On January 15, 2014, TetraLogic Pharmaceuticals (NASDAQ:TLOG) stock jumped 23% in mid-day trading. Nobody really knows why, but some suspect the jump was a reaction to media reports such as "Cancer Cure Found For Metastasizing Cells? TRAIL Treatment 100 Percent Effective In Mice," "Scientists Discover Cancer-Killing Protein," and "Big Scientific Breakthrough Could Prevent 90% of Cancer-Related Deaths."
- According to Seeking Alpha, "Market chatter suggests the move is attributable to optimism surrounding the company's research on "targeted cancer therapeutics designed to specifically induce cancer cell death," which traders are apparently linking to a study from researchers at Cornell who have reportedly developed a way to prevent metastasis (see here and here) - the research is being billed (by some) as somewhat of a "cure" for cancer."
Amidst the flurry, over 1.3 million shares of TetraLogic stock were traded. The stock rocketed from $11.21 to an all time high of $14.75. Then the stock started descending. By market close, the stock was at $12.07. The stock kept falling, By the end of January, TetraLogic stock was falling below $9. Still not bad for a company that had its initial public offering (NYSEARCA:IPO) on December 12, 2013 with its stock priced at $7 per share.
Malvern, Pennsylvania-based TetraLogic Pharmaceuticals is a $140M market cap company pioneering the discovery and development of small molecules called "SMAC (second mitochondriaderived activator of caspase) Mimetics" for the treatment of cancers. SMAC Mimetics are a new class of targeted cancer therapeutics. SMAC Mimetics are designed to specifically induce cancer cell death and inhibit fundamental mechanisms of cancer cell survival and resistance, forcing tumors to die.
SMAC activates apoptotic cell death in cancer cells by removing Inhibitor of Apoptosis Proteins (IAPs). IAPs are over-expressed in most cancers and help tumors survive. The central role between SMAC and IAPs in cancer cell death renders SMAC mimetics a promising new class of cancer therapeutics that may be able to treat many types of solid tumors and hematological malignancies.
Is an investment in TetraLogic Pharmaceuticals a good buy?
In Brief/Pro and Con
- TetraLogic's birinapant (TL32711) is a member of a new class of targeted anti-tumor agents known as SMAC-mimetics or antagonists of the IAP proteins that enable apoptotic cell death in cancer cells. By targeting and eliminating IAPs, birinapant addresses a fundamental property of human cancer and resistance to therapies that is applicable to all types of solid tumor and hematological cancers, representing a potential multi-billion dollar market.
- TetraLogic has affiliations and collaborations with leading cancer centers and medical researchers in the fields of apoptosis and SMAC mimetics that support the advancement of the company's programs. The company owns a large library of SMAC mimetics, both dimer and monomer compounds, for the development of follow-on compounds and new indications.
- Several stock analysts are very optimistic about TetraLogic. On January 6, 2014, Oppenheimer started coverage on shares of Tetralogic with an outperform rating and a $19 price target on the stock. Needham & Company also initiated coverage on shares of Tetralogic with a buy rating on the stock and $16 price target. Analysts at Guggenheim initiated coverage on shares of Tetralogic in a research note to investors. They set a buy rating and a $15.00 price target on the stock.
- Due to its expertise in SMAC mimetics, TetraLogic could be an attractive acquisition target for a larger pharmaceutical company that would like to enter this new, cutting edge field of cancer research. Pfizer (NYSE:PFE) and Amgen (NASDAQ:AMGN) have made large investments in the company.
- Investing in micro-cap stocks is always risky. TetraLogic has a low $140M market capitalization. All investments involve risk, but investing in micro-cap companies like TetraLogic is especially risky. These stocks are often extremely volatile, may be illiquid, and are often subject to manipulation.
- Since TetraLogic has limited financial and managerial resources, the company is focusing on research programs limited to one agent, birinapant. As a result, the company is especially susceptible to the risks associated with product failure. If birinapant proves to be unsafe or ineffective or the SMAC-mimetic class of product candidates is considered to be inadequate for clinical development or commercialization, TetraLogic would not have alternative agents in its pipeline to develop.
