Thinking Boldly: Alkermes Acquires Rodin Therapeutics

Posted November 18th, 2019 in Business Development, Exits IPOs M&As, Portfolio news, Science & Medicine | Leave a comment

Today Alkermes announced its acquisition of Rodin Therapeutics, a leader in the field of synaptic dysfunction and neuronal epigenetics.

Alkermes extensive experience in CNS diseases made them an ideal partner for Rodin, and this acquisition helps expand Alkermes’ efforts into a wide range of neurodegenerative disorders. Importantly, Alkermes appreciated the broad nature of Rodin’s epigenetic HDAC complex-selective pipeline of small molecule therapeutics. Under the terms of the definitive agreement, Alkermes will purchase the company for $100 million and Rodin’s shareholders will be eligible to receive future payments of up to $850 million for development, regulatory, and commercial milestones.

Here’s a summary of the scientific story behind Rodin’s approach. The loss of synapses in neurodegenerative patients is the best correlate of cognitive decline, and synaptic dysfunction drives clinical symptoms regardless of the underlying pathology. Decades of literature have demonstrated the pro-synaptic, pro-cognitive effects of HDAC inhibitors, including compelling work from the MIT lab of Li-Huei Tsai on memory and learning (here, here, here). Historically, the challenges for using conventional HDAC modulators in CNS diseases have been their hematopoietic toxicity, limited HDAC class selectivity, and poor brain penetration – and Rodin was set up to address these and bring pro-synaptic epigenetic modulators to patients.

Several different discovery approaches were explored by Rodin to overcome those challenges and resulted in an extensive chemistry estate of complex-selective HDAC modulators. As a primer in epigenetics, HDAC enzymes only function in large multi-protein complexes inside the cell that direct their activity towards different loci in the genome: the major Class I HDAC complexes include CoREST, NCoR, Sin3, and NuRD. By using state-of-the-art enzymatic complex assays, the Rodin team was able to establish structure-activity relationships for inhibiting the CoREST complex vs the others. This selectivity profile completely changes their safety and tolerability profile, while maintaining the efficacy on synaptic function. In preclinical studies, our CoREST modulators address the molecular, structural, and functional deficits that occur in many synaptopathies, like Alzheimer’s and other dementias.

Based on its stellar preclinical profile, we took our lead program, RDN-929, into Phase 1 studies in late 2018, where our SAD/MAD data support that the compound is safe, well-tolerated, and active in engaging the target (including pharmacodynamic measures of epigenetic changes). It’s the first reported brain-penetrant, complex-selective HDAC inhibitor and shows no signs of hematological toxicity.

From a corporate perspective, Rodin’s history reveals much about the journey: Atlas Venture started looking at HDAC inhibition for memory and learning as early as 2006, and we almost started a company in the space on several occasions over the next seven years. In 2013, the venture creation stars aligned around a credible non-conventional chemistry strategy, and we embarked on a seed investment with J&J (in the “seed class” of 2013). With emerging signal that the discovery effort was advancing, we closed a Series A in 2014. I had the privilege of being the Acting CEO of Rodin for its early years while it incubated at Atlas, but in 2015 we recruited serial entrepreneur Adam Rosenberg to run the startup. Shortly thereafter, we closed on an option deal with Biogen that brought capital and a possible exit path to the story.  As can happen with option deals, a change in strategy and a new head of R&D at Biogen led to terminating that agreement in 2017, which enabled us to raise a Series B financing, bringing several great co-investors to the story, including GV, Hatteras Venture Partners, Remeditex Ventures, and Third Point Ventures.

With the support of the Series B funding, we advanced into the clinic and continued to build out a platform of complex-selective compounds in preclinical studies. Other promising, earlier-stage molecules are being directed at multiple additional indications where safe HDAC-complex inhibitors could be explored, such as sickle cell disease and oncology. With modest seed, Series A, and Series B funding rounds, Rodin was incredibly capital efficient over the last six years, having spent only ~$40M to deliver the story to this point.

We look forward to watching Alkermes progress Rodin’s platform forward to longer term studies in patients.

