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Wall Street in October Proves Tumultuous for Four RNAi/microRNA Shops

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NEW YORK (GenomeWeb) — October was a turbulent month on Wall Street for several key RNAi/microRNA players, with two companies — Regulus Therapeutics and Alnylam Pharmaceuticals — seeing major gains on encouraging clinical data and two others — Arrowhead Research and Tekmira Pharmaceuticals — taking hits amid investor worries about certain key drug-development programs.

Leading the upward surge is Regulus, a one-time joint venture between Alnylam and Isis Pharmaceuticals, which late last month released Phase I data indicating that its subcutaneously administered hepatitis C therapy RG-101 could cut viral load levels in patients as well as currently approved treatments, but with just a single dose.

Specifically, all 14 patients receiving a 2 mg/kg dose of RG-101 — the lowest tested in the trial — expected a virological response, with a mean 4.1-log viral load reduction at day 29. The range of viral load reductions among these patients was 5.8 log to 2.3 log. Additionally, by day 29, six patients had HCV RNA levels below the limit of quantification.

Existing HCV drugs such as Gilead Sciences' Sovaldi (sofosbuvir) can achieve similar results, but are taken once a day for between one and three months.

While it is known that RG-101's target, miR-122, is key to HCV's ability to replicate and infect hepatocytes, such a robust effect from a single dose was not expected, especially given the modest performance of Santaris Pharma's rival miR-122 inhibitor miravirsen. In a Phase II trial, that drug achieved a maximum of a 2.73-log reduction in HCV RNA with four weekly doses at 7 mg/kg.

Wall Street reacted strongly to the Regulus data, sending shares of the company's stock up more than 100 percent on the Nasdaq. Since then, the stock has continued its ascent, closing at $19.96 on Oct. 31 after beginning the month at $6.66. Regulus' market capitalization, meanwhile, climbed from $289 million to $866.1 million over the same period.

Alnylam's stock also got a shot in the arm in the middle of last month after the company reported that its lead drug candidate, the TTR-mediated amyloidosis therapy patisiran, could stabilize neurological impairment in patients after six months of treatment in an open-label extension study of an ongoing Phase II trial.

The drug is being developed for a manifestation of the disease called familial amyloidotic polyneuropathy (FAP).

The extension study is designed to provide the company with long-term safety and tolerability data of patisiran when it is dosed once every three weeks at .3 mg/kg. Among the study's specific endpoints are changes in neuropathy impairment clinical scoring system known as mNIS+7 that evaluates muscle weakness, sensory and autonomic function, and nerve conductance.

Importantly, the mNIS+7 measurement is the primary endpoint of a Phase III trial of patisiran that is currently underway, and so its readout in the extension study is seen as offering hints as to how the drug might perform in that pivotal trial.

After six months, 19 patients in the extension study were found to have experienced a mean .95 point decrease in mNIS+7 scores, compared with a seven to 10 point increase observed in historical datasets of untreated FAP patients.

On the news, Alnylam's shares jumped more than 20 percent to top $89 a share, steadily rising on the Nasdaq to finish October at $92.74. The company's market cap, meanwhile, rose from $5.9 billion to $7.1 billion over the course of last month.

At the other end of the spectrum is Arrowhead Research, whose stock was slammed in early October, dropping more than 40 percent after the company released Phase IIa data showing that its hepatitis B drug ARC-520 led to a less-than-expected reduction in surface antigen levels (s-antigen).

The company had previously indicated that it hopes to achieve at least a 1-log drop in s-antigen levels — a key indicator of active infection — with its drug. The data, however, showed that single 2 mg/kg doses of ARC-520 led to only a .3 log reduction.

Although the ongoing Phase IIa trial is testing 3 mg/kg and, possibly, 4 mg/kg doses of ARC-520, the interim data surprised many given earlier statements by company management. For example, in August Arrowhead COO Bruce Given announced that the data, while blinded at the time, suggested "surprisingly large reductions in surface antigen" at 2 mg/kg.

The company has since issued a statement addressing the matter, stating that it has "always believed that our public communications surrounding the ARC-520 Phase IIa study have been consistent and, more importantly, properly reflected the data we were seeing in the initial two cohorts."

Such assurances, however, have not been sufficient for some investors, and in mid-October two law firms announced the filing of class action lawsuits alleging that Arrowhead was misleading about the Phase IIa data.

After its precipitous drop on the Nasdaq from $13.76 at the beginning of October to about $7 when the ARC-520 data was released, Arrowhead's stock mostly leveled out and finished the month at $6.52. This reflects a decrease in market cap from $728 million to $345 million.

Tekmira Pharmaceuticals also had a difficult October, but unlike Arrowhead there hasn't been any one event to explain its stock decline. But since the recent Ebola outbreak in West Africa, the company's shares have been on a rollercoaster.

One of Tekmira's lead compounds is the Ebola treatment TKM-Ebola, which has reached Phase I testing but been plagued by a series of setbacks over its life.

In 2010, the company received a contract from the US Department of Defense worth up to $140 million to develop the drug through US approval. But after beginning Phase I testing in 2012, Tekmira chose to scrap the drug's original formulation in favor of one that uses next-generation lipid-based delivery nanoparticles. By 2013, the company was back on track with its new Ebola drug and it initiated a new Phase I study in early 2014.

In mid-July, however, that study was put on hold by regulators until the company provided additional safety data on the drug — something the company hopes to do before the end of this year.

Meanwhile, the Ebola outbreak has spread and although Tekmira has said that it has provided its drug to infected individuals under emergency protocols enacted by the US Food and Drug Administration, the company has made no public statements regarding the effect of its treatment in patients other than to say that repeated infusions have been well tolerated.

Amid all this, the company's stock has been on a pendulum, reaching highs around $29 in March, shortly after announcing that TKM-Ebola had received a fast-designation from the FDA, and in early October as concerns over Ebola outside of Africa increased. The stock is riding a downswing, however, falling $16.68 at the end of the month. Tekmira's market cap began October at $552.4 million, falling to $368.7 million on Oct. 31.

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