- Several companies are developing product candidates that target the same cancer pathways that TetraLogic is targeting or that are testing product candidates in the same cancer indications that TetraLogic is testing. More established companies may have a competitive advantage over TetraLogic due to their greater size, cash flows and institutional experience. Compared to TetraLogic, many of its competitors may have significantly greater financial, technical and human resources. Curis Inc. (NASDAQ:CRIS), Debiopharma SA, and Novartis AG (NYSE:NVS), are all developing IAP inhibitors.
- Even if successdul, TetraLogic is still many years away from commercializing birinapant since the investigative drug is only in Phase 1 and Phase clinical 2 trials.
- TetraLogic has not had any products approved by the US Food and Drug Administration (FDA). The company will continue to incur significant research, development and other expenses related to its ongoing operations since its inception in 2003. As a result, TetraLogic had an accumulated deficit of $83.2 million at September 30, 2013.
TetraLogic's expertise is in SMAC mimetics, small molecule peptide mimetics that mimic SMAC for the treatment of cancers. SMAC is an endogenous cellular protein that activates programmed apoptosis. SMAC activates apoptotic cell death in cancer cells by removing Inhibitor of Apoptosis Proteins (IAPs). IAPs are over-expressed in most cancers and help tumors survive. The central role between SMAC and IAPs in cancer cell death makes SMAC mimetics a promising new class of cancer therapeutics with the potential to treat many types of solid tumors and hematological malignancies.
Birinapant is TetraLogic's lead SMAC mimetic for the treatment of cancers. Birinapant, also known as TL32711, is a synthetic, small molecule peptidomimetic, a small protein-like chain designed to mimic a peptide, of SMAC that selectively targets IAPs, inhibits their activity and drives tumor cells to apoptosis. TetraLogic scientists have found that by targeting and eliminating IAPs, birinapant addresses a fundamental property of human cancer and resistance to therapies that appears to be applicable to all types of solid tumor and hematological cancers.
Birinapant is currently being studied in:
- a Phase 1b/Phase 2a study of Birinapant in combination with 5-azacitidine in subjects with myelodysplastic syndrome who are naïve, refractory or have relapsed to 5-azacitidine therapy;
- a Phase 1/Phase 2 study of Birinapant in patients with acute myelogenous leukemia, myelodysplastic syndrome and acute lymphoblastic leukemia;
- a Phase 1b study of Birinapant in combination with Conatumumab in subjects with relapsed epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer;
- a Phase 1b/Phase 2a study of Birinapant in combination with chemotherapy in subjects with advanced or metastatic solid tumors;
- a Phase 2 study of Birinapant in relapsed platinum resistant or refractory epithelial ovarian cancer, primary peritonea;
- a Phase 1 study of Birinapant in combination With gemcitabine in patients with advanced solid tumors.
Birinapant is being developed for the treatment of both solid tumors and hematological malignancies. In Phase 1 clinical trials as a single agent and in combination with chemotherapies, birinapant demonstrated effective suppression of its molecular target at well-tolerated doses and has shown promising anti-tumor activity.
Birinapant has shown clinical activity in both hematological malignancies and solid tumors, including acute myelogenous leukemia (AML), and colorectal cancer (NYSEMKT:CRC). Initial response and safety data from the Phase 1/Phase 2 solid tumor trial were reported at the 2013 Annual Meeting of the American Society of Clinical Oncology (OTC:ASCO).
Myelodysplastic Syndromes (NYSE:MDS)
A myelodysplastic syndrome (MDS) is a type of cancer in which the bone marrow does not make enough healthy blood cells and there are abnormal (blast) cells in the blood or bone marrow. In MDS, bone marrow becomes defective, blood cells produced develop abnormally, too few healthy blood cells are released into the blood stream, which leads to low blood cell counts. As a result, many patients with MDS require frequent blood transfusions. Usually, MDS progresses and the disease worsens and the patient develops progressive bone marrow failure. In advanced stages of MDS, blasts leave the bone marrow and enter the blood stream, leading to AML, which occurs in about one-third of MDS patients.
