Cadence Pharmaceuticals Inc., of San Diego, said it revised the expected timing of its announcement of the results for the CLIRS trial, its Phase III trial of Omigard (omiganan pentahydrochloride 1 percent topical gel) for the prevention of catheter-related infections, from the fourth quarter of this year to the first quarter of 2009. If the trial is successful, Cadence plans to submit a new drug application for Omigard in the second quarter of 2009. The primary efficacy endpoint of the trial is to evaluate whether Omigard is superior to 10 percent povidone-iodine in the prevention of local catheter-site infections.
Generex Biotechnology Corp., of Toronto, said enrollment for its pivotal Phase III trial of Generex Oral-lyn reached the milestone of more than 200 subjects. The study plans to involve up to 750 subjects with Type I diabetes at centers in the U.S., Canada, Bulgaria, Poland, Romania Russia and Ukraine. The objective of the study is to compare the efficacy of Generex Oral-lyn and the company's RapidMist diabetes management system with prandial injections of regular human insulin as measured by HbA1c. Generex Oral-lyn is approved for commercial sale in India and Ecuador.
GTx Inc., of Memphis, Tenn., said safety analysis data from a Phase III trial showed that fewer men treated with toremifene 80 mg had prostate-specific antigen (PSA) progression over time compared to placebo in its Phase III trial for the treatment of multiple serious side effects of androgen deprivation therapy for advanced prostate cancer. Among men in the intent-to-treat population with a detectable PSA (PSA = 1 ng/ml) at baseline (n = 419), significantly fewer men treated with toremifene 80 mg had PSA progression over time compared to men taking placebo (27 percent vs. 37 percent, respectively; p < 0.05). That subgroup analysis is consistent with the recommendations of the Prostate Cancer Clinical Trials Working Group to measure prostate cancer progression in clinical studies. In another analysis among men with an undetectable PSA (PSA < 1 ng/ml) at baseline (n = 698), there was no difference in PSA progression in men treated with toremifene 80 mg compared to men taking placebo. Data were presented at the annual meeting of the American Society for Bone and Mineral Research in Montreal.
ImClone Systems Inc., of New York, said an analysis of previously reported positive Phase III CRYSTAL study data of Erbitux (cetuximab) plus Folfiri in patients with previously untreated metastatic colorectal cancer showed it failed to meet a secondary endpoint of increasing overall survival. In the study of 1,198 patients, the median overall survival of all Erbitux-treated patients was 19.9 months vs. 18.6 months for those treated just with chemotherapy, a difference that was not statistically significant. ImClone said it will submit the additional study results to the FDA for registrational purposes
Javelin Pharmaceuticals Inc., of Cambridge, Mass., announced the completion of patient enrollment in the second of two U.S. pivotal Phase III studies for its injectable pain drug Dyloject (diclofenac sodium). The double-blinded study evaluates Dyloject in patients with moderate-to-severe postoperative pain following elective orthopedic surgery. The primary measure of efficacy is the sum of pain intensity differences as measured on the 0-100 mm visual analogue scale. The company is planning to file a new drug application for the treatment of acute postoperative pain in 2009.
MediGene AG, of Martinsried, Germany, said that after 12 months of treatment in a controlled Phase II study of pancreatic cancer patients, those treated with EndoTAG-1 in combination with standard therapeutic Gemcitabine showed noticeably higher survival rates than patients treated with Gemcitabine alone. The 12-month survival rate of patients treated with Gemcitabine alone was 17 percent, while it was 22 percent (low dose), 36 percent (medium dose) and 33 percent (high dose) for patients receiving EndoTAG-1 in combination with Gemcitabine. In the EndoTAG-1 groups, the second half of patients enrolled had the opportunity to receive treatment with EndoTAG-1 repeatedly and for a longer period of time. The 12-month survival rates of those patient groups were higher still, with 25 percent (low dose), 52 percent (medium dose) and 40 percent (high dose). Final data will be available in the fourth quarter.
Novavax Inc., of Rockville, Md., started vaccination of healthy volunteers in a Phase II trial of its virus-like particle-based seasonal influenza vaccine. The randomized, placebo-controlled study will evaluate the safety and immunogenicity of different doses. The vaccine will be studied in approximately 300 healthy adults who will receive a single injection of either a placebo or an influenza vaccine at doses of 5 mcg, 15 mcg or 30 mcg. The goals are to select a dose for evaluation in a subsequent Phase III efficacy study and to continue the safety evaluation.
