VentiRx Pharmaceuticals Inc.
This article was originally published in Start Up
Executive Summary
VentiRx Pharmaceuticals Inc. has been working since 2007 to develop TLR8 agonists for allergic rhinitis and cancer, while considering how they might also be used in other indications. The company reported positive data from Phase I clinical trials in both areas within the past year, but has recently decided to move forward in cancer only.
Aiming to treat cancer via immunostimulation
1700 Seventh Avenue
Suite 1900
Seattle, WA 98101
Phone: (206) 689-2259
Web Site: www.ventirx.com
Contact: Robert Hershberg, MD, PhD, EVP & CMO
Industry Segment: Biotechnology
Business: Immune system modulation
Founded: June 2006
Founders: Robert Hershberg; Michael J. Kamdar, CBO
Employees: 11
Financing to Date: $53.9 million
Investors: ARCH Venture Partners; Domain Associates; Frazier Healthcare Ventures; MedImmune Ventures
Board of Directors: Steven Gillis, PhD (ARCH Venture Partners); Elliott B. Grossbard, MD (Rigel Pharmaceuticals Inc.); Patrick Heron (Frazier Healthcare Ventures); Robert Hershberg; Michael J. Kamdar; Atul Saran (MedImmune Ventures); Kent Snyder (Senomyx Inc.); Nicole Vitullo (Domain Associates)
Scientific Advisory Board: Nora Disis, MD (University of Washington); H. Kim Lyerly, MD (Duke Comprehensive Cancer Center); Tadataka Yamada, MD (Frazier Healthcare Ventures)
Like many start-ups striving to develop novel drug candidates, VentiRx Pharmaceuticals Inc. believes its approach to stimulating the human immune system has broad potential. But even with $53.9 million in financing to date, the company is reining in its development plans for agonists of Toll-like receptor 8 (TLR8). A growing body of literature suggests this receptor type, one of 13 TLRs identified to date, is integral to the innate human immune system, which recognizes foreign substances and organisms as soon as they enter the body through airway mucosa, the skin and the gut lining. The innate immune system is distinct from and sometimes a precursor to the adaptive immune system, which produces B cells and T cells that remember specific pathogens and stay on patrol for them.
VentiRx has been working since 2007 to develop TLR8 agonists as treatments for allergic rhinitis and for cancer, while considering how they might also boost vaccines or mitigate inflammatory disorders. The company reported positive data from Phase I clinical trials in both allergy and cancer within the past year, but has recently decided to move forward in cancer only. VentiRx plans to begin four clinical trials in 2011, testing the compound it calls VTX-2337 against multiple forms of cancer, in combination with approved anti-cancer treatments including monoclonal antibodies, chemotherapy and radiation.
As yet, just one drug that acts on a TLR has won regulatory approval: Aldera (imiquimod) for skin disorders such as genital warts. A follow-on product, resiquomod, is in development. VentiRx's president Robert Hershberg says the company "takes encouragement" from those approvals of drugs interacting mostly with TLR7, but thinks TLR8 is "a more significant component of the immune response."
TLR8 is still unvalidated as a drug target, but it has recently begun gaining recognition as a potentially powerful one, Hershberg asserts: "If you Googled it just five years ago, you wouldn't find much, but now there is far more scientific literature on the biology of TLR8 and its linkages to various diseases." VentiRx in-licensed VTX-2337 and its other former lead anti-allergy compound VTX-1463 from Array BioPharma Inc. in 2007, [See Deal] when the small molecules were more than a year away from being ready for human testing. Preclinical testing has been uniquely challenging: whereas almost all of the molecular targets biotech companies pursue today can be studied in mice and rats, that is not the case with TLR8.
The protein product of the TLR8 gene is expressed differently in mice and rats than in humans, so researchers have to test compounds meant to interact with it in more evolved animals or specially altered ones. VentiRx studied its allergy drug candidate in beagles, but is testing the anti-cancer compound in a humanized mouse model developed by George Coukos, MD, PhD, director of the Ovarian Cancer Research Center at the University of Pennsylvania. This quirk increases the complexity and expense of research, but Hershberg says he believes the data from this model will be highly predictive of how the cancer drug candidate will function in humans.
In the humanized mouse, Hershberg says VentiRx is observing that stimulating TLR8 increases expression of interleukin-12, interferon gamma and TNF-alpha, inflammatory mediators that tend to activate the immune cells called macrophages and dendritic cells, whose job is to gobble up foreign invaders. Macrophages are also known to recruit other immune system cells. "We think the data indicate that we are promoting a profound immune response, one that will turn out to be robust and long-lasting," Hershberg declares, noting that patients and doctors alike are deeply interested in drugs that can engage a person's own immune system.