The pharmaceutical and health care research and advisory firm, Decision Resources, anticipates that MDS therapeutic options will be expanded with the approval of five drugs between 2014-2018: Pharmion Corporation's oral azacitidine for transfusion-dependent lower-risk MDS; Onconova Therapeutics' (NASDAQ:ONTX)/Baxter International's (NYSE:BAX) intravenous formulation of rigosertib (Estybon) for HMA-refractory higher-risk MDS; Merck's (NYSE:MRK) vorinostat (Zolinza) for combination therapy with azacitidine in higher-risk MDS; Cyclacel Pharmaceuticals' (NASDAQ:CYCC) oral sapacitabine for HMA-refractory higher-risk MDS; and GlaxoSmithKline's (NYSE:GSK) eltrombopag (Revolade) for HMA-refractory higher-risk MDS, with a focal goal of reducing thrombocytopenia.
"The near-term MDS drug market will grow modestly as lenalidomide obtains approval in Europe, but the next wave of noteworthy market growth will come between 2014 and 2018," said Decision Resources Vice President Kim Crowell. "While experts acknowledge that the approvals of azacitidine and lenalidomide were groundbreaking, they also report significant remaining unmet need in MDS. Citing the dearth of second-line options for higher-risk MDS patients, experts are hopeful that several Phase 2 and 3 drugs will provide valuable alternative therapeutic options, although they do not expect any drug during the next decade to completely shift or uproot the MDS therapeutic landscape. Improving overall survival, without sacrificing quality of life, is the key therapeutic goal in higher risk MDS patients, while functional quality of life via hematologic improvement is the primary goal in lower-risk patients."
A Phase 1/Phase 2 investigator-initiated clinical trial in AML, MDS and acute lymphoblastic leukemia (NYSE:ALL), is ongoing at the University of Pennsylvania. In this study, 23 study subjects have been treated with birinapant as the sole agent or administered with hydroxyurea (if deemed necessary by the treating physician). The majority of subjects enrolled are over 70 years with AML secondary to MDS and have received multiple prior treatments.
In preliminary data, birinapant treatment-related adverse events included Grade 3 and Grade 4 increases in serum levels of the digestive enzymes amylase and lipase, as determined by laboratory testing, with no subject-reported symptoms of abdominal pain. The preliminary data also showed reductions in leukemic blasts (tumor bulk) in some subjects. Researchers also noted increases in the normal white blood cells (neutrophils), with the first birinapant dose in some subjects. One subject continued on treatment with birinapant as sole agent for approximately 10 months.
In preclinical studies, TetraLogic researchers observed synergy between birinapant and Celgene Corporation's (NASDAQ:CELG) Vidaza (azacitidine) in subjects with AML secondary to MDS. In August 2013, TetraLogic initiated a Phase 1/Phase 2 clinical trial of birinapant administered with azacitidine in high-risk MDS subjects who have relapsed or do not respond to treatment with, or are refractory to, azacitidine.
TetraLogic plans to expand this clinical trial to include subjects who have not been previously treated with, or are naïve to, azacitidine. The company initially intends to enroll 15 subjects in a dose escalation phase, which may be followed by an expansion arm of the trial at a selected dose. Subject enrollment is expected to be completed in the first half of 2014. If the results from these clinical trials are positive, TetraLogic intends to commence a Phase 3 clinical trial in high-risk MDS subjects in the second half of 2014.
Epithelial ovarian cancer is the most common and most fatal type of gynecologic cancer. In 2012, more than 22,000 women were predicted to receive an ovarian cancer diagnosis. Approximately 15,500 were expected to die from the disease.
Most cases of ovarian cancer, along with the biologically similar fallopian tube and primary peritoneal cancers, initially respond to surgery and combination chemotherapy. Some women cannot undergo surgery, and not all respond to chemotherapy. About 80% of those who do respond to initial treatment will eventually experience a relapse.
Although subsequent chemotherapy may help, the disease almost always returns and develops drug resistance. As a result, new treatments are desperately needed.