SemBioSys Genetics Inc., of Calgary, Alberta, said it is eligible to proceed with its planned Phase I/II trial of plant-produced insulin now that the 30-day review period of its investigational new drug application has passed. The FDA advised SemBioSys that safflower-produced insulin is eligible to receive approval through an abbreviated 505(b)(2) approval process. SemBioSys also plans to initiate a Phase I/II trial of its safflower-produced insulin in the UK during the fourth quarter. Prior to proceeding with the trial, the company must await clearance from the UK's Medicines and Healthcare products Regulatory Agency.
Stem Cell Therapeutics Corp., of Calgary, Alberta, received a no objection letter from Health Canada for the Phase IIa single-center, open-label study to characterize the safety of human chorionic gonadotropin and erythropoietin in severe traumatic brain injury. The company's NTx-265 regimen being tested seeks to stimulate the growth and differentiation of new neurons to replace brain cells that were lost or damaged by a severe brain injury, and to direct functional recovery of motor, visual and cognitive capacity.
Threshold Pharmaceuticals Inc., of Redwood City, Calif., said it initiated a Phase I/II trial of TH-302, a proprietary hypoxia-activated prodrug that specifically targets tumor hypoxia, in combination with doxorubicin in patients with advanced soft-tissue sarcoma. The primary objective of the dose-escalation component of the study is to establish the maximum tolerated dose and dose-limiting toxicities of TH-302 in combination with doxorubicin. The primary objective of the dose expansion component of the study is to make a preliminary assessment of the efficacy of TH-302 in combination with doxorubicin as measured by the progression-free rate at six months in patients previously untreated with chemotherapy.
BIOWORLD Today - Sep. 21, 2008
Acologix Inc., of Hayward, Calif., said results of two preclinical studies demonstrated that AC-100, its therapeutic product candidate derived from endogenous human protein produced by bone and dental cells, promoted cartilage regeneration in large animal models. In two goat studies, AC-100 dose dependently promoted cartilage repair compared to placebo and increased cartilage regeneration both with and without microfracture. Data were presented at the American Society for Bone and Mineral Research meeting in Montreal.
Ariad Pharmaceuticals Inc., of Cambridge, Mass., said its board approved a transaction to merge Ariad Gene Therapeutics Inc. (AGTI), an 80 percent-owned subsidiary, into Ariad. Under the terms, each outstanding share of AGTI common stock owned by AGTI's minority stockholders will be converted into the right to receive two shares of Ariad common stock. The merger was approved by Ariad's board.
Bionovo Inc., of Emeryville, Calif., said a paper published in Drug Metabolism and Disposition described in vitro metabolism of Liquiritigenin, which is almost exclusively metabolized by cytochrome P450 3A4. Liquiritigenin is one of the active compounds of MF101, the company's drug candidate set to start Phase III testing in menopausal hot flashes.
Cleveland BioLabs Inc., of Buffalo, N.Y., was awarded a $774,183 grant from the National Institutes of Allergy and Infectious Diseases to further study mitigating properties of Protectan CBLB502 in the context of hematopoietic damage from radiation exposure. The grant program, Medical Countermeasures to Enhance Platelet Regeneration and Increase Survival Following Radiation Exposure, is funded through the Project BioShield Act of 2004 and administered by the Department of Health and Human Services.
Emergent BioSolutions Inc., of Rockville, Md., said the Department of Health and Human Services said the company's proposal to provide a recombinant protective antigen anthrax vaccine is technically acceptable and within the competitive range. Emergent's proposal was in response to HHS' request for proposals (RFP) for the development and delivery of 25 million doses of an rPA anthrax vaccine for the strategic national stockpile. HHS has indicated that any awards under the rPA RFP would be granted at the end of this year, at the earliest.
InSite Vision Inc., of Alameda, Calif., said it disagrees with the recommendation of the RiskMetrics Group (formerly Institutional Shareholder Services) that it should vote for four of the six board nominees from the slate of dissident shareholder Pinto Technology Ventures at its Sept. 22 shareholder meeting. InSite said it believes its own board nominees are better suited and more qualified than those proposed by Pinto.
