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[p=24, null, left]On October 8, Arrowhead (ARWR) announced that it will present the data from the ongoing Phase IIastudy of ARC-520 for the treatment of chronic hepatitis B (HBV) infection in the late-breaking poster session at the 2014 American Association for the Study of Liver Diseases (AASLD) Liver Meeting being held on November 7-11, 2014, in Boston.[p=24, null, left]This phase IIa is a randomized, double blind, placebo controlled study, which will enroll up to 24 chronic HBV patients in three dose cohorts with patients receiving either ARC-520 or placebo in combination with entecavir. Patients are randomized to placebo or ARC-520 at a ratio of 1:3 and continue daily entecavir. Primary endpoints will be safety and tolerability as well as depth and duration of surface antigen knock down. Patients will be followed until surface antigen levels return to baseline.[p=24, null, left]The Phase IIa trial began doing patients on March 24, 2014 in Hong Kong. Three single doses of ARC-520 at 1 mg/kg (Cohort 1, 8 patients), 2 mg/kg (Cohort 2, 8 patients) and 3 mg/kg (Cohort 3, 6 patients) have been evaluated. Cohorts 1 and 2 have been evaluated through Day 85 and are unblinded. Cohort 3 is enrolling and remains blinded.[p=24, null, left]The Company released the data from its abstract for the meeting.[p=24, null, left]According to the abstract, ARC-520 was safe and well tolerated in all three cohorts. There were no SAEs, no signs of hypersensitivity, no dose limiting toxicities and no discontinuations due to AEs. There were no treatment emergent changes in vital signs, physical exams or ECGs rated clinically significant by the investigator. There have been few abnormal laboratory values, with no clinically significant, treatment emergent, changes in ALT, AST, GGT, LDH, bilirubin, BUN or creatinine or apparent trends. All AEs reported to date (n=4) have been mild or moderate and rated as unrelated to study drug by the investigator.[p=24, null, left]Efficacy of ARC-520 was measured as HBsAg decline from baseline. In the 1 mg/kg cohort, mean nadir HBsAg was -39% (range -22 to -57) with a mean change on day 85 of -31% (range -14 to -39). In the 2 mg/kg cohort, mean nadir HBsAg was – 51% (range -46 to -59) with a mean change on day 85 of -22% (range -7 to -40). For 2 mg/kg cohort, the HBsAg reduction was statistically significant vs placebo for Days 3 through 43 post dose.[p=24, null, left]Our Takeaways from the Preliminary Phase IIa Data[p=24, null, left]
Following the release of the initial Phase IIa data, share price of Arrowhead declined more than 50%. We think this is an overreaction.[p=24, null, left]First, we think that in general the preliminary data are positive. ARC-520 demonstrated a strong safety profile and a modest efficacy for chronic HBV patients in the Phase IIa study. Remember, this is the first time that an HBsAg reduction is mediated through RNAi in chronic HBV patients.[p=24, null, left]Second, we have seen the dose dependent reduction of HBsAg in the Phase IIa study with a 39% reduction in the 1 mg/kg dose and 51% reduction in the 2 mg/kg dose. We expect further HBsAg reduction in the 3 mg/kg dose when the data are unblinded later this year.[p=24, null, left]Thirdly, according to management, if ARC-520 is safe in the 3 mg/kg dose, an increase of dose to 4 mg/kg is possible, which could further reduce HBsAg in HBV patients.[p=24, null, left]Further, the multi-dose, multi-national Phase IIb trial will proceed as planned.[p=24, null, left]With the positive data, why the market overreacted to the positive data negatively? We think there is a misunderstanding the market has about the anticipated data.[p=24, null, left]Misunderstanding number 1: the market has been anticipating a much deeper knockdown of HBsAg (about 1 log, 90%). Management did say in recent conference calls, that their goal is toidentify a dose of ARC-520 capable of achieving HBsAg reduction of around 1 log after a single administration.[p=24, null, left]On the surface of it, the 51% reduction (about 0.3 log) at the 2 mg/kg dose is far from the 1 log (90% reduction) goal. But we remind investors that the Company is still waiting for data from the 3 mg/kg dose. Since ARC-520 has demonstrated excellent safety profile in healthy humans at 4 mg/kg dose, a dose increase to 4 mg/kg is possible if ARC-520 is safe and tolerated at the 3 mg/kg dose.[p=24, null, left]Further, our understanding is that the goal of 1 log reduction is based on scientific literature. A small number of patients who achieve functional cure from Interferon therapy demonstrate ½ log reduction in HBsAg (70% knockdown) after 12 weeks and 1 log (90% knockdown) after 24 weeks. If ARC-520 can lead to more rapid reduction, particularly on repeat dosing, a 1 log reduction may not be needed after a single administration. A 0.5 log to 0.8 log (70% to 85%) reduction in HBsAg may still work for ARC-520 after single administration.[p=24, null, left]Misunderstanding number 2: The Phase IIa data are weak than data from animal model.[p=24, null, left]In the chimpanzee study, ARC-520 achieved 80-85 reduction in HBsAg at the dose of 3 mg/kg. At 2 mg/kg dose, ARC-520 achieved 50% reduction in HBsAg, which was similar to the reduction in the Phase IIa trial. With the data from 3 mg/kg coming in, we may see similar knockdown of HBsAg in humans compared to that in chimpanzee.[p=24, null, left]Our Conclusion[p=24, null, left]
We think the initial data from the ongoing Phase IIa trial were not that bad and market overreacted to the generally positive data.[p=24, null, left]Arrowhead just completed the first two dose cohorts in the Phase IIa dosing finding study, and has not yet identified a dose in humans that will meet the HBsAg knockdown goal.[p=24, null, left]Arrowhead just finished dosing all 8 patients in the 3 mg/kg cohort. The Company will decide whether to escalate to 4 mg/kg after seeing the actual data from the 3 mg/kg does. Even with the dose increase to 4 mg/kg, the Phase IIb will proceed as planned.[p=24, null, left]That said, we do see increased uncertainty in this program due to the not that strong data from the first 2 cohorts. The increase of the dose may increase safety risks and impact the timeline of this program. Also the increase of dose may not guarantee an increased efficacy.[p=24, null, left]With all these in mind, we think the ARC-520 program is still viable, but with increased risks. Therefore we reiterate our Outperform rating on Arrowhead shares but lower our price target to $15 per share reflecting the increased risks. |
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发表于 2014-10-11 10:58
