The deal-making furor surrounding Toll-like receptors (TLRs) is continuing, with Merck KGaA agreeing to pay up to $421 million for worldwide rights in cancer indications to Idera Pharmaceuticals Inc.'s for TLR9 agonists.

Just last month, Pfizer Inc. offered to buy TLR specialist Coley Pharmaceutical Group Inc. for about $164 million, following up on a $505 million deal that previously gave Pfizer the rights to Coley's lead TLR9 agonist in cancer. Meanwhile, Merck & Co. Inc. signed a $136.5 million deal with Dynavax Technologies Corp. for the Phase III hepatitis B virus vaccine Heplisav, also a TLR9 agonist. (See BioWorld Today, March 25, 2005, Nov. 2, 2007, and Nov. 19, 2007.)

In the latest TLR deal, Cambridge, Mass.-based Idera will get $40 million cash up front and as much as $381 million in milestone payments from Darmstadt, Germany-based Merck. Idera CEO and Chief Scientific Officer Sudhir Agrawal told BioWorld Today the milestones are "not back-loaded" and include payouts tied to Phase I, Phase II and Phase III trials as well as regulatory filings and commercialization. Idera also stands to get "very decent" royalties on Merck's sales of any TLR9 agonists, Agrawal said.

In exchange, Merck gets exclusive worldwide rights to therapeutic oncology applications of the oligonucleotide TLR9 agonists IMO-2055 and IMO-2125.

IMO-2055 is being evaluated in a Phase IIa renal cell carcinoma trial and two Phase I solid tumor trials, all of which Merck will fund moving forward. In a previous Phase I solid tumor trial, the combination of IMO-2055 with gemcitabine and carboplatin resulted in overall survival of 12.9 months.

IMO-2125 is undergoing a Phase I trial in hepatitis C virus infection, which Agrawal estimated will produce data in early 2009. Idera will continue the clinical program with IMO-2125 for HCV, while Merck will advance the drug against cancer. Idera and Merck also agreed to collaborate on research into additional TLR9 agonists. Agrawal said Idera already has generated a portfolio of such compounds, and Merck has the right to select a prespecified number for development in cancer.

Not included in the Merck deal is the use of TLR9 agonists in cancer vaccines. Idera previously licensed vaccine applications for its TLR7, TLR8 and TLR9 agonists to Merck & Co. Inc. in a deal worth up to $455 million. Idera also has a $136 million partnership with Novartis Pharma AG for TLR9 agonists in allergy and asthma. (See BioWorld Today, June 5, 2005, and Dec. 12, 2006.)

All told, Idera's three big pharma partnerships are worth more than a billion dollars, but they've left the biotech with a somewhat diminished internal pipeline. Agrawal said Idera's focus moving forward will be to continue clinical development of IMO-2125 for HCV as well as pursue preclinical programs focusing on IMO-2125 for other infectious diseases, TLR7 and TLR8 agonists for cancer, and TLR7 and TLR9 antagonists for autoimmune diseases.

Agrawal said Idera also has "started to explore" TLR3. Although most companies in the TLR space focus on TLR7, TLR8 and TLR9, Hemispherx Biopharma Inc. has a double-stranded RNA TLR-3 agonist under FDA review for chronic fatigue syndrome, and Vaxart Inc. is developing a similar technology as an oral vaccine adjuvant.

Altogether, there are 10 TLRs in humans. Their job is to recognize foreign structures and trigger an innate immune response, making them attractive targets for drugmakers seeking to regulate immunity.

So far, the theory of TLR-targeted drugs has proven difficult to put into practice. Just one TLR drug has made it to market - Graceway Pharmaceuticals LLC markets the TLR7 drug Aldara (imiquimod) for superficial basal cell carcinomas, actinic keratosis and genital warts - while many have suffered setbacks. Anadys Pharmaceuticals Inc. had to suspend dosing of its TLR7 drug for HCV, Dynavax discontinued a Phase III trial with its TLR9 allergy drug and Coley suspended development of its TLR9 HCV drug and halted Phase III trials of its TLR9 cancer drug. (See BioWorld Today, June 27, 2006, Jan. 9, 2007, Jan. 24, 2007, and June 21, 2007.)

Although both Idera and Coley are pursuing oligonucleotide TLR9 agonists, Agrawal said Idera's are synthetic molecules resulting from its DNA chemistry platform, while Coley's use natural DNA. Using synthetics allows Idera to modify the structure of its molecules to optimize activity and potentially decrease side effects, he added.

Shares of Idera (NASDAQ:IDRA) dipped 9 cents to close at $11.20 on Wednesday.