QPI-1007, an siRNA targeting the gene Caspase 2, is a neuroprotective drug candidate in development for non-arteritic anterior ischemic optic neuropathy (NAION) and other optic neuropathies. Following type C meeting with the US FDA, Quark initiated a global Phase III pivotal clinical study for the treatment of NAION. The study is performed in collaboration with Quark’s licensee in China – RiboQuark, Quark’s joint venture company with Suzhou Ribo Life Science Co., Ltd (Ribo), and in India – Biocon. QPI-1007 has been granted orphan drug designation by the FDA.

The drug candidate

QPI-1007 is a double-stranded chemically-modified, synthetic small interfering RNA (siRNA) targeting the mRNA of the caspase 2 gene and is designed to temporarily inhibit the expression of caspase 2 via the RNA interference (RNAi) pathway. The chemically modified structure of QPI-1007 was developed internally by Quark and is covered by Quark’s patent applications. The compound is designed to allow high, specific RNAi activity while attenuating off-target and immunostimulatory effects. QPI 1007 is being developed as a neuroprotectant for the treatment of non-arteritic ischemic optic neuropathy (NAION) and other optic neuropathies such as glaucoma that result in the death of retinal ganglion cells (RGCs). QPI-1007 has been granted orphan designation by the FDA for the indication of NAION.

Apoptosis (programmed cell death) is thought to be the main cause of the death of retinal ganglion cells (RGCs) following ischemic injury in non-arteritic anterior ischemic optic neuropathy and other optic neuropathies including glaucoma. Caspase 2 is a member of a family of pro-apoptotic peptidases that is uniquely positioned in the apoptosis pathway integrating receptor-induced and mitochondrial apoptosis. Animal studies of QPI-1007 demonstrated (i) caspase 2 activation in RGC; (ii) uptake of siRNA in retinal ganglion cells following intravitreal administration, (iii) RNAi-mediated mechanism of action of QPI-1007 in ocular tissues harvested after intravitreal administration and (iv) efficacy of QPI-1007 in four animal models involving RCG loss (Ahmed Z, et al, Cell Death Dis. 2011 Jun 16;2:e173PMID:21677688; Vigneswara V et al, Brain. 2014 Jun;137(Pt 6):1656-75.. Epub 2014 Apr 10. PMID:24727569; Lidster K et all PLoS One. 2013 Nov 4;8(11):e79188) . QPI-1007 exhibited a favorable safety profile in toxicity studies.

Previous clinical studies

QPI-1007 has been evaluated in the first in-human, open-label, dose escalation, Phase I/IIa study (Protocol QRK007 NCT01064505 ), delivered by single intravitreal injection to Optic Nerve Atrophy patients with low visual acuity and thereafter in acute NAION patients in Stratum II. The study was conducted at 22 sites in the US and 6 sites in Israel. This study has been completed. QPI-1007 was also evaluated in a Phase IIa double-masked randomized sham controlled trial (Protocol QRK208 NCT01965106), delivered by a single IVT injection to subjects with acute primary angle-closure glaucoma
In the Phase I/IIa NAION study, a single intravitreal injection of QPI-1007 was well tolerated in subjects with long-standing low vision or acute NAION.
No study subject lost 3 or more lines of visual activity at Months 6 after a single intravitreal injection. Only one subject, out of 30 included in the study, lost 3 or more lines of visual acuity at Month 12. This result is in contrast to available historical data that show 15-20% of subjects lose 3+ lines of visual acuity at 6 months (e.g. Hayreh SS, Zimmerman MB. (IONDT) Ophthalmology. Feb 2008;115 (2):298-305 e292.).

Non Arteritic Ischemic Optic Neuropathy

Ischemic optic neuropathy (ION) is an optic neuropathy that includes a variety of disorders associated with ischemia of the optic nerve. The more common form of ION is anterior ischemic optic neuropathy (AION), which is the result of disturbances in blood flow through the posterior ciliary arteries leading to ischemic injury of optic nerve axons in the optic nerve head and subsequent loss of retinal ganglion cells (RGC)s. of the two types of AION, non-arteritic AION (NAION) is the most common cause of sudden optic nerve-related vision loss in patients over age of 50. NAION is episodic in nature with acute onset and causes painless and unilateral visual loss that results from overall poor circulation, thromboses or embolisms. Once vision is lost, there is little chance to fully regain it (Hayreh SS, Podhajsky PA, Zimmerman B. Am J Ophthalmol. 2001 Nov;132(5):734-42. PM:11704035). 15% of patients with NAION develop the disease in the fellow eye within 5 years [Newman N, Scherer R, Kelman S, et al. Am J Ophthalmol.2002;134:317–28.) The reported incidences of NAION in the US are 2.3 -10.3 per 100,000 persons over the age of 50 (Johnson LN, Arnold AC (1994). J Neuroophthalmol 14: 38-44, Hattenhauer MG, Leavitt JA, Hodge DO, Grill R, Gray DT. Am J Ophthalmol. 1997 Jan;123(1):103-7. PM:9186104)

There is a general lack of therapies for most optic neuropathies. Many of these, including NAION , are unmet medical needs. NAION represents an unmet medical need. Currently there are no approved therapies for NAION and no secondary prevention of NAION.Optic neuritis is managed by corticosteroids, which does not affect the long term course of the disease. There is an unmet need for a neuroprotective agent to avoid or reduce vision loss by preserving RGCs. Similar to the optic neuropathy of NAION, glaucoma can result in loss of RGCs and resultant vision loss if untreated . While glaucoma is treated in part by lowering intraocular pressure,many patients continue to demonstrate clinical loss despite control of initially raised IOP.