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Discovery & Development Drug Delivery, Clinical Trials, Formulation

A Matter of Cellular Integrity

The process of normal wound healing is complex, relying on an exquisitely choreographed interaction between a variety of bioactive proteins and other factors. When wound healing goes awry, conventional “one-drug, one-target” approaches have struggled to restore the intricate balance. 

But back in the 1970s, scarless fetal wound healing was first observed following in utero surgeries as a treatment for spina bifida. The phenomenon has been attributed to the numerous growth factors and cytokines secreted by the amnion epithelial cell layer of the placenta; notably, fetal skin contains a higher ratio of collagen type III to collagen type I compared with adult skin. The findings pointed to powerful wound healing capabilities, and scientists soon began to investigate numerous components of the fetal environment. 

Not surprisingly, there has been significant interest in fully harnessing these healing properties for therapeutic uses. For example, Noveome Biotherapeutics is developing a novel platform biologic, ST266, as a therapeutic for diverse disease indications. ST266 is a cell-free biologic secreted by a novel population of select amnion-derived epithelial cells, which have been collected from full-term placentas that are normally discarded after birth. These cells are cultured using a proprietary method and produce many of the biological factors found in amniotic fluid that may be responsible for the remarkable healing capabilities and lack of scarring observed following in utero fetal surgery.

Here, we speak to Noveome’s Larry Brown, Executive of Research & Development/Chief Scientific Officer and Randall Rupp, Executive Vice President of Manufacturing and Development, to find out more about the clinical-stage company and its objectives.

What does Noveome hope to achieve?

Larry Brown: In short, we’re focusing on biotherapeutics for the promotion and restoration of cellular integrity of inflamed or damaged tissues. Our lead candidate is ST266, which contains hundreds of biologically active molecules, including proteins and other biomolecules. ST266 has potential in a number of therapeutic areas including neuro-protection, ophthalmology, brain injury and dermatology. Many of these conditions currently have no or limited therapeutic options, in part because they are often too complex to be treated with traditional “one-drug, one-target” therapies. Our results thus far are exciting and may lead to promising treatments for currently underserved patients.

What are the key events in the evolution of Noveome?

Randall Rupp: In the company’s early days, we sent the cells from which ST266 would ultimately be derived to different labs to see what effect they would have in their model systems. The Walter Reed Army Institute of Research was among one of the first institutions that we partnered with, testing our product in traumatic brain injury models in rats. In their experiments, they inserted and inflated balloon catheters into the brains of these animals so that they lost their ability to walk. When our cells were introduced, they regained their motor ability and the rats’ brain tissue underwent healing. Interestingly, they found that if the cells were introduced on the opposite side of the brain from the wound, the wound was still repaired, indicating that it was the secreted product of the cells rather than the cells themselves that had the wound healing properties. In other words, the result suggested that the cells were only facilitating the delivery of the secretome to the damaged tissue rather than affecting the wound healing process themselves. And it led us to test the effects of the cell secreted products alone and encouraged us to continue developing ST266.

What main disease areas are you looking into – and what are the challenges?

Brown: Neuro-ophthalmology,brain injury and neurodegenerative diseases are important areas we are focusing on. Injuries and diseases to the brain and related sensory organ structures such as the optic nerve can’t be treated using conventional oral or injectable drug delivery systems. This is because the drugs are either too large or are not capable of circumventing the blood-brain barrier. When we conducted traumatic brain injury studies at Walter Reed Army Institute of Research, ST266 was directly administered into the brain. Yes, we observed positive functional neuroprotective and anti-inflammatory effects; however, direct injection into the brain is extremely invasive and an impractical delivery route. Therefore, we proposed using a targeted intranasal delivery that would be able to bypass the blood-brain barrier. 

