West Coast Editor

Among people who ponder symbols, the number nine means an ending or completion, since literally it's the last of the single-digits. But research into toll-like receptors hardly finishes with investigations of popular TL9.

The Phase III agonist TLR9 - formerly known as ProMune, or CpG7909 - is partnered between Coley Pharmaceutical Group Inc. and Pfizer Inc. Trials by the pharma firm are testing the compound against first-line non-small cell lung cancer. (See BioWorld Financial Watch, March 22, 2004.)

Coley finished its $96 million initial public offering in 2005, a few months after closing the potential $505 million deal with Pfizer. PF-3512676 cropped up again in the news earlier this month, when Timothy Ruane, INEX's president and CEO, pointed to preclinical data with an INEX drug candidate, INX-0167, offered in December at the annual meeting of the American Society of Hematology.

The lead INEX compound boosts immune cells to enhance potency of monoclonal antibodies such as Rituxan (rituximab) for lymphoma from Genentech Inc. and Herceptin (trastuzumab) for breast cancer, also from Genentech. Data with INX-0167 "were pretty clear that we were superior to the Coley product in primate models," Ruane told BioWorld Financial Watch. INEX's compound will start Phase I trials later this year.

Alnylam Pharmaceuticals Inc.'s expanded deal with INEX was the occasion for remarks by Ruane. The firms have broadened their work together on lipid-based delivery, and Alnylam has taken a license to INEX's liposomal approach.

Also working in the TLR9 space is Dynavax Technologies Corp., which last fall entered its first major collaboration, signing a preclinical deal worth as much as $136 million with AstraZeneca plc to discover and develop therapies to treat asthma and chronic obstructive pulmonary disease using Dynavax's second-generation TLR9 agonist immunostimulatory sequences.

The ASH meeting featured news as well from Dynavax, which disclosed preliminary data from an ongoing open-label Phase IIa study of the TLR9 agonist used in combination with Rituxan against non-Hodgkin's lymphoma. Patients who showed clearly increased expression of TLR9 agonist- and interferon-inducible genes came up with a prolonged time to progression as compared to patients who were less responsive to the drug and to historical controls. The combo proved well tolerated, too.

Earlier in December, Dynavax kicked off a Phase I dose-escalation trial with the TLR9 agonist in combination with a standard chemotherapy regimen for metastatic colorectal cancer. The enrollment target of the three-center, U.S. trial is 15 patients, all of whom will have been previously treated for colorectal cancer but had a recurrence. Designed to identify the optimum dose and to yield safety and tolerability data for escalating doses of the drug when given with irinotecan and Erbitux (cetuximab, ImClone Systems Inc. and Bristol-Myers Squibb Co.), the trial is expected to finish in the first half of next year.

The TLR strategy might also work against influenza. In October, VaxInnate Corp. raised $40 million in a Series C financing to move its TLR-based flu vaccines into the clinic. VaxInnate's core technology fuses a vaccine antigen to flagellin, a component of the long, hair-like tails that help bacteria swim. As in most vaccines, the antigen component stimulates an adaptive immune response characterized by the production of pathogen-specific antibodies and T cells. The flagellin factor, though, brings about a broad innate immune response through the antagonism of TLR5.

Evolving particularly far past TLR9 is Idera Pharmaceuticals Inc., which signed a deal last month with Merck & Co. Inc. that brought $30 million up front and as much as $425 million in potential milestone payments for the broad use of TLR receptor agonists in oncology, infectious diseases and certain central nervous system disorders. Specifically, the arrangement includes an upfront licensing fee of $20 million, and the sale of $10 million worth of Idera's stock at $5.50 per share, along with royalties if any products hit the market. Shares of Idera late last week were trading at about two dollars higher than the amount paid by Merck.

The deal marks Idera's second with a big-time pharma player. Under its former name of Hybridon Inc., the company in June 2005 signed a potential $136 million deal with Novartis Pharma AG, aimed at finding TLR9 drug candidates for asthma and allergy.

Idera wouldn't break down specifics of the Novartis deal at the time of signing, but SEC paperwork since then shows a $4 million up front fee, with the rest due in milestone payments. After a two-year research collaboration, Novartis has an option to expand the deal and use identified immune modulatory oligonucleotides for more indications (other than oncology and infectious diseases), which also would be subject to agreed-upon milestone money.

Although its most-advanced compound, IMO-255 in Phase II for renal cell carcinoma, is an agonist of TLR9, Idera is working on other agonists and antagonists, too, for a wide variety of illnesses. In May of last year, the company offered preclinical data during the annual meeting of the American Association of Immunologists, unveiling an expanded portfolio of drug candidates targeting TLRs to include RNA compounds that activate immune responses through TLR7 and TLR8. IMO-2025, another TLR9 agonist, is due to enter the clinic soon, targeting hepatitis C virus.

Companies tend to like TLR9 - stimulated by unmethylated, double-stranded CpG-rich DNA - for cancer, asthma and infectious diseases because it's present in dendritic cells and B cells in the immune system. Agonists might jump-start those cells and start Th1 cytokine secretion, thus boosting interferon-alpha levels and killer immune cells.

TLR7 and TLR8 are stimulated by single-stranded RNA, and could work against infectious disease by inducing not only Th1 cytokine and interferon-alpha but also interleukin-12.

With bets across the board, Idera finds itself with about $41 million in pro forma cash and cash equivalents, enough to last about two years, analysts estimate, given the burn rate of about $18 million annually.

Ren Benjamin, analyst with Rodman & Renshaw, echoed the oft-heard biotech mantra, "Cash is king," in an Idera research report this month, as he rated the company "market outperform" with a price target of $9. Idera has successfully morphed into one of the few players with TLR drugs beyond TRL9, and Benjamin finds the stage set for growth.

Thanks to the Merck money, Idera can finish its ongoing Phase II trial with the lead candidate as well as Phase I/II combination study in solid tumors, while moving the earlier stage compounds ahead.

"With the additional funds, the company could also pursue combination trials of IMO-2055 with other targeted therapies" - an approach more likely to realize the drug's potential, Benjamin wrote.