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Central Nervous System Therapies: Where We’ve Been and the Road Ahead

Posted by Varun Renjen, M.D. and Jose Quejada, Ph.D. on November 16th, 2020.

“Life moves pretty fast. If you don’t stop and look around once in a while, you could miss it.”

Some readers might recognize that as a memorable line from the ‘80’s classic movie, Ferris Bueller’s Day Off.  Those same readers might also ask what it has to do with central nervous system (CNS) therapies.

In fact, it’s quite a fitting statement.  In recent years, much attention has been focused on the dramatic advancements in oncology, with the rise of immuno-oncology and cell-based therapies, some of which show curative potential.  However, while attention was focused on those developments, significant changes have been taking place in CNS with less fanfare.

These changes are being driven by a handful of key trends, and they could facilitate a revolution in CNS treatments in the coming years.  This article is the first in a two-part series in which we’ll explore where we’ve been regarding central nervous system (CNS) therapies, as well as where we’re headed.

Here, in part 1, we share a brief history of some key developments in CNS that have helped get us to the present point.  In addition, we’ll outline the key trends that are driving change now (and that will continue to drive change over the next few years).

In part 2, we’ll look further down the road.  In particular, we will explore deal activity in the CNS space and make some predictions for CNS markets in 2021.

Let’s dive in!

Brief History and Key Developments

Without going into too much detail, it’s fair to say that many of the earlier drugs for use in psychiatric and other CNS disorders were discovered under serendipitous circumstances.  During the 1980’s and 1990’s, a better understanding of receptor theory and the use of structure activity relationship studies led to a range of newer therapies, particularly in psychiatric disorders like depression.

However, our understanding of CNS-related diseases often remained limited.  For many diseases, we did not fully understand the natural history; we generally did not have adequate models that reliably replicated the diseases seen in patients; we were often unable to determine the true underlying causes, and our abilities to specifically target those causes were limited or non-existent.

CNS Treatments Often Did Not Address Root Causes

As a result, CNS therapies were more often developed to help manage the key manifestations of a disease rather than the root causes.  This was evident in a range of diverse CNS diseases throughout the 1990’s and early 2000’s.

In Alzheimer’s disease, for example, mainstay therapies such as Aricept (donepezil) or Namenda (memantine) are mainly focused on masking the symptoms of the disease rather than targeting underlying causes or actually modifying the disease itself.

In multiple sclerosis (MS), different immunology-based approaches have been successful and have been disease modifying, but the root cause of myelination has still not been addressed. This reality was highlighted by the recent failure of Biogen’s anti-LINGO approach.

In another example, one of the core therapies for Parkinson’s disease, levodopa, is basically a dopamine replacement therapy that doesn’t actually modify the disease itself.  Across a range of different disorders, such as Huntington’s disease, amyotrophic lateral sclerosis (ALS), and many others, the theme was consistent. This has been highlighted with the litany of failures across those diseases.

CNS Deprioritized for a While but Now a Resurgence

During the decades mentioned above, many companies moved out of CNS or reduced their investments in the space, including Pfizer, Lilly, AstraZeneca, and others.  Relative to other therapeutic areas, biopharma companies deprioritized neuroscience.

However, even with the reduced attention, science marched forward.  Our understanding of many CNS diseases began to improve, especially as researchers increased their knowledge of the genetic factors involved.

With greater understanding comes increased opportunities to develop effective, disease modifying treatments.  Plus, the reality of many CNS-related diseases never changed:  They can be quite debilitating for patients and incredibly costly for society, meaning that the underlying demand for effective treatments has always been strong.  When you couple increased understanding of those diseases with robust markets, excitement and investment dollars are sure to follow.

Over the past 10 years, more attention, more venture capital money, and more research muscle has been focused on a wide range of CNS-related diseases.  Also, big companies have come back into the mix as others continue to invest, including Roche, Biogen, Novartis, Johnson & Johnson, Otsuka, and others.  Several smaller companies focused on CNS such as Sarepta and Sage have also emerged.

This added focus is beginning to bear fruit. Gene and targeted therapies are now available for Duchenne Muscular Dystrophy (DMD) and spinal muscular atrophy (SMA).  In addition, Biogen’s investigational therapy, aducanumab, could become the first Alzheimer’s therapy approved to impact the underlying disease pathophysiology. Though the AdComm meeting was negative in November 2020; there is still a possibility the drug may be approved at their PDUFA in March 2021

We’re also seeing advancements in MS, psychiatric disorders, a range of rare neurological disorders, and more.  With this situation as a backdrop, let’s now explore some of the trends that are helping drive the change.

Key Trends Driving Change in CNS

Technology Expansion

A range of innovative technologies are now being expanded into CNS, potentially enabling the development of a numerous therapies.  These include RNA technologies (both RNAi and antisense oligonucleotides), adeno-associated viruses (AAV) gene therapy, and CRISPR.

RNAi, for example, involves a method for silencing the expression of targeted proteins in an effort to halt development of a disease.  Originally, RNAi therapies had challenges with poor efficacy and high toxicity.  However, further advancements are helping to address these issues.  RNAi therapies were initially limited to treating diseases through the liver, but they are fast becoming usable to target other organs and RNAi is now being leveraged in CNS.  Here are a few examples:

  • Alnylam’s ONPATTRO (patisiran), approved in 2018, is indicated for hereditary transthyretin-mediated amyloidosis (or HATTR) with polyneuropathy.
  • Alnylam and Regeneron are teaming up with a major deal focused on developing new CNS therapies using RNAi, as are Eli Lilly and Dicerna.
  • Sarepta is also in the mix, leveraging RNA splicing (antisense) technology. It has two drugs currently on the market (EXONDYS 51 and VYONDYS 53) for DMD.

