PharmaShots Interview: Paul Brennan Shares Insights on NVG-291 and its Interim Data for the Treatment of Neurodegenerative Diseases

In an interview with PharmaShots, Paul Brennan, President, CEO & Director at NervGen shared his views on the interim data of NVG-291 for the treatment of Neurodegenerative Diseases

Shots:

• The P-I clinical trials evaluate NVG-291 vs PBO in healthy volunteers with neurodegenerative diseases such as AD and MS. The interim results were presented at ANA 146th annual meeting
• The interim data from the SAD cohort of the study showed that NVG-291 was well tolerated and had favorable PK properties
• NVG-291 is a PTPσ modulator & has the potential to promote repair mechanisms in the CNS. Additionally, the company is expected to initiate the P-Ib clinical trial for patients with AD in 2022, based on an ongoing P-I safety trial for NVG-291 & will proceed to the MAD portion of the study which is expected to complete in early 2022

Tuba: Tell us more about NVG-291. Discuss its key features, MoA, and its working principle on the treatment of neurodegenerative diseases such as Alzheimer’s disease and multiple sclerosis.

Paul Brennan: NVG-291 originated from the research of Dr. Jerry Silver at Case Western Reserve University. Dr. Silver and his team identified chondroitin sulphate proteoglycans (“CSPGs”) as playing a key role in inhibiting repair following nervous system injury. In collaboration with researchers at Harvard University, Dr. Silver and his team also identified protein tyrosine phosphatase sigma (“PTPσ”) as the receptor through which CSPGs inhibit nervous system repair. His research team then identified a series of peptidic modulators that block CSPG signaling through the receptor, which enables neural repair and functional improvement in animal models. NVG-291 is a very close analog of one of the peptidic modulators identified. 

The key features of NVG-291, and NervGen’s drug development program focusing on PTPσ, are:

• our peptides are the only technology in a company that NervGen is aware of that is being developed to target the PTPσ-CSPG mechanism; modulation of the receptor has multiple pharmacodynamic effects which include enhanced plasticity, axonal regeneration, and remyelination; and
• we have demonstrated functional improvement in six different disease models, crossing the major neurological functions (fine and gross motor function, sensory function, autonomic function, and cognitive function). 

Mechanism of Action – Following an acute injury to the nervous system, such as spinal cord injury (“SCI”), or because of chronic neurodegenerative diseases in the central nervous system (“CNS”), such as multiple sclerosis (“MS”) or Alzheimer’s disease (“AD”), there is a dramatic upregulation in the CNS of a class of molecules called CSPGs. In the short term, CSPGs play a role in containing damage; however, chronically CSPGs inhibit CNS repair mechanisms, including axon regeneration, plasticity, and remyelination. PTPσ was identified as the predominant receptor through which CSPGs mediate their inhibitory effect. NVG-291 is a peptide mimetic that attenuates the inhibitory signaling that would otherwise have been caused by CSPGs binding to PTPσ. Functional efficacy has been demonstrated in animal models of MS, SCI, optic neuritis, cardiac arrythmia associated with heart attack, peripheral nerve injury, and stroke. CSPGs have been shown to be upregulated around sites of CNS damage in several diseases in humans, including AD, MS, and SCI.

Tuba: Highlight your ongoing P-I trial & its design.

Paul Brennan: Our Phase 1 study is currently being conducted on healthy volunteers. The objective of the study is to determine the side effect profile of NVG-291, the maximum dose at which NVG-291 is well tolerated, the pharmacokinetic characteristics of NVG-291, and to set the dose for the subsequent trials in patients. The study is a two-part, triple-blind, randomized, placebo-controlled study. Part one of the study was the single ascending dose (“SAD”) portion, which has now been completed. Pending successful review of the SAD data by the ethics review committee, NervGen will proceed to the second part of the study, which is the multiple ascending dose (“MAD”) portion, where subjects will be dosed with NVG-291 once a day for 14 consecutive days. The study is being conducted under a partial clinical hold by the U.S. Food and Drug Administration (“FDA”) as they await results from additional preclinical studies that have been requested. Under the partial clinical hold, the SAD portion of the study is limited to females and the MAD portion of the study will be conducted in post-menopausal females. Following completion of the preclinical studies requested by the FDA, NervGen intends to apply to the FDA to remove the partial clinical hold and will then conduct bridging studies in healthy volunteers to include males and premenopausal females. 

Tuba: Discuss in detail about clinical/preclinical results of NVG-291.

Paul Brennan: NVG-291 has been studied in multiple in vitro and in vivo studies, showing functional benefits in animal models of SCI, peripheral nerve injury, MS, optic neuritis, stroke, and acute myocardial infarction. The results in each of the models are as follows: 

