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Re: GSK bails on Ionis TTR studySorry for flooding the board, but here is a related article. Not sure I have seen this site before. http://www.bioworld.com/content/ionis-sinks-company-investors-fret-over-meaning-platelet-signal-0 Ionis sinks as company, investors fret over meaning of platelet signal By Marie Powers Shares of Ionis Pharmaceuticals Inc. (NASDAQ:IONS) were pummeled Thursday, sinking to a three-year low of $21.09, after the company clarified that “less than a handful of patients” enrolled in its phase III NEURO-TTR study evaluating IONIS-TTRRx in transthyretin (TTR) familial amyloid polyneuropathy (FAP) experienced a serious decline in platelets. The small number of events, in seriously ill patients often taking other medications, might have been a minor blip on the radar screen except that partner Glaxosmithkline plc (GSK), which holds an option to license IONIS-TTRRx exclusively, decided to postpone a phase III cardiovascular study, CARDIO-TTR, that was planned to evaluate IONIS-TTRRx in patients with TTR amyloid cardiomyopathy. On an early morning call with analysts, Stanley Crooke, Ionis’ chairman and CEO, dropped the other shoe by revealing the company learned the previous day that platelet declines were seen with a second pipeline drug, volanesorsen, raising bigger questions about the platform. The uncertainty surrounding the thrombocytopenic events, which Crooke repeatedly declined to specify, and his admission of “surprise” at their occurrence started a stampede on the stock. Shares closed at $21.36, for a loss of $13.90, or 39.4 percent. Nearly 27 million shares were exchanged, or more than 15 times the company’s three-month average. Investors might have been just as troubled about the circuitous path Crooke wove through his explanation of the IONIS-TTRRx program as they were about the events themselves. The second-generation antisense drug, designed to reduce the production of TTR to treat all forms of TTR amyloidosis, is in a broad development program as a single weekly injection to treat patients with FAP, familial amyloid cardiomyopathy (FAC) and wild-type TTR amyloidosis (wt-TTR amyloidosis). Crooke explained on the call that the company’s phase III study, NEURO-TTR, in patients with FAP was proceeding as planned, with a high retention rate. The global randomized, double-blind, placebo-controlled study, launched In February 2013, was designed to support an application for marketing approval of IONIS-TTRRx in patients with FAP. Patients in the 15-month study are randomized 2-to-1 to receive 300 mg/week of IONIS-TTRRx or placebo, with endpoints measuring the effects of IONIS-TTRRx on neurological dysfunction and quality of life. With targeted enrollment reached, data are expected to report next year. Most patients from the study are rolling over into an open-label extension study, according to Crooke. IONIS-TTRRx also is in an investigator-initiated phase II open-label study in patients with TTR-related amyloid cardiomyopathy, and Crooke said Ionis was “encouraged by what we’re seeing in that study.” In November 2015, the company reported preliminary data showing evidence of cardiac disease stabilization in patients with TTR amyloid cardiomyopathy (FAC and wt-TTR amyloidosis) treated with IONIS-TTRRx for 12 months. On the call, Crooke promised Ionis will share additional data in early July at the International Symposium on Amyloidosis and present the same data during its R&D day in mid-July. “The combination of data from these studies should contribute to the design of an optimal cardiac outcome study, potentially shortening and simplifying the design of a pivotal study in cardiac patients,” Crooke said. “Of course, that’s why GSK decided to wait for those data to ensure that they have the best trial design to take forward.” In 2010, Ionis, then Isis Pharmaceuticals, inked a potential $1.5 billion RNA drug alliance with London-based GSK that provided $35 million up front and entitled the Carlsbad, Calif.-based biotech to another $155 million in pre-licensing milestones, or about $20 million across each of five programs. (See BioWorld Today, April 1, 2010.) But last month, Ionis reported that the CARDIO-TTR study was on an FDA clinical hold while GSK responded to protocol questions from the agency. That update also was the first revelation of concerns about platelet reductions in TTR patients in the NEURO-TTR study. Crooke called CARDIO-TTR “an important and expensive study that GSK had to design in a patient population about which little was known,” maintaining that the NEURO-TTR and phase II data would plug those holes and allow GSK to move forward with CARDIO-TTR. The FDA posed the same questions to Merrill Benson, the investigator in the phase II IONIS-TTRRx study, but he responded quickly and the study proceeded as planned. “Because GSK has decided to delay the outcome study, it decided not to seek permission from the FDA to initiate that study at this time,” Crooke maintained, adding that Ionis is “quite confident” the FDA will allow the CARDIO-TTR study to proceed “once GSK is ready to start.” No changes have occurred in the relationship between the partners, according to Crooke. As proof of GSK’s commitment to the program, he said the companies “are working aggressively” to prepare for a rapid new drug application filing once the NEURO-TTR data are in hand, and GSK is actively preparing for commercial launch