Palisade Therapeutics is a new venture with a novel therapeutic approach for treating age-related dementia, an unmet, emerging clinical market with a value estimated at $20 billion. Current dementia drugs suffer from two major shortcomings: they are not personalized and they are not disease-modifying; in other words, they manage symptoms without understanding or treating the underlying causes of neurodegeneration. We discovered a previously unknown but widespread cause of age-related neuropathology, involving decline in the health of the vasculature resulting in blood-brain barrier (BBB) failure during aging, which allows molecules to leak from the blood into the brain. One key molecule, albumin, triggers an injury response by activating the transforming growth factor beta (TGFβ) signaling pathway, leading to neurodegeneration and cognitive impairment. We treat this target with a two-fold, personalized, disease-modifying approach: 1) Using companion MRI diagnostics to screen dementia patients for vascular permeability; and 2) Using IPW, a small molecule TGFβ receptor (TGFβR1) kinase inhibitor, to reduce the symptoms and progression of dementia in the target population. Our rodent studies show improvement in cognitive function after 7 days of IPW treatment in naturally aged, 24 month old mice, and our translational human studies show the presence of albumin and TGFβ signaling in postmortem tissue, and vascular permeability in MRI imaging of aged patients. Beyond age-related dementia, many other diseases have early vascular damage and similar patient outcomes, including stroke, head injury, surgical patients, and others, demonstrating the long-term value of this platform as a new strategy for treating neurological disease.
Building from a core team of researchers who developed our new technology, we assembled advisors with the expertise in clinical and business approaches needed to bring our discoveries from the lab and into an early stage start-up.
Co-founders: Vlad Senatorov and Aaron Friedman are UC Berkeley Neuroscience PhD Candidates. Both are recipients of the NSF Graduate Research Fellowship, and have published articles in top journals including Neuron, PNAS, Molecular Psychiatry, and Journal of Neuroscience. Their research investigates how vascular damage contributes to cognitive decline in aging and tests therapeutic interventions for its prevention and reversal. Vlad and Aaron also pursue translational entrepreneurship through UC Berkeley’s Management of Technology Innovation (a 1-year “mini MBA” course) and Startup-in-a-box programs. They are leaders of a Sutardja Center for Entrepreneurship Venture Collider that brings together UC students from different areas of expertise (MBA, law, etc.) and engages them in market analysis supporting the Palisade Therapeutics venture.
Scientific Directors: Daniela Kaufer, Ph.D. and Alon Friedman, M.D., Ph.D. have been collaborating for 15 years, using complementary skills to establish a novel role for vascular pathology in neurological disease. Dr. Kaufer is an expert in molecular neuroscience and the role of vascular damage and inflammatory signaling in neurodegeneration; Dr. Friedman is an expert in electrophysiology, epilepsy, and novel imaging methods for detecting blood-brain barrier disruption.
Drug Development Partnership: Barry Hart, Ph.D., founder of Innovation Pathways, has over 15 years of industry drug-development experience. Barry partners with early-stage researchers to rapidly develop new drugs for emerging targets. He also serves as Director of Business Development at AlloStem, and has served as project lead in drug development at Scios (acquired by Johnson & Johnson), Bayer, ViroBay, Medivation, and SRI International. Barry’s expertise spans drug synthesis and development, safety and toxicology approaches, GMP and scaling, and oversight of CROs.
Clinical Advisors: Mike Rogawski, M.D., Ph.D. is chair of Neurology at UC Davis, and former Chief of the Epilepsy Research Section at NINDS. His research focuses on pharmacology, neurophysiology and neurological therapeutics, with emphasis on novel and experimental antiepileptic drugs. With extensive clinical trial experience and previous roles in translational start-ups, and as co-director of the NIH’s national course Training in Neurotherapeutics Discovery and Development for Academic Scientists, he offers unique insight in bringing a novel therapy from the lab and to the clinic. Bill Jagust, MD, is endowed chair of Geriatrics at UC Berkeley, leader of PET imaging in the NIH Alzheimer's Disease Neuroimaging Initiative, and former director of the Alzheimer’s disease center at UC Davis. He offers expertise in imaging methods for detecting Alzheimer’s and clinical approaches.
