Factor-D inhibitor ACH-4471 poised for trials in man
The Factor D program, which targets complement-mediated diseases, was initiated in house through Achillion’s own research platform as a therapeutic target holding promise in a variety of ultra-rare diseases and serious conditions. A validated and druggable target, Factor D’s low plasma concentration enhances the target value, which is amenable to potent inhibition by small molecules. The company held a symposium on its complement Factor D program on 6 December at the ASH, at which time expert speakers presented on complement immune-biology, and relative risks of infection associated with immune modulation of the complement system. Achillion’s chief medical officer, David Apelian (M.D., Ph.D.), profiled the company’s lead small-molecule Factor D inhibitor compound ACH-4471 just before the company filing an IND regulatory package for the drug.
Achillion is initially focusing its research on the orally dosed ACH-4471 in PNH, a disease caused by the deficiency of complement-regulated proteins CD55 and CD59. The only approved treatment for PNH is Alexion’s Soliris, or eculizumab, (2014 sales $2.2bn), which has significant limitations including intravenous administration, a black box warning of serious meningococcal infections, while ~25% of patients have suboptimal response to the treatment due to partial protection. Achillion aims to provide consistent and potent inhibition of complement for all PNH patients. A Phase I single and multi-ascending dose study is planned in healthy volunteers for initial investigation of safety and pharmacokinetics and will begin in the coming weeks once the company receives a green light on its regulatory submission. A Phase Ib/IIa proof of concept trial is also planned in 2016 in multiple ascending doses (seven to 14 days) in treatment-naïve PNH patients whereby a marker of hemolysis – lactate dehydrogenase (LDH) – will be used to establish efficacy. The oral ACH-4471 compound will also begin Phase I trials in one other yet to be disclosed ultra-rare disease in H216. Achillion reports its overall portfolio of Factor D inhibitors looks to be potent and highly specific with early safety assessments, including repeat-dose toxicity studies, supporting clinical development. Research is ongoing with distinct new chemical entities (NCEs) in indications with varied patient population sizes, including dry age-related macular degeneration (AMD), chronic obstructive pulmonary disease, myasthenia gravis and atypical haemolytic uremic syndrome (aHUS). Additional compounds undergoing evaluation are capable of alternative routes of administration including ocular and inhalation.
Exhibit 1: Select complement-mediated diseases
Disease |
Characteristics |
Epidemiology (prevalent population US/EU-5) |
Current treatment (approved and/or supportive care) |
PNH 1,4 |
Acquired: rare form of hemolytic anemia |
8,000-10,000 |
Eculizumab RBC transfusion |
aHUS1-3 |
Commonly genetic: thrombocytopenia |
2,000-3,000 |
Eculizumab RBC transfusion |
Myasthenia gravis 5,6 |
Autoimmune: neuromuscular junction (NMJ) destruction and muscle weakness |
80,000-100,000 |
Cholinesterase inhibitors, steroids, immunosuppression |
Dry AMD (geographic atrophy, GA) 1,3,7-10 |
Complex and multifactorial; loss or atrophy of retinal pigment epithelium |
2,000,000-3,000,000 |
No treatments (prophylactic only) |
Two clinical studies underway by Janssen in Hep-C
Achillion, through its partner Janssen, is moving forward with the development and commercialization of a short-duration, highly effective, pan-genotypic Hep-C treatment, aiming to initiate Phase III development in the early part of next year. The link up with Janssen has increased the odds of marketing the first triple combination – NS5A, NS3 and nucleotide polymerase – and best-in-class Hep-C treatment serving to firm up Achillion’s positioning in Hep-C by adding multiple options for combination (see Exhibit 2 below), enabling many shots on goal. Janssen brings two additional Hep-C candidates for inclusion in the potential triple regimen: NS5B polymerase inhibitor ALS-335 and the already approved NS3/4A protease inhibitor (PI), Olysio or simeprevir, both of which are included in trials currently underway. Notably, both milestones and royalties will be paid on any regimen containing any one Achillion compound.
The following studies have been initiated by Janssen since its acquisition in mid-2015 of the worldwide licensing rights to three Hep-C drugs in the Achillion portfolio:
■
A Phase 1 drug-drug interaction study in healthy volunteers with a triple DAA (direct acting antiviral) regimen assessing the combination of Achillion’s odalasvir (ACH-3102) with Jansenn’s simeprevir, and ALS-335.
■
Dosing of patients in a Phase IIa ~60 patient clinical trial for treatment-naïve genotype 1 chronic HCV with a once-daily combination of odalasvir (ACH-3102), simeprevir, and ALS-335 with randomized treatment durations of eight, six, or four weeks. The study’s primary endpoint is safety, while secondarily the trial will study pharmacokinetics, SVR and viral resistance.
As indicated by the companies, Olysio’s status as a currently marketed PI could allow for an accelerated time to commercialisation for the triple regimen (and Olysio is therefore being pursued as a component in the mix). Olysio was previously heavily prescribed with Gilead’s Sovaldi before Gilead’s launch of Harvoni (Ledipasvir/Sofosbuvir NS5B polymerase inhibitor) in late 2015.
In the meantime in H215 Achillion also announced positive confirmatory results in a second cohort of its Phase II proxy study evaluating its own NS5A inhibitor, odalasvir (ACH-3102) and Gilead’s sofosbuvir for genotype 1 HCV. The company reported 100% SVR12 (HCV undetectable after 12 weeks) in the second cohort of patients treated for just six weeks, which followed on to previously announced SVR24 in two earlier cohorts receiving eight and six weeks of therapy.
Exhibit 2: Hep-C triple regimens NS5A+nuc+PI
Achillion and competitor triple combination regimens |
|
|
NS5A inhibitor |
NS5B polymerase inhibitor (nuc) |
NS3/4A protease inhibitor |
Achillion with Janssen |
ACH-3102 (A) |
ACH-3422 (A) ALS-335 (J) |
Sovaprevir (A) Olysio/Simeprevir (J) |
Gilead |
Ledipasvir GS-5816 |
Sofosbuvir |
GS-9857 |
Merck |
MK-8408 |
MK-3682 |
Grazoprevir |
Source: Achillion Pharmaceuticals
.