The research and advisory firm, GlobalData found the ovarian cancer therapeutics market grew at a compound annual growth rate (OTCPK:CAGR) of only 1% between 2002 and 2011. The patent expires of major branded products, such as Taxol (paclitaxel), Paraplatin (carboplatin), Gemzar (gemcitabine), Hycamtin (topotecan hydrochloride) and the subsequent launch of generics, have acted as restraining factors to the market. The introduction of new and promising therapies such as Genentech's/Roche's (OTCQX:RHHBY) Avastin (bevacizumab), Amgen's AMG 386, Endeocyte's (NASDAQ:ECYT) Vintafolide ((EC145)), Eisai's (OTC:ESALF) Farletuzumab (MORAb-003), BioNumerik Pharmaceuticals' Karenitecin (BNP1350), Cell Therapeutics' (NASDAQ:CTIC) Opaxio (paclitaxel poliglumex), OPT-821, Oasmia Pharmaceutical's Paclical (paclitaxel), Boehringer Ingelheim's Vargatef (BIBF 1120) and GlaxoSmithKline's Votrient (pazopanib) are expected to drive the market from 2011-2020.
In 2011, GlobalData found the ovarian cancer therapeutics markets in key countries (the United States, the United Kingdom, Germany, France, Italy, Spain, Japan, Brazil, Russia, India and China) were worth $736.7 million collectively. GlobalData forecasts the ovarian cancer therapeutics market to experience three-fold growth by 2020, reaching $2.35 billion at a CAGR of 13.8%. This high growth rate is expected due to the strength of the pipeline candidates, which are anticipated to change the treatment paradigm of ovarian cancer when launched
Many experts, including ovarian cancer researchers at the National Cancer Institute (NYSE:NCI), believe birinapant shows promise as a treatment for recurrent or treatment-resistant ovarian cancer. IAPs are an essential part of a cellular signaling pathway that is often activated in ovarian and related cancers. Preclinical studies by NCI researchers suggested that birinapant may disrupt this signaling pathway, which ultimately causes ovarian cancer cells to undergo apoptosis.
In a Phase 2 trial being conducted by the NCI, women with metastatic or otherwise unresectable epithelial ovarian, fallopian tube, or primary peritoneal cancer that has recurred after, or has not responded to, previous therapies will receive birinapant intravenously once a week for the first three weeks of each four-week cycle. Treatment will continue until disease progression or unacceptable toxicity occurs.
"Birinapant has shown very good activity in preclinical in vitro studies and mouse models of ovarian cancer cells," the NCI's Christina Annunziata, MD, PhD stated. "We've conducted in vitro studies in our lab of this drug both with and without tumor necrosis factor (TNF), and it looks like TNF increases the ability of birinapant to kill cancer cells that express the TNF receptor. Tumor necrosis factor levels have been found to be very high in some women with ovarian cancer, especially in ascites fluid. Birinapant seems to reprogram the TNF response from a cell stimulatory pathway to a cell death pathway."
Researchers are determined to find the efficacy of birinapant in these cancers, as measured by overall response rate or stable disease lasting at least six months. They will also look at overall survival, toxicity, and the effect of birinapant on molecular markers, such as TNF, as secondary endpoints.
In pre-clinical studies, TetraLogic researchers observed synergy between birinapant and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor agonist antibodies. In collaboration with Amgen , TetraLogic is exploring the combination of birinapant administered with Amgen's TRAIL receptor agonist antibody, conatumumab.
TetraLogic is also currently recruiting for a Phase 1 dose escalation study in female subjects with relapsed ovarian cancer (including epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer). Approximately 30 to 40 subjects will be administered a combination of conatumumab and birinapant.
In the initial dose-escalation stage of the study, adult female subjects will receive conatumumab in combination with increasing doses of birinapant in dose-escalation cohorts to determine the MTD of birinapant when administered with a fixed dose of conatumumab.
In safety expansion stage, adult female subjects will receive conatumumab in combination with birinapant at the MTD of the combination.
Colorectal Cancer (CRC)
Colorectal cancer (CRC) is the most deadly cancer in the United States. among non-smokers and the second most deadly cancer overall. The American Cancer Society estimates that there will be approximately 142,000 new cases and approximately 51,000 deaths in the United States from CRC in 2013, accounting for 9% of all cancer deaths. Almost 50% of the patients with a new diagnosis of CRC will die within five years. According to the National Cancer Institute (NCI), the prevalence of CRC in the U.S. in 2010 was estimated to be 1.2 million cases. CRC is the third most common cancer in both men and women. The risk of CRC increases with age; 90% of cases are diagnosed in individuals 50 years of age or older. Despite effective screening, leading to a reduction in the mortality from CRC, the number of cases remains high and is expected to increase worldwide to 2.2 million by the year 2030. We believe that there is a medical need for a treatment option that improves outcomes of standard of care regimens for patients with CRC.
