12:00 AM
Oct 20, 2014
 |  BioCentury  |  Product Development

Walking the toll road

Why investors have started placing bets on toll-like receptors again

Even after a series of clinical setbacks in the mid-2000s cooled investor and pharma interest in the once white-hot field of toll-like receptors, several companies continued toiling away. Now the spark may be rekindling as new TLR biology has been elucidated, and new methods have been developed to improve safety and efficacy by delivering TLR modulators to the right cells at the right time.

Because of their role in the immune response against bacteria and viruses, TLRs were flagged early on as targets for infectious disease. But they were also considered targets for diseases where the immune response is under- or overactivated, such as cancer, allergy and inflammatory conditions.

In the two years between 2005 and 2007, pharmas executed at least 11 discovery or development deals. Seven of those with disclosed upfront payments totaled $186 million. The period also saw two acquisitions of TLR companies: Corixa Corp. by GlaxoSmithKline plc for $300 million, and Coley Pharmaceutical Group by Pfizer Inc. for $230 million.

Then in 2006, Novartis AG and Anadys Pharmaceuticals Inc. suspended a Phase Ib trial of ANA975 to treat chronic HCV infection after animal toxicology studies showed intense immune stimulation. In 2007, the partners abandoned development of the prodrug of the TLR7 agonist isatoribine.

Also in 2007, Pfizer and Coley's PF-3512676 (formerly ProMune), a CpG-containing oligonucleotide agonist of TLR9, failed to provide additional efficacy when added to chemotherapy in a pair of Phase III studies to treat advanced non-small cell lung cancer (NSCLC).

"That cast a pall over the entire use of CpGs in cancer for some years. Only now the skies are clearing and people understand better what went wrong," said Robert Coffman, SVP and CSO of Dynavax Technologies Corp.

Only five new TLR collaborations between biotechs and larger players were announced over 2008-11. The only one with disclosed terms was a 2008 discovery pact between GSK and Dynavax for TLR inhibitors to treat autoimmune and inflammatory diseases, worth $10 million up front and up to $200 million in milestones, plus tiered royalties up to double digits.

But investment in TLRs began to pick up.

In October 2012, Celgene Corp. paid $35 million for an exclusive option to acquire VentiRx Pharmaceuticals Inc. at an undisclosed price following Phase II data from TLR8 agonist motolimod in ovarian cancer and head and neck cancer. Ovarian cancer data are expected by the end of 2015.

Last month, VentiRx announced it raised $50.6 million from its existing syndicate plus new investor Celgene.

The momentum has continued. Since the beginning of 2013, 11 other companies with lead programs targeting TLRs or with a TLR-based adjuvant platform have raised a total of at least $500 million in private and public financings, including three IPOs in 2014: VBL Therapeutics Ltd., Immune Design Corp. and Innate Immunotherapeutics Ltd.

A 2013 series C round raised by Opsona Therapeutics Ltd. included the venture arms of several strategic investors, including Baxter International Inc., Amgen Inc., Roche and Novartis. The company closed the oversubscribed round at €33 million ($43 million).

Opsona's OPN-305 is in Phase II trials to prevent delayed graft function after renal transplantation. The humanized IgG4 mAb against TLR2 blocks the receptor by preventing it from dimerizing.

And last week, Sanofi and Immune Design made a deal to pool immune therapies for HSV. Immune Design's contribution includes the company's glucopyranosyl lipid A (GLA) adjuvant, which is a TLR4 agonist.

One of the things fueling new interest is a better understanding of the ligand specificities of different TLR subtypes and how they relate to disease, as well as a new appreciation for the role of the receptors in sensing tissue damage unrelated to pathogens, which may open new disease space.

"We now know TLRs are not only activated by external pathogens, but are also sensing stress signals - native signals that occur during abnormal conditions like chronic inflammation settings," said Erez Feige, VP of business operations at VBL.

Several companies also are developing new delivery strategies to avoid on-target toxicities and to improve efficacy by increasing cellular uptake.

Moreover, advances in cancer immunotherapy have started a buzz about TLR combinations (see "A Rising Tide," page 3).

Cooling trend

TLRs are a family of membrane-bound receptors that detect danger signals from pathogens or endogenous processes and stimulate inflammatory processes in response.

Subtypes TLR 3, 7, 8 and 9 reside on endosomes and other internal cellular membranes, and sense nucleic acids. TLRs 1, 2, 4, 5, 6 and 10 are located on the cell surface and recognize pathogen surface components such as proteins or lipids.

Activation of the receptors causes them to dimerize and recruit signal adapter proteins, which in turn activate a signaling cascade resulting in the expression and release of inflammatory cytokines, chemokines and other immune system modulators.

Production of pro-inflammatory cytokines or interferons can activate innate defenses against pathogens. TLR signaling can also prime further immune responses by activating antigen-presenting cells and regulating cell proliferation and survival, which helps expand populations of immune cells and coordinate inflammatory responses with tissue repair processes.

The first marketed TLR-targeted product, imiquimod, was approved in 1997 to treat genital warts. Its target was unknown when it was approved, but later it proved to be an agonist of TLR7.

In the early...

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