Above and beyond in head and neck

CARLSBAD, Calif.—The investigational compound danvatirsen—formerly going by the more unwieldy moniker of IONIS-STAT3-2.5_Rx, based on being a Generation 2.5 antisense therapy targeting signal transducer and activator of transcription 3, or STAT3—has made a good showing for Ionis Pharmaceuticals Inc. Specifically, recently reported new data on danvatirsen that were presented at the 2018 European Society for Medical Oncology (ESMO) Annual Congress demonstrated clinical and safety results from a Phase 1b/2 trial evaluating danvatirsen in combination with durvalumab (Imfinzi), AstraZeneca’s anti-PD-L1 (programmed death ligand-1) antibody, in recurrent metastatic head and neck cancer.

How good a showing? Well, according to Ionis, the drug combo ended up giving 7 percent of patients a complete tumor response and 23 percent of them a partial or complete tumor response, which is a response rate estimated—based on previous studies in this difficult to treat patient population—to be double that with durvalumab alone.

Danvatirsen is Ionis’ most advanced antisense therapy containing the company’s Generation 2.5 chemistry, which was developed to increase the potency of antisense drugs. Danvatirsen inhibits the production of STAT3, a previously undruggable target and an important regulator of immune responses to cancer cells. Inhibition of STAT3 has been shown to broadly enhance the activity of several immune checkpoint therapies in preclinical studies.

The news isn’t only music to the metaphorical ears of Ionis, but also AstraZeneca, because the two companies have a broad collaboration under which AstraZeneca is developing five drugs, one of them being danvatirsen. In fact, roughly a year ago, the two companies shared data about the same two drugs, also from the ESMO annual meeting, saying that “the combination treatment resulted in encouraging antitumor activity with a safety and tolerability profile supportive of continued development.”

As for the more recent data, “At AstraZeneca, we are exploring new modalities such as antisense oligonucleotides to expand the range of druggable targets. Our strategy is also to develop novel combinations to overcome key immunosuppressive mechanisms, and thereby expand the potential for anti-tumor activity of immune checkpoint inhibition,” said Susan Galbraith, senior vice president and head of the Oncology, Innovative Medicines and Early Development Biotech Unit at AstraZeneca. “We are encouraged by the results observed in the SCORES trial of patients with head and neck cancer, and remain excited about the potential for this combination.”

“AstraZeneca has made important progress in advancing the danvatirsen clinical program. The clinical responses observed in this study along with the strong safety profile exhibited by danvatirsen hold great promise for patients with head and neck cancer and other intractable cancers,” added Dr. Brett P. Monia, Ionis’ chief operating officer. “The results from this study provide additional evidence that our antisense platform can address previously undruggable targets and difficult to reach cell types in the tumor microenvironment. We believe that our Generation 2.5 chemistry will one day deliver new, potent treatment options to patients suffering from a variety of cancers.”

AstraZeneca is evaluating danvatirsen in a range of cancer types as part of a broader oncology partnership evaluating Generation 2.5 antisense therapies against undruggable targets either alone or in combination with immuno-oncology agents, including in non-small cell lung cancer, bladder cancer and head and neck cancer. Ionis earned a $17.5-million milestone payment from AstraZeneca for advancing the Phase 2 program for danvatirsen. Ionis is eligible for additional developmental and regulatory milestone payments from AstraZeneca, plus royalties on commercial sales of the drug.

In other recent news, Ionis announced nearly two weeks earlier a new collaboration with another Big Pharma player, Roche, to develop IONIS-FB-L_Rx for the treatment of complement-mediated diseases. This collaboration will leverage Ionis’ leadership in RNA-targeted therapeutics to develop IONIS-FB-L_Rx targeting factor B (FB) for a broad range of diseases. The first indication the two companies will pursue is the treatment of patients with geographic atrophy, the advanced stage of dry age-related macular degeneration. A Phase 2 study in patients with GA is planned to begin in early 2019.

“Ionis is committed to bringing new therapies to patients living with unmet medical needs. The collaboration is designed to maximize both the potential benefit to patients and the likelihood of success, while optimizing our commercial participation in IONIS-FB-L_Rx. This new agreement builds upon our productive relationship with Roche on IONIS-HTT_Rx (RG6042), an antisense drug for the treatment of people with Huntington’s disease,” said Monia. “Our antisense technology is the first to demonstrate robust, dose-dependent and sustained reduction of FB in a clinical study. We believe that we have found the right partner whose experience in retinal disease drug development and commercialization will enhance our efforts to effectively develop IONIS-FB-L_Rx for patients who currently have no adequate treatment options.”

IONIS-FB-L_Rx, an antisense drug using Ionis’ advanced LIgand Conjugated Antisense (LICA) technology, reduces the production of FB, a key protein in the complement innate immune system. FB is predominately produced in the liver and circulates throughout the vascular system, including vessels in the eye and kidney. This complement protein plays a pivotal role in an innate immunogenic cascade that, when overactivated, has been associated with the development of several complement-mediated diseases, including dry AMD.