Alzheimer’s disease: How is the treatment landscape changing?
In that context, we spoke to an industry insider, Gene Kinney, CEO of Prothena, to get a perspective on R&D in the AD space.
Prothena is developing a monoclonal antibody, PRX012, and vaccine that are reportedly showing promise in AD treatment and prevention.
The company was spun off from Elan back in 2012, and Kinney first talked to us about the pioneering work undertaken by its former owner in the area of AD science.
“If you think about these first generation compounds that are moving us from treating the symptoms of AD to now starting to address the underlying pathophysiology, which are looking to slow the overall progression of the disease, that science got its start in earnest at Elan, with some amazing scientists there.
“The first ‘mouse model’ of AD was developed at Elan by researcher, Dora Games. Dale Schenk actually did some of the first experiments to understand if it was possible to target these proteins like amyloid beta that are implicated in the progression of the disease.
“And from that science, we’ve actually watched not only the basic research science develop over the years but, importantly, also the clinical science - how we think about which patients might be most appropriate [in terms of] evaluation of and treatment with these therapeutics. And [we have been looking at] how the regulatory science [has developed], how regulators at the FDA and their equivalents across the world think about the different aspects of these types of treatments - because it is a paradigm shift.
“As we saw all of that science progressing, we at Prothena started to invest in this space. We looked to address what we thought would be the ways that we could further progress the science and the value to patients as these first generation approaches started to be successful,” said Kinney.
Investor interest in the AD space
The level of interest in the AD space is higher now from a research and investor perspective than it was five years ago, according to the executive.
“In large part, what that is attributable to is a maturation of our ability to assess these types of therapeutics. I think there is a greater understanding of the basic biology, there is more sophisticated use of biomarkers and ways to assess clinical trial design. There has been a maturation of clinical assessment scales – how we actually measure change over time. AD is a slowly progressing disease in the context of a lifespan of an individual, and, in order to see change over time, you have to measure the right way and that has been developing over the years.
“As those technologies and those approaches have matured, there has been a growing recognition of that across the investor spectrum, to the benefit of new approaches that have the ability to continue to push the ball forward,” said the Prothena lead.
First generation disease modifying agents notably include Aduhelm (aducanumab).
“Aducanumab showed about a 22% slowing of disease progression in the EMERGE trial on a clinical assessment scale called the CDR Sum of Boxes. That is, as a marker of a first approach to slow progression of disease, a wonderful accomplishment but we think the goal now has to be to do better.”
Investment in the space helps to continue to push that down the line, said Kinney.
Looking at treatments in other fields, such as HIV, the chief executive said first generation approaches like AZT provided real benefit for patients and changed the whole treatment paradigm. “But no one stopped there. HIV focused researchers and scientists continued to develop medicines to the point whereby we can now consider HIV a chronically manageable disease. And that is what we want for Alzheimer's disease. And I think we are right on the precipice of the start of that.”
In terms of the level of growth and diversification that there has been in the Alzheimer's disease R&D pipeline over the past three years, Kinney said, clearly, the first generation approaches are targeting amyloid beta, and doing so in a very precise fashion, focusing on a specific place on the amyloid beta peptide. “That is important from a biological understanding.”
A lot more data is starting to emerge around the targeting of the tau protein, he added.
“Ultimately, I, and others, believe that we will be combining these approaches with the hope of a better effect and better impact for patients, either by broadening the total number of patients that would be potentially helped by these sorts of treatments or by increasing the efficacy profile, or both.”
But there is investment in other areas of AD research and development as well. “One of things we know about these proteins, when they start to act improperly, is that they can cause inflammation and other problems in the brain, so some [developers] are beginning to focus on that neuroinflammatory component and other aspects of the disease as well.”
A certain cell type in the brain known as microglia is thought to be critical to regulating those proteins, he said. “Ultimately. the development and the exploration of these different areas of biology within brain function are going to be quite important in respect of treating patients suffering from these type of central nervous symptoms (CNS) diseases.”
Preventing AD from occurring
Evidently, the objective for researchers in the field would be to understand the biology well enough to halter or slow the progression of the disease once it has begun, and then move on to patients that are earlier in their disease course and look to try and prevent the disease from occurring in the first place, with the end goal of secondary and primary prevention trials, he said.
Prothena has an active vaccine in its portfolio that has the potential to generate a response to both the amyloid beta and the tau proteins, reported Kinney.
“We think this is a really interesting candidate, not just for treating patients with disease, but also in terms of thinking of secondary prevention type trials. And, down the line, if we had success there, we could think about primary prevention trials, the ultimate goal.”
Looking to additional technologies and platforms, future treatments in the AD field, he talked about the benefits to patients of potential restorative therapies, which some researchers and scientists already have on their radar. “How do we get in and restore function back to ‘normal’ as opposed to just slowing progression, etc.?”
Overall, Kinney is hopeful.
There have been key learnings from failures along the development pathway: “It takes an entire community to propel the science forward. It is a complicated [field] but the fact that progress is being made and it is tangible is really exciting.”
Dr Gene Kinney has served as CEO of Prothena since September 2016. He is a member of Prothena’s founding leadership team, and, between 2012 and 2016, held the position of chief scientific officer and head of R&D.
Before joining Prothena, he held positions with Elan Pharmaceuticals Inc., including senior vice president of pharmacological sciences and vice president, pharmacology. While in those positions, Dr Kinney also served as head of nonclinical research for Janssen Alzheimer Immunotherapy.
Before joining Elan, he held several senior positions at Merck Research Laboratories and Bristol-Myers Squibb, and was an Assistant Professor at the Emory University School of Medicine. Dr Kinney earned his BA from Bloomsburg University and his MA and PhD from Florida Atlantic University.