Business Strategy Advisors: Ed Penhoet, Ph.D. is director of AltaPartners, and Professor Emeritus and former dean of the UC Berkeley School of Public Health. He is co-founder of Chiron Corporation, and the former president of the Gordon and Betty Moore Foundation. Ed is also on President Obama's Council of Advisors on Science and Technology (PCAST) – an advisory group comprised of 20 of the nation’s leading scientists and engineers who directly advise the President and the Executive Office of the President. He is a member of both the Institute of Medicine of the National Academies and the American Academy of Arts and Sciences. He offers vast experience in business strategy and regulatory approaches. Andrew Dillin, Ph.D. is a Howard Hughes Medical Investigator focused on aging research and the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research at UC Berkeley. As co-founder of two successful start-ups spun out of his lab, Mitobridge and Proteostasis Therapeutics, Andy brings a wealth of experience in technology transfer and early-stage business strategy. Bob Knight, M.D. is professor of Neuroscience and Psychology at UC Berkeley, and adjunct professor of Neurology and Neurosurgery at UCSF, as well as the former director of the Helen Wills Neuroscience Institute. He has served as founder or advisor in multiple start-ups, including Nielsen Consumer Neuroscience (EEG and behavior); Brainguard Technologies (helmet Design for TBI); Elminda (EEG and drug evaluation); and Cortera Technologies (brain recording devices). He has 39 issued and 53 pending patents in the US and abroad, and contributes his expertise in technology development and start-up approaches.
Many types of neurological disease develop slowly, with progressive neurodegeneration wreaking irrevocable damage in the brain. Patients afflicted by such diseases are caught in medical limbo: while there may be indicators that they are at risk, there are no reliable diagnostics to predict outcomes, or therapies to prevent disease progression.
Our vision is to characterize the earliest stages of various progressive neurological diseases, and identify underlying biological triggers that cause damage to the brain. By uncovering a previously unknown role for vascular damage as a key cause of neural pathology and cognitive decline, we identified a novel target that can be readily detected in patient populations (via companion MRI diagnostics), and treated to not only reduce symptoms, but slow disease progression. In other words, a personalized, disease-modifying treatment.
Short term, we are focusing on a targeted entry market to treat age-related cognitive decline that results from BBB damage during aging. The current dementia market, lacking effective treatment, is $3 billion, but is projected to be over $20 billion for an effective drug. Long term, treating the therapeutic target of vascular induced pathology has broad applications for a range of diseases, including post-traumatic epileptogenesis, stroke, concussion, and chronic traumatic encephalopathy (CTE).
Our studies revealed that vascular damage plays a previously unknown role in initiating many neurological diseases. A variety of insults – aging, head injury, stroke, CNS infection, and brain tumors – all cause disruption of the BBB, allowing molecules to leak from the blood into the brain. In clinical studies, these seemingly different injuries have remarkably similar secondary outcomes, in which patients develop cognitive decline, neurodegeneration, and seizures. We identified a single molecule from the blood, albumin, that in rodents causes all of these secondary pathologies. After BBB disruption, albumin enters the brain and binds to the TGFβR, triggering activation of the inflammatory TGFβ signaling cascade and causing neurodegeneration, cognitive decline, and epilepsy.
Our approach for implementing this technology is two-fold: Firstly, we have developed new MRI diagnostic software to quantify BBB disruption, allowing us to identify at-risk patients. Because dementia arises heterogeneously within the aging population, this allows us to take a personalized approach to screen and identify patients who are suffering from previously unknown vascular dysfunction. Secondly, we use IPW, a TGFβR1 kinase inhibitor, to reduce pathological inflammatory TGFβ signaling and mitigate the progressive neurodegeneration and neural dysfunction causing cognitive impairment.
BBB breakdown occurs widely during aging. Though hidden from the view of most clinicians, it appears time and again in imaging studies, leading to speculation that it could be a major, untreated contributor to cognitive decline1–4. However, until now, there has been no mechanism to link BBB disruption to cognitive decline, and thus no feasible treatment strategy. Our research identified a key molecule, albumin, that enters the brain after BBB disruption and activates TGFβ signaling to cause a range of pathological outcomes, with symptoms strikingly similar to those seen in aging. These outcomes result from the inflammatory actions of TGFβ signaling, which causes gliosis and remodeling of neural networks, leading to neural dysfunction and neurodegeneration5–16.
We found that otherwise healthy, normally aging mice show chronic leakiness of the BBB and have high levels of albumin in the brain, whereas young adult mice have healthy, intact BBB (Fig. 1). Post-mortem sections from aged human brains showed similar evidence of albumin and inflammatory TGFβ signaling (Fig. 1). Aged mice also have aberrant neural activity, detected in direct ECoG brain recordings, that is absent in young mice but appears after albumin is infused into the brain (Fig. 2). Together, these data suggest that BBB breakdown and inflammatory TGFβ signaling are a major cause of age-related neural impairment.
To test the efficacy of clinical intervention, we treated mice with daily doses of IPW. Mice given one week of daily IPW showed significant improvement in memory (Fig. 3) in established tasks for age-related cognitive dysfunction. Furthermore, one week of IPW treatment drastically reduced the vulnerability of aged mice to seizures induced by pentylenetetrazol (PTZ), decreasing mortality and seizure severity (Fig. 3).
To address the role of this pathway in human age-related dementia, we performed imaging in aging patients exhibiting mild cognitive impairment (MCI). Importantly, MCI involves only subtle impairments detected via neurological mental status testing, without the major deficits that interfere with daily life, and is considered to be the earliest stage for detecting future dementia risk. We show that BBB disruption is already present in MCI patients, but absent in healthy individuals (Fig. 4). These data demonstrate that MRI imaging of BBB has diagnostic potential to identify at-risk patients before pathology progresses to a critical stage.
We are preclinical venture, spun out of our academic lab at UC Berkeley under a technology transfer licensing model. Our immediate goal is to complete final proof-of-concept (POC) and IND enabling safety and toxicology studies, supported by fundraising targeted at grants and seed investors, as a foundation for clinical trials in age-related dementia. Our final POC study is designed to exactly replicate the target clinical trial in aged mice: first screening mice for BBB status via small animal MRI and behavior testing, then treating with IPW and following personalized outcomes within individual animals in follow-up cognitive testing. Furthermore our toxicology schedule is designed for maximum efficiency by first screening cardiac risk (the most likely risk associated with TGFβ17,18) before investing in full rodent and non-rodent toxicology. Our long-term vision is to develop a new platform targeting vascular pathology to treat a wide variety of neurological diseases. Thus our short-term plan includes basic R&D to establish translatability of treatment in other disease models, as well as divisional patents (under the umbrella of our original use patent), seeking other indications such as mild head injury leading to CTE and stroke. This plan is detailed in our Gantt chart (Fig. 5)
|Material||Scale up synthesis of IPW (GMP) (Jubilant, India)||$ 80,000|
|Other||• Final proof of concept studies–OneStart Funding ($30,000)|
• Rat and dog 3 dose range finding – OneStart Funding ($100,000)
• Cardiovascular toxicology ($30,000)
• 14 day tox study and recovery in rat and dog including histopathology and clinical chemistry ($600,000)
• CNS and respiratory safety ($120,000)
Clinical TrialsOur budget covers the items listed in our Gantt chart, except for R&D activity which is covered by academic grants. Funding from OneStart would provide a key bridge, supporting final POC studies in age-related dementia and initial toxicology. POC studies are performed in lab, while safety and toxicology will be conducted via CROs. CRO prices reflect cited quotes, or estimates averaged from multiple quotes.
For each major area of risk, we implemented mitigating strategies to increase our likelihood of success.
Whether or not a new technology will translate from promising animal models to actual efficacy in human clinical treatments is an inherent risk in drug development, particularly in new treatment domains such as ours. We seek to reduce this risk as much as possible through the following actions:
1) Relevant animal models. Many studies use reductionist models, for example conferring partial disease phenotype via transgene expression. While such models allow for rapid development, they may not recapitulate the true biology and heterogeneity of the target disease (such as dysfunctional BBB), and so may yield “false hits” that eventually fail. In contrast, we use naturally aged mice in all of our studies, which have the full host of complicated biological impairments associated with aging, and as such more closely approximate the true human clinical population. Our approach is effective in genuinely improving cognitive function in naturally aged mice, suggesting that it is much more likely to translate to the human target population experiencing BBB breakdown.
2) Reproducibility across multiple models. If inflammatory TGFβ signaling induced by vascular damage is a fundamental disease-causing pathway, inducing this pathway should produce reliable, predictable disease outcomes. In line with our vision to develop a new platform for treating vascular causes of neurological disease, we have tested this target across multiple models and methods, and have demonstrated remarkably robust and reproducible outcomes8,5,10,9,11. Similarly, in addition to our lead drug IPW, we have used several other tool compounds to block TGFβ signaling, including neutralizing antibody, other kinase inhibitors (SB and SJN), and the angiotensin drug, losartan, which has off-target effects suppressing TGFβ signaling. Again, these distinct approaches show highly similar outcomes, reducing inflammatory signaling and intermediate pathological markers, and preventing end-stage pathology10,9,11,13.
3) Parallel human studies. As much as possible, we have sought to validate our pathway in human patients. We performed imaging studies in human patients at early disease stages, for example football players suffering repeated mild head injury12 and aging patients with early mild cognitive impairment, and have found significant, previously unknown BBB disruption in these populations. Furthermore, we have performed analysis on post-mortem tissue from aged patients, and found the same pathological markers that are induced in rodent models following BBB disruption.
2. Safety and Tolerability
The TGFβ pathway is a ubiquitous, master regulatory pathway involved in a variety of biological processes, and as such has appealing potential as a disease-modifying target but also raises safety concerns. We note the following in mitigating this risk: 1) TGFβR antagonists have been a major focus for cancer applications, and several candidates have passed through stringent drug development programs at major pharmaceutical companies. Eli Lilly has a TGFβR kinase inhibitor (Galunisertib) in phase II clinical trials for liver cancer and glioblastoma19,20. For existing TGFβ drugs, safety concerns are partially mitigated based on dosing strategy designed to modulate and reduce, rather than completely suppress, the level of TGFβ signaling. Such strategies reduce side effects by leaving baseline TGFβ signaling intact. Similarly, because we target abnormally high TGFβ signaling after BBB disruption, our dosing strategy is aimed to reduce this pathway to healthy, baseline levels without abolishing overall TGFβ signaling. 2) We have dosed IPW for up to 12 weeks in young mice, and up to 2 weeks in aged mice, without observing any health concerns. In future studies, we will address long-term safety (how to optimally modulate TGFβ signaling in chronic treatment) and explore treatment duration needed for optimal disease-modifying outcomes.
3. Clinical Trials
Clinical trials for new therapy approaches face major difficulties in heterogeneous patient populations and in establishing a measurable outcome in health improvement. We mitigate this risk by using companion MRI diagnostics as an inclusion criterion, targeting therapy to potential responder patients. We also mitigate risk by following established clinical trial designs implemented for approval of existing dementia drugs. These approaches have used well-defined and monitored patient populations in assisted care facilities, which exploit regular staff contact to provide quantified pre-post assessment of cognitive function.
4. IP Strategy
Our Method-of-Use patent, though less typical, is appropriate for our broad platform approach to develop new treatments for a variety of diseases by targeting vascular damage. Additional to our filing firm (Bozicevic, Field & Francis), our outside review with IP attorneys at WilmerHale and Wilson Sonsini support this approach for a viable IP protection. We also have several new TGFβR inhibitors in our pipeline based on a novel scaffold (already synthesized and being screened), for which we will seek composition of matter patents.
There are two classes of dementia drugs, acetylcholine esterase inhibitors (donepezil, civastigmine, and galantamine) and a glutamate modulator (memantine), both based on the premise of modulating neurotransmitter signaling to boost cognitive function21. These drugs are widely recognized as having poor efficacy, primarily because they are symptom-modifying rather than disease-modifying: even if they provide a temporary boost to cognitive function, the underlying neurodegeneration of the disease will continue to progress to a stage where the drug is no longer effective. More significant competition will arise from other next generation approaches: disease-modifying strategies such as attacking tau and amyloid pathology, mitigating oxidative damage, inhibiting apoptosis, and most closely related to us, attenuating inflammatory damage. Given that many of these strategies have advanced to clinical trials, we do not expect to be first to market. Rather, we aim to segment the market by targeting patients with BBB disruption (detected by companion diagnostics). Furthermore, by treating a unique pathway, we have the potential for combination therapy that gives us opportunities to partner with, rather than compete against, other emerging strategies.
We filed a method-of-use patent, with our Scientific Directors as inventors, via UC Berkeley’s IP office, claiming the method of treating neurological disease after BBB disruption by targeting the TGFβR. Correspondence from the patent office recently deemed this claim allowable, and we expect it to be granted within 3 months. Under a tech transfer model, we will exclusively license this IP from the university.
Use of IPW is enabled by this claim. IPW was originally developed as a TGFβR inhibitor for cancer by Scios (in a team led by our advisor Barry Hart). After Johnson & Johnson acquired Scios seeking other assets, they cut all other programs and abandoned the associated patent filings, placing IPW in the public domain. Thus IPW represents a relevant and clinical-ready drug with potential to be quickly developed and deployed.
In partnership with Barry Hart we also synthesized novel TGFβR antagonists (unique scaffold), which we are screening as candidates. These novel antagonists will allow us to complement our Method-of-Use protection with original composition of matter patents.
We are developing a novel approach to treat age-related cognitive decline. Unlike current therapies, our disease-modifying strategy attacks the underlying causes of neural dysfunction and has the potential to slow the progression of dementia, while also alleviating cognitive dysfunction even in acute treatment in our rodent models. Building on over 10 years of our research showing a new link between vascular damage, TGFβ signaling, and disease outcomes, we are now working to bring this new therapy into the clinic by completing safety and toxicology studies. As an early stage venture, we face considerable risk, yet we have developed a risk mitigation plan supported by strong translational data in animal models, and human imaging diagnostics that not only identify the hallmarks of BBB pathology in human patients, but also give us the capacity to deploy our drugs in a targeted, personalized manner.
1. Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis. Neurobiol Aging 2009; 30: 337–52.
2. Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z et al. Blood-Brain Barrier Breakdown in the Aging Human Hippocampus. Neuron 2015; 85: 296–302.
3. Rosenberg GA. Blood-Brain Barrier Permeability in Aging and Alzheimer’s Disease. J Prev Alzheimer’s Dis 2014; 1: 138–139.
4. Zeevi N, Pachter J, McCullough LD, Wolfson L, Kuchel GA. The blood-brain barrier: geriatric relevance of a critical brain-body interface. J Am Geriatr Soc 2010; 58: 1749–57.
5. Tomkins O, Friedman O, Ivens S, Reiffurth C, Major S, Dreier JP et al. Blood-brain barrier disruption results in delayed functional and structural alterations in the rat neocortex. Neurobiol Dis 2007; 25: 367–77.
6. Seiffert E, Dreier JP, Ivens S, Bechmann I, Tomkins O, Heinemann U et al. Lasting blood-brain barrier disruption induces epileptic focus in the rat somatosensory cortex. J Neurosci 2004; 24: 7829–36.
7. David Y, Cacheaux LP, Ivens S, Lapilover E, Heinemann U, Kaufer D et al. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? J Neurosci 2009; 29: 10588–99.
8. Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O et al. TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 2007; 130: 535–47.
9. Cacheaux LP, Ivens S, David Y, Lakhter AJ, Bar-Klein G, Shapira M et al. Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci 2009; 29: 8927–35.
10. Bar-Klein G, Cacheaux LP, Kamintsky L, Prager O, Weissberg I, Schoknecht K et al. Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann Neurol 2014; 75: 864–75.
11. Weissberg I, Wood L, Kamintsky L, Vazquez O, Milikovsky DZ, Alexander A et al. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol Dis 2015; 78: 115–25.
12. Weissberg I, Veksler R, Kamintsky L, Saar-Ashkenazy R, Milikovsky DZ, Shelef I et al. Imaging blood-brain barrier dysfunction in football players. JAMA Neurol 2014; 71: 1453–5.
13. Friedman A, Bar-Klein G, Serlin Y, Parmet Y, Heinemann U, Kaufer D. Should losartan be administered following brain injury? Expert Rev Neurother 2014; 14: 1365–75.
14. Levy N, Milikovsky DZ, Baranauskas G, Vinogradov E, David Y, Ketzef M et al. Differential TGF-β Signaling in Glial Subsets Underlies IL-6-Mediated Epileptogenesis in Mice. J Immunol 2015; 195: 1713–22.
15. Chassidim Y, Veksler R, Lublinsky S, Pell GS, Friedman A, Shelef I. Quantitative imaging assessment of blood-brain barrier permeability in humans. Fluids Barriers CNS 2013; 10: 9.
16. Veksler R, Shelef I, Friedman A. Blood-Brain Barrier Imaging in Human Neuropathologies. Arch Med Res 2014. doi:10.1016/j.arcmed.2014.11.016.
17. Anderton MJ, Mellor HR, Bell A, Sadler C, Pass M, Powell S et al. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol Pathol 2011; 39: 916–24.
18. Roberts RA, Kavanagh SL, Mellor HR, Pollard CE, Robinson S, Platz SJ. Reducing attrition in drug development: smart loading preclinical safety assessment. Drug Discov Today 2014; 19: 341–7.
19. Rodón J, Carducci M, Sepulveda-Sánchez JM, Azaro A, Calvo E, Seoane J et al. Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Invest New Drugs 2015; 33: 357–70.
20. Brandes AA, Carpentier AF, Kesari S, Sepulveda-Sanchez JM, Wheeler HR, Chinot O et al. A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro Oncol 2016. doi:10.1093/neuonc/now009.
21. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008; 148: 379–97.