This blog was written by Kevin Pojasek, CEO at Quartet and Atlas EIR, as part of the “From the Trenches” feature of LifeSciVC.
Therapeutic areas and modalities regularly fall in and out fashion usually when promising scientific approaches run aground in development. These head winds are met with a flight from the space into areas viewed as greener pastures for investment. Although as improvements in understanding disease biology, technology development and clinical development strategies, overlooked therapeutic areas or modalities come back into fashion. Surges in VC-backed investments in gene therapy (Bluebird, Dimension, Voyager, etc.), anti-bacterials (Spero, Tetraphase, Cempra, etc.) and vaccine platforms (Genocea, ImmusanT, SutroVax, etc.) exemplify how downtrodden areas can swing back into vogue. Chronic pain is another therapeutic area that is quietly undergoing a similar cyclical renaissance.
The pain field has been littered with clinical trial failures for many oft-cited reasons. “In addition, widely used pain therapies that reduce pain are under siege,” notes Dr. John Markman, the Director of the Translational Pain Research Program at the University of Rochester, highlighting the negative societal impact of opioid abuse and side effect-based limitations of NSAIDs and acetaminophen. Clearly, there is an undeniable need for better, innovative pain medications to address the 1.5 billion people globally living with chronic pain (See 2011 IOM Report).
Utilizing improved insights into new pain mechanisms provided by human genetics, sensory phenotyping, pharmacology and biomarkers, investments in R&D in pain are starting pay dividends. In parallel, improvements in clinical trial design are being implemented after years of hard lessons. And this is all happening at a time of relative biotech industry strength – venture capital funds are flush with cash, public markets are (still?) attractive for clinical stage companies and Big Pharma is hungry for new programs having spent years whittling internal discovery engines.
The initial Quartet investment thesis when we started the company at Atlas in late 2013 was, in part, a counter-cyclical bet that the chronic pain field will return to favor (of course, we also are excited about the role of BH4 in chronic pain and inflammation!). A couple of recent deals highlight the resurgence of the pain field:
- Biogen-Convergence Pharmaceuticals – Announced on the eve of this year’s JP Morgan Healthcare Conference, Biogen shelled out $200M up-front plus $475M in milestones to buy Convergence’s NaV1.7 antagonist program now known as raxatrigine (formerly CNV-1014802). The up-front generated a ~6X return on invested capital for Apposite, New Leaf Venture Partners, and SV Life Sciences who backed Convergence as the company was spun out from GSK in 2010. The program had recently demonstrated successful clinical proof-of-concept in 2 well designed studies in patients with trigeminal neuralgia (TGN) and lumbosacral radiculopathy (LSR), respectively. “The NaV1.7 target is a compelling one, underpinned by both positive erythromelalgia and negative congenital insensitivity to pain genetics – this is the type of target that is attractive to any therapeutic area,” commented Dr. Samantha Budd Haeberlein, a Vice President of Clinical Development at Biogen. “We are excited about the development of ratraxigine which will allow Biogen to extend its footprint into different pain areas and really start to progress in this high area of unmet need.”
- Novartis-Spinifex Pharmaceuticals – Novartis acquired Spinifex for $200M up-front with approximately $500M in milestones this past June after their program targeting the angiotensin II type 2 (AT2) receptor established clinical proof-of-concept in treating post herpetic neuralgia (PHN). Spinifex had raised a total of $70M from Canaan Partners, Novo Ventures and a mix of Australian investors. Although, only a portion of this money had likely been spent as their $45M Series C closed in April 2014 making the up-front on this deal another reasonable return on invested capital.
There are a few important similarities in these transactions, beyond just the terms, that bode well for other pain field:
- Deals represent moves by new entrants into the space. Novartis had no obvious strategic interest in chronic pain prior to the Spinifex deal. And while Biogen has long had their Neublastin program, the Convergence deal represented a renewed investment in the pain space. Hopefully, both acquirers will expand their pain-focused R&D efforts and will be followed by other large companies into the space.
