R&D In Brief

Roche initiates PI/PI combo HCV trial early: Roche announces the first patients have been dosed in its INFORM-1 trial Nov. 10, almost a year early. The trial is the first dual-combination study with oral antivirals in hepatitis C in the absence of interferon, which, in combination with ribavirin, is the standard of care for HCV. Roche will dose patients with its protease inhibitor ITMN-191 (R7227), partnered with InterMune, and its polymerase inhibitor R7128, partnered with Pharmasset, over 14 days in treatment-naive patients infected with HCV genotype 1. Roche recently dropped its lead polymerase inhibitor candidate, R1626, for safety reasons, and shifted focus to R7128 (1"The Pink Sheet" DAILY, Oct. 21, 2008). Top-line data from the combination trial could come as early as the second quarter of 2009. The trial combines the two most promising mechanisms for HCV therapy. Panelists at the recent ICAAC conference predicted that the protease inhibitors should reach the market in 2011, followed by polymerase inhibitors in 2014. Initially protease inhibitors will be used in combination with interferon/ribavirin therapy, but there is potential that combination therapy with protease and polymerase inhibitors will eventually replace the older standard regimen

Roche initiates PI/PI combo HCV trial early: Roche announces the first patients have been dosed in its INFORM-1 trial Nov. 10, almost a year early. The trial is the first dual-combination study with oral antivirals in hepatitis C in the absence of interferon, which, in combination with ribavirin, is the standard of care for HCV. Roche will dose patients with its protease inhibitor ITMN-191 (R7227), partnered with InterMune, and its polymerase inhibitor R7128, partnered with Pharmasset, over 14 days in treatment-naive patients infected with HCV genotype 1. Roche recently dropped its lead polymerase inhibitor candidate, R1626, for safety reasons, and shifted focus to R7128 (¹ (Also see "Roche’s HCV Changes Boost Pharmasset Compound" - Pink Sheet, 21 Oct, 2008.)). Top-line data from the combination trial could come as early as the second quarter of 2009. The trial combines the two most promising mechanisms for HCV therapy. Panelists at the recent ICAAC conference predicted that the protease inhibitors should reach the market in 2011, followed by polymerase inhibitors in 2014. Initially protease inhibitors will be used in combination with interferon/ribavirin therapy, but there is potential that combination therapy with protease and polymerase inhibitors will eventually replace the older standard regimen.

AstraZeneca's oral anticoagulant delayed until 2009: A stability issue with AstraZeneca's selective and reversible direct thrombin inhibitor will push the Phase III program initiation back to 2009, the firm says during its Oct. 30 earnings call. The oral anticoagulant AZD0837, a backup compound to the failed Exanta (ximelagatran), did not meet various criteria during tests on the Phase III batches. AstraZeneca is trying to determine the cause. The delay for '0837, being studied for prevention of stroke and systemic embolic events in patients with atrial fibrillation, means falling even further behind competitors including Johnson & Johnson/Bayer's Xarelto (rivaroxaban), filed with FDA in July, and Pfizer/Bristol-Myers Squibb's Phase III apixaban (² Pharmaceutical Approvals Monthly October 2008, p. 3).

Rigel's R788 shows RA efficacy, hypertension signal: Rigel's syk inhibitor R788 (fostamatinib) has shown efficacy in rheumatoid arthritis comparable to biologics, according to the firm. In a Phase IIb trial in 189 patients with active RA already taking methotrexate, published in the November 2008 Arthritis and Rheumatism, patients on 150 mg twice-daily fostamatinib showed a 57 percent response rate on the ACR50 measure versus 19 percent for those on placebo (p<0.001). Patients on the 100 mg b.i.d. dose had a 65 percent response rate on ACR20 compared with 38 percent response for placebo (p=0.008). Neutropenia was found in 15 percent of treated patients, compared with none in the placebo group. Some increase in hypertension was seen, with a 2 percent increase in the 100 mg group and a 4 percent increase in the 150 mg group over placebo. Adverse events were manageable and reversible with reduced dosing, Rigel said. In June, Rigel started a six-month, placebo-controlled Phase IIb trial of 100 mg b.i.d. or 150 mg q.d. in 420 patients who failed to respond to methotrexate and a three-month, placebo-controlled Phase IIb trial of 100 mg b.i.d in 195 patients who failed at least one biologic RA agent. The firm also is studying the compound to treat immune thrombocytopenic purpura and chronic lymphoma.