Decision Resources found that the CRC drug market totaled $8.3 billion in 2011 and is expected to decrease to $7.8 billion in 2021 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan. The advisory service also finds that Genentech/Roche /Chugai's Avastin (bevacizumab) will be minimally challenged as the sales leader in the CRC market over the next ten years. Avastin will dominate the CRC market with total sales hovering around $2.5 billion, comprising nearly one-third of total CRC treatment sales in 2021, despite erosion from biosimilar versions and launches of new angiogenesis inhibitors such as Zaltrap (Sanofi/Regeneron Pharmaceuticals (NASDAQ:REGN)) and ramucirumab (ImClone Systems (OTCPK:IMCL)/Eli Lilly's (NYSE:LLY) IMC-1121B).
TetraLogic conducted a Phase 1/Phase 2 clinical trial of birinapant administered with irinotecan (Pfizer's Camptosar) in 71 CRC subjects who had previously failed standard chemotherapies. The trial has not been formally closed because one subject continues on treatment without disease progression for over 21 months. The clinical trial showed activity, with six subjects (8%) showing partial responses, or PRs, defined as at least a 30% decrease in the sum of all measurable tumor lesions by Response Evaluation Criteria in Solid Tumors ((RECIST)). RECIST is a set of published rules that define when cancer patients improve (or respond), stay the same (or stabilize), or worsen (or progress) during treatment. The median progression-free survival, or PFS, was 2.2 months. Researchers found that 34% of study subjects were alive without progression of their tumor at four months and 21% were alive without progression of their tumor at six months.
Researchers found that the combination of birinapant administered with irinotecan was generally well tolerated. Compared to treatment with irinotecan alone, birinapant administered with irinotecan led to a modest increase in anemia (or a decrease in red blood cells) and a modest increase in thrombocytopenia (or a decrease in platelets). As 65 of 71 (92%) subjects in the trial had disease progression on prior irinotecan treatment, TetraLogic researchers believe that this data supports the view that the activity seen in this study is being driven by the synergistic effect of birinapant and irinotecan. Based on the clinical data that has emerged from the study of birinapant administered with irinotecan, a randomized clinical trial is planned in third-line CRC subjects, meaning those who have already failed two prior treatment regimens for advanced disease to commence enrollment. This trial is subject to the company obtaining sufficient funding.
Hepatitis B Virus (HBV)
Hepatitis B is a liver disease that results from infection with hepatitis b virus (HBV). In pre-clinical studies, birinapant significantly reduced HBV. The clearance was additive when given in combination with entecavir (Bristol-MyersSquibb's (NYSE:BMY) Baraclude). TetraLogic is conducting pre-clinical studies and regulatory activities before start a Phase 1 clinical trial in the fourth quarter of 2014.
On January 21, 2014, TetraLogic announced that it entered into a research collaboration with the Walter and Eliza Hall Institute of Medical Research (WEHI) to examine birinapant in viral infections. Preclinical studies performed at the WEHI have indicated that SMAC-Mimetics decrease the viral burden in mice with human HBV by inducing apoptosis of virally infected hepatocytes while sparing the non-infected cells.
TetraLogic has entered into a license agreement with WEHI for worldwide exclusive rights to a patent application filed by the institute relating to a method of treating intracellular infections involving the administration of an Inhibitor of Apoptosis (IAP) antagonist.
"Our work with TetraLogic, if successful, will provide a truly novel approach," said Professor Douglas Hilton, Director, WEHI. "This is further evidence of our commitment to perform research that has a direct impact on the lives of patients."
WEHI is Australia's oldest medical research institute. It is home to almost 750 researchers who are working to understand, prevent and treat diseases including infectious diseases, cancers and immune disorders. WEHI is located in Parkville, Melbourne, and is closely associated with The University of Melbourne and The Royal Melbourne Hospital.
In connection with its clinical programs, TetraLogic is conducting research to uncover biomarkers, or biological parameters that can be measured to characterize a disease state or the effect of therapy, that can be used to identify subjects most likely to respond to birinapant. These studies are focused on detecting IAP gene amplification in different tumor types, on examining the expression of genes important in the TNF/IAP/NF- k B pathway and on examining the activation status of NF- k B itself.