Isogenica Ltd., of Cambridge, UK, said it entered a license agreement granting Centocor Research & Development Inc., of Horsham, Pa., with nonexclusive rights to its CIS display technology for the discovery of certain therapeutic proteins. Under the terms, Isogenica will receive multimillion-pound initial license fees paid over the first three years of the agreement, as well as ongoing license maintenance fees and milestone payments associated with the clinical development of products using Isogenica's technology. Specific financial terms were not disclosed.
King Pharmaceuticals Inc., of Bristol, Tenn., said it commenced a tender offer, through a wholly owned subsidiary, to acquire all of the outstanding shares of Bridgewater, N.J.-based Alpharma Inc. at $37 per share, for a total value of about $1.6 billion. The tender offer is expected to expire at 5 p.m., Oct. 10. Alpharma rejected the $37-per-share offer last week, and King opted to take its bid directly to shareholders in a hostile takeover. (See BioWorld Today, Sept. 12, 2008.)
OrthoLogic Corp., of Tempe, Ariz., said preclinical data of AZX100 in the management of excessive dermal scarring showed that, in human cells stimulated with transforming growth factor beta 1, the product decreased the production of both connective tissue growth factor (CTGF) and collagen compared to controls. AZX100 also significantly decreased expression of CTGF and collagen caused by endothelin and lysophosphatidic acid. Results of the study were published in the Journal of Investigative Dermatology. AZX100 is a synthetic 24-amino acid peptide in development for pulmonary disease, the prevention of hypertrophic and keloid scarring and intimal hyperplasia.
Polydex Pharmaceuticals Ltd., of Toronto, said the Nasdaq hearings panel decided to delist the company's securities from Nasdaq and suspended trading as of Friday. The decision stemmed from the company's failure to meet bid price requirements. Polydex is evaluating alternative listing or quotation services for its common shares.
Sigma-Aldrich Co., of St. Louis, said it entered an exclusive agreement with IsoSciences LLC, of King of Prussia, Pa., to distribute isotopically labeled bioactive compounds and their metabolites through its Aldrich division. Financial terms were not disclosed.
Talecris Biotherapeutics Inc., of Research Triangle Park, N.C., said the FDA has approved Gamunex, an intravenous immunoglobulin product, for the treatment of chronic inflammatory demyelinating polyneuropathy, a rare autoimmune disorder characterized by progressive weakness and impaired sensory function in the legs and arms, which affects about 25,000 people in the U.S. Gamunex was designated an orphan drug, and as such, will have seven years of marketing exclusivity. The drug already was approved in the U.S. and Europe for idiopathic thrombocytopenic purpura. The FDA based its approval of Gamunex for CIDP on clinical trials that showed the drug was effective at improving certain motor functions for up to 48 weeks after the initial treatment. Results of the trials showed patients' muscle function improved after receiving Gamunex every three weeks for a 24-week period. Of the 59 patients treated with Gamunex, 28 had improved function compared with 13 out of 58 in the placebo group. In a follow-up trial for an additional 24 weeks, 86 percent of the patients who continued to receive Gamunex maintained their improved function compared with 61 percent of the patients in the placebo group. Talecris announced last month that it was being acquired by Victoria, Australia-based CSL Ltd. in a $3.1 billion cash merger. (See BioWorld Today, Aug. 14, 2008.)
Valeant Pharmaceuticals International, of Aliso Viejo, Calif., said it completed the sale of certain business operations in Western Europe, Eastern Europe and certain export markets to Stockholm, Sweden-based Meda AB and received about $425 million in cash at closing. Valeant announced the deal last month as part of its plan to streamline operations. (See BioWorld Today, Aug. 5, 2008.)
When trial results for a novel cancer drug were trumpeted in July, the rheumatology field felt the ripples. The drug is ofatumumab, a monoclonal antibody (mAb) targeting the CD20 molecule on B lymphocytes. Its makers, London-based GlaxoSmithKline (GSK) and Genmab of Copenhagen, announced that the mAb had met its primary and secondary endpoints in chronic lymphocytic leukemia (CLL). But with two double-blind phase 3 studies of ofatumumab for rheumatoid arthritis already underway in Italy and Eastern Europe, these companies are clearly looking beyond cancer indications to lucrative autoimmune disease markets for their second-generation molecule.
