HDAC Inhibitors
Targets: Hematological Cancer & Solid Tumors
Cancer has traditionally been considered a disease of genetic defects
such as a gene mutations and deletions, Close
DeletionsA loss of genetic material in which a part of a chromosome or a sequence of DNA is missing. as well as chromosomal
abnormalities, that result in the loss of function of tumor CloseTumorAn abnormal growth of cells that may be the result of cancer.suppressor
genes and/or gain of function or hyperactivation of oncogenes. CloseOncogenesA gene that, when mutated or expressed at high levels, helps turn a normal cell into a cancer cell
Cancer is characterized by genome-wide changes in gene expression CloseGene expressionThe process of how genetic information is used to create what is patterned by DNA. within the tumor. These changes favor a tumor’s ability to progress through the cell cycle, to avoid apoptosis, CloseApoptosisA term meaning programmed cell death or cell suicide, usually involves an orderly interruption of cell functions resulting in cell death. or to become resistant to chemotherapy. HDAC inhibitors are able to reverse several of these changes, and restore a pattern more like that of a normal cell.
The human genome CloseGenomeIncludes both the genes and the non-coding sequences of the DNAconsists of a complex network of genes which are turned on or off depending on the needs of the cell. One of the ways in which genes are turned on or off is by means of chemical modification of histone proteins. Histone proteins are structural components of chromosomes, and form a scaffold CloseScaffoldA series of proteins that bring together various other proteins in a signaling pathway and allows for their interactionupon which DNA, CloseDNADeoxyribonucleic acid (DNA) - A nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information. DNA is often compared to a set of blueprints or a recipe, or a code, since it contains the instructions needed to construct other components of cells, such as proteins and RNA molecules. the genetic material, is arranged. A well studied histone modification is acetylation CloseAcetylationA reaction that introduces an acetyl functional group into an organic compound.and deacetylation, CloseDeacetylationA reaction that removed an acetyl group from an organic compound
modifications that are catalyzed by a family of enzymes known as histone acetyl transferases (or “HATs”), and histone deacetylases (or “HDACs”).
Inhibition of HDAC enzymes by a selective HDAC inhibitor such as the Pharmacyclics compound PCI-24781, tips the balance in favor of the acetylated state, a state that allows transcription ClosetranscriptionTranscription is the synthesis of RNA under the direction of DNA.to occur, which can be thought of as turning a gene “on”. When a cell is treated with PCI-24781, waves of previously silenced genes are initially turned on. Some of these genes are regulators themselves, and will activate or repress the expression of still other genes. The result is an orchestra of changes to gene expression: some genes being turned on, while others are kept in the off state.
Following chemotherapy or radiation treatment, some patient’s tumors may turn on certain genes as a strategy by the tumor to adapt to the therapy and become resistant to cell death .One example of a genetic change that occurs in many cancers is the activation of the DNA repair gene RAD51. CloseRAD51A protein involved in repairing double strand breaks in DNA. In response to treatment with DNA-damaging chemotherapy or radiation, tumors will often turn on DNA repair genes (including RAD51) as an adaptive strategy to help the tumor repair the DNA damage done by these agents. In pre-clinical models, PCI-24781 was able to turn off RAD51 (and other DNA repair genes), effectively blocking the ability of the tumor to repair its damaged DNA, sensitizing the tumor to chemotherapy and radiation.
Market
Pan-HDAC inhibitors have the potential for broad anti-cancer indications in hematologic and solid malignancies when used in combination with numerous chemotherapeutic drugs and radiation.
Specific HDAC isoforms have been implicated in many other physiological processes and there is growing interest in using pan- and isoform-specific HDAC inhibitors in many disease areas including metabolic, neurological and immunological disorders as well as for treating bacterial and parasitic infections. For instance, in CNS indications, HDAC inhibitors have shown activity in models of epilepsy, and migraine headaches, dementia, Alzheimer's, Parkinson's and Huntington's disease. (Recently reviewed in Kazantsev & Thompson, Nat Rev Drug Discov. 2008 7(10):854-68; Steffan JS et al. Nature. 2001 Oct 18;413(6857):739-43.) HDAC inhibitors have shown substantial activity in inflammatory models including rheumatoid arthritis, CloseRheumatoid arthritisAn auto-immune disease that causes the swelling and stiffening of the joints. juvenile RA, multiple sclerosis, CloseMultiple SclerosisAn autoimmune condition in which the immune system attacks the central nervous system, leading to demyelination. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are wrapped in an insulating substance called myelin. In MS, the body's own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals. psoriasis, ClosePsoriasisA common chronic, inflammatory skin disease characterized by scaly patches. This is a non-contagious disorder which affects the skin and joints. lupus CloseLupusA chronic inflammatory disease that occurs when your body's immune system attacks your own tissues and organs.
