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PMN.TO: Exposin’ Those Epitopes

10/15/2018
By John Vandermosten, CFA

TSE:PMN.TO | OTC:ARFXF

On Thursday, ProMIS (TSE:PMN.TO) (OTC:ARFXF) announced another milestone with the identification of several potential monoclonal antibody (mAb) candidates that target toxic oligomers for α-synuclein, which is associated with Parkinson’s Disease (PD). The press release highlights the company’s efforts with biotech strategists Red Sky Partners’ to find collaborators for PD candidates.

Animal studies conducted by Neuron Experts in France examined the neuroprotective effects of the identified antibodies on primary dopaminergic neurons injured by exposure to α-synuclein toxic oligomers. They found that the mAbs targeting the identified epitopes significantly blocked the death of neurons induced by these oligomers. Just last month, ProMIS appointed James Kupiec, MD as Chief Medical Officer, who was Global Clinical Leader for Parkinson’s Disease at Pfizer. His background, relationships and understanding in PD will be instrumental in the success of the program.

The PD program follows the Alzheimer’s Disease and ALS programs in the company pipeline, which are all built on a platform for identifying targets that are presented on misfolded proteins. The process starts with identifying epitopes on the toxic oligomers, then monoclonal antibodies that specifically target these epitopes are developed and tested for efficacy.


View Exhibit I - ProMIS Pipeline and Anticipated Timeline

ProMIS’ development platform consists of a pair of algorithms called ProMIS and Collective Coordinates that use protein thermodynamics to predict disease-specific epitopes on the surface of misfolded proteins. These computer simulated modeling applications are able to identify likely epitopes which express themselves on the surface of these misfolded proteins and also eliminate from consideration other epitopes that appear on non-target molecules. The algorithm is able to detect unique signatures that are particular to misfolded toxic oligomers but do not appear on other proteins. This specificity allows the company to identify mAbs that can avoid off-target effects and provide greater efficacy at a lower dose.

Parkinson’s Disease

Parkinson’s Disease (PD) is a chronic neurodegenerative disease characterized by progressive movement disorder and a loss of neurons that synthesize and release dopamine. The disorder takes years to develop as the brain slowly reduces production of dopamine, a critical neurotransmitter that helps the body regulate its movements and emotions. While the disease itself is not fatal, complications from PD can cause death. Symptoms include rigidity, resting tremors, akinesia, bradykinesis, loss of facial expression and altered gait and posture. The neurons responsible for the production of dopamine that helps control movements are largely centered in the substantia nigra. When this structure fails to generate dopaminergic neurons, it results in PD. Dopamine is the messenger between the substantia nigra and other parts of the brain to control movement and functions as a neurotransmitter to send signals to other nerve cells.


View Exhibit II - Substantia Nigra1

α-synuclein

α-synuclein is a neuronal protein that comprises Lewy bodies, a marker for PD. It is linked neuropathologically and genetically to PD. In many cases of the disease, the α-synuclein (SNCA) gene produces an excess of α-synuclein protein or an aberrant soluble oligomeric form of the protein which may be toxic to brain cells and cause neuron dysfunction. Excess or misfolded α-synuclein proteins may cluster together to form Lewy bodies and impair the function of dopamine-producing neurons in specific regions of the brain. In turn, the regulation of dopamine is disrupted, and the accumulation of the neurotransmitter can damage neurons.

Diagnosis

Diagnosis of PD is difficult due to the lack of standard diagnostic tests, and reliance on clinical data, rather than laboratory tests, to make the determination. Generally, after an initial assessment by an internist or family physician the patient will be referred to a neurologist. The neurologist, with a specialty in movement disorders, will provide an additional exam to identify several factors. These include observations regarding:

‣ Facial expression
‣ Tremor in limbs, when at rest or extended
‣ Stiffness in arms, legs or neck
‣ Ability to rise from a chair
‣ Gait
‣ Balance

There are other diseases that may have similar symptoms as PD, including stroke and hydrocephalus, therefore the neurologists’ skill is necessary to make a proper diagnosis. A favorable response to the drug levodopa is supportive of a PD diagnosis as it restores dopamine to the brain.

There are a few types of PD, including tremor dominant and postural instability gait dominant (PIDG) which comprise 75% and 25% of the PD population respectively.

PD has several distinct stages as it progresses. The duration of the transition from stage to stage varies widely and can be from just a few years to twenty years. We provide a brief summary of each of the five stages below.

First Stage: Symptoms are mild and do not interfere with a person’s lifestyle. Tremors may occur, but they are mild and may only occur on one side of the body. Posture and facial expressions may show a slight change.

Second Stage: Symptoms become worse, with tremors increasing and spreading to both sides of the body (bilateral). Walking becomes more difficult and posture is affected (balance). A person’s activities may begin to be affected by the disease.

Third Stage: At this point, balance becomes difficult and movements slow. Falls may occur and daily activities become more difficult.

Fourth Stage: Symptoms become severe and limit activities. At this point, the PD sufferer requires active care and cannot live alone. Walking by oneself may be difficult or impossible.

Fifth Stage: This is the final stage and the individual is frequently confined to the bed or wheelchair. Nursing care is required at all times and the patient may suffer hallucinations and delusions. There are also other non-motor symptoms such as mood disorders and cognitive changes which occur.

Treatment

Treatment of PD attempts to improve the presence of dopaminergic neurotransmitters with dopamine replacement therapy (DRT) recognized as first line treatment. It is not a cure. Dopamine cannot cross the blood-brain barrier, so it is not administered directly as a medicine. Therefore, the alternative levodopa is prescribed, which is able to enter the brain and is converted there into dopamine. This conversion process is brought about by the enzyme aromatic amino acid decarboxylase, which is also present in tissues outside the brain. Due to levodopa’s rapid conversion to dopamine when administered to a patient, and to avoid the resulting side effects of nausea and vomiting, carbidopa is added to the drug regimen. Carbidopa, a DOPA decarboxylase (DDC) inhibitor, is responsible for the peripheral conversion of levodopa to dopamine.

The benefits of levodopa frequently wear off after five to ten years and when its effects begins to decline, dose or frequency may be increased and other dopamine agonists such as ropinirole may be used as is combination treatment with levodopa.

Number Afflicted

According to the Parkinson’s Disease Foundation, as many as one million Americans have PD and about 60,000 new cases are diagnosed each year. The Foundation sees as many as 10 million people worldwide suffering from the disease. The European Parkinson’s Disease Association cites slightly lower figures of 6.3 million suffering from PD worldwide and 1.2 million in Europe. The Michael J Fox Foundation estimates about one million people in the US and 5 million worldwide have PD. China and India also have large populations of PD sufferers which are estimated to both be larger than that in the US. The average age of onset for PD is 60 with risk increasing as one ages. Therefore, growth in the PD population is expected to be faster than that of the population overall given population dynamics.

Summary

ProMIS is developing a portfolio of mAbs to address the most important neurodegenerative diseases that exist. Their biologics are built on a proprietary discovery engine that can identify specific targets on toxic oligomers in a variety of neurodegenerative diseases. While still early stage, we believe ProMIS has built its approach, targets and strategy on the shoulders of giants and represents an attractive opportunity to gain exposure to an immense disease area with no other approved therapies. With the latest announcement regarding Parkinson’s Disease, the company is advancing into another area where there is no cure and there are about one million persons in the US and ten million outside of the US that suffer from the disease. ProMIS sees the PD program as an ideal one for partnering and a potential source of upfront and milestone cash to support other programs in the portfolio.
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1 Animated Dissection of Anatomy for Medicine (ADAM)

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