership, under which C4 will perform the preclinical work, while Calico will be responsible for clinical development and commercialization of whatever emerges from what he termed "a highly collaborative partnership."


Is Calico reimbursing C4 for R&D expenses or taking an equity position in the Cambridge, Mass.-based biotech? What targets or indications will the collaboration focus on? No one is saying yet, which is par for the course for Calico.

C4, which unveiled itself in January 2016 with the Series A announcement and a collaboration with Roche, has been a bit more forthcoming. [See Deal] Its technology derives from intellectual property licensed from the Dana-Farber Cancer Institute around the concept of naturally degrading targeted proteins via a cell's ubiquitin/proteasome system. (Also see "C4 Therapeutics Start-up Starts With Roche Tie-Up, $73m Series A" - Scrip, 7 Jan, 2016.)

Its drug candidates, called Degronomids, offer potential in any therapeutic area featuring disease-causing proteins. Dana Farber's research focused on cancer, of course, but Degronomid therapeutics could be applied in any number of areas, such as central nervous system disorders. [See Deal] At its inception, Chairman Marc Cohen said C4 likely would sign numerous target-specific collaborations so that the potential of targeted protein degradation can be pursued as broadly as possible.

C4 also is advancing its first candidate toward the clinic, with a goal of initiating a Phase I study in 2018. Phillips couldn't say much about the first candidate, other than that it focuses on an oncology target. But he did say that C4 had gotten a bit behind its initial goal of producing a first clinical candidate in 18-24 months, because of the high standards it has set for its initial program.


"I should think that every organization in the world should aspire to put high-quality molecules into people as fast as humanly possible," the exec said. "We've done a lot of work over the past year here at C4 to ensure that we bring forward something that doesn't scrape over the bar in 18-24 months, but that actually profoundly raises the bar for the science that we want the world to see as targeted protein degradation."

Single Molecules Offering Capabilities Similar To ADCs

Phillips describes Degronomids as more similar to small-molecule drugs than to antibodies or antibody-drug conjugates, although the chimeric, bivalent molecules will offer a benefit profile similar to that of an ADC. Degronomid therapeutics will be extremely potent, selective and powerful, he said, due to their mechanism of action.

In theory, targeted protein degradation molecules are labeled with ubiquitin, allowing them to bind to disease-causing proteins and prompting their destruction and clearance from the cell via the ubiquitin/proteasome system. Ubiquitin/proteasome is a natural pathway that is critical for degrading cell-cycle regulatory proteins and misfolded proteins.

"In the case of ADCs, you have a targeting moiety, an antibody usually, and a remarkably potent payload, often a profoundly cytotoxic molecule," Phillips explained. "We're not that, but we have all of those features in the Degronomid model … they sort of have two ends to them. One end is the targeting moiety – that's a little bit like the antibody component of an ADC. And then the other end is a piece that recruits the remarkable and powerful therapeutic effect which comes from leveraging the body's proteasome for

degrading proteins."

The collaboration with Calico is C4's second, following the January 2016 tie-up with Roche, which included an undisclosed upfront payment, with the potential for milestones and royalties that could bring the deal's value to more than $750m. Few details were provided about the Roche deal, but as in the Calico partnership, C4 will perform preclinical development up to a certain point. Roche then holds option rights to acquire the compounds derived from C4's work against targets agreed upon with the pharma.

Phillips said Calico brings expertise to the table that juxtaposes ideally with C4's areas of strength, which include chemistry, biochemistry and biophysics. In this regard, the deal serves as a model for future partnerships the company might sign, he noted. C4 will seek partners who don't offer much overlap within areas of utility. But scientific, philosophical and cultural commonalities will be viewed as important in potential future partners.

"Calico, clearly, has credible depth in drug development, molecular biology, genetics," Phillips said. "This is a team that has expertise and excellence in all of those areas and also other areas that are [in contradiction] to what we have at C4. For example, computational science is not something we have deep investments in at C4, [but is] something that Calico does have. It doesn't necessarily mean that we will have a focus on that in the collaboration; it's just an example of how the expertise of both organizations is, I think, very complementary."

The deal with C4 is the third biopharma partnership that Calico has announced publicly. It follows a 10-year R&D partnership signed in 2014 with AbbVie Inc. focused on cancer and neurology, and another unveiled in 2015 with the California Institute for Quantitative Biosciences to investigate the biology of aging and longevity. [See Deal] Calico holds option rights to acquire potential treatments resulting from the latter partnership. [See Deal]

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