William Querbes's research while affiliated with Alnylam Pharmaceuticals and other places

Background and aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and results: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

Background Induction of delta aminolevulinic acid synthase 1 (ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis. Methods We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of body weight) or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated. Results A total of 23 patients in parts A and B and 17 patients in part C underwent randomization. Common adverse events included nasopharyngitis, abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point). Conclusions Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372.)

Objective: Acute intermittent porphyria is a rare metabolic disorder that affects heme synthesis. Patients with acute intermittent porphyria may experience acute debilitating neurovisceral attacks that require frequent hospitalizations and negatively impact quality of life. Although clinical aspects of acute intermittent porphyria attacks have been documented, the experience of patients is not well known, particularly for those more severely affected patients who experience frequent attacks. The aim of the present study was to qualitatively characterize the experience of patients with acute intermittent porphyria who have frequent attacks, as well as the impact of the disease on daily living. Methods: Patients with acute intermittent porphyria who experience frequent attacks were recruited and took part in 2-h qualitative one-on-one interviews with a semi-structured guide. Interviews were anonymized, transcribed, and coded. The inductive coding approach targeted textual data related to acute intermittent porphyria attack symptoms, chronic symptoms, and the impact of the disease. Saturation analysis was conducted to assess whether the research elicited an adequate account of patients' experiences. Results: In total, 19 patients with acute intermittent porphyria were interviewed (mean age 40 years; 79% female). Eighteen patients (95%) experienced both attack and chronic symptoms. Patients described attacks as the onset of unmanageable symptoms that generally lasted 3-5 days requiring hospitalization and/or treatment. Pain, nausea, and vomiting were considered key attack symptoms; pain, nausea, fatigue, and aspects of neuropathy (e.g., tingling and numbness) were considered key chronic symptoms. Conclusions: In this study population of acute intermittent porphyria with frequent attacks, most patients had symptoms during and between attacks. In these patients, acute intermittent porphyria appears to have acute exacerbations as well as chronic day-to-day manifestations, and is not just intermittent as its name implies. As a result, patients reported limitations in their ability to function across multiple domains of their lives on a regular basis and not just during acute attacks.