Sign up to SCR Digest, our FREE weekly newsletter, and receive our Notes emailed directly to you.
Email Address *
First Name
Mailing Lists *

AMBS: Amarantus Receives Orphan Drug Designation for MANF in Retinitis Pigmentosa


By Jason Napodano, CFA


According to the U.S. FDA's Website, Amarantus BioScience Holdings, Inc (OTC:AMBS) preclinical drug candidate, human recombinant mesencephalic astrocyte derived neurotrophic factor (MANF), was granted an Orphan Drug designation for the treatment of Retinitis Pigmentosa (RP) on December 22, 2014. Amarantus confirmed the news via a press release this afternoon. In the U.S., an Orphan Indication is one that affects fewer than 200,000 people or has a prevalence rate of less than 5 per 10,000 in the community. As a result of MANF being designated as an Orphan Drug, Amarantus is now entitled to certain R&D tax credits equivalent to 50% of the qualified clinical testing expenses for development, a waiver of PDUFA fees, access to government grants and contracts totalling $30 million per year, and seven years of market exclusivity post approval for the target indication. 

The news on MANF receiving Orphan Drug designation comes 67 days after the company announced they filed the application with the FDA - one of the fastest turnarounds we recall in recent years. We believe the quick turnaround by the agency was due to a combination of factors, including a wealth of available scientific literature and preclinical data on MANF and a clear Orphan market well below the upper limit of the FDA's threshold.

Background On RP

Retinitis Pigmentosa is a rare inherited, degenerative eye disease that causes severe vision impairment. Onset can be rapid and often leads to blindness. The disease is characterized by loss of the light sensing photoreceptor cells that line the back of the eye. In fact, diagnosis of RP relies upon documentation of progressive loss in photoreceptor cell function by electroretinography (ERG) and visual field testing. Usually the rod photoreceptors (responsible for night vision) are affected first, which is why loss of night vision (nyctalopia) is usually the first symptom. Loss of daytime vision, mediated by the cone photoreceptors, is usually preserved until the late stages of the disease. According to the American Society of Retina Specialists, RP affects about 80,000 Americans.

There is no cure for RP. Current treatment options include a combination of nutritional supplements and retinal implants. For example, the progression of the disease can be reduced by the daily intake of 15,000 IU (equivalent to 4.5 mg) of Vitamin A (Berson, E.L., 1993). In fact, recent studies have shown that proper vitamin A supplementation can postpone blindness by up to 10 years (Berson, E.L., 2007). Retinal implants, such as the Argus II Prosthesis System, have recently received approval in the U.S. The device may help adults with RP who have lost the ability to perceive shapes and movement to be more mobile and to perform day-to-day activities.

Background On MANF

MANF is an evolutionary conserved neurotrophic factor expressed in response to endoplasmic reticulum (ER) stress. Increase in endogenous MANF occurs in response to cerebral ischemia and epileptic insults in the hippocampus and in the cerebral cortex (Lindholm P, et al, 2008). MANF is expressed in many human tissues and by virtue of its autocrine / paracrine growth factor function may display anti-apoptotic activities in a broad range of neuronal and non-neuronal target tissues. For example, MANF has been shown to offer selective neuroprotection of dopaminergic neurons (Petrova PS, et al, 2004) by modulating GABAergic transmission in the substantia nigra (Zhou C, et al, 2005). This lead to initial animal work studying the molecule in Parkinson's Disease (Voutilainen M, et al, 2009). Animal research has also shown the potential utility of MANF in improving neurological and motor activity post stroke (Airavaara M, et al, 2010).

...Initial Data In Ocular Disease, Retinitis Pigmentosa...

Back in August 2013, an abstract (#2581) was presented by Wen et al from the University of Miami's Bascom Palmer Eye Institute at the Association for Research in Vision and Ophthalmology annual conference held back in May 2012. The abstract was titled, "Mesencephalic Astrocyte-derived Neurotrophic Factor Protects Rod and Cone Photoreceptors from Degeneration in Transgenic Rats Carrying the S334ter Rhodopsin Mutation."

The purpose of the study was to examine the neuroprotective effects of MANF on photoreceptors. In the study, recombinant human MANF (6 µg) was intravitreally injected to the left eyes of transgenic (S334ter) rats. The right eyes were injected with a phosphate buffered saline (PBS) control. Eyes were collected 12 days later and examined by light microscopy. To examine the effect of MANF on cone photoreceptors, MANF (6 µg) was injected intravitreally to the left eyes of the transgenic rats, and the right eyes were injected with PBS as controls. Retinas were collected ten days later and cone outer segments were stained with Alexa-488 conjugated peanut agglutinin (PNA). Flat-mounted retinas were examined by confocal microscopy.

Results with MANF suggest significant protection of rod photoreceptors. For example, in MANF-treated retinas, three to four rows of nuclei remained in the outer nuclear layer (ONL), as compare to only one row of nuclei in PBS-treated fellow eyes. The thickness of ONL in MANF-treated retinas (superior region) (17.47±3.96 µm, mean±SD, n=5) is significantly greater than that in PBS-treated retinas (7.07±1.12, n=5) (P < 0.001, student t-test). Loss of cone outer segments was characterized by many PNA-negative areas distributed across the retina in PBS treated retinas, as reported previously. In RdCVF treated eye, however, the PNA negative areas became much smaller or in many cases completely disappeared. Quantitative analysis showed that PNA-positive cells are significantly more in MANF treated retinas (569.5±46.5/0.1 mm2, mean±SD, n=6) than in PBS-treated retinas (398.7±25.4, n=6) (P< 0.001, student t-test).