NF-kN (nuclear factor kappa-light-chain-enhancer-of-activated-B-cells) is a protein complex that controls the transcription of DNA. Researchers have found that NF-kB is activated in certain cancers and in response to chemotherapy and radiation. NF-kB inhibition may become an important new approach for the treatment of certain hematological malignancies and is also being studied as an adjuvant therapy to be used with chemotherapy or radiation for a variety of cancers.
Since its inception, TetraLogic has incurred net losses and negative cash flows from its operations. The company incurred net losses of $18.9 million for the year ended December 31, 2011 and $16.2 million for the year ended December 31, 2012.
The company incurred a net loss of $13.3 million for the nine months ended September 30, 2013. Tetralogic incurred a net loss of $12.4 million for the nine months ended September 30, 2012.
Operating activities used $17.3 million and $15.9 million of cash flows during the years ended December 2011 and 2012, respectively, and $12.5 million and $10.1 million of cash flows during the nine months ended September 30, 2012 and 2013, respectively.
At September 30, 2013, the company had an accumulated deficit of $83.2 million, negative working capital of $12.8 million and cash and cash equivalents of $2.5 million.
Historically, TetraLogic has financed its operations principally through private placements of preferred stock and convertible debt. Through September 30, 2013, the company has received gross proceeds of $79.2 million from the issuance of preferred stock and convertible debt. In October 2013, TetraLogic issued additional convertible notes in the aggregate amount of $6.2 million. In connection with this additional issuance of the convertible notes, the noteholders received additional warrants to purchase $1.9 million of our equity securities.
TetraLogic had an accumulated deficit of $83.2 million at September 30, 2013.
TetraLogic's institutional investors include Clarus Ventures, HealthCare Ventures, Quaker Partners, Novitas Capital, Nextech Invest Ltd, Hatteras Venture Partners, Pfizer Ventures, Latterell Venture Partners, the Vertical Group, Amgen Ventures, and Kammerer Associates who have invested millions in the company.
TetraLogic is led by CEO J. Kevin Buchi who joined the company in August 2013. Buchi was most recently Corporate Vice President, Global Branded Products, at Teva Pharmaceutical Industries Ltd. (NASDAQ:TEVA), Prior to joining Teva, he was CEO of Cephalon, Inc., which was acquired by Teva for $8 billion in October 2011. Buchi appears to have a clear vision for TetraLogic, and in the near future, plans to:
- • pursue regulatory approval for birinapant administered with other therapies for the treatment of first-line higher-risk MDS. The company intends to initiate a randomized Phase 2 clinical trial in the first half of 2014. The data from the randomized Phase 2 clinical trial will determine the size of the treatment effect of birinapant administered with azacitidine versus azacitidine alone and will form the basis of a Phase 3 clinical trial in first-line higher-risk MDS;
• pursue regulatory approval for birinapant administered with irinotecan for treatment of third-line colorectal cancer. TetraLogic plans to initiate a randomized clinical trial upon the availability of additional financing;
• continue pre-clinical studies of birinapant as a potential antiviral therapeutic agent, with the intent of starting an antiviral clinical program in the fourth quarter of 2014; and
• consider collaborations to accelerate development of clinical programs outside of the United States,
With strong management and scientific teams and a leadership position in SMAC mimetics, TetraLogic is at the forefront of discovering and developing a new class of cancer therapies that are demonstrating the potential to overcome the limitations of current anticancer therapies.
TetraLogic's birinapant could become a blockbuster drug as a potential treatment for solid tumors and hematological malignancies, as well as viral infections such as hepatitis B, but this investigative drug is still in relatively early Phase1/Phase 2 clinical development. As a result, investing in TetraLogic is an extremely high risk/high reward opportunity. All investments involve risk, but investing in micro-cap biopharma companies like Tetraphase is especially risky. These stocks are often extremely volatile, may be illiquid, and are subject to manipulation.
TetraLogic was formerly known as Gentara Corporation and changed its name to TetraLogic Pharmaceuticals Corporation in January 2006. The company was incorporated in 2001.
Disclosure: I am long AMGN. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.