During his distinguished career, Dr. Daniel G. Chain, Ph.D. discovered various novel therapeutics to treat Alzheimer's disease which were licensed to multiple Big Pharma giants.
Dr. Chain trained as a Post-doctoral Research Fellow at the Center for Neurobiology and Behavior at Columbia University in New York. Dr. Chain obtained his B.Sc. in Biochemistry from the Institute of Biology in London and obtained his Ph.D. in Biochemistry from the Weizmann Institute of Science in Israel.
He currently serves as Chairman of Intellect Neurosciences, Inc. (OTCQB:ILNS), where he has also been Chief Executive Officer since October 2005.
In an exclusive interview with BioMedReports, Chain says that biotech investors should remain undeterred by the challenges currently being faced by those trying to find a cure for Alzheimer's disease and other age-related cognitive impairments.
BioMedReports: How would you characterize the mood among Alzheimer’s researchers after the phase 3 results for Bapineuzumab and Solanezumab?
Dr. Daniel G. Chain, Ph.D.: Obviously, people were very disappointed by the results from the two sets of major Alzheimer’s Phase 3 trials, but there were also glimmers of light that renewed hope and even strengthened the prevailing belief that beta amyloid (Aβ) plays a central and causative role in the pathogenesis of Alzheimer’s disease. Few now doubt that immunotherapy represents a realistic path forward pending improvements in drug design and the way we conduct clinical trials. Ely Lilly’s drug solanezumab showed modest improvement in clinical outcomes when data was pooled from two clinical trials. The drug is to be further tested in a third phase 3 trial by the company and two independent trials conducted by leading academic groups. While bapineuzumab failed to show clinical benefit, the use of biomarkers clearly demonstrated the drug had engaged the target, reduced the amount of plaque and slowed neurodegeneration based upon the decrease in the amount of tau protein measured in the cerebral spinal fluid (CSF). Unfortunately, the drug also caused a significant incidence of vasogenic edema and microhemorrhages, especially in patients that carried the APOE4 gene. A Phase 2 trial is ongoing using a subcutaneous formulation that may avoid these side effects. There is a feeling of optimism among researchers that next generation drugs will have an improved probability of success because of the lessons we have learned from these results and other important recent developments in the field. I experienced this first-hand when I was invited as a Distinguished Speaker to the 6th Annual Alzheimer’s Drug Discovery Summit in December and had the opportunity to listen to foremost leaders in the field including academic researchers and industry experts.
Among the themes that have become prevalent is that there is a compelling case for early intervention in the treatment of the disease in which relevant biochemical and neuropathological changes in the brain start many years - in some case two decades or more - before symptoms occur! Moreover, the rate of change is far greater before the appearance of symptoms such that the stage we commonly refer to as “Mild”, is in fact relatively far advanced, reflecting significant damage to the brain, which is probably beyond repair.
Q: What are the main areas of progress in Alzheimer’s research?
Dr. Daniel G. Chain: The development of sensitive brain imaging techniques such as structural MRI to measure brain atrophy, FDG-PET to measure glucose metabolism, and PET amyloid imaging agents represent some of the most important recent advances in the field laying the foundation for studies such as by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Dominantly Inherited Alzheimer’s Network (DIAN) that provided extremely valuable information regarding the sequence of changes preceding and leading to AD. In fact, these studies led to a new way to think about the disease in which presymptomatic AD is just as much a disease state as symptomatic disease.
Q: Describe the main programs at Intellect Neurosciences.
Dr. Daniel G. Chain: Intellect has four main programs underway at the moment: CONJUMAB-A, TAUC3, TOC-1 and RVO3. We are pioneering the use of antibody-drug conjugates and bi-specific vaccines for the treatment and prevention of multifactorial neurodegenerative conditions such as Alzheimer’s disease, Huntington’s disease and age-related macular degeneration. Increasingly we hear researchers emphasizing the need to target more than one disease component where, for example, Aβ, tau protein and oxidative stress act in concert and synergistically causing irreversible damage to nerve cells. The use of combination therapies may even allow intervention after symptoms have begun in contrast to monotherapies, targeting only Aβ, for example. However, regulators are averse to the idea of combining two independent investigational drugs before testing each one singly in human clinical trials and demonstrating clinical benefit. That issue is circumvented by the use of antibody drug conjugates in which two different molecules are combined chemically into a single entity as is the case with our CONJUMAB platform.
I am excited about the therapeutic potential of CONJUMAB-A, our lead preclinical program which I believe offers important advantages to other Aβ antibodies currently in clinical development. All the other antibodies e.g. solanezumab, bapineuzumab, gantenerumab and crenzeumab are designed for a single purpose, namely to clear Aβ from the brain. None of these antibodies act on secondary neurotoxic mechanisms such as oxidative stress which causes most of the damage from Aβ. By contrast, CONJUMAB-A, an antibody drug conjugate, is empowered with additional neuroprotective properties to alleviate the damage while also potentially enhancing the clearance of Aβ. In principle our approach could be applied to improve many different types of antibodies including those that previously disappointed in clinical trials. However, we are currently focused on optimizing CONJUMAB-A using our own antibody IN-N01 which targets the N-terminus of Aβ. We believe IN-N01 to be superior to bapineuzumab because of its reduced potential to cause inflammation which results from our reengineering of the originally produced IG1 class antibody into an IgG4 class antibody. We believe this safety feature is particularly important for antibodies that bind Aβ aggregates and not just soluble single monomeric Aβ. Among several potential indications, we have decided to focus on age related macular degeneration (AMD) for proof of concept studies since AMD and AD share several similarities while the eye offers less challenge for delivering the drug.
Over the past two years, Intellect has established its position as a leader in tau immunotherapy using funds from our deal with ViroPharma to support new patent filings by the company, in-license new technologies and initiate an important collaboration with leading Alzheimer’s research groups led by Dr. Frank LaFerla and Dr. Kim Green at the University of California, Irvine. Tau immunotherapy is rapidly gaining traction in the Alzheimer’s field and has potential applications for many orphan indications as well, such as frontotemporal dementia. However, in contrast to other approaches that have targeted tangles, Intellect is targeting the earliest steps in tau pathology focused on two different pathogenic forms, a truncated form known as delta tau and an aggregated from known as oligomeric tau – each of which occurs before filaments leading to tangle formation. Over the next several months we expect to generate important in vivo data in relation to the two monoclonal antibodies, TauC3 and TOC-1 that we acquired from Northwestern University under an exclusive license agreement.
Finally, we continue our development of our RECALL-VAX platform focusing on a bi-specific chimeric peptide vaccine approach that targets both Aβ and delta tau in a flu-shot like vaccine approach. Vaccines against multiple antigens have precedent so this is another approach for combination therapies. Disease-modification itself is becoming less attractive as an approach for treating Alzheimer’s disease for two main reasons. First, as evidenced by the Phase 3 clinical trials results, patients who are symptomatic probably have disease that is too far advanced to benefit significantly from treatments that slow the degenerative process. Second, treating very early stage or presymptomatic patients will be extremely expensive and prove too costly a burden for healthcare systems. An article by scientists from the Karolinska Institute in Sweden, published in the October issue of Current Alzheimer’s Research, indicated the economic cost of treatment with a chronically and frequently administered disease-modifying drug would outweigh the cost of palliative care, including full-time nursing care of patients with advanced disease. This economic model leads one to conclude that a vaccination given on an annual or semi-annual basis may be the only economically feasible approach to prevent and manage Alzheimer’s disease. Therefore, a vaccine such as RV03 being developed by Intellect Neurosciences offers a promising prophylactic approach that could potentially be administered to tens of millions of people around the world. Although still at an early stage, we are confident about our ability to produce a high value asset.
Q: Do you feel confident regarding Intellect’s pipeline?
Dr. Daniel G. Chain: We are very confident in the science behind our pipeline, and are encouraged by the interest shown in our programs by several global pharmaceutical companies some of which have already signed confidentiality agreements. In addition, many independent papers have been published recently that support many of our hypotheses for the development of these assets. Further, we are beginning to see encouraging early stage results that we hope to share soon regarding each of our pipeline programs.
Q: What challenges do you face?
Dr. Daniel G. Chain: The biggest challenge is the funding needed to support our R&D activities and also to grow and maintain our substantial global patent portfolio, which is the heart of Intellect’s business model. We need to dispel the skepticism that pervades among many stakeholders in the pharmaceutical industry resulting from previous disappointments in the AD field, or at least separate ourselves from it.
One of Intellect’s strengths is its diversified portfolio, which provides us “multiple shots on goal.” We are extremely cost-efficient as the result of effective outsourcing R&D to highly specialized contract research organizations. Even so, as a small company, maintaining adequate funding to continue all of our programs concurrently is quite challenging. We are currently in talks with potential licensing and co-marketing partners to help maintain the pace of our research, but in this environment, we are facing the same challenges as all other companies of our relative size. We, therefore, have to choose which programs to push forward at any given moment, which often disrupts the momentum of other programs, all based upon the funding we receive and the goals of potential partners who continue nevertheless to show considerable interest and have expressed an eagerness to see validation in preclinical models.
Q: Do you have anything you wish to add?
Dr. Daniel G. Chain: It is imperative that the company and its investors remain undeterred by the challenges currently being faced both by the industry and within Intellect itself. Intellect has continued to grow and develop new strategies to continue on regardless of what the market has done. We wish to communicate to our current and potential investors that significant advances have been made in the Alzheimer’s area and express our confidence in our ability to prevail where others have failed. While one set of compounds for which we hold licenses has met with challenges, that is not the entirety of Intellect Neurosciences. Intellect has never relied solely on one program to sustain it, and we have continuously executed on our plans to license our programs, and anticipate being able to do so again as we generate new data and advance our earlier-stage programs through proof of concept.
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