AAVs (adeno-associated viruses) provide another example.  AAVs which originated as naturally occurring viruses have become a delivery platform for non-integrating gene therapy.  Historically, they have not been very effective.  However, the third generation of AAV, most relevantly AAV9, has represented a significant leap forward and is being used in CNS-related applications.  It is able to cross the blood-brain barrier and is particularly effective when coupled with intrathecal or intracranial delivery.

A good example of a therapy leveraging AAV technology is is AveXis’ ZOLGENSMA, indicated for SMA in boys under two years of age.  Incidentally, ZOLGENSMA is one in a series of breakthrough therapies for SMA.  Five years ago, there were no treatments available.  That changed in 2016 when Biogen’s SPINRAZA (nusinersen) was approved.  2019 brought ZOLGENSMA, which is potentially curative.  This year (2020), Evrysdi (risdiplam) was approved as an oral treatment for SMA in infants, children, and adults. Despite the advancements, ZOLGENSMA is expected to be the market leader in SMA, given its curative potential; especially if the label expansion happens for older children.

Clearly, AAV9 shows great promise in CNS applications.  Coupled with multiplexing CRISPR technology (targeting multiple genes at once), the potential for the technology is expanded greatly.

As a range of technologies are expanded for use in CNS, the breakthroughs will continue.  We are closer to the beginning of this process than we are to the end.

Increased Mental Health Awareness

If we look back in time around 20-30 years, we would see very different attitudes to some CNS-related disorders than what we see today.  There was still a prevailing attitude among many in society that things like bipolar disorder, depression, ADHD, and the like weren’t “real” diseases.  Kids with ADHD, for example, simply lacked discipline.  People with depression just needed to “snap out of it,” especially if there seemed to be no external reasons for their depression (such as physical health, marital, financial, or other problems).

As time went on, attitudes began to change.  People increasingly realized that there are underlying pathophysiological drivers of these disorders.

Fast-forward to today, and the COVID-19 pandemic—with its resultant lock-downs—has further raised awareness of mental health issues and the need for a better therapeutic armamentarium.  We’re now seeing increased innovation in this area, for example:

  • The FDA issued guidance on expediting digital technologies for treating mental health issues during the COVID-19 pandemic.
  • Well-known—and sometimes taboo—compounds are now being studied for their therapeutic benefits in CNS-related indications. Janssen’s Spravato is a derivative of ketamine (a well-known “club drug” from the 1980’s onward). Others are exploring THC-based therapies, and psilocybin (from “magic mushrooms”) for depression and anxiety.

The increased awareness of mental health issues—made even more acute by the COVID-19 pandemic—is driving increased attention and development resources into the space.  This will result in exciting developments in the years to come.

The Push for Non-Opioid Alternatives for Pain

It has long been known that opioids are effective at treating pain but have the drawback of being highly addictive.  The FDA and others have tried numerous methods to prevent addiction—such as rationalizing prescribing and controlling the amounts dispensed—but persistent patients are typically able to defeat those measures.

Over time, aggressive marketing of opioid pain killers led to over-prescribing by physicians and over-use by patients, primarily in the US.  This has resulted in a much-publicized opioid crisis.

Several pharma companies were required to make large payouts due to their marketing approaches, which allegedly contributed to the crisis.  Key examples were Purdue, Teva, and Mallinckrodt.  Purdue was required to pay $10 billion alone.

In the wake of this, there is significant demand for non-addictive pain treatments.  This demand has sparked more research into pain and the FDA has shown a willingness to lower barriers to entry for non-opioid alternatives.

Much of the research that’s being done is related to the root causes of pain.  For example, migraine-related pain is much different than back pain, so why should anyone treat them with similar medications?  This new research on addressing root causes is analogous to the difference between a systemic cancer treatment (such as a chemotherapeutic) vs. a targeted treatment.  A few highlights illustrate the trend:

  • Some interesting developments are underway with nerve growth factors (NGFs), with Eli Lilly, Pfizer, Regeneron, and others working on treatments for back pain, arthritic pain, etc.
  • The advent of the CGRP (calcitonin gene-related peptide) class has revolutionized treatment for migraines.
  • There is also a move away from opioids in treating post-operative pain (e.g., following knee or shoulder surgery). Longer-lasting anesthetics are being studied in this area.

When one considers that 25% to 33% of people live with some type of pain, the market potential for effective, non-addictive alternatives for pain is significant.

The Rise of Advocacy in CNS

From the 1980’s through the 1990’s, advocacy groups were extremely effective in drawing attention to HIV/AIDS.  That attention was critically important in driving research dollars and focus to HIV/AIDS and the payoff from a therapeutic standpoint has been phenomenal.

More recently, advocacy attention migrated to cancer.  Those efforts are definitely beginning to bear fruit, with exciting new therapies on the market and in development.

Now, advocacy for neuroscience-related diseases is on the rise.  Change doesn’t happen overnight, but we’re beginning to see the shift:

  • The National Alliance on Mental Illness (NAMI) has emerged as a strong advocacy organization.
  • The Alzheimer’s Foundation has also grown in size and impact.
  • Michael J Fox has helped draw more attention to Parkinson’s disease while things like the ALS “Ice Bucket Challenge” have been effective at raising awareness and research funding.
  • Disease-specific advocacy groups have been instrumental in the development of therapies for DMD (Sarepta’s Exondys 51 and Vyondys 53) and other rare diseases

The rise in advocacy in CNS-related diseases will, over time, generate similar impacts to what we’ve seen in HIV/AIDS and oncology.

What’s Next?

In part 2, we will use these trends as a backdrop to explore where investment dollars are flowing in CNS and take a look at the direction M&A activities have been headed.  We’ll also make a few predictions of where CNS markets are headed in 2021 and in the years to follow.