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Early-Stage Clinical Data Highlights from AACR 2013

The 2013 annual meeting of the American Association for Cancer Research was held between April 6-10th in Washington D.C., and we saw quite a variety of promising data from companies of all sizes. Big pharma data releases, like Roche's (OTCQX:RHHBY) presentation for antibody immunotherapy MPDL3280A, received the bulk of the media attention although the conference also shone some light on a few early-stage oncology programs being developed by small pharma companies that look quite interesting.

Although this list is by no means exhaustive, this article points to four of the programs (and parent companies) that caught our attention

1.) Astex (NASDAQ: ASTX), SGI-110, and small-molecule therapeutics

Astex may be best-known for its marketing of the DNA methyltransferase inhibitor Dacogen, which is approved as a treatment for myelodysplastic syndromes. At AACR, Astex presented results from many of the drug candidates being developed from its proprietary small-molecule platform, including a hypomethylation agent SGI-110 which is now in the process of recruiting for phase II trials and is arguably Astex's most exciting program. The drug works in a similar fashion to Dacogen in that has the ability to restore the function of tumor suppressor genes in cancer cells that have been methylated (silenced).

Putting it simply, these drugs help to "reactivate" genes that are part of the body's natural cancer defense mechanism.

SGI-110 was featured in an oral presentation on Tuesday (April 9th), which highlighted preclinical results targeting ovarian cancer xenografts with a combination of SGI-110 and the common chemotherapeutic agent cisplatin. Mice with subcutaneous xenografts of platinum sensitive or drug resistant human ovarian cancer cells were treated with SGI-110 and cisplatin. Significant anti-tumor activity was observed, and the effect was greater with SGI-110 alone versus cisplatin alone (an encouraging sign). Several indications that demethylation occurred were also noted, which implies that the compound's mechanism of action works not only on paper, but in vivo.

Overall, SGI-110 looks interesting as it is being developed for a number of indications, including ovarian cancer, hepatocellular carcinoma, AML (acute myeloid leukemia), and myelodysplastic syndromes. Its efficacy relative to other DNA methylation inhibitors Dacogen and Pfizer's Azacitidine is untested, but the company and its investors remain confident.

2.) DelMar Pharmaceuticals (OTC: DMPI) and VAL-083

DelMar recently became a public company through a reverse merger, and focuses on the development of oncology drugs that target orphan indications. VAL-083 is the company's flagship drug, and is a treatment for glioblastoma multiforme (GBM). The current treatment options for glioblastoma are limited and often ineffective - consider that first & second line treatments for GBM end up failing in roughly 4/10 patients.

VAL-03 is a DNA alkylating agent that disrupts DNA replication and induces the destruction of cancerous cells. Interesting to note about VAL-03 is that it was originally developed by the National Cancer Institute, and was put through a number of preclinical & clinical trials before it was left on the backburner. Oddly enough, it's also approved and currently marketed in China for the treatment of chronic myelogenous leukemia (CML), as well as lung cancer which bodes well for its path to FDA approval.

At AACR, DelMar announced positive results for VAL-083 in an open label, safety, tolerability, and pharmacokinetic study in patients with recurrent malignant glioma or secondary brain tumors. These patients must have already failed the current first and second-line therapies for glioblastoma: Temodar and Avastin. The primary endpoint in the trial is the maximum-tolerated dose (MTD), although efficacy is also being studied through the progression-free survival (PFS) secondary endpoint.

The interim results are not conclusive, but the data we've seen up to this point have been quite good. No serious treatment-related adverse events were reported in the nine patients that were treated up to the AACR presentation, and none have reached the maximum-tolerated dose yet. Dose-dependent increases in the plasma concentration of VAL-083 demonstrated a strong dose-dependent uptake of the drug as well.

More importantly, DelMar's data also indicated noticeable efficacy of VAL-083 in three out of nine patients with one of these patients experiencing a partial response and two of these patients experiencing stable disease.

