ACHN 2017 Annual Report

ACH-4471 with the objective of optimizing trough exposures and reducing dosing frequency. We initiated a phase I bio-availability assessment of a series of controlled release formulation systems in healthy volunteers in 2017 and plan to complete our feasibility assessment of these formulations in 2018. • Safety . Six-month and nine-month toxicology studies testing the effects of ACH-4471 in rats and dogs, respectively, have been completed and supported progression of ACH-4471. In single-ascending and multi-ascending dose phase I clinical trials in healthy volunteers, at doses ranging from 75mg three times daily to 200mg, 500mg, 800mg, and 1200mg twice daily, ACH-4471 has been generally well tolerated with no treatment-related serious adverse events reported. In the multi-ascending dose 14-day phase I clinical trial, two cases of self-limited, alanine aminotransferase, or ALT, elevations (Grade 3 and 4) were observed post-treatment at doses of 500mg and 800mg twice daily, respectively, with neither subject exhibiting signs or symptoms of hepatic decompensation. Both subjects’ ALT levels normalized without intervention during follow-up. Further, no treatment-associated fever or infections were observed. In an on-going dose ranging phase II clinical trial in PNH patients, doses start at 100mg or 150mg three times daily, or TID, with allowance for intra-patient dose escalation. To date, 225mg TID has been the highest dose administered. In August 2017, we announced that interim data from this trial showed that to date a favorable tolerability profile had been observed with no reports of clinically meaningful increases in liver enzymes. Three of the four patients we reported on in August 2017 continue to be dosed in this phase II clinical trial, including two who have been on therapy with ACH-4471 for longer than nine months and one who has been on therapy for longer than six months, with ACH-4471 showing a good tolerability profile and normal liver enzyme levels. • Efficacy . ACH-4471 has been demonstrated to be highly specific for inhibition of factor D, a protein critical to the amplification of the complement system. After oral administration of ACH-4471 in phase I clinical trials in healthy volunteers, we noted complete suppression of alternative pathway activity to 24 hours post-dosing. C3G & IC-MPGN. We initiated a phase II clinical trial of ACH-4471 in patients with either C3G or IC-MPGN in September 2017 and we continue to add additional clinical trial sites and enroll patients. A sentinel group of two patients received an initial dose of 100mg TID for a period of 14 days with a 7-day taper period. Subsequent groups of patients are being dosed at 200 mg TID. This clinical trial is designed to measure C3, a complement protein in blood plasma that is typically low in C3G and IC-MPGN patients, as well as other measures of kidney function or damage characteristic of C3G and IC-MPGN. Preliminary data from this 14-day phase II trial suggest that ACH-4471 may reverse the alternative pathway hyperactivity in C3G based upon the observed improvements in the first two sentinel patients in complement biomarkers and proteinuria following 14 days of treatment with ACH-4471. In both sentinel patients, the primary clinical manifestation was significant proteinuria, or protein in the urine. In both cases, a greater than 50% reduction in proteinuria was observed during the treatment period. We also plan to conduct a phase II open-label, 12-month treatment trial for patients with biopsy- confirmed C3G or IC-MPGN in which patients will receive treatment with ACH-4471 with periodic assessment of clinical endpoints including proteinuria and estimated glomerular filtration rate, or eGFR. Patients from our 14-day phase II clinical trial in C3G will be eligible to continue therapy under this protocol after a wash-out period. We also plan to conduct a phase II randomized, placebo-controlled, double-blinded 6-month trial for patients with biopsy-confirmed C3G. This trial is expected to assess post-treatment renal biopsy findings, as well as changes in complement biomarkers, and clinical endpoints such as proteinuria and eGFR. We anticipate initiating each of these trials in the first half of 2018. PNH. A phase II clinical trial of ACH-4471 in patients with PNH is on-going and continues to enroll untreated PNH patients. To date, four PNH patients have been treated, three of whom have 4