We found that when ST266 was administered to the nasal passages in rats, it was absorbed by the olfactory nerves in the very back of the nose. The olfactory nerves penetrate the cribriform plate allowing the ST266 to bypass the blood-brain barrier and be delivered to the optic nerve and brain. However, depositing ST266 to the back of the nose in humans requires a specialized intranasal delivery device. Noveome demonstrated that it could deliver radioactively labeled ST266 to the brain of non-human primates (monkeys) using an intranasal delivery device developed by SipNose LLC, an Israeli medical device company. We observed that the highest ST266 concentration was in the optic nerve.   

The optic nerve deposition led us to explore neuro-ophthalmic conditions. We worked with Kenneth Shindler, Associate Professor of Ophthalmology at the University of Pennsylvania Medical School who is an expert in optic nerve disease. Optic neuritis is inflammation of the optic nerve accompanied by vision loss and is often the presenting symptom of multiple sclerosis. Shindler’s research group demonstrated that intranasal ST266 reversed retinal ganglion cell loss, preserved visual acuity and significantly reduced demyelination of optic nerves in an animal model of optic neuritis.  As a result, we have begun human trials of targeted intranasal ST266 using the SipNose device.

In addition to leveraging this targeted intranasal approach to address “back of the eye” conditions, we have also administered ST266 topically to the eye, skin, and oral mucosa to treat a diverse range of other disease indications. For example, ST266 was shown to help prevent UV light burn damage and reduce the DNA cross-linking associated with UV damage to the skin.

Rupp: It’s also important to consider that there are many ophthalmic disorders whose needs are currently poorly or unmet. For example, currently available products that deliver growth factors to the vitreous of the eye are expensive and require uncomfortable intravitreal injection. We’re also working to address these issues with products in our pipeline. 

What were the most exciting moments for the company in 2019?

Rupp: First,in June 2019, we began a phase two open-label trial for ST266 in patients with persistent corneal epithelial defects (PEDs). PEDs are the loss of the corneal epithelium through mechanical trauma, dryness, neurotropic disease or post-surgical change, especially in patients with medical impairments, such as diabetes. In these patient, promoting healing, reducing scarring, minimizing inflammation and retinopathy remains a clinical challenge. ST266 has been shown to promote corneal healing in rabbit studies. We hope that our ongoing phase II study will show efficacy and tolerability of ST266 in patients with PEDs and ultimately provide a therapeutic option they deserve. Second, in October 2019, we initiated a phase one open-label trial to establish the safety of ST266, when delivered intranasally in patients diagnosed with intraocular hypertension who have not yet developed optic nerve damage. We hope to expand this patient population to include all glaucoma suspects not just intraocular hypertension patients.

And what is Noveome looking forward to?

Brown: There is a lot of exciting research taking place in the biopharma industry as a whole, but in our view it’s important that we keep our focus on disease indications where there is a lack of effective treatment. There are many patients that have spent years feeling neglected by the industry. We’re excited that ST266 could be used for a variety of indications where patients have been underserved. As well as the areas mentioned above, a new focus for us is necrotizing enterocolitis (NEC). NEC is a devastating bacterial inflammatory disease that affects the intestine of premature infants and is the most common gastrointestinal emergency in neonatal intensive care units. The disease occurs in nearly 10 percent of premature infants and has a mortality rate of 32 percent – a rate that has not seen a decrease in the last three decades. We are currently conducting preclinical studies and are hopeful we can someday have an impact on this serious condition.

To date, 238 patients have been treated with ST266 in nine clinical trials in various indications. In all cases, ST266 demonstrated a strong safety profile with no reported drug-related serious adverse events. We are excited about both our current clinical trials and what the future holds for ST266, a remarkable secretome.

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About the Author
Maryam Mahdi

Deputy Editor

After finishing my degree, I envisioned a career in science communications. However, life took an unexpected turn and I ended up teaching abroad. Though the experience was amazing and I learned a great deal from it, I jumped at the opportunity to work for Texere. I'm excited to see where this new journey takes me!

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