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Alnylam Presents New Phase II, Preclinical Data from TTR Amyloidosis Programs

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NEW YORK (GenomeWeb) – Alnylam Pharmaceuticals this week unveiled new Phase II data on its transthyretin-mediated amyloidosis (ATTR) therapy patisiran, which showed that the drug is capable of knocking down its disease-causing protein target by about 80 percent in patients — in line with previous clinical findings.

Release of the findings come as the company moves ahead with a recently initiated Phase III trial of patisiran in patients with a manifestation of ATTR known as familial amyloidotic polyneuropathy that is characterized by damage to the peripheral nervous system.

Also this week, Alnylam released preclinical data from its ATTR program that the company says highlights the potential of RNAi as a treatment modality for the disease.

The data were presented at this year's International Symposium on Amyloidosis (ISA) held in Indiana.

ATTR is caused by mutations in the transthyretin (TTR) gene, which triggers accumulation of abnormal amyloid proteins in the body. Patisiran comprises siRNAs designed to inhibit both the wild-type and mutant forms of the protein, and is formulated with lipid nanoparticles for intravenous delivery.

Alnylam is also developing a subcutaneous version of the drug — ALN-TTRsc — that is in Phase II testing in ATTR patients with a form of the disease called familial amyloidotic cardiomyopathy characterized TTR accumulation in heart tissue. A Phase III trial for this drug is expected to begin by the end of 2014.

Alnylam previously conducted a Phase II study of patisiran in 28 ATTR patients, who received the drug either once every four weeks or once every three weeks at doses ranging from 0.1 mg/kg to 0.3 mg/kg. At the highest dose, treatment was able to cut TTR protein levels by up to 96 percent, with average reductions of around 80 percent, and was found to be generally safe and well tolerated.

Data on one additional patient who was not included in the initial Phase II analysis mirrored the outcome of the other study participants, Alnylam noted this week.

Given these positive findings, Alnylam kicked off an open-label extension study of patisiran in late 2013, which enabled patients from the Phase II trial to continue receiving 0.3 mg/kg doses of the drug — the dose level that is being pursued in Phase III — for an additional two years. After that time, patients may continue receiving treatment in another extension study, according to Alnylam.

This week, Alnylam presented preliminary data from that extension study demonstrating that in the 23 patients reported on, continued treatment was able to sustain target protein knockdown of 80 percent through 168 days.

Notably, the company also observed a significant decrease in infusion-related reactions in patients in the extension study compared with those in the original phase II trial, with the incidence of such events falling to 2 percent from 15 percent. Alnylam attributed the improvement to an improved micro-dosing regimen that it has developed.

"The potent, rapid, and durable knockdown of TTR achieved by patisiran, which is now confirmed to be sustained with multi-dosing, is important since TTR protein reduction in patients with ATTR may have the potential to delay or even reverse disease progression with associated clinical benefit," David Adams, head of neurology at the French Reference Center for FAP and one of the study's investigators, said in a statement. "It is also encouraging to see the favorable tolerability profile for multiple dose administration of patisiran, including the clear reduction in the occurrence of infusion reactions."

Also at ISA, Alnylam scientists released data from a 283-patient natural history study of patients with FAP, which was designed to help the company characterize the severity and rate of progression of neuropathy.

The company said that the study demonstrated a rapid progression in neuropathy impairment scores — an evaluation of muscle weakness, reflex decrease or loss, and sensation decrease or loss — and a high correlation of this measurement with disease severity.

These findings, Alnylam CMO Akshay Vaishnaw said in a statement, give the company confidence that the ongoing Phase III trial of patisiran in FAP patients is "robustly powered to show the potential impact of TTR lowering on the [neuropathy impairment score] endpoint [being] used."

During ISA, Alnylam also presented preclinical data confirming that the degree of TTR protein knockdown in a mouse model of ATTR was "highly correlated" with regression of TTR tissue deposits.

In the company's studies, the animals exhibited deposition of TTR at greater than 12 months of age in similar target organs to those seen in ATTR human disease, including dorsal root ganglion, sciatic nerve, duodenum, esophagus, stomach, and colon.

When treated with ALN-TTRsc, the degree of TTR reduction at steady state knockdown was highly correlated in a linear relationship with regression of TTR deposits, Alnylam said. "Regression of TTR deposits was greater with every additional level of plasma TTR knockdown, and was most pronounced at the highest dose of siTTRsc tested, which achieved over 95 percent TTR knockdown."

Further, at doses that only resulted in 50 percent TTR knockdown, protein deposits in mice were found to be significantly reduced compared with control animals.

Alnylam also compared RNAi-based ATTR treatment approaches to tafamidis — a drug currently that has been shown to stabilize TTR levels — and an antisense oligonucleotide targeting TTR.

Specifically, lipid nanoparticle-conjugated siRNAs were administered to mice at a dose that triggered 95 percent TTR knockdown, which researchers then compared with a dose of tafamidis sufficient to produce a greater than 100 percent stabilization of TTR tetramers.

The RNAi treatment was able to cut TTR protein deposits in all affected tissues by mean levels greater than 75 percent, with maximum levels lowered by up to 95 percent compared with controls. Tadamidis treatment, meanwhile, resulted in only a "modest" TTR deposit regression, and only in dorsal root ganglion and sciatic nerve tissue.

When Alnylam compared ALN-TTRsc to a subcutaneously delived TTR-targeting antisense compound, it found that the RNAi agent achieved a more rapid and significant reduction in TTR levels at 100-fold lower drug exposure in liver and bystander tissues such as kidney.

"We believe that the ability of RNAi therapeutics to achieve potent TTR knockdown with lower tissue exposure could result in a more favorable efficacy and tolerability profile" compared with other treatment modalities," Alnylam Vice President of Research Rachel Meyers said in a statement.

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