Alnylam Pharmaceuticals ($ALNY) lost about a half-billion dollars in market cap in trading on the news that it halted development of RNAi liver disease candidate ALN-AAT after Phase I/II resulted in three patients with liver enzyme elevation at the highest dose.
Given this issue, Alnylam is advancing a new development candidate instead and hopes to submit to regulators to start a clinical trial next year. ALN-AAT was being developed to treat AAT deficiency-associated liver disease.
The company “presented clinical results from our ALN-AAT program showing potent, dose-dependent, and durable knockdown of the target protein, just as we've seen in clinical data presented from all of the other RNAi candidates in our pipeline to date,” said Alnylam’s EVP of R&D and CMO, Dr. Akshay Vaishnaw, in a statement. “In this case, however, we observed a low incidence of asymptomatic, transiently elevated liver enzymes.”
“We plan to advance a follow-on molecule in efforts to optimize the tolerability profile for this program, and we aim to file a CTA for ALN-AAT02 in 2017,” he added. “We remain committed to developing RNAi therapeutics for alpha-1 liver disease, a rare genetic disease with significant unmet need where liver transplantation is the only treatment option beyond supportive care."
The data presented at the Oligonucleotide Therapeutics Society (OTS) meeting in Montreal was from a 20-patient study with 4 patients in each of 5 ascending dose groups. Each patient received a single subcutaneous dose of ALN-AAT. The trial also included a second part in which 6 patients were randomized 4 to 2 on drug versus placebo. The treatment group received four doses of ALN-AAT, one every 28 days.
The response was dose-dependent, but a single 6 mg/kg dose of ALN-AAT had an AAT knockdown of up to 88.9% with a mean maximal knockdown of 83.9 ± 2.6%. After 6 months, that knockdown of serum AAT prove durable, with that mean data being of 75.0 ± 1.2% at approximately 6 months.
Alpha-1 antitrypsin (AAT) deficiency is a rare genetic disorder that causes disease of the lungs and liver. Mutations in AAT can cause the protein to misfold, which slows its release into the blood thereby causing hepatocytes and leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma.
About 200,000 people are homozygous for the Z allele, the most common location of AAT mutations; an estimated 10% have associated liver pathology with no treatment options other than supportive care or liver transplantation.
Jefferies’ Gena Wang held steady on her Buy rating and $86 share price target for Alnylam, arguing in a Sept. 28 note that “reported increases in liver enzymes are likely specific to the ATT siRNA and we see limited read-through to other clinical programs with the ESC-GalNAc chemistry,” referring to the 6 programs based on the same platform.
Alnylam shares were down about 8% to around $71 in trading on the news. The company has a market cap of more than $6 billion.