Neuroscience has had a tough run of news lately. With Amgen deprioritizing neuro this year, Pfizer doing the same last year, and others like BMS, GSK, and AZ cutting back on CNS a few years earlier, it would seem dark times for neuroscience R&D. Add to that the recent unpredictable complexity around Biogen’s aducanumab, where hugely expensive Phase 3 trials are caught in the maelstrom between negative futility and positive analysis, and it might further question why anyone would want to work in the space.
Despite all this, I’m not negative on the field – in fact, I’m bullish on neuroscience.
Sure, it presents some unique challenges: uncertain diagnoses, long progressive burdens of disease, multiple etiologies, complicated clinical trials, among others. But new ways of thinking about neurologic diseases, informed by human genetics and a better understanding of the brain, are emerging out of basic and clinical research and are very encouraging; these offer new paths to develop targeted medicines in specific subsets of patients. The wonderful progress in SMA is a good example of what can happen with precision targeting of the genetic underpinnings of familial forms of neurodegeneration. When armed with novel translational tools, these present attractive opportunities for potentially addressing patient needs in a number of neurodegenerative settings.
And it’s hugely important for patients and society that we work to tackle these conditions; the moral imperative to make medicines in these challenging settings is important. I’d argue this is another element of our industry’s social contract: we’ll work on tough diseases with high morbidity and mortality in exchange for knowing that innovations in these areas will be rewarded.
Frontotemporal Dementia (FTD)
As an example of why I’m optimistic about (and committed to working in) neuro, let’s take a quick look at Frontotemporal Dementia. FTD is a tragic disease that robs one of their personality, alters behavior and memory, and can affect use of language and motor functions. It is the most common form of dementia under the age of 60, with more than 60,000 people suffering from FTD in the US. Check out this 60 Minutes episode from earlier in the year for some very moving patient and caregiver testimonials.
There are two primary molecular subsets of FTD, depending on the type of misfolded protein found in the frontal and temporal lobes of the brain: those involving tau and those involving TDP43. Loss of function mutations in either progranulin or C9orf72 are both linked with the form of FTD involving TDP43 accumulations. Each of these genetic subsets of FTD represent roughly 10% of the total FTD population.
How these mutations lead to FTD is unknown, though multiple signs seem to point to dysfunctional lysosomal biology. Many of the genes associated with FTD, as well as Parkinson’s Disease, are involved in lysosomal activity or localized there: progranulin/GRN, C9orf72, GCase, TMEM106b, GALC, SMPD1, etc… Sphingolipid biology in the lysosome appears important. Several of these neurodegenerative “risk factor” heterozygous mutations lead to lysosomal storage diseases when presented as homozygous loss of function mutations. Dysfunctional lysosomes lead to impaired protein degradation and autophagy. There’s an emerging consensus that a better understanding of the lysosome could provide insights into how to treat these various neurodegenerative conditions; a fantastic and thorough review titled “Lysosomal Dysfunction at the Centre of PD and FTD/ALS” was just published earlier this month in Trends In Neurosciences.
Much like the Michael J. Fox Foundation in Parkinson’s Disease, research in FTD has in part been catalyzed by a number of patient advocacy groups (like AFTD) and non-profit foundations, most notably the Bluefield Project to Cure FTD. Bluefield has been funding researchers in progranulin-deficient FTD for over a dozen years, including over 26 investigators, with an eye to translational studies and drug discovery. These and other efforts have helped advance the field considerably, and have helped leverage the more basic research of the NIH.
Beyond the molecular understanding of the causes of FTD, in order to develop new medicines we need to better understand the actual progression of the disease. Here we turn to several large multi-center natural history studies of FTD patients, called ARTFL and LEFFTDS, in the US and the GENFI study in Europe/Canada. Of particular note, LEFFTDS and GENFI enrolled patients with FTD that have known genetic mutations linked to the disease (e.g., mutations in progranulin, C9orf72, or tau). These are hugely important studies for the field. Last month the NIH announced $63M of funding to integrate ARTFL and LEFFTDS into one integrated research consortium (ALLFTD) to continue the natural history study another five years.
The goal of all of these studies is to improve our understanding of how to accurately identify FTD patients and measure the progression of different types of FTD. Fluid and imaging biomarkers are also important outputs of this consortium. For example, CSF levels of neurofilament light chain (NfL) appears to rise dramatically in patients as they progress from asymptomatic into clinical manifestations of FTD, along with associated brain loss.
These large consortia-driven insights around the genetics, progression, and biomarkers for FTD provide real value to future investigators and drug developers, and are strong reasons for optimism around thinking through opportunities for new therapeutics. Other drug developers seem to share our enthusiasm: for example, Alector has made good early clinical progress in FTD.
The future of neurodegenerative medicines will likely involve a greater reliance on precision therapies: patients identified by their genetics, monitored through fluid and imaging biomarkers, and treated with drugs designed to ameliorate their specific genetic pathophysiology. This is both an inspiring and realistic vision.
We’ve put our capital behind this vision. Over the past few years, we’ve been increasingly excited about “contrarian” neuroscience concepts more generally, as described here in “Venturing Boldly Into Neuroscience”.
As one of many examples, back in 2014 we helped launch Lysosomal Therapeutics (LTI), focused on GBA mutation in Parkinson’s Disease (GBA-PD), which is now in clinical development with a GCase activator (here).
Continuing this theme of targeting genetic subsets of neurodegenerative conditions, last week we announced the launch of Arkuda Therapeutics, a new startup focused on developing medicines based on progranulin and lysosomal biology. The launch was well covered by others in the media (here, here, here, here).
As described above and in the attached illustration, progranulin-deficient FTD is an important subset of temporal lobe dementia. Arkuda has a clear therapeutic thesis: increase progranulin back to normal levels inside of the brain, and in the neurons in particular, so it can elicit both its immuno-modulatory functions and also be processed into its effectors (granulins) and improve the activity of the lysosome in maintaining protein homeostasis.
As background, we helped co-found Arkuda with serial biotech entrepreneurs Gerhard Koenig and Duane Burnett. Both were scientifically trained in large pharma and moved into biotech 10-20 years ago, where they worked together at Forum Pharmaceuticals. In addition, Gerhard and I had worked together in a prior Atlas company, called Quartet Medicine, where he drove its very disciplined “successful failure” as a biotech. His judgement and leadership at Quartet, as well as dialogues around other neuro topics, gave me great confidence in his drug hunter bona fides. When he and Duane described the approach they wanted to take for treating FTD-GRN by increasing the level of functional progranulin, and the downstream granulins themselves in the lysosomes of neurons, it was a quick decision.
After a year of seed stage confirmation that our discovery approach was delivering quality chemical equity and stellar preclinical animal data, we raised an oversubscribed Series A of $44M to power up the story with new co-investors from Pfizer Ventures, Tekla, Bioinnovation Capital, and others. This multi-tranche financing should bring the program to patients in the clinic over the next several years.
To support this drug discovery and development effort, we’ve assembled a strong core team of scientists, leveraging a hybrid virtual/lab model including both incubation within Atlas Venture and a modest wet lab footprint at LabCentral. CFO Joanna Bryce and CBO Andy Hu round out the leadership team and provide the financial and business strategy support to this exciting young company. We’re also very fortunate to have Robert Urban, former J&J executive, on the Board as an independent. Teams are always critically important to the trajectory of a startup and Arkuda has brought together an incredibly strong group dedicated to this fight against neurodegeneration.
It’s a great time to be bullish about neuroscience R&D – we’ve got great teams tackling great science to help patients in great need. Onward and upward.