Safety and efficacy of RNAi therapy for transthyretin amyloidosis.

BACKGROUND: Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. METHODS: We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. RESULTS: Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively. CONCLUSIONS: ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).

Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment. METHODS: We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059. FINDINGS: Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001). INTERPRETATION: Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings. FUNDING: Alnylam Pharmaceuticals.

The use of sildenafil in patients with erectile dysfunction in relation to diabetes mellitus--a study of 1,511 patients.

Erectile dysfunction (ED) seriously impairs the quality of life. Patients with diabetes mellitus (DM) are prone to ED due to various factors, including vasculopathy, neuropathy and sex hormone abnormalities. This is a retrospective study involving 1,511 patients taking sildenafil. Patients with DM have significantly more comorbidities like hypertension and ischaemic heart disease. They are also more likely to be on medications which may affect erectile function, including various antihypertensive drugs. 77.9% of patients with DM reported success with sildenafil, as compared to 86.5% of patients without DM. A significant number of patients with DM require a higher dose of sildenafil as compared to those without DM.

Clinical efficacy and safety of sildenafil citrate (Viagra) in a multi-racial population in Singapore: A retrospective study of 1520 patients.

BACKGROUND: Sildenafil citrate (Viagra), a selective inhibitor of cGMP-specific phosphodiesterase type-5, has been used as an oral therapeutic drug for erectile dysfunction. The present paper is a clinical study of the success rate and side-effects of the use of sildenafil in a multi-racial population in Singapore. METHODS: From April 1999 to May 2000, 1520 patients were given sildenafil citrate. Of these, 912 patients (mean age, 54.6 years; age range, 22-99 years) were followed up and evaluated for clinical efficacy and safety of the drug. The mean duration of erectile dysfunction (ED) and follow-up periods were 31.5 and 3.0 months, respectively. RESULTS: Satisfactory erections assessed by single global efficacy question (GEQ) occurred in 83% of patients, major side-effects in the form of flushing (3.48%), headache (1.97%), blurred vision (1.25%), giddiness (1.18%), warmth (1.11%) and others (4.92%) were recorded in 127 patients (13.9%). Racially, Chinese men with ED had higher efficacy (85.7%), compared to Indian men (74.2%) and Malay men (72.8%). With respect to comorbid profiles, an efficacy of 77.8% (n = 271), 83.9% (n = 292), 86.4% (n = 44) and 83.3% (n = 199) was recorded in diabetic, hypertensive, ischemic heart disease patients and in benign prostatic hyperplasia patients, respectively. Patients who smoked (n = 135) and drank alcohol (n = 118) showed an efficacy of 80%. Baseline hormonal profiles of luteinizing hormone, follicle stimulating hormone, testosterone and prolactin did not affect the success rates of sildenafil citrate. Many patients had earlier received other forms of treatment (medicated urethral suppository for erection (MUSE; 84.9%); vacuum devices (86.8%), traditional medicines (100%) and other oral medications (89.2%)), but this did not influence the success rate of sildenafil citrate. But patients previously treated with prostaglandin-E intracavernosal injections were less successful on sildenafil citrate (77.3%). In the total cohort, 50 mg sildenafil citrate was an effective dose in 49% of patients and 46.5% patients needed 100 mg sildenafil citrate, while 4.1% of the total cohort needed only 25 mg sildenafil citrate. CONCLUSION: Oral sildenafil citrate has been shown to be an effective, safe and well tolerated drug in Singaporean men with ED, as in men from other parts of the world.