The idea is to follow the trail blazed by Genentech of South San Francisco, Roche of Basel and Biogen-Idec of Cambridge, Massachusetts, with Rituxan (rituximab), their anti-CD20 chimeric mAb. Rituxan was approved by the US Food and Drug Administration to treat B-cell lymphomas and leukemias in 1997 and then as a third-line therapy against rheumatoid arthritis in 2006. Currently marketed by Roche in Europe as MabThera, it surpassed $5 billion in worldwide sales in 2007 alone.
GSK has invested heavily in ofatumumab. The company made headlines at the end of 2006 when the licensing agreement to co-develop this fully human IgG1- mAb for cancer and rheumatoid arthritis was announced. The deal, potentially worth $2.1 billion, saw Genmab receive an upfront $102 million as a sweetener for their anti-CD20 mAb. GSK also took a 10% stake in the biotech firm by purchasing $357 million in shares. The transaction was deemed to be the largest ever in Europe for a single product; if all milestones are met it will exceed the $2.0 billion deal between New York–based Bristol-Myers Squibb and New York–based ImClone Systems for blockbuster cancer chimeric mAb Erbitux (cetuximab).
The meteoric rise of tumor necrosis factor (TNF)- blockers over the past decade ushered in the age of biologic therapies for rheumatoid arthritis. Anti-TNF agents—Enbrel (etanercept), Humira (adalimumab) and Remicade (infliximab)—are now labeled for second-line use after failure of methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs). But there is no product that works for everyone—about a third of those with rheumatoid arthritis do not respond to first- or second-line therapy.
Rituxan is currently a third-line therapy for rheumatoid arthritis after failure of methotrexate and anti-TNF- products. "We'd like to try it in patients much earlier on, and we're working towards that at the moment," says immunologist Geraldine Cambridge, who has collaborated for many years with rheumatologist Jonathan Edwards, both of the Center for Rheumatology Research at University College London. The two have done much of the basic science groundwork as well as overseen clinical trials over the past decade to establish the effectiveness of B-cell depletion with CD20 blockade. "You need to get these patients in remission as early as possible," she says. "If you lose one year while patients are slowly failing on methotrexate and TNF-inhibitors, that means they've lost their job by then and will probably never get back to work again."
The clinical approach by which B cells are ablated to treat rheumatoid arthritis has only recently gained acceptance. Treatment with Rituxan has brought relief to many patients whose synovitis symptoms, including pain and stiffness, subside, as do the swollen hand joints that accompany the more advanced stages of the disease. Today treating rheumatoid arthritis with anti-CD20 blockers is well accepted, but this was not the case a few short years ago.
The transformation in thinking began in 1997 when Rituxan was approved for blood cancers. As the drug became accessible to investigators like Cambridge and Edwards, they were able to test the idea that B cells were driving autoimmune disease. This was anathema at the time because most research in autoimmunity focused on T cells. The confusion is understandable because B cells and T cells signal back and forth continuously in a highly integrated and dynamic network. B cells present antigens to T cells, which in turn activate and excite B cells to produce autoantibodies such as rheumatoid factor. These RF antibodies latch on to the Fc portions of IgGs to form immune complexes, which in turn trigger a cascade of events that finally attract macrophages and neutrophils. As these phagocytic cells engulf immunocomplexes, they release lysosomal enzymes that ratchet up inflammation and further damage the synovial apparatus, leading to chronic disease.
Anti-CD20 agent Rituxan interrupts this self-perpetuating cycle by wiping out B-cell populations. This may seem an extreme measure, but it has allowed a sizable proportion of rheumatoid arthritis patients to manage their disease. Not all CD20 blockers are equivalent, however. CD20 is a tetra-membrane-spanning protein with a rather serpentine configuration weaving in and out of the B-cell membrane. Different anti-CD20 antibodies might bind epitopes far apart on the molecule, and these differences could account for variations in intracellular signaling cascades affecting potency, efficacy or even immunotoxicity. Different antibody formats may also have different advantages in terms of functionality, pharmacodynamics and pharmacokinetics.
One novel antibody format targeting CD20 currently under development is Seattle-based Trubion Pharmaceuticals' TRU-015. This molecule—one third of the size of a true antibody—consists of single-chain variable regions (VL and VH) that bind CD20, which are fused by means of a modified human IgG1 hinge domain to engineered constant regions that encode human IgG1 constant heavy domains (CH2 and CH3). Because the fusion protein includes the Fc portion it allows antibody-dependent cellular cytotoxicity (ADCC) to take place whereas its smaller size is thought to improve tissue biodistribution.