1. Spinal cord injury: In rat models of SCI, in which animals were treated with a subcutaneous (“s.c.”) dose once a day for 7 weeks, statistically significant improvements compared to control animals were seen in fine and gross motor function, sensory function (pain and temperature) and autonomic function (bladder control). In some cases, the amount of recovery was dramatic, including some animals that almost improved to full motor function following severe injury (Lang et al., Nature, 2015; Rink, S. et al., Experimental Neurology 309, 148–159 (2018)). 
2. Peripheral nerve injury: In rat models of peripheral nerve injury, in which animals were treated with an s.c. dose once a day for 3, 6, or 12 weeks, statistically significant improvements compared to control animals were seen in motor function, motoneuron survival and regeneration, as well as a reduction in muscle atrophy and a reduction in electromyography abnormalities (Li, H. et al., Scientific Reports, 5, 1–14. (2015); Lv, S.Q. et al., Neural Regen Res, 16, 1598. (2021)). 
3. Multiple sclerosis: In MS models, where myelin in the spinal cord has been damaged with a detergent, lysophosphatidylcholine (“LPC”), animals treated with NVG-291 have a more rapid and complete recovery of myelin compared to non-treated animals. The recovery in myelin is accompanied by a restoration of nerve conductance. In the experimental autoimmune encephalomyelitis (EAE) model, NVG-291 treatment initiated either at symptom onset or when symptoms are fully developed promoted functional recovery in motor control (Luo, F. et al., Nature Communications, 9, 1–16. (2018)).  
4. Optic neuritis: Following lysolecithin/ LPC lesion of the optic chiasm, mice treated with an s.c. dose once daily for 3, 7, or 14 days showed statistically significant improvements in in-depth perception and enhanced visual signal conductance, as well as increased remyelination compared to control (Niknam, P. et al., Molecular and Cellular Neuroscience, 99, 103391. (2019)).
5. Stroke: In the middle cerebral artery occlusion (MCAo) mouse model of stroke, animals treated with NVG-291 once daily for 28 days showed statistically significant enhanced axonal sprouting around the lesion and in the spinal cord, along with statistically significant improvements in spatial learning and memory, and in sensory and motor function (unpublished data provided by Dr. Agnes Luo, University of Cincinnati).   
6. Myocardial infarction: In a mouse model of acute myocardial infarction, in which animals were treated with an intraperitoneal dose of NVG-291 once a day for 11 days, statistically significant sympathetic reinnervation of the heart lesion was observed along with higher levels of norepinephrine in the lesion of treated animals compared to control. A statistically significant reduction in arrhythmias was also seen in treated animals compared to control (Gardner, R.T. et al., Nature Communications, 6, 6235. (2015)).   

NervGen recently presented the following data from the SAD cohort of our Phase 1 clinical trial at the Society for Neuroscience’s Neuroscience 2021 conference:

1. 37 subjects have been dosed in the trial; 
2. side effects were mild and transient, with the most common being injection site-related events;
3. no effects on vital signs, electrocardiograms, or laboratory assessments;
4. NVG-291 has been administered and was well tolerated in doses as high as 0.864 mg/kg (170% higher than the equivalent highest dose in our efficacy studies and >100x higher than the lowest efficacious dose seen in studies); 
5. NVG-291 was rapidly distributed in the blood (Tmax was ~10-45 minutes);
6. the calculated half-life of NVG-291 was longer in humans compared to rodents; and
7. NVG-291 was detected in the blood up to 12 hours post-dose.

Tuba: What makes NVG-291 different from other drugs in development in neurological disorders? 

Paul Brennan: There are multiple factors that differentiate NVG-291 from other drugs in development for neurological disorders.

• NVG-291’s mechanism of action works through repairing and restoring neurological function. Most other drugs in development in the CNS space are focused on slowing the progression of the disease, and most neurological diseases are very slowly progressing. With this differentiated approach, we should see a quicker response, and that response should be seen with fewer patients. 
• Whereas most drugs in development have only one pharmacodynamic response, NVG-291 has a multi-modal mechanism of response (axon regeneration, increased plasticity, remyelination). 
• The scope, pattern, and magnitude of response seen in functional studies with NVG-291 are broad and deep compared to other products in development. For example, firstly, NervGen believes it has the potential to be effective in any disorder where there is damage to the nervous system, whether acute or chronic. Secondly, NVG-291 demonstrates pharmacological activity across the major neurological functions (autonomic function, sensory function, cognition, and motor control). And thirdly, in some experiments, such as SCI, the magnitude of response seen with NVG-291 treatment has never been seen before. 

Tuba: Are you planning to explore the potential of NVG-291 beyond neurodegenerative diseases?

Paul Brennan: NervGen believes that NVG-291 has the potential to be used any time there is damage to the nervous system, either as a result of trauma or neurodegenerative disease. Efficacy has been demonstrated in animal models of MS, SCI, optic neuritis, cardiac arrythmia associated with heart attack, peripheral nerve injury, and stroke. We are initially focusing our efforts on MS, AD, and SCI.

Tuba: Highlight the NervGen efforts in the field of neurodegenerative diseases. Any more molecules planned to be assessed for the same indication?

Paul Brennan: We are initially focusing our efforts on MS, AD, and SCI with NVG-291. In the future, we will look at alternate formulations and modes of administration of NVG-291 for different indications, as well as alternate molecules with the same mechanism. 

Tuba: What are NervGen’s other programs in a pipeline to help patients overcome their disease and live a better life?

Paul Brennan: For now, we are focusing on NVG-291 in MS, AD, and SCI. 

Tuba: Are you open to collaborations to advance the development and commercialization of NVG-291 globally?

Paul Brennan: Currently we are not actively pursuing collaborations. However, as we progress into more clinical trials and indications, we will consider a partnership if the right circumstances present themselves (those being a partnership that provides value for the compound in development and the shareholders of NervGen). 

Source: UT Southwestern Medical Center

About Author: Paul Brennan is the President, CEO & Director of NervGen. He has over 30 years of experience in the pharmaceutical and biotech industries in leadership roles in general management, corporate strategy, commercial planning, business development, and regulatory affairs in Canada, Sweden, the United Kingdom, and the United States. Mr. Brennan holds an MSc in Physiology, and a BSc (Hons) in Life Sciences from Queen’s University in Kingston, Ontario.

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