and sepsis, CloseSepsisthe presence of toxins in the blood or tissue. diabetes and hemorrhagic shock. CloseHemorrhagic ShockBlood loss due to trauma. (Reviewed in Chipoy C.Drug Discov Today. 2005 1;10(3):197-20; Gray SG, Dangond F. Epigenetics. 2006 Apr-Jun;1(2):67-75. Epub 2006 Mar 5; Susick L et al;. J Cell Mol Med. 2009 epub Jan 28). Finally HDAC inhibitors have shown substantial activity in antiviral, CloseAntiviralA compound used to stop the reproduction of a virus by binding to receptors or causing cellular change. antibacterial and antiparasitic CloseAntiparasiticA compound that is used to treat a class of diseases transmitted by parasites such as lyme disease or trichinosis. applications (Elaut G, et al. Curr Pharm Des. 2007;13(25):2584-620).
Pharmacyclics is actively involved in exploring many of these non-oncology clinical indications internally as well as with outstanding academic collaborators. Our internal programs include applications for RA and juvenile RA and atopic dermatitis. CloseAtopic dermatitisAn allergic disorder of the skin like eczema. Currently Pharmacyclics is actively reviewing potential clinical options in these areas and would likely undertake these with a pharmaceutical partner.
Patents
Key patent protection in US and international territories will extend beyond 2024 with the possibility of patent term extensions during development.
Competition
Merck's vorinostat CloseVorinostatA member of a larger group of compounds that inhibit histone deacetylases (HDAC).
(Zolinza®) has been approved by the FDA for cutaneous CloseCutaneousRelating to the skin.T-cell CloseT-CellA group of white blood cells known as lymphocytes that play a central role in cell-mediated immunity.lymphoma CloseLymphomaA cancer that is detected in the lymph nodes and ducts as well as in the blood. patients who have progressive, persistent or recurrent disease on or following failure of two systemic CloseSystemicAffecting the body as a whole.
therapies, making the oral drug the first in its class to reach the market . A number of structurally distinct HDAC inhibitors are currently in clinical trials including Novartis' LAQ-824 LBH-589, the natural product depsipeptide CloseDepsipeptideA member of a class of HDAC inhibitors that is currently being used to treat some cancers. (FK-228) from Gloucester, and the benzamide, CloseBenzamideA chemical derived from benzoic acid that may be useful as an HDAC inhibitor. SYND 275. HDAC inhibitors have exhibited clinical activity against a variety of human malignancies in initial clinical trials. For example, clinical improvements have been observed in patients with renal cell carcinoma, CloseRenal cell carcinomaA form of cancer in kidney cells. head and neck squamous carcinoma, CloseHead and neck squamous carcinomaA malignant tumor of epithelial origin. mesothelioma, CloseMesotheliomaCancer caused by asbestos fibers.
cancer, small-cell lung cancer, and melanoma, papillary thyroid carcinoma, ClosePapillary thyroid carcinomaThe most common form of thyroid cancer. It forms in follicular cells in small finger-like shapes. and B- and T-cell lymphomas. Thrombocytopenia CloseThrombocytopeniaLow blood platelet count, usually occuring in people who have leukemia, an immune system malfunction, or as a medication side effect.was identified as a dose-limiting toxicity for patients administered a number of these agents. Several of the competitors have reported cardiovascular toxicities such as Grade 3 QTc prolongation, CloseQTc prolongationIn electrocardiogram readings, the QT interval is dependent on the heart rate. Prolongation of the QT interval is associated with high risk for disturbance in the rhythm of the heart. arrhythmias and atrial fibrillation, CloseAtrial fibrillationWhen irregular rhythm prevents the heart's ventricles (chambers) from pumping blood efficiently to the rest of the body, blood pools in the heart, restricting blood flow to the rest of the body. in addition to fatigue, anorexia, infection, headache and nausea. To date, significant side effects, (other than reversible thrombocytopenia), have not been observed in clinical studies with PCI-24781 suggesting that PCI-24781may offer a less toxic modality for the treatment of cancer than its competitors.
Partnering
Through its preclinical ClosePreclinicalStudies done in animals or in cell cultures to show that a new drug should be tested in humans.and Phase 1 and early Phase 2 development of PCI-24781, Pharmacyclics has built substantial product value by reducing product risk while identifying clinical activity. We believe that a drug in a Phase 2 program is an optimal value and risk/benefit inflection point in which to seek corporate partnerships for co-development. A strategic goal for Pharmacyclics is to retain US sales and marketing rights, while partnering ex- US territories, which management believes will return maximal value for shareholders. Partnering ex-US development and commercialization of PCI-24781 is an important goal for Pharmacyclics in 2009.