In collaboration with Madison, New Jersey-based Wyeth, Trubion is studying this anti-CD20 scFv-Fc fusion protein (TRU-015) in phase 2 trials for rheumatoid arthritis and in preclinical development for systemic lupus erythematosus (SLE). CEO and founder Peter Thompson says the product is "significantly attenuated" with respect to complement-dependent cellular cytotoxicity (CDCC) of B cells, but "very potent" with respect to ADCC and direct apoptotic activity (these are two of the mechanisms by which existing anti-CD20 antibodies are thought to deplete B cells). Such toned-down CDCC activity, relative to Rituxan, is presumably advantageous because complement cascades have been shown to herald signs and symptoms of some infusion reactions, which can range from very mild to severe. "We have not really seen grade three or grade four infusion reactions with TRU-015 in contrast to the experience previously published with Rituxan," says Thompson. Trubion also has another scFv-Fc fusion (SBI-087) targeting CD20 in phase 1 trials for SLE and rheumatoid arthritis.
In the early days of Rituxan as a rheumatoid arthritis treatment, rheumatologists were concerned over what might happen if the patient's B-cell population were to be wiped out, and if their immunoglobulin levels were to drop to unacceptably low levels. Some of these worries have now been dispelled. B cells give rise to long-lived immunoglobulin-producing plasma cells that persist for many months, and because they do not have the CD20 antigen on their cell surfaces, these plasma cells remain untouched by anti-CD20 agents. Also, plasma cells retain some memory of previous exposures to infectious agents, so they continue to offer protection to the patient. "Patients treated with rituximab [Rituxan] still mount an immunoglobulin response to vaccines after rituximab therapy," says rheumatologist Peter Taylor, who is head of clinical trials at the Kennedy Institute of Rheumatology in London. "But humoral responses can be reduced," he says.
The critical question for clinicians is what happens to the patients' bone marrow stem cells and their ability to generate plasma cells after repeated cycles of anti-CD20 therapy. As bone marrow precursors are not CD20 positive, presumably they are not affected by anti-CD20 agents. "In my own practice, we've gotten up to four or five cycles," says Taylor. Cambridge and Edwards have doubled the cycles without observing substantial drops in immunoglobulin levels. They believe that after B cells in the periphery are depleted, the bone marrow somehow reboots to produce new lymphocytes that no longer churn out rheumatoid arthritis–causing autoantibodies. Indeed, Cambridge has been tracking a group of rheumatoid arthritis patients whose symptoms have not returned for 18 months after the last Rituxan treatment. Cambridge won't go out on a limb and say there's been a complete response, but she says, "One patient has been in remission for three years or longer."
Still, Taylor expresses some mild concerns. "When you get past about five or six cycles of therapy, there is a proportion of patients with robust and well-maintained, really good responses, that at some point don't recover B-cell levels, and their immunoglobulin levels drop down below the normal range," he says. "If B-cell depletion were thought to be the optimal therapy for individuals with rheumatoid arthritis, it may have a finite shelf life as to how long you could use that approach. It may be perhaps that you could use rituximab [Rituxan] in a responsive patient for 5 years, 10 years or 12 years. But it's not yet clear that you could go on [long term], as we do, with methotrexate for a lifetime."
Time will tell if newer anti-CD20 therapies in pipelines work any better. Because ofatumumab is fully human and Rituxan is chimeric, the supposition is that ofatumumab would present fewer infusion reactions or other adverse events, particularly the human anti-chimeric antibody response. But not much information is publicly available, and, in fact, there have been no head-to-head trials of ofatumumab versus Rituxan in rheumatoid arthritis. Taylor is principal investigator in one ongoing phase 3 trial of ofatumumab for rheumatoid arthritis, which is scheduled to wrap up in 2011, but a confidentiality agreement prevents him from discussing it.
One thing Taylor will say, however, is that there's been a revolution in the mind-set of rheumatologists around the globe, who are losing their trepidation about using cancer drugs in rheumatoid arthritis patients. "I think there's a massive change," he says. "People often use the phrase 'aggressive early therapy'. To me, it really means optimally suppressing synovitis."
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