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Alnylam Reports Positive Phase II Data on TTR Drug, Aims for Phase III by Year End

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Alnylam Pharmaceuticals this week announced positive clinical results from an ongoing phase II trial of ALN-TTR02, an investigational treatment for TTR-mediated amyloidosis, reporting that the drug was able to knock down levels of the protein that causes the disease by as much as 93 percent.

The gene inhibition was rapid, dose-dependent, and durable, Alnylam said. Additionally, ALN-TTR02 was generally safe and well tolerated in the trial — all of which puts the company on track to move into phase III before the end of the year.

ATTR is caused by mutations in the TTR gene, which triggers accumulation of abnormal amyloid proteins in the body. ALN-TTR02 comprises siRNAs designed to inhibit both the wild-type and mutant forms of the protein, and is formulated with a lipid nanoparticle technology licensed from Tekmira Pharmaceuticals.

About a year ago, Alnylam reported phase I data that showed the systemically administered compound could trigger up to 94 percent reductions in target protein levels after a single dose (GSN 7/19/2012). A few months later, the company inked a deal giving Sanofi subsidiary Genzyme the Asian rights to the drug, which had advanced into phase II a few months prior (GSN 10/25/2012).

The phase II, open-label trial is evaluating two doses of ALN-TTR02, ranging from 0.01 mg/kg to 0.30 mg/kg, in up to 30 patients with ATTR polyneuropathy. Patients are treated either once every four weeks or once every three weeks.

Thus far, 25 patients in eight cohorts have been treated, and all patients for the final cohort have been scheduled for dosing, Alnylam said.

The newly released data, which were presented at the 2013 Biennial Meeting of the Peripheral Nerve Society in France, come from the first 19 patients enrolled in the study and show that multiple 0.15 mg/kg and 0.30 mg/kg doses of ALN-TTR02 led to rapid, dose-dependent, and durable knockdown of serum TTR levels.

“At 0.30 mg/kg administered once every four weeks, mean TTR knockdown at nadir of 82.6 percent and 84.8 percent was observed following the first and second doses, respectively, and maximum TTR knockdown was up to 90.8 percent,” Alnylam said. “At 0.30 mg/kg administered once every three weeks, mean TTR knockdown at nadir of 83.1 percent and 87.4 percent was observed following the first and second doses, respectively, and maximum TTR knockdown was up to 92.8 percent.”

The investigators in the study conducted a number of additional analyses, the company added, including one based on a proprietary mass spectrometry method that was used to measure serum levels of wild-type and mutant proteins in patients with ATTR V30M, the most common form of the disease.

The scientists found an essentially one-to-one knockdown of mutant and wild-type TTR with superimposable pharmacodynamic effects toward both protein species, Alnylam said. A similar degree of TTR knockdown was also observed in patients on concurrent TTR stabilizer therapy versus those who received ALN-TTR02 alone.

“These results demonstrate the absence of any interference by TTR stabilizer drugs with the pharmacologic activity of ALN-TTR02,” the firm stated. Additionally, serum TTR reductions were “highly correlated” with parallel changes in retinol binding protein and vitamin A levels — an expected outcome.

There were no significant adverse events associated with the drug up through the highest dose tested, and a favorable safety profile was seen with both the once-every-three-weeks and once-every-four-weeks dosing regimens.

No abnormalities were observed in liver function, renal function, or hematologic parameters, and a mild infusion-related reaction observed in one patient was overcome with the slowdown in the rate of infusion.

There was a single episode of self-limiting cellulitis of the arm — a serious adverse event — but this was due to drug extravasation in a patient with poor intravenous access, the company noted.

The phase II study is continuing, with the three remaining cohorts receiving 0.30 mg/kg doses of ALN-TTR02 once every three weeks using a simplified pre-medication regimen, which includes a reduced steroid dose prior to infusion with the RNAi drug.

Final results of the trial, including data from these last patients, will be presented in November at the International Symposium on Familial Amyloidotic Polyneuropathy in Brazil.

Alnylam also continues to anticipate that it will initiate an open-label extension study of ALN-TTR02 for patients treated in the phase II trial, with data available in 2014.

In addition to the planned phase III trial of ALN-TTR02 later this year, the company is also moving ahead with a subcutaneous version of the drug called ALN-TTRsc, which uses a proprietary conjugation strategy based on the triantennary N-acetylgalactosamine, or GalNAc, ligand.

Alnylam’s shift toward its GalNAc conjugate technology is widely seen as driven in part by a desire to reduce the company’s reliance on Tekmira’s lipid delivery vehicles, which were the subject of an acrimonious legal battle between the firms that was settled late last year (GSN 11/15/2012).

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