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PMN.TO: How Can ProMIS Contribute to the AD Treatment Setting?

01/03/2019
By John Vandermosten, CFA

OTC:PMN.TO | OTC:ARFXF

The prevailing consensus on the cause of Alzheimer’s Disease (AD) has evolved over the last decades. In the 1980s, amyloid plaques or tau tangles were broadly but exclusively identified as the cause of the disease and the research community embarked on a search for a therapy that addressed one of these etiologies. In 1991 the amyloid hypothesis was proposed, further focusing development efforts. However, as research advanced, thought leaders in the space have expanded their view to see the disease arising from multiple factors including genetics, lifestyle, diet and environment. A number of different pathological processes have been identified that contribute to AD including cerebrovascular insufficiency, damaging protein occlusions, oxidative stress and neuroinflammation among others.

There are also other diseases that are strongly associated with dementia, including diabetes, atherosclerotic cardiovascular disease, high cholesterol, high blood pressure and obesity. Active research is seeking to understand the relationship among these diseases and identify therapies that can arrest their advance and potentially even reverse the degeneration associated with AD.

A professor at UCLA, Dr. Dale Bredesen, MD, has identified six subtypes of AD including inflammatory, atrophic, glycotoxic, toxic, vascular and traumatic. The causes of these different categories of AD range from high levels of inflammation, to exposure to toxins, or head trauma. Other sources have classified AD as inflammatory, non-inflammatory and cortical depending on the specific biomarker reading. AD is also divided into early-onset AD, which is genetically linked and late-onset AD which impacts individuals over 65. With so many categorizations of the disease, there is also the potential for a variety of treatments.

Genetics is only seen as contributing to a small percentage of AD cases1 but other risk factors, such as head injury, heart health, diabetes, high blood pressure, obesity, smoking, depression, cognitive inactivity or low education, and physical inactivity can play a part in the disease2. With a multitude of contributing factors to AD, it stands to reason there must also be a variety of treatment models that can be effective.

As we recognize the many contributors to AD, we must also acknowledge that it may take several therapeutic approaches to succeed against it. PMN appreciates this approach and is developing multiple antibodies to address the root causes of AD. The dominant focus by the medical community at large in AD has been to find one drug to completely cure the disease. However, this approach fails to recognize that a multitude of factors must likely be addressed for comprehensive treatment.

We have discussed ProMIS’ (OTC:PMN.TO | OTC:ARFXF) monoclonal antibody, PMN310, at length in our initiation. The biologic targets toxic oligomers and is ProMIS’ lead candidate. The mAb was developed using proprietary algorithmic software designated ProMIS and Collective Coordinates and is able to bind to epitopes that are unique to toxic misfolded forms of amyloid β. ProMIS is also developing a mAb to target misfolded, pathological forms of tau. Tau holds microtubules together, which are important for transporting nutrients and other cellular material to neurons. Abnormal tau is unable to hold the microtubules together and allows them to dissociate, leading to neuron death. ProMIS’ mAb can potentially neutralize abnormal tau in the space between cells so that there is no spread of dysfunction throughout the brain in AD.

Neurofibrillary tangles are composed of hyperphosphorylated tau and are associated with the progression of AD. These neuronal inclusions are comprised of paired helical filaments that are highly insoluble and consist of the microtubule-associated protein tau. When tau proteins become defective, they can cause AD, Parkinson’s Disease (PD) and other neurodegenerative conditions and fail to stabilize microtubules.

At the end of October, ProMIS announced an advance in its tau program. The company’s science team was able to identify several targets specific to misfolded forms of tau using its proprietary discovery platforms. ProMIS has completed the target identification stage of development and has moved into the antibody generation stage. We anticipate that the company will follow a similar pathway to what was accomplished with PMN310, and develop murine monoclonal antibodies to identify the best candidates for clinical development. This will be followed by screening for binding specificity and final validation and selection for clinical development.

Diagnostics

Drug development and disease identification requires effective and accurate diagnostic measurement of a specific disease. Until recently, only an autopsy could diagnose AD with certainty. Imaging has advanced to a stage where PET scans are able to identify tau tangles and amyloid β; however, this type of testing is costly. Other approaches use cerebro-spinal fluid (CSF), but require an invasive and painful spinal tap that is not without risks. An improved approach would employ a blood test, and there are many researchers working on such an effort currently. Blood is easy to obtain, and blood based tests can be processed in large volumes cheaply.

Characteristics of a successful test include an ability differentiate, with a high degree of certainty, those with and without a likelihood for the disease. This will allow physicians to focus on those that are predisposed to AD and increase their focus on these patients and advance them on to additional more conclusive testing, such as a PET scan. The presence of an effective blood-based diagnostic would also be very effective for drugs in development as it would help accurately identify target study populations and also measure the effectiveness of therapies as they progress. Now that the FDA has encouraged the use of biomarkers in AD trial design, we anticipate a variety of benefits to accrue to new AD trials including shorter durations and expedited approval.

Some of the leading diagnostics for measuring AD include assays of amyloid-β40 and amyloid-β42, TNF-α, Filamin A, tau and Neurofilament Light Chain (NfL) among others. ProMIS is researching the feasibility of the NfL biomarker as a viable measure for screening patients for trial inclusion and also for measuring efficacy of applied therapies. NfL has been found to be highest in individuals with AD (51.0 pg/mL), at moderate levels in those with mild cognitive impairment (MCI) (42.8 pg/mL) and lowest in individuals without cognitive impairment (34.7 pg/mL)3.

The efficacy of blood-based diagnostics can be confirmed with more expensive and invasive tests such as CSF or PET scans when needed.

Summary

As the research community’s understanding of Alzheimer’s Disease improves and causes of the disease are refined and elucidated, we expect researchers will develop a suite of treatments drawing from a collection of approaches that address the type of AD a person has. We see the precedent in the immune-oncology (IO) space as a template for what may happen in AD. Checkpoint inhibitors were introduced and have shown increased success when used in combination with chemotherapy, cancer vaccines and other therapies improving the efficacy of monotherapies. New IO candidates are in development for combination use and can revolutionize the treatment of cancer. ProMIS has two candidates in development that address the root causes of AD and there exists the potential for them to be used in combination with other approved therapies as well. Combined with an accurate diagnostic, both trials and approved therapy can be tailored for each individual increasing the potential for success.

With a large and rapidly growing end market, no approved disease modifying therapies and a lead candidate that can uniquely bind to toxic oligomers we see an attractive program in development. ProMIS can potentially obtain approval for candidates that can be used in combination therapies tailored to contributing factor and subtype of Alzheimer’s Disease.

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1 According to the Alzheimer’s Association, it is estimated that less than 1 percent of Alzheimer’s cases are caused by deterministic genes.
2 These risk factors were identified in the FINGER trial. Rosenberg, A. et al. Multidomain lifestyle intervention benefits a large elderly population at risk for cognitive decline and dementia regardless of baseline characteristics: The FINGER trial.
3 Zakaib, G.D.; Blood Neurofilament Light a Promising Biomarker for Alzheimer’s? March 31, 2017.
 
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