of IONIS-TTRRx in FAP. ‘We’re not confident of anything’ As for the more pressing platelet issue, Crooke said the company had ruled out several potential culprits, including bone marrow suppression and heparin-induced thrombocytopenia. “We believe the most likely explanation is that there’s an interaction between the drug and some component of TTR amyloidosis that is precipitating the serious platelet declines,” he said. “What we found so far is that in some TTR patients, but not all, we detect drug-independent antiplatelet antibodies that emerge during treatment. Obviously, we are very early in the process of understanding these events, so we cannot be certain that the antiplatelet antibodies we have observed in some TTR patients are in any way related to those platelet declines, but we continue to investigate.” Crooke stressed that the incidents of platelet decline did not result from prolonged exposure, noting that the observed cases of thrombocytopenia typically occurred after three to four months of dosing. “This makes these observations all the more perplexing because we have quite a bit of experience at 300 milligrams in TTR patients with dosing much longer than three to four months,” he said. “This is all happening in real-time and so the efforts to understand the molecular mechanisms responsible for the serious platelet reductions in patients who have advanced TTR amyloidosis is still very much in progress,” Crooke added. The company has stepped up its monitoring and does not expect the FDA to place additional holds on its programs, he said. After expressing confidence that the limited incidents of thrombocytopenia seen in the NEURO-TTR study were not “a class effect associated with 2 prime methoxyethyl second-generation antisense drugs” and offering details about the company’s safety database for incidents of platelet declines, Crooke stunned analysts by disclosing the new concern about “severe” platelet declines in patients treated with volanesorsen in the company’s familial chylomicronemia syndrome (FCS) trial. The declines also occurred after relatively short dosing periods, also despite the company’s experience with longer dosing of volanesorsen in FCS patients. “We believe that we, with TTRRx, are seeing some disease-IONIS-TTRRx interaction that is causing a small incidence of these severe platelet declines,” Crooke said. “However, we also have just observed a severe platelet decline in patients being treated with volanesorsen and so we need to understand that more.” Crooke was clearly uncomfortable discussing the predicament facing the company, responding to a query from Leerink Partners LLC analyst Michael Schmidt about the potential role of dose effect in TTRRx by stating that “we’re not confident of anything, other than the things I said I’m confident about.” Among those assertions was Crooke’s insistence that “we’re very confident that the drugs we have are working. This is a problem we can manage now that we understand it.” Analysts were less certain of that. In a flash note, Schmidt predicted a “likely” compound or class effect, “given the observation in multiple trials at this point and preclinical findings published previously by GSK scientists.” He added, “Regardless of the specific mechanism, we believe these observations clearly increase the risk around [Ionis’] platform, especially with respect to systemically administered antisense-oligonucleotides (ASOs).” Piper Jaffray analyst Joshua Schimmer dropped the company’s price target to $35 from $60, observing in his research note that “the company is struggling to identify the cause of thrombocytopenia, and maintains this is a not platform issue but one that is most likely related to the underlying disease, and has ruled out several possibilities. These issues, combined with the company’s checkered history, work to diminish management’s credibility.” Considering the number of details that Ionis must confront, “all said, the company (and we agree) does not believe this will be sorted out anytime soon,” he added. For much the same reason, Cowen and Co. analyst Eric Schmidt lowered the company’s rating to “market perform” from “outperform,” citing concern that the severe cases of thrombocytopenia reported in two pivotal programs “could be seen with other candidates until clarity can be gained.” And J.P. Morgan analyst Jessica Fye – who one day earlier weighed the prospects of Ionis and competitor Alnylam Pharmaceuticals Inc. in a lengthy analysis – weighed in that “the safety concerns that had been percolating around the [Ionis] TTR program (and platform) are clearly more serious than previously expected.” Meanwhile, Cambridge, Mass.-based Alnylam was the beneficiary of Ionis’ woes. Piper Jaffray analyst Edward Tenthoff wrote in a research note that the Ionis delay “reduces the competitive risk for Alnylam’s revusiran and increased monitoring in Ionis’s polyneuropathy program could translate to a competitive advantage for patisiran.” The phase III APOLLO study of patisiran is fully enrolled, with data expected to report in the third quarter of 2017, while the ENDEAVOR study of revusiran should be fully enrolled by year-end with data expected in 2018, Tenthoff pointed out, reiterating an “overweight” rating for Alnylam and increasing the company’s price target to $118 from $102. Alnylam’s shares (NASDAQ:ALNY) closed Thursday at $70.57 for a gain of $7.02, or 11 percent. |
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