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Opko Halts Phase III Study of siRNA Treatment for AMD on Poor Preliminary Data

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A phase III trial of bevasiranib, a treatment for wet age-related macular degeneration and the most advanced RNAi drug candidate in human testing, has been halted early after being deemed "unlikely" to meet its primary endpoint, the therapy's developer said last week.

According to Opko Health, the trial's independent data-monitoring committee had recommended ending the study after reviewing preliminary data, which "showed activity of bevasiranib … [but] indicated that the trial, as structured, was unlikely to meet its primary endpoint."

"While we are clearly disappointed with the preliminary results of this fully enrolled study, the indications of activity are encouraging, and we look forward to fully analyzing the data in the coming weeks," Opko Chairman and CEO Phillip Frost said in a statement.

Despite the setback, Frost indicated that the company, which also works on non-RNAi drugs and instrumentation for ocular disease, has not turned its back on RNAi, noting that "we remain committed to the continued development of our siRNA portfolio targeting vascular endothelial growth factor."

Bevasiranib is an unmodified siRNA that targets VEGF, which promotes the abnormal blood-vessel growth associated with AMD. Originally developed as Cand5 by Acuity Pharmaceuticals, which was acquired by Opko in early 2007 (see RNAi News, 3/29/2007), the drug was the first RNAi therapeutic to enter human trials (see RNAi News, 11/12/2004) and the first to reach the final stage of clinical testing.

The phase III study was designed to evaluate the safety and efficacy of bevasiranib as a maintenance therapy in combination with Genentech's approved AMD treatment Lucentis (see RNAi News, 6/28/2007).

In the trial, roughly 330 patients were randomized to receive bevasiranib, either every eight weeks or every 12 weeks, via intravitreal injection after an initial pre-treatment with three doses of Lucentis or the standard Lucentis treatment regimen of one monthly intravitreal. The trial was set to run for 104 weeks.

The study's primary endpoint was prevention of vision loss, with secondary outcome measures including the need for rescue therapy and the number of patients with improved visual acuity.

Opko said that a review of the study's preliminary data showed bevasiranib to be active when used adjunctively with Lucentis and that there were no systemic or local ocular safety issues associated with treatment. Still, the company decided to follow the IDMC's recommendation to terminate the trial, which was set to run until December 2010. The data required to fully determine whether the study had met its primary endpoint was expected to be ready at the end of 2009.

Opko officials did not return requests for additional comment.

Writing on the Wall

Despite bevasiranib's ostensible success early in the clinic (see RNAi News, 6/8/2006 & 9/14/2006), questions about the drug have persisted for some time.

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According to one industry executive familiar with the development of VEGF-targeting siRNAs, a hint that there might be issues with the drug was seen in the design of the phase II and phase III studies, which both examined bevasiranib as an adjuvant to Lucentis rather than as a first-line treatment itself.

This suggested that "if the drug worked, it was minimally effective" as a standalone therapy, said the executive, who asked not to be named.

Further positioning bevasiranib to fail was the "ambitious" dosing regimen examined in the phase III study — every eight or 12 weeks rather than every four weeks as with Lucentis, he told RNAi News.

Although the relatively infrequent dosing would appeal to patients given the unpleasantness of intravitreal injections, the regimen is "asking a lot from a molecule" and required bevasiranib to have been especially potent.

The field's optimism about bevasiranib was further shaken when a team of investigators unaffiliated with Opko reported data suggesting that the drug's apparent efficacy may not have been a result of the RNAi mechanism.

About a year ago, researchers from the University of Kentucky reported in Nature results from a study showing that any dsRNA at least 21 nucleotides in length activated toll-like receptor 3, which in turn suppressed angiogenesis, in the retinas of a mouse in which a laser injury triggered choroidal neovascularization (see RNAi News, 3/27/2008). Among the siRNAs tested were ones targeting the same sequences as bevasiranib and Allergan's RNAi-based AMD drug AGN211745.