Transgenic S334ter rats were created to model retinal degeneration. They are commonly used for preclinical testing in RP and macular degeneration. The data presented at ARVO above demonstrates that intravitreal injection of recombinant human MANF protein protects both rod and cone photoreceptors from degeneration, thus offering potential utility in RP, along with other degenerative eye disease such as macular degeneration. Two additional models showing the utility of MANF in RP have also been presented, a photoreceptor-specific transcription factor model called Crx-tvrm65 and a protein complex model called Rd1-RP. Both models demonstrated reduced TUNEL+ cells and preserved ONL thickness in the eye.
...Recent Presentation At Ocular Disorders 2014...

In October 2014, animal data on the use of MANF in ocular disorders was presented by Roman Urfer, PhD, at the Targeting Ocular Disorders (TOD) conference in Boston, MA. The presentation, "MANF - A Novel Neurotrophic Factor for the Treatment of Retinal Disorders," demonstrated that MANF provided positive protective functional effects in animal models of central retinal vein occlusion (cRVO), as well as central retinal artery occlusion (cRAO) and glaucoma.

The study was designed to evaluate the efficacy of MANF intravitreal injection after an optic nerve ischemia/reperfusion injury in albino rats, as well as gain a better understanding of the MANF dose/effect relationship. Data presented at the conference show that a single intravitreal administration of MANF in rats with ischemia-related optic nerve damage resulted in a statistically significant protective effect of MANF on retinal function, compared to control animals, as measured by B-wave amplitude electroretinogram (ERG) at day 7. Note the positive control was Allergan's Alphagan, a franchise that generated roughly $500 million in global sales in 2013.

The study also showed that MANF effects in the retina mirror the dose-effect relationship observed for MANF in models of Parkinson's disease. Additionally, MANF dose levels were significantly lower than the equivalent dose used in the recent rabbit ocular tolerability study, thereby establishing a preliminary safety margin for MANF in the treatment of optic nerve ischemia.
Targeting Additional Ocular Orphan Indications With MANF
On December 19, 2014, Amarantus filed a second Orphan Drug application for MANF in Retinal Artery Occlusion ("RAO"). RAO is a rare eye condition caused by a loss of blood supply to the inner layer of the retina resulting in acute and often severe vision loss. RAO is further classified as central or branch retinal artery occlusion, respectively, depending on the location of the occlusion. The currently-available treatments are aimed at opening the occluded artery before irreversible damage occurs and most often do not improve visual acuity above natural history. There are no effective neuroprotective agents for the treatment of acute retinal ischemia available. According to Jain & Juang, 2009, the incidence of retinal artery occlusion in the U.S. is 0.85 per 100,000 per year, with a 10-year cumulative incidence of retinal emboli of between 1% and 2%. The mean age at onset is about 60 years (Duker, 2003). The target population in the U.S. is between 10,000 and 15,000 individuals.

Another potential orphan indication for MANF is in Wolfram’s Syndrome (WS), an ultra-rare disorder resulting from pituitary gland dysfunction and a shortage of insulin in the body. Symptoms include high blood sugar levels (diabetes mellitus) and progressive vision loss due to degeneration of the nerves that carry information from the eyes to the brain (optic atrophy). Hearing loss is another common manifestation of the disease. Amarantus believes that conducting small clinical studies and generating proof-of-concept data in WS may facilitate partnering opportunities in Type-1 diabetes. But we believe potential applications with MANF in ocular manifestations of the disease make MANF a very attractive potential candidate for WS as well.

The company secured additional intellectual property around MANF in WS from the University of Massachusetts Medical School in December 2013. In June 2014, Amarantus entered into research collaboration with the Washington University School of Medicine to evaluate the efficacy of MANF to treatment WS-induced blindness in animals.


Regardless of the specific indication, it is clear that ocular diseases have become the leading area of focus for Amarantus with MANF. The market exclusivity and strong pricing power conferred by the granting of a U.S. FDA Orphan Drug destination in RP make things attractive from a partnering standpoint. Amarantus has another application pending in RAO, and we suspect that WS-induced blindness is yet another pending application scheduled for 2015.

Companies that are marketing drugs targeting ocular diseases include Regeneron, Sanofi, Novartis/Alcon, Pfizer, Roche, Bayer, and Santen. We believe any one of these companies may be interested in an early-stage research collaboration with Amarantus around MANF. Beyond Orphan indications, MANF may also show utility in Glaucoma. Glaucoma affects approximately 4 million people in the U.S. alone. It's a $3 billion market. Data presented at AVRO and TOD provide the basis for moving MANF into human clinical studies in 2015. This creates a very interesting development pathway for Amarantus and a potential development partner - i.e. secure market exclusivity and aggressive pricing with Orphan Drug indications such as RP and RAO, then expand the approval to blockbuster markets like Glaucoma.

The company is currently wrapping up translational development and preclinical toxicology work on MANF prior to filing the first investigational new drug (IND) application to being human clinical studies next year. If Phase 1 clinical studies go well with MANF in RP, we expect the company to expand research into new indications and seek a larger development and commercialization partner that would come with a handsome upfront payment and backend milestones and royalties.

SUBSCRIBE TO ZACKS SMALL CAP RESEARCH to receive our articles and reports emailed directly to you each morning. Please visit our website for additional information on Zacks SCR and to view our disclaimer.

User ID:
Remember my ID: