Only a few months after raising $70.5 million in a heavily oversubscribed Series D financing this May, REGENXBIO filed their S-1 on August 17, 2015 in preparation for an Initial Public Offering. REGENXBIO is a private company co-founded by Dr. James M. Wilson M.D., Ph.D. and leveraging their adeno-associated virus “NAV” (NAV is what REGENXBIO calls their AAV vectors) technology platform to develop AAV gene therapies.
Dr. Wilson is one of the pioneers in the gene therapy space, infamous primarily as the primary investigator in the Adenovirus gene therapy program for the treatment of Ornithine Transcarbamylase (OTC) Deficiency, which unfortunately resulted in the death of Jesse Gelsinger in 2000. This was the first death in clinical trials attributable to a gene therapeutic and led to the FDA halting all human studies of the technology. Gene therapy research was decimated for the next decade as interest and funding dried up completely.
REGENXBIO is a company I’ve been waiting to see IPO, not only because they’re headquartered across the street from a Chipotle I visit frequently in Rockville, MD, but because they have a broad reach with respect to other AAV-centric gene therapy developers that have licensed technology/IP from REGENX. The company essentially owns IP covering a number of naturally occurring adeno-associated vectors (AAV), which they’ve licensed to a broad swathe of drug developers and researchers for incremental royalties, in addition to developing a handful of internal therapeutics.
With their IPO possibly around the corner [pending market conditions, of course], I thought it might be interesting to expand on the science behind the company.
Brief History of REGENXBIO
REGENXBIO was formed in February 2009 via a collaboration between FoxKiser LLP, the University of Pennsylvania, and Dr. Wilson. REGENXBIO quickly entered into exclusive licensing agreements with the University of Pennsylvania (UPenn) and GlaxoSmithKline (GSK) in order to acquire rights to its current AAV suite. In addition, REGENXBIO entered into a sponsored research agreement with UPenn under which REGENXBIO funds the nonclinical AAV research of Dr. Wilson, and obtained an option to acquire an exclusive worldwide license to certain intellectual property (Details in the S-1)
REGENXBIO’s portfolio of AAV vectors is entirely naturally occurring, yet the company refers to the platform as “next-generation.” Why? These vectors, including AAV7, AAV8, and AAV9 were all discovered AFTER the first wave of naturally occurring vectors, like AAV1 and AAV2. I’ve written at length in the past about “next gen” vectors HERE, defining them as NOT naturally occurring and thus far created via directed evolution or rational techniques; thus for the sake of simplicity, I’ll call these otherwise.
REGENXBIO’s NAV vectors were discovered by “searching for capsid gene sequences in a variety of tissues isolated from non-human primates and from humans” . AAV7, AAV8, AAV9, and AAVrh.10 are a few examples of AAV NAV vectors discovered using this process and are included in the 100+ AAV NAV vectors that REGENXBIO claims in their portfolio. The company believes these vectors all have improved properties over earlier generations (AAV1-5), including :
Higher gene expression
Longer gene expression
Broad and novel tissue specificity
Improved immune response
Of note, per their S-1, it also sounds like REGENXBIO is exploring the design of ‘next-generation’ vectors.
To put the significance of this portfolio in perspective, according to the company, ~70% of AAV gene therapy INDs posted to clinicaltrials.gov from 2012-2014 use NAV vectors. REGENXBIO has provided a table detailing the 14 clinical trials using AAV NAV vectors (more on these later) :
What does that mean for REGENXBIO? The company has in place licensing agreements with 8 of the re-emerging gene therapy players, meaning that the company has an economic stake in the future of 15+ potential therapeutics. The significance won’t be lost on many readers given the broad market opportunity for successful assets. The details and terms of these licensing agreements are outlined in the tables below:
As mentioned, NAV vectors have been used in 14 clinical trials since 2010, which presents some compelling validation. One of these is St. Jude’s AAV8 hemophilia B asset – AAV8-hFIX – which I discussed in detail in my initial uniQure research HERE (vector rights acquired via agreement with GSK prior to REGENXBIO license). Further clinical validation recently emerged from Lysogene’s AAVrh.10-SGSH-SUMF (SAF-301) phase I/II clinical trial for MPSIIIA (Sanfilippo A) which I discussed in another recent blog post blog HERE. The third clinical stage NAV licensee program that has offered some validation of REGENXBIO’s vectors is AveXis’ Spinal Muscular Atrophy Type I (SMA Type I) program, which is ongoing now.