Although the optimization of Val-083 dosing will be integral to DelMar's success in later trials, it seems that the safety profile has been well defined at this point (especially since the drug is already on the market in another country). It will be the drug's performance in the phase II portion of its current trial that will allow this to become another FDA approved option for oncologists that want another DNA alkylating agent. Although GBM is a tough disease to treat, DelMar will at least be able to issue optimized dosing that will maximize VAL-083's future demonstration of efficacy in GBM.

3.) Tekmira (NASDAQ: TKMR) and PLK1

Tekmira is a biopharmaceutical company that focuses on the RNAi space, and is heavily watched by investors who follow RNA drug developers (myself included). The company showcased a RNAi candidate that targets PLK1, a proto-oncogene (a gene that can cause cancer due to mutations or increased expression), in patients with advanced solid tumors. The company uses a lipid nanoparticle-based system that effectively targets RNA molecules to cells, allowing for a reduction in gene-specific expression.

Tekmira announced positive Phase I results using their candidate TKM-PLK1 in a presentation on Tuesday, April 9th.

The trial is an open-label, non-randomized, dose-escalation study in patients with advanced solid tumors or lymphoma. The primary endpoints are safety, maximum tolerated dose, and finally tolerability. A total of 23 patients received doses of TKM-PLK1, and the treatment was generally well tolerated. Common adverse events were rigors (33%) and fever (25%), and no noticeable changes in liver function were found in correlation to dosage of TKM-PLK1. A maximum-tolerated dose was estimated from the study, and a 10-patient expansion is currently undergoing the enrollment process.

Results from the trial suggested an initial indication of efficacy as well. Of nine patients that met the dosing requirements for a response evaluation, four (44%) showed clinical benefit. One of those patients experienced a partial tumor response that lasted for more than 10 months, while the remaining 3 experienced stable disease. This news is exciting for TKM-PLK1 as a treatment for solid tumors, and also indicative that the potential of RNAi technology isn't just a bunch of hype.

4.) ArQule (NASDAQ: ARQL)

ArQule is another biopharmaceutical company that develops small molecules that can be used in the treatment of cancer. A notable candidate is ARQ 092, which is an early-stage (Phase I) AKT inhibitor. AKT (Protein Kinase B or PKB) is a protein that has a wide variety of functions but plays a key role in cancer due to its role in cell proliferation and apoptosis (programmed cell death). Cancer cells often benefit when AKT is deregulated, which is why there is are a good number of AKT inhibitors under development by both large and small pharmaceutical companies in various cancer indications.

On Tuesday, April 9th, ArQule announced the results of a Phase I safety, tolerability, and dose-escalation trial for ARQ 092 in patients with a broad range of advanced or metastatic solid tumors. A total of twenty two patients had been enrolled up to AACR, and the study has identified treatment-emergent adverse events in twenty patients that include nausea, fatigue, and anorexia. Dose-limiting toxicities were triggered at a dose of 80 mg every other day, although the maximum-tolerated dose has yet to be established. Six patients saw stable disease for over four months, and one patient experienced a 20% reduction in tumor burden. Note that the results are preliminary, and the dosage of ARQ 092 isn't set.

ARQL 092 joins what seems to be a crowded world in terms of its mechanism of action, although it's important to note that the drug has yet to finish Phase I trials. Speculation of ARQL 092's efficacy versus another AKT inhibitor like RX 0201 for solid tumors is impossible.

The Takeaway

I see an overall bright future for cancer therapeutics and the companies that develop them. Biotech investors often look for specific opportunities in small pharma (and may hone in on the cancer drug developers) because of the inherent ability of these specific companies to generate absurdly high return on investment (ROI) during the clinical development process. This may take years, and involves substantial risk, although a successful cancer drug can end up being worth billions of dollars.

Source: Early-Stage Clinical Data Highlights From AACR 2013