Breaking New Ground in Precision Medicine for Alzheimer's Disease

October 8, 2017

World CDx Voices

Martin Tolar, Founder

President & CEO, Alzheon

For you, why is a biomarker and diagnostic strategy so important and where is the most value gained from this approach?

In Alzheimer’s disease (AD) drug development, over the past 15 years everything has failed. We finally understand and are targeting amyloid oligomers – the key pathogen of Alzheimer’s. Also, we have learned from amyloid PET imaging that there is over 30 percent misdiagnosis of AD, if you diagnose the patient based only on the clinical symptoms. So, it is critical to have a diagnostic that can help to improve this accuracy. Alzheon uncovered a very clear correlation between the efficacy of our drug, genetic markers and accurate clinical diagnosis. This is where APOE4 genotype and risk factor comes into our program for developing a new medicine for AD. The diagnostic biomarker and diagnostic strategy is an essential component of this Precision Medicine strategy, as we break new ground as one of the first companies to implement a Precision Medicine approach to Alzheimer’s.

How is Alzheon championing Precision Medicine drug development?

The AD field has evolved tremendously since we founded Alzheon in 2013. We started focusing on a genetically-defined population of AD patients with a Precision Medicine approach and evaluating a drug that we believed would show efficacy in this population. Since then, it has become clear that this population of AD patients with an APOE4 genotype is the population with the most aggressive disease in late stage Alzheimer’s, and this genetic marker also provides a very reliable proxy for diagnostic accuracy for somebody who has Alzheimer’s

with amyloid pathology. That is how our program has evolved to become a pioneer in Precision Medicine for Alzheimer’s. We started with the insight to focus on a genetically-defined population to be assured that we can reliably assess if a treatment will or will not work. Then, the field has provided additional support for our approach with data confirming that the same genetic marker plays a key role in the diagnosis and the progression of the disease in this population. This is the crux of a Precision Medicine approach. If you find the population that you understand well, you can reliably diagnose the disease in this group of patients. You can then understand their disease and progression, and also find the best drug for them. It’s obvious to think of cancer or certain orphan diseases as genetically defined, but in AD or cardiovascular disease, which are more prevalent diseases, people haven’t traditionally thought about them as having such distinct populations.

What is the biggest challenge currently facing the Precision Medicine community?

The first challenge is realizing that Precision Medicine should also apply to common diseases. People don’t think about Alzheimer’s as a disease where Precision Medicine can be applied because there are so many patients. However, emerging science and medicine are revealing that there are well-defined, distinct biological phenotypes and populations in Alzheimer’s that should be targeted with the ‘right drug for the right patients and at the right time’. Secondly, the mentality of many pharmaceutical companies is still to develop a pill that’s going to work for everybody. But this is not likely to work for many diseases and treatments, particularly as the role of genetics becomes more evident. We need to find the population where a treatment truly provides a robust benefit with acceptable safety profile. There is a reluctance from some pharmaceutical companies to commit to this approach because it is more complex, expensive, and can limit the patient population in product marketing. Payers are supporting such a shift to more defined patient populations for drug products since there is a clearer risk/ benefit profile. But there are new considerations to bear in mind, as drug development with a genetic marker is more expensive and can fragment the development process.

Where does the greatest opportunity lie/ what is the next breakthrough needed to accelerate the robust stratification of patients and the subsequent development of targeted therapeutics?

The greatest opportunity for breakthroughs comes from advancing understanding of the disease biology. Once you understand the biology and the deeper differences between distinct biological phenotypes, then you can perform the correct diagnosis and develop or administer the right treatment for the right patient.

A key mystery of Alzheimer’s has been the mystery of amyloid at a deeper level of disease biology and, until recently, amyloid’s pathogenic driver and step in the disease process was not entirely clear. Understanding the role of amyloid oligomers has been essential to break the gridlock on Alzheimer’s. Oligomers play a distinct role in different Alzheimer’s populations, and this new insight has emerged from researchers, including those at Alzheon, who have taken an innovative look at the disease biology. Stratifying prevalent diseases, such as Alzheimer’s, has not traditionally been the way drug development has been conducted in pharmaceutical companies.

What does the industry need to achieve in order to deliver the true value of diagnostic enabled therapeutics to patients?

We must understand the biology of disease, we have to develop the diagnostic and we have to find out where a therapy is most effective. Ultimately, it comes down to the physician and patient. We have to determine the patients for which a treatment is most appropriate, and what the risk/benefit is for that specific patient population. And this is where the work for drug developers is increasingly being focused.

Which technologies are you most excited about regarding the future development of diagnostics?

For our AD work, mass spectroscopy has been the most useful for measurements of the disease biomarkers. The most important breakthrough in Alzheimer’s is understanding the role of oligomers and aggregates of amyloid – key drivers of the disease – and these can only be reliably measured with mass spectroscopy. In addition, blood diagnostics can be very useful and there was a report in a recent Alzheimer’s meeting in London about a blood test using mass spec to measure different forms of amyloid in plasma, which correlated well with the pathological diagnosis.

I think that the real need is to have point of care diagnostics – and there are some ways to do this now for genetic risk factors for AD, including APOE4 genotype. If you can visit your physician’s office and get your diagnostic outcome by the end of the visit, this is what is going to drive the acceptance for companion diagnostics.

What are you most looking forward to at World CDx & Clinical Biomarkers 2017?

There has been a revolution in the way we use biomarkers, clinical tests and companion diagnostics across all indications. However, in AD, it has been very slow coming. For me, the conference is about learning from other therapeutic areas and then sharing what we do in Alzheimer’s. The crucial reason that we have been failing in AD drug development for 15 years, costing tens of billions of dollars, is the lack of understanding of the biology. It is exciting to see our field evolving to have useful biomarkers and also the diagnostics that can help us guide drug development.

It seems like exciting times ahead for Alzheon, what should we be looking out for on the horizon in the near future?

From the start, our goal has been to develop an effective treatment for Alzheimer’s. Our lead drug has the potential to slow progression or even prevent disease in AD patients. But

it is the Precision Medicine approach for the high-risk patients –APOE4 homozygotes in particular – which has allowed us to accelerate the development and demonstrate the benefit for those patients, along with potential advantages and reduced side-effects compared to some of the treatments that are currently in development. We are energized by the opportunity ahead of us to pursue the first Precision Medicine drug approval for Alzheimer’s and to bring an effective treatment to patients and their families.