This is Part I of a 2-part series from the Neurotech Investing & Partnering Conference. Read Part II here.
The Annual Neurotech Investing & Partnering Conference celebrated its tenth anniversary this year in San Francisco on April 7-8, 2015. Hosted by the Neurotechnology Industry Organization (NIO) and NeuroInsights, the meeting provides a unique opportunity for leaders from the pharmaceutical, medical devices, software and diagnostics industries to discuss partnership and investments opportunities to advance development of new therapies for diseases of the nervous system. While the meeting spanned a range of thought-provoking topics, two sessions were of particular relevance to those interested in ALS, presenting new treatments for multiple sclerosis and cutting-edge approaches to drug delivery across the blood brain barrier (BBB, Part II).
Multiple sclerosis (MS) is an autoimmune disease in which the body’s immune system attacks the myelin sheath surrounding nerve fibers in the central nervous system (CNS). Approximately 80% of patients are initially diagnosed with relapsing-remitting MS (RRMS), which is characterized by exacerbations of symptoms followed by partial of complete recovery periods. The majority of these patients will transition to a progressive form, in which neurological function progressively deteriorates with no periods of remission.
The immune system has also been tied to ALS disease progression, although its precise role is a matter of debate (see Feb 2015 news story; Jan 2013 news story; Sept 2008 news story). Despite this complexity, the potential mechanistic link between MS and ALS has spurred clinical testing of several MS drugs for treatment of ALS. One such notable example is Gilenya, a sphingosine 1-phosphate (S1P) receptor modulator, which inhibits lymphocyte entry into the CNS and is under development by ALS TDI in collaboration with Novartis Pharmaceuticals (see Feb 2012 news story).
Unlike ALS, where there is only one drug available approved by the U.S. Food and Drug Administration (FDA), there are currently twelve FDA-approved disease-modifying medications for relapsing-remitting forms of MS. The session on “New Strategies in Multiple Sclerosis” revolved around efforts to improve treatment options for progressive disease, characterized by steadily worsening neurologic function with no recovery periods (remissions). Christine Foster, Vice President of Search and Evaluation at Teva Pharmaceuticals, which developed the MS drug Copaxone, introduced the session by pinpointing the unmet needs in MS, including the need for drugs of greater efficacy and tolerability, as well as more orally bioavailable drugs. She also emphasized the lack of treatment options and biomarkers for progressive disease.
Following the introduction, the first to present was Simon Wilkinson, CEO of Innate Immunotherapeutics based in Australia and New Zealand. He opened with a broader discussion of the silos that have impacted therapy development for MS, where intense focus on RRMS has diverted all the efforts to the autoimmune component of the disease. However, these therapies are no longer effective in progressive stages of the disease, which appears in approximately 70% of the RRMS patients in the 20 years following their initial diagnosis. Innate Immunotherapeutics is focusing their drug development efforts on modulators of myeloid-derived innate immune cells, which have been implicated as an important target in progressive disease, albeit with both proinflammatory and anti-inflammatory functions, depending on the stage and severity of disease (see Feb 2015 conference news; news). Wilkinson presented the company’s core technology – a therapeutic microparticle, composed of multiple receptor ligands cross-linked to a stable microparticle to efficiently target immune cells. The lead drug candidate, MIS416, is a microparticle linked to naturally occurring TLR-9 and NOD-2 ligands, which acts by both upregulating anti-inflammatory effectors and increasing expression of trophic factors such as VEGF. In a recent Phase IIa clinical trial, 80% of subjects exhibited at least 30% improvement in a least one measure of MS clinical status. In addition, in a New Zealand based compassionate use program, 82% of the 19 patients reported sustained improvement in motor function. A larger Phase IIb 12 month double-blind placebo controlled study is now enrolling.
Next to present was Robert Peach, Chief Scientific Officer and Founder of Receptos, a company based on technology from the Scripps Research Institute. The company is focusing on developing best-in-class compounds with better safety and efficacy profiles than competitors. The company’s lead compound, RPC1063, has a similar mechanism of action as Gilenya, and is a sphingosine 1-phosphate (S1P) receptor modulator that inhibits lymphocyte trafficking and reduces inflammation. However, unlike Gilenya, which is associated with serious side effects such as cardiac conduction abnormalities, hypertension and fibrosis, RPC1063 exhibits an outstanding safety profile due to increased receptor selectivity of the drug. In a Phase II placebo controlled clinical trial, PRC1063 demonstrated superior efficacy compared to placebo, with a significant reduction in number of brain lesions determined by MRI, and remarkably, no increase in cardiac effects as compared to placebo. For the ALS community, this would be an interesting drug to follow in parallel to watching how Gilenya performed in the Phase II trial in ALS.
Next up, Maurice Zauderer, CEO of Vaccinex presented promising data on their lead therapeutic monoclonal antibody under development for MS and Huntington’s disease, VX15. VX15 is an anti-semaphorin 4D (SEMA4D) antibody, which demonstrated beneficial effects in preclinical studies by promoting oligodendrocyte migration and differentiation, and reducing BBB permeability. Vaccinex has completed a Phase I clinical trial of safety and tolerability of VX15 in MS, and is also pursuing a program in Hungtington’s disease (HD) based on some exciting, recently published results in HD (Southwell, AL et. al., 2015). In the YAC128 transgenic mouse model of HD, VX15 treatment significantly inhibited cortical and corpus callosum atrophy and improved spatial memory and cognitive function in adult mice. These findings have led the company to move forward with a development plan for HD, with a Phase II placebo-controlled efficacy and safety study planned to begin in June 2015. Zauderer underscored that this therapeutic indication is viewed by Vaccinex as particularly attractive due to the ability to identify genetically predisposed patients even prior to disease onset in combination with advances in imaging, motor and cognitive biomarkers in HD.
Shifting from drugs to devices, the final presenter was Blake Gurfein, CSO of Rio Grande Neurosciences (RGN). RGN is a neurotechnology company focused on developing non-pharmacologic therapies to treat diseases of the CNS, in particular traumatic brain injury and neuroinflammation. Their lead device is a non-invasive, FDA-cleared pulsed electromagnetic field (PEMF) device, which delivers weak electric fields to the underlying tissue, and is already approved for post-operative pain and edema. PEMF treatment exerts anti-inflammatory effects, with evidence suggestive of a mechanism of action via modulating nitric oxide (NO) signaling to promote vasodilation and tissue oxygenation. In preclinical studies in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, PEMF treatment twice daily for 15 minutes delayed disease onset as compared to sham treated mice. Gurfen emphasized that this simple, battery-operated device is a dramatic improvement over current drug therapies: it exerts anti-inflammatory and neuroprotective effects in a single treatment, delivery is not impeded by the BBB, and there are no known side effects. The company plans to launch a pilot study in progressive MS in late 2015.
Although at this time ALS is not the therapeutic focus of these companies, the mechanistic relevance of some of these approaches to ALS and the significant unmet need may make this an attractive indication as these drugs/devices advance through clinical development. For more from the conference on approaches to crossing the BBB, see Part II.