SMA Type I is a genetic disorder characterized by progressive skeletal muscle atrophy due to the loss of motor neurons in the spinal cord. This loss is a direct result of mutations in the survival motor neuron 1 (SMN1) gene resulting in non-existent or non-functional protein. SMA Type I is the most common form of SMA and is the second most severe (Type 0 being most severe, Types III & IV less so), and patients diagnosed typically see onset of symptoms before their first birthday; they generally do not survive beyond 2 years of age. SMA occurs in approximately 1 in 10,000 births, with SMA Type I affecting ~50% of those diagnosed . There are no FDA/EMA approved treatments that correct the underlying cause (SMN1 deficiency) though ISIS Pharmaceuticals (ISIS), in partnership with Biogen (BIIB), are currently advancing ISIS-SMNRx through clinical trials. ISIS-SMNRx is designed to correct the underlying deficiency of SMN1 by converting the mRNA responsible for producing truncated SMN2 (a very similar protein to SMN1) into full length SMN2 – modifying the disease severity. For more on the recent developments of ISIS-SMNRx and recent data see RNAi expert Dirk Haussecker’s recent blog post HERE.
In 2014, Avexis entered into an exclusive license agreement with REGENXBIO for the development and commercialization of products to treat SMA using AAV9. scAAV9.CB.SMN (scAAV9.SMN) is a self-complementary AAV2/9 vector with a transgene cassette consisting of a CMV enhancer, chicken β-actin promoter, and the human SMN gene.
Avexis presented the first clinical data from patients diagnosed with SMA Type I at the 2015 CureSMA conference this June. The primary endpoint of this open-label phase I trial is safety, with secondary endpoints of mortality, time to prescribed respiratory assistance required 16+ hours per day, and CHOP INTEND (a measure of muscle function) motor function outcome. The investigators also assigned a ‘definition of efficacy’ as 50% of SMA type I subjects ventilator free at 2 years. Patients received either 6.7E13 (low-dose; n=3) or 2.0E14 [vg/kg] (high-dose; n=6) of a scAAV9.SMN via a single intravenous (IV) infusion. As of June 15, 2015, all patients treated remain event-free with the first patient event-free over 1 year post-gene transfer. Although these data were not made available, the investigators stated that the CHOP INTEND score improved in all patients, with a dose-dependent response evident. Unsurprisingly, treatment response was best in youngest patients (<2 months old) .
There have been no unexpected therapy-related SAEs; however, the first patient treated did present an immune response at day 26 post-gene transfer and received prednisolone (steroids) . Following, the investigators have opted to pretreat all patients with prednisolone one day prior to gene transfer in order to temporarily suppress the immune system. Investigators in the scAAV9.SMN trial most likely felt comfortable administering immuno-suppressive therapy prior to transfer because of existing proof-of-concept data from other CNS-targeted AAV gene therapies using pretreatment, such as Lysogene’s SAF-301 for Sanfilippo A (MPSIIIA). Investigators in the SAF-301 trial used a robust pretreatment regimen consisting of tacrolimus, mycophenolate mofetil, and prednisolone. Despite this, treated patients still demonstrated signs of efficacy (I wrote about this program HERE) .
I’m tempted to compare the data for scAAV9.SMN to the current ISIS-SMNRx data package, however it’s simply too early to compare and contrast these programs. But, the data available to date are certainly promising.
In addition, Avexis is pursuing delivery directly to the CNS via injection into the cerebral spinal fluid (CSF) – potentially improving performance. The benefits of CSF delivery have been demonstrated in a mice model and non-human primates. Without getting into the details, the benefits of CSF injection are believed to be :
Reduced vector dose required for efficacy
Lower risk of immunogenicity due to the CNS being to a degree an immune-privileged region
Circulating neutralizing antibodies could be avoided since the CNS is to a degree an immune-privileged region
Avexis’ scAAV9.SMN program for Type I SMA has generated intriguing early data, offering some validation of the AAV9 vector, though it’s too early to compare data with competitors such as ISIS-SMNRx especially as Avexis explores a new delivery route.
REGENXBIO’s Internal Gene Therapy Pipeline Candidates and Manufacturing
REGENXBIO is focused on developing internal gene therapy programs (shown below) that fall into their three core areas: metabolic, neurodegenerative, and retinal diseases .
REGENXBIO utilizes HEK293 manufacturing with improvements in areas such as purification and packaging yield pioneered in Dr. Wilson’s lab. In May 2015, the company entered into a collaboration agreement with WuXi Apptech, Inc. to establish a proprietary production process for NAV gene therapies. The process is designed to enable manufacturing of REGENXBIO’s and NAV technology licensees’ therapeutic programs from clinical trials all the way through commercialization.
If REGENXBIO is able to execute an IPO in the current market, I suspect it will be well-received. My readers already know my optimism about the re-emerging gene therapy field, and the company has done a nice job leveraging their NAV platform for future economics from a myriad of therapeutic assets. In addition, the three key clinical stage programs described herein offer some validation for the vectors in REGENXBIO’s NAV suite: AAV8, AAV9, and AAVrh.10. Of importance, REGENXBIO has also secured a plan for scaled-up manufacturing for their in-house programs & licensee’s via their collaboration with WuXi Apptech. Considering everything I have highlighted above, it does not surprise me that top tier funds such as /Perceptive Advisors and QVT Financial LP have participated in private funding rounds with REGENXBIO to date.
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