VentiRx had thought it might be able to demonstrate "true disease modification," in allergy sufferers, by stimulating the immune system. The hope was that such a basic response would be equally helpful in people suffering grass allergy in the US as for pine allergy in Japan or ragweed in the EU. Exciting as that premise is, proving disease modification as distinct from mere symptom relief is an expensive undertaking in any field, primarily because clinical trials must be long.
By now focusing primarily on cancer, VentiRx can limit its clinical and commercial challenges while still positioning itself to attain significant upside. For one thing, the company won't have to concern itself with coordinating clinical trials to coincide with the various bloom cycles of different kinds of allergenic plants around the world. Nor will VentiRx have to prove, as it would have needed to do to be competitive in the allergy market, that a single compound can modify disease in a robust and long-lasting way.
To win approval for a new cancer treatment, the company need "only" show that stimulating the immune system with a TLR8 agonist can boost the efficacy of already approved therapies. There are plenty of those around, and relatively small, simple Phase Ib and IIa trials will help determine if VTX-2337 looks particularly beneficial in combination with one or another type of therapy. So far, VentiRx is beginning to collect data from a Phase Ib human trial with the same chemical combination successfully used by George Coukos in the animal experiments: VTX-2337 with Doxil, a PEGylated, liposomal formulation of the standard chemotherapy doxorubicin. Doxil was initially developed by Alza, and now belongs to its acquirer Johnson & Johnson. [See Deal] Although it will soon lose patent protection, Doxil may not immediately or fully succumb to genericization because of the complexity of its formulation.
Whereas the number of major drugmakers committed to competing in the allergy market is shrinking, especially since Merck & Co. Inc. acquired Schering-Plough in 2009, [See Deal] plenty of Big Pharmas remain interested in cancer drugs. Ditto, mid-sized and small companies. That market dynamic alone gives impetus for VentiRx to expand its partnering options by choosing to focus on cancer. Ideally, VTX-2337 will turn out to be broadly useful way of revving up cancer patients' innate immune system, regardless of the primary therapy choice. That scenario would create a big potential market for the compound: much larger, than for, say, a drug initially approved to treat just one specific type of cancer.
Hershberg says his company's investors are "really focusing us on doing trials that provide clinical data of commercial and strategic value." So the company is looking at VTX-2337 in combination not only with Doxil, where animal data suggest strong biological relevance, but also with other drugs that already are completely generic. It will also test the candidate in combination with antibodies, because they appear to work by similar mechanisms, for instance by lysing (opening holes in) tumor cells. All four of the upcoming combination studies have been planned on the basis of both preclinical and market data.
Like any other organization aiming to treat disease by broadly stimulating the immune system, VentiRx will have to prove that its drug candidate does not over-stimulate patients' bodies and cause other problems. Excessive immune activity is the hallmark of inflammatory and autoimmune diseases such as arthritis, psoriasis and Crohn's disease.
Early clinical data for VTX-2337 are positive. At the start of June 2011, VentiRx presented data at the American Society for Clinical Oncology Annual Meeting from a multi-center, open label Phase I study of 33 patients with solid tumors. Patients received treatment with one of eight dose levels, once weekly for three weeks out of a four-week cycle. One quarter of enrolled patients showed disease stabilization at eight weeks, and these individuals continued to receive VTX-2337 for one to six additional cycles. One patient with metastatic melanoma showed tumor regression after treatment was stopped, and as of early June had remained cancer-free for 18 months post-treatment. VentiRx told the audience at ASCO that the pharmacological and biological data it collected during this trial supported its hypothesis that VTX-2337 is stimulating an innate immune response.
Like many companies developing potential new treatments for cancer these days, VentiRx is actively seeking biomarkers that could distinguish patients most likely to respond to its TLR8 receptor. "We have been successful at using biomarkers to identify the activity of the compound, to show dose-dependent biological activity," Hershberg declares, adding, "Now the emphasis is shifting to use of biomarkers in more prognostic ways. We are actively working on this."
To date, VentiRx has raised $53.9 million from investors including ARCH Venture Partners, Domain Associates, Frazier Healthcare Ventures and MedImmune Ventures, the investment arm of AstraZeneca PLC. [See Deal] – Deborah Erickson