A few notable themes jump out from the Rodin experience:

  • Biotech, like life, isn’t linear. We started out on 2013 focused on a chemistry strategy with one discovery partner, but followed the data to find a new path with a different angle. J&J was involved, and then wasn’t. We had a deal with Biogen, and then we didn’t. The story evolved, and like most stories in the real world this one wasn’t a straight line. But amidst all the chutes and ladders in this story we’ve brought a potential medicine forward into the clinic.
  • Success is 100% dependent on the team. The Rodin team, under Adam’s exemplary leadership, has been an incredibly productive and capital efficient crew, and the esprit de corps of this tight roup is very strong. I’ll call out the leadership team specifically – Michael Ryan, Anne Sullivan, Ajim Tamboli, Magnus Ivarsson, and Steve Sweeney – but there is also a great bench of scientists behind this story that have delivered impressively, including Nate Fuller, Rodin’s head of chemistry, who was instrumental in driving Rodin’s successful efforts to design complex-selective molecules. Teams also change over time, as per the first theme: it’s interesting to note that the current leadership team all joined after 2015, recruited to the story by Adam as he added talent over time, reflecting a common reality in many biotechs around team turnover and evolution.
  • Better living through chemistry. Riffing off that great DuPont slogan, it’s very true here that the chemistry advances made by the Rodin team have been central to our success. Cracking open new frontiers in complex-selective modulation with novel chemotypes created the opportunity to bring these medicines to patients. Nate and the rest of the chemistry team (along with our very engaged chemistry advisory board of “greybeards” John McCall, Bill Greenlee, and John Lowe) delivered an impressive chemical estate for Rodin (here).
  • New tools can open up translational research. Because neuroscience is so challenging, early translational tools are critical. One of the reasons for our optimism has been the advances in disease-relevant fluid and neuroimaging biomarkers, like the SV2A PET ligand that we’ve explored in a non-interventional clinical study in both healthy volunteers and Alzheimer’s patients. A key Rodin team member, Berkley Lynch, was part of the group that characterized SV2A years ago at UCB Pharma. This allows for the imaging of synaptic density in the brain real-time, and has now been used across multiple diseases to observe the changes in the brains of patients over time.
  • Contrarian neuroscience is exciting neuroscience. Neuroscience isn’t easy and with large pharma’s deprioritizing R&D in the space (like Amgen recently, and Pfizer, AZ before that), it’s been a contrarian bet for years. Even within neuro, there’s been a lack of diversity in approaches (e.g., all the investment “oxygen” has been consumed by amyloid in AD), and typically small biotechs generally shy away from diving into Alzheimer’s and other dementias. Further, epigenetics outside of cancer has also fallen out of favor, amplifying the contrarian nature of Rodin’s approach. Adam has been on the bully pulpit multiple times with his blogs on the subject (here, here, here).
  • Conviction of the few is critical. Because it’s contrarian, finding partners to help fund projects in neuroscience isn’t easy. But we found a great group of likeminded co-investors at Rodin, who share the conviction that these are approaches worth advancing to patients: Clay Thorp of Hatteras, Ben Robbins at GV, John Creecy at Remeditex, and Jason Hong at Third Point. Neuroscience isn’t in the risk appetite for every investor, but finding a coalition of the willing is critical – and we found that with these great partners.
  • Rodin’s science is personal. Everyone knows someone with dementia, and almost all of us have a family member that suffers or did suffer from it. Rodin embraced that and really integrated that aspect into their culture. In fact, the “Why” page of their corporate website (look at it soon before it disappears!) so beautifully captures the personal nature of dementia by showing pictures of our team’s loved ones affected by dementia.My grandmother, Evelyn, is one of the pictures. She passed away from dementia, likely Alzheimer’s Disease, almost 25 years ago.

It’s been a wonderful and dynamic six-year journey for Rodin, and it’s been an honor to be a part of it.

I’m truly excited to see Rodin’s cutting-edge neuronal epigenetic approaches advance deeper into the clinic and to patients in the hands of a neurology leader like Alkermes.

 

 

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The Promise Of Precision Neuroscience And Launch Of Arkuda Therapeutics

Posted November 14th, 2019 in Portfolio news, Rare Diseases, Science & Medicine, Translational research | Leave a comment

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.

Atlas Venture & Arkuda Therapeutics

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.

 

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