Sam Reich, executive vice president of ophthalmologics at Opko, told RNAi News at the time that the paper's findings, at least in regards to bevasiranib, were inaccurate.

“We respectfully disagree with the conclusions [the authors] have drawn,” he said at the time. “We stand by our data [that] shows that our molecule mediates VEGF silencing, which is anti-angiogenic, using the appropriate controls.”

The senior author of the paper, Jayakrishna Ambati, later defended his findings to RNAi News, and noted that Reich and colleagues previously retracted a 2004 paper in Retina that claimed to demonstrate the ability of intravitreally injected siRNAs to inhibit VEGF and suppress vascular growth and permeability in a primate model of choroidal neovascularization.

According to the retraction, a dataset sent to a biostatistician for analysis “had an error in linking the codes for each animal with the gradings for angiographic leakage. Therefore, the results reported for the effect of treatment on leakage were not correct.”

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After the angiograms were re-graded, it was found that there was “no statistically significant effect of dose,” the authors wrote in their retraction.

Other Avenues

Although it is Opko's most-advanced RNAi drug, bevasiranib is not the only siRNA in the company's pipeline.

The company has several early-stage preclinical drug candidates based on the gene-silencing technology, including one targeting a subunit of the transcription factor hypoxia-inducible factor 1 called HIF1-alpha, which may be used to address pathogenic angiogenesis in the eye; and one targeting transforming growth factor beta receptor 2, which is associated with inflammation and fibrosis, Opko's Reich told RNAi News last summer (see RNAi News, 6/5/2008).

Meanwhile, Opko recently disclosed that it is developing a next-generation siRNA designed to inhibit VEGF A165, but not the anti-angiogenic VEGF A165b isoform.

According to poster data Opko is slated to present at the Association for Research in Vision and Ophthalmology's upcoming annual meeting in May, VEGF A165b is an endogenous isoform of VEGF that inhibits new blood vessel growth rather than promoting it.

To identify VEGF A165b-sparing siRNAs, Opko researchers transfected 14 different siRNA candidates in ARPE19 cells, which were then treated with transforming growth factor-beta II in order to induce angiogenesis, according to the poster.

"ELISA results demonstrated several siRNA candidates inhibited the production of [TGF-beta II]-induced VEGF in ARPE19 cells," the poster states, while RT-PCR confirmed that two candidates inhibited production of VEGF A165 but not VEGF A165b.

As such, VEGF A165b-sparing siRNAs "may be potent therapeutic candidates for the treatment of ocular neovascularization," the investigators concluded.

And although Opko's Frost said that a place for anti-VEGF siRNAs remains in the company's pipeline, it is not clear whether bevasiranib will remain in development or be shelved in order to make way for the new RNAi candidates. At the same time, Opko has been facing a cash crunch that may force it to curtail certain of its clinical and research and development programs.

In November, the company warned in a filing with the US Securities and Exchange Commission that it wouldn't be able to fund its operations for the coming year without obtaining additional financing in the first half of 2009 (see RNAi News, 11/20/2008).

As such, Opko said in the filing that it “may have to delay, reduce the scope of, or eliminate one or more of our clinical trials or research and development programs," and possibly “take other actions designed to reduce our cost of operations, all of which may not significantly extend the period of time that we will be able to continue operations without raising additional funding.”

Last week, however, Opko disclosed in a new SEC filing that a private investment group controlled by Frost had agreed to pay $20 million for 20 million shares of the company. According to another SEC filing, $3 million of this total payment has already been given to Opko.

"This capital inflow will provide additional financial resources to support our ongoing efforts to bring our ophthalmic drugs and instrumentation products to the market," Opko said in the filing.

Opko did not disclose in the SEC filing for how long the cash infusion would allow it to continue its operations; the company has yet to release its fourth-quarter and full-year 2008 financial results.

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