- New targets demonstrating clinical proof-of-concept. This is no small feat given that 72% of pain programs fail to advance beyond Phase 2. Interestingly, the Convergence and Spinifex programs were both run at clinical sites outside the US, a notable fact that may have been instrumental in their successes according to a recent publication. Jeff Mogil and colleagues recently published a fascinating study showing that placebo rates have risen dramatically in chronic pain studies over the last 20 years, but primarily for studies conducted in the US. These studies also tended to larger and longer, include more patients being treated for more than typical 4-week proof-of-concept study.
- Utility of innovative clinical trial designs – “The industry as a whole is increasingly focused on learning lessons from numerous clinical failures by attempting a variety of techniques to improve assay sensitivity by reducing patient variability,” commented Dr. Markman. For example, the Convergence team utilized creative Phase 2a study designs on their path to human proof-of-concept. Their TGN study was an enriched enrollment randomized withdrawal study where all patients received open label drug treatment for 21 days with responders then randomized to either placebo or active in a 28 day double blind period. Efficacy was measured as the delta in number of treatment failures between the treated and placebo groups. The second indication run by Convergence in LSR was not your average parallel design. Here they ran a cross-over study design where all subjects received active and placebo for 22 days with 2-week washout in between. The study also included a 2-week placebo run-in period to filter placebo responders and ensure subjects had stable pain scores of at least 4 on a scale of 0 to 10.
In their clinical development, Spinifex utilized a couple of strategies designed to increase the assay sensitivity of their study. “Blinding the sites to everything in the protocol that they don’t need to know helps reduce the risk of site and patient misconduct which has become a real problem, “according to Dr. Robert Dworkin, Professor of Anesthesiology, Neurology, and Psychiatry at University of Rochester and a leading clinical trial advisor. “In addition, the use of a centralized, algorithm-based procedure for excluding patients with variable pain scores during the placebo run-in phase may have also helped with the assay sensitivity in the Spinifex PHN study.”
- Emergence of peripheral targets for treating pain – NaV1.7 has been a hot target in the pain field since the initial publication of the loss of function mutations in the gene leading to a congenital insensitivity to pain. The target is expressed primarily on the peripheral pain nerve fibers where it is thought to produce an effect on the aberrant sensory input that is a driver of chronic neuropathic pain. There is NaV1.7 expression in the dorsal horn and brain, though, so some degree of central bioavailability might be required for peak efficacy. The AT-2 receptor pursued by Spinifex is a target expressed primarily on the dorsal root ganglion of peripheral nerve fibers.
In addition, there has also been resurgence in the anti-NGF approaches to treating osteoarthritis (OA) pain after the FDA lifted the clinical hold on all NGF-targeted approaches, including Pfizer’s tanuzemab program, after unexplained acceleration of joint damage is some patients. Prior to the hold being lifted, the strong clinical data seen in Phase 2 trials of OA enticed Lilly to join up with Pfizer on tanezumab for a $1.8B co-development deal. Furthermore, biotech entrants, such as Levicept that was co-founded and backed by Index Ventures, are taking a more nuanced approach to the NGF by pathway by selectively modulating subset of NGF activity using a p75NTR-Fc receptor antagonist out-licensed from Pfizer. In addition, VM Pharma recently partnered their TrkA NGF receptor antagonist with Purdue Pharmaceuticals for up to $213M upon completing a Phase 1 study.
So what’s next for the pain field? Clearly, replicating the efficacy seen in the Convergence and Spinifex Phase 2a trials is of paramount importance for Biogen and Novartis, respectively, as well as for the field. Watching for the potential expansion of human proof-of-concept with these new mechanisms beyond the initial narrow indications of TGN and PHN into larger markets like post-traumatic and post-surgical nerve injury pain will also be an interesting bellwether for the field. Advances in device-based neurostimulation are also starting to demonstrate clinical proof-of-concept. In April, St. Jude exercised its option to acquire Spinal Modulation for $175M plus milestones based on their promising results of dorsal root ganglion stimulation for treating chronic pain.
Hopefully, the recent clinical successes and deals will encourage additional early stage investment in more new pain mechanisms based on better mechanistic insights. In fact, this may already be occurring as two of the CROs that we rely on at Quartet have reported an uptick in interest in their preclinical pain models after 3-5 years of dormant business.
Kudos to the teams, investors and clinicians behind the recent advances in the pain field. This is certainly an exciting time to be developing new medicines to treat the millions of patients whose lives are disrupted by chronic pain.
