Alnylam plunges after deaths force it to pull PhIII blockbuster candidate revusiran

Alnylam was down 41% after hours last night when it made the shock announcement that testing of its hereditary ATTR amyloidosis med would be halted after more patients died on its treatment than on a dummy drug.

The Cambridge, MA-based gene-silencing pioneer said in a release that revusiran would stop being developed altogether after a Data Monitoring Committee (DMC) told the co it should stop dosing in the late-stage Endeavour trial.

The DMC told Alnylam ($ALNY) that the “benefit-risk profile for revusiran no longer supported continued dosing,” and the unblinded data later showed an “imbalance of mortality in the revusiran arm as compared to placebo,” i.e., more patients died using revusiran than placebo.

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Of the 206 people in the study, 18 died--predominately as a result of heart-related issues, according to a call with investors the biotech made yesterday. The drug was tipped to be a blockbuster by the next decade, according to analysts, meaning this is a major blow to the biotech’s future balance sheet.

John Maraganore, CEO at Alnylam, said: “Patient safety comes first. We have stopped all dosing and are actively monitoring patients across revusiran studies to ensure their safety. We will also continue to evaluate Endeavour data to understand the potential cause of these findings.”

On the investor call, Maraganore was unable to detail just what had happened: “There is no current explanation for the cause of these findings, and we don't have all the answers that we would like to have and that you will ask of us,” he said. “Our decision to discontinue development has been communicated to investigators, study sites, regulatory authorities and our collaborators.”

Akshay Vaishnaw CMO and EVP of research and development at the biotech, tried to walk investors through what led to its halting of the program. “Later in the summer after ISA, there were three serious adverse events of new-onset or worsening peripheral neuropathy that were deemed possibly drug-related SUSARs or suspected unexpected serious adverse reactions.

“Peripheral neuropathy is a document clinical finding in the natural history of both hATTR-CM and wild-type ATTR, and an independent review by two separate clinical neurology experts led to conclusion, in late August, after investigation, that these events were likely part of the patients' underlying disease. We provided an update to all revusiran investigators and to the DMC and to the regulatory agencies after this assessment was completed and continued to monitor patients carefully.

“Very recently, we received the fourth SUSAR of progressive neuropathy and separate report of elevated blood lactate levels. Following these reports, we requested that the Endeavour Phase III study DMC assemble on an ad hoc basis to review these events and the corresponding Endeavour data on an unblinded basis.

“The DMC met yesterday [Tuesday, Oct.4] and after their review, informed the company that there was no conclusive evidence for a drug-related neuropathy progression signal in Endeavour. However, they recommended we suspend dosing in the Phase III trial due lack of favorable benefit risk. Subsequent to their recommendations, the company reviewed unblinded data, which revealed an imbalance of mortality in the revusiran arm. Based on this finding, we discontinued development of revusiran.”

He reiterated that in terms of what caused these deaths, “we don't have an explanation for these safety findings.” He added: “This is a sick, older patient population with multiple comorbidities who are taking many concomitant medications. In addition to our highest priority for following these patients for safety, we will thoroughly evaluate all revusiran data to understand the cause of the findings.”

The biotech was also swift to point out that the halting of this program does not affect its plans for patisiran, which is in Phase III for hATTR amyloidosis with polyneuropathy (hATTR-PN), or “any other Alnylam investigational RNAi therapeutic program in development,” according to the company.

The company was also quick to say that after looking at the safety data across its other programs, which includes the ALN-PCSsc program partnered with The Medicines Company, it concluded that “there is no evidence of a drug-related neuropathy signal in over 800 treated subjects and patients with exposure of up to 34 months.”

The Medicines Company ($MDCO) still, however, saw its shares tumble last night by over 10% on the news after hours, and there are concerns that this could be a read-through for other gene-silencing research work. 

Despite this setback, which nearly halved its $6 billion market cap literally overnight, Alnylam said it “reaffirms its ‘Alnylam 2020’ guidance and remains committed to the advancement of these investigational RNAi therapeutics for treatment of diseases with high unmet medical need.”

The biotech has been well regarded by the industry in the past, seeing Sanofi ($SNY) pay up a $700 million buy-in and further deals over the past two years.