What is the IP foundation underlying the rRNA Biogenesis and CX-3543?

Cylene Pharmaceuticals has an aggressive program that captures new intellectual property as well as protects its existing disclosures. To do this, Cylene files broadly on meaningful findings using a carefully designed patent strategy. Rather than relying on a single application to cover a technology, Cylene uses suites of patent applications to build Picket Fences around its inventions. This includes but is not limited to patent applications for: composition of matter, utility, processes, formulation, assays, and mechanism of action. Several quinolone compositions of matter patents have already been issued to Cylene as part of its comprehensive IP suite.

Why does CX-3543 selectively kill tumor cells without killing highly-proliferating normal cells like those found in the bone marrow, skin, and gut?

CX-3543 targets a protein:DNA complex that is overexpressed during ribosomal RNA biogenesis in tumor cells. This protein:DNA complex is only created during transcription of rRNA; therefore, the amount of this complex scales with the rate of rRNA biogenesis. During tumorgenesis, the nucleolus erupts into a hyperactive factory to create excessive amounts of ribosomal RNA, inducing the cell to produce excessive amounts of ribosomes which, in turn, produce excessive levels of protein that fuel the unbridled growth and proliferation of cancer cells. The rate of ribosomal biogenesis of cancer cells is well beyond that of those found in normal cells, even highly proliferating normal cells.

For which types of cancer is CX-3543 best suited?

We expect CX-3543 to work on cancers that exhibit more rapid rates of rRNA biogenesis, as well as those cancers with a greater extent of nucleolar abnormalities, such as prostate cancer.

Why is there a broad range of action?

Conceptually, many of the mutations that occur in cancer cells arise in the signaling pathways (kinase pathways) and in tumor suppressor genes. Such mutations modify proteins that are upstream of the rRNA biogenesis apparatus. CX-3543 directly targets the rRNA biogenesis apparatus downstream of many of the mutations. Thus, one would expect CX-3543 to have a broad anti-tumor range of activity.

Why aren't we encountering drug resistance?

Cylene has made numerous attempts to induce drug resistance in cancer cells. Techniques include: induction of natural resistance in presence of sub-optimal concentrations of drug; induction of mutations by UV radiation that could give rise to drug resistance; and, dominant suppressor analysis using a cDNA expression library. CX-3543 is targeting a quadruplex motif in the rRNA gene, of which there are more than 40 quadruplexes in each of more than 400 copies of the gene. One might expect that drug resistance would require simultaneous mutations in numerous copies of the gene.

Do you expect CX-3543 to work well in combination with other drugs?

Ongoing studies in murine xenograft models are targeted at identifying the most effective drug combinations for different types of cancers. Studies to date have demonstrated additive to synergistic activity of CX-3543 in combination with camptothecin against HCT-116 colorectal cancer in murine xenograft models.

Do you expect tumor regression by a targeted anti-cancer agent of any kind in Phase I trials?

Typically, in contrast to conventional cytotoxins that often demonstrate tumor regression in animal models and in human Phase I clinical trials, targeted agents are expected to only demonstrate disease stabilization in the target population.

What other targets exist in ribosomal biogenesis and what are further applications for our drugs?

Cutting edge research has demonstrated that multiple types of quadruplex: protein interactions exist, as well as providing evidence that other types of DNA and RNA three-dimensional structures exist. We find potential targets in the RNA Pol I enzyme, the upstream binding factor (UBF), the regulatory SL1 proteins, PARP, and in a series of kinase enzymes that directly regulate activity of the pre-initiation complex.

Are other indications applicable to rRNA biogenesis inhibition?

Abnormalities in rRNA biogenesis have been associated with cancers, certain inflammatory diseases, certain viral diseases, and senescence. Indeed, Cylene has filed for intellectual property protection for all these potential indications.

Do you have other RBIs in your product pipeline?

Cylene has created a platform based on RBI technology. We have second and third generation RBI's in our pipeline, and due to our drug's broad range of action and down-stream approach, we expect our technology to have enourmous pipeline potential.

Is the RBI approach scientifically validated?

The RBI approach is built on scientifically validated methods, standing on the shoulders of drugs such as Erbitux®, Iressa®, Gleevec®, Rapamycin®, and Cisplatin. These drugs target other protein or DNA structures upstream of the rRNA biogenesis apparatus, thereby indirectly reducing rRNA levels in cancer cells and inducing cancer cell apoptosis. Due to its targeting of the rRNA Biogenesis apparatus, CX-3543 offers a highly effective drug that acts through the validated RB pathway, albeit downstream of many cancer mutations.

Are RBI's administered orally or intravenously?

Because CX-3543 is a first-in-class drug, it was designed for intravenous administration in order to carefully control exposure levels. The first Phase I trial utilizes an IV administration route. Ongoing efforts are aimed at the creation of orally bioavailable variations.

How is this relevant to c-Myc?

The c-Myc proto-oncogene has been reported to contain a DNA sequence in its promoter region that may give rise to a G-quadruplex motif. This quadruplex in c-Myc falls into the structural class of parallel/mixed conformations, and CX-3543 was designed to target such a class of quadruplexes. However, intracellularly, CX-3543 demonstrates no direct effect on the transcription of the c-Myc proto-oncogene. Rather, CX-3543 targets the parallel/mixed class of quadruplexes that are overexpressed in the rRNA gene during rRNA biogenesis in cancer cells.

At which clinical sites are you studying CX-3543?

We selected the Mayo Clinic in Scottsdale, AZ and CTRC in San Antonio, TX, as well-reputed trial sites for CX-3543. Both of our clinical investigators, Dr. Rob Marscke and Dr. Kanakos Papadopoulos, are experienced oncology investigators with impressive clinical records.

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