Positive if early stage data from Alnylam (ALNY) this morning represents encouraging progress in hereditary amyloidosis, a very rare orphan condition that last month saw a Pfizer (PFE) candidate declined approval.
Alnylam reported potent suppression of the disease-causing protein after just one dose and said the results raise hopes the drug might be suitable for once-a-month or possibly once-every-other month dosing. Considering lack of progress in the RNAi space to date and the fact that the drug, ALN-TTR02, is one the company’s biggest pipeline hopes, this makes encouraging news, particularly as a phase II study has already started. With Pfizer now having to conduct a confirmatory pivotal study with its candidate, Vyndaqel, to satisfy US regulators, the US biotech is not necessarily too far behind.
Hereditary amyloidosis, or ATTR, is caused by mutations in the gene encoding the transthyretin (TTR) protein. The protein is misfolded, leading to its accumulation in tissues such as the heart, gastrointestinal tract and peripheral nerves. TTR is primarily produced in the liver and liver transplants are currently the only really effective treatment for the progressive and fatal condition, although not all patients are eligible. After diagnosis, which tends to happen with patients are in their 30s or older, survival is typically 5-15 years.
Research into the condition has seen several candidates move into the clinical in recent years – in no small part fuelled by the industry’s interest in rare conditions – although progress has been slow (Therapeutic focus – Amyloidosis options emerging from Pfizer, Alnylam, May 31, 2012).
Pfizer received a complete response letter for its candidate, generically called tafamidis meglumine, in mid-June. The FDA requested a second efficacy study to establish the product’s effectiveness; the pharma giant gained the product via its acquisition of FoldRx in 2010.
The small molecule drug works by stabilising TTR, preventing the formation of misfolded proteins and therefore amyloid deposits. Pfizer has been developing it to specifically treat familial amyloid polyneuropathy or TTR-FAP, where the amyloid gather in the nerves causing sensory loss and pain. Sufferers are eventually confined to a wheelchair.
Lack of evidence
Phase III studies with tafamidis failed to show a statistically significant improvement in neurological symptoms, the primary measure, although assay readings measuring transthyretin stabilization showed this occurred in 98% of patients after 18 months.
Evidence on this surrogate measure was enough for European regulators, who granted approval at the end of last year. Even an FDA advisory committee seemed to lean towards approval on the basis of the assays – although they failed to endorse the drug’s efficacy based on the clinical neurological measures they voted 13-4 in favour of the data providing substantial evidence of efficacy for a surrogate endpoint that they agreed is reasonably likely to predict a clinical benefit.
The regulator demanded a pre-approval confirmatory study, however, and as such there is nothing approved in the US to treat TTR-FAP, where Pfizer estimates 3,000 people are sufferers.
Knock out blow
Massachusetts-based Alnylam, meanwhile, believes its candidate, by knocking out the gene responsible for the mutant protein, will lead to a more profound impact on disease and be able to treat both FAP patients and those afflicted with familial amyloid cardiomapthy or FAC, where the amyloid accumulates in the heart muscle.
In a phase I study of 17 healthy volunteers serum TTR protein levels were reduced by up to 94%, with suppression of TTR occurring quickly, in some cases after just a single dose. Even at the lowest dose tested substantial TTR suppression was achieved, making once-a-month dosing look achievable, the company said this morning. There were no serious adverse events or discontinuations reported.
Alnylam’s product must be intravenously administered, while Pfizer’s tafamidis is a once-a-day pill. However considering the progress and chronic nature of TTR a monthly infusion is unlikely to prove a barrier to the medication, particularly if it proves more effective; obviously the less frequently the infusions are needed the better.
On a conference call today Alnylam executives said six times a year dosing could also be worth exploring, although for now the ongoing phase II study will remain a once-every-four weeks trial. Having commenced last month, the study is seeking to recruit 20 ATTR patients, with results due sometime next year. The primary objectives are safety and tolerability of multiple doses of ALN-TTR02, while circulating serum TTR levels will also be measured.
Given that patients will only be dosed for two months the study is unlikely to generate any robust insight into the drug’s impact on more clinically meaningful endpoints such as pain. That will have to wait for phase III studies, which Alnylam hopes to start later next year.
Executives also pointed out that although Pfizer’s study failed on clinical measures, signs of efficacy over the longer term were seen, with a product with a much more benign impact on circulating protein. As such, although these phase I data remain early stage and further evidence of both safety and efficacy is needed, hopes are likely to rise for ALN-TTR02.
This is all good news for Alnylam, which has been plugging away in the RNAi field for many years now, with very little to show for it in terms of advanced clinical projects. The company was also quick to point out today the broader significance of ALN-TTR02’s success for the RNAi field.
Investors seem to agree - Alnylam shares were trading 27% higher in early trade today at $15.90, a two-year high. However with its pipeline still thoroughly early stage, further good news will be needed to sustain this rally.