Tibotec to file 96-week data for Prezista: Tibotec, a subsidiary of Johnson & Johnson, will submit 96-week data from the TITAN study of its protease inhibitor Prezista (darunavir) to FDA. The trial, presented Nov. 13 at the International Congress on Drug Therapy in HIV Infection, showed darunavir plus ritonavir is non-inferior to lopinavir plus ritonavir in lopinavir-ritonavir-naive, treatment-experienced HIV1 infected adults. At 96 weeks, 67 percent of Prezista patients reached a viral load of <400 copies/mL compared with 59 percent of lopinavir patients. At 48 weeks, 77 percent of the Prezista arm versus 68 percent of the lopinavir arm had reached the <400 copies/mL viral load. Prezista was approved Oct. 21 for treatment-naive HIV-1 infected adults.

Bicifadine fails, again: XTL Biopharmaceuticals is evaluating the bicifadine program after the triple reuptake inhibitor failed to show efficacy in a Phase IIb placebo-controlled clinical trial in diabetic neuropathic pain, the firm says Nov. 18. Using a design similar to Lilly's registration trials for Cymbalta (duloxetine), the randomized, double-blind trial compared 200 mg t.i.d. and 400 mg t.i.d. bicifadine versus placebo on the primary endpoint of reduction in pain associated with diabetic neuropathy from baseline to week 14. Pain was measured using the 11-point Pain Intensity Numeric Rating Scale. Bicifadine also failed to meet key secondary analyses. Numerical results were not released. XTL in-licensed the drug candidate, which is a serotonin and norepinephrine reuptake inhibitor with a moderate inhibitory effect on dopamine reuptake, from DOV in early 2007. DOV had mixed results with the compound, taking it into Phase III for chronic lower back pain before halting development (³ Pharmaceutical Approvals Monthly October 2006, p. 2).

SciClone reaches SPA for melanoma candidate: SciClone and FDA have reached agreement on a special protocol assessment for the stage IV melanoma therapy thymalfasin, SciClone announces Nov. 17. In a randomized, open-label, 488-patient Phase II trial, thymalfasin ( Zadaxin ) tripled overall response rate and extended overall survival by three months compared to standard of care dacarbazine and interferon alfa. The only FDA-approved therapies for stage IV melanoma - dacarbazine and interleukin-2 - used alone or in combination with IFN, are effective in extending overall survival, according to SciClone. Thymalfasin, a toll-like receptor 9 activator, is approved to treat hepatitis B and C in several countries and was granted orphan drug designation for stage IIb through stage IV melanoma in March 2006. SciClone is also developing thymalfasin as an HCV candidate in the U.S.; the company is awaiting full Phase III results and could launch the drug in late 2009 or early 2010 (⁴ (Also see "SciClone’s Zadaxin For Hepatitis C Rises From Ashes" - Pink Sheet, 11 Feb, 2008.)).

NicOx anti-inflammatory agent reduces blood pressure: NicOx's first-in-class naproxcinod significantly reduced systolic blood pressure compared to naproxen in osteoarthritis patients with controlled hypertension, the firm announces Nov. 4. Top-line results from the 12-week ambulatory blood pressure monitoring trial, a 118-patient randomized study, showed naproxcinod lowered SBP by 2.3 mmHg from baseline while naproxen raised SBP by 1.5 mmHg (p=0.011). COX-2 inhibitors and other NSAIDs such as naproxen treat symptoms of OA but can destabilize controlled hypertensive patients. The primary objective of the study, characterizing the 24-hour arterial blood pressure profile of three doses of naproxcinod, was met and showed a decrease in the mean SBP and diastolic BP from baseline in all doses compared to naproxen. The drug, a member of the new cyclooxygenase-inhibiting nitric oxide-donator class, is in Phase III trials for the treatment of signs and symptoms of osteoarthritis. NicOx projects a mid-2009 NDA filing, with results from two additional pivotal trials in OA and hip OA expected by year-end 2008.