We have been thinking for some time about the importance of biomarkers in both drug discovery and clinical medicine as they relate to Alzheimer’s (and our In Vivo publication also addresses this topic in depth). At the recent American Academy of Neurology (AAN) conference, there was also widespread interest in this topic, spurred in part by the U.S. Food and Drug Administration decision to make biomarkers a centerpiece of a new set of draft guidelines for the development and regulatory review of Alzheimer’s disease therapeutics. And in fact, the discussion at AAN went beyond Alzheimer’s disease, to consider — and report on — the use of biomarkers in the diagnosis of dementias generally.
While the use of specific biomarkers for diagnosis of dementia in the clinic is still at an early stage, researchers presented several case studies that showed how existing imaging technologies could help to distinguish dementia subtypes, like frontal-temporal dementia, from Alzheimer’s. One question under debate at AAN was whether biomarkers could/should be used alone to diagnose Alzheimer’s — or other dementias — or whether they should be used only along with clinical diagnostic methods or other tests. While the general agreement was that clinical diagnosis is still important, there was widespread speculation that this might change in the future.
We’ll be exploring the importance and use of Alzheimer’s biomarkers in both drug development and clinical medicine further in a few weeks at BIO2018, as we moderate a panel on June 6 at 1:45pm ET, entitled “Priming Diagnostics for the Future of Alzheimer’s Treatment.”
Also exciting AAN attendees this year were discussions centering on new therapeutic approaches under development for neurological diseases, most notably gene therapy and RNA-based antisense treatments.
Of particular interest at AAN was the discussion of AveXis’ gene therapy for spinal muscular atrophy (SMA), AVXS-101. SMA is a rare genetic disorder that, in the Type 1 (most severe form), affects infants from birth and often causes death by the age of two. AveXis is currently conducting a pivotal trial of AVXS-101, with 11 of 15 planned patients now dosed. While data from this study is still limited, new reporting on patients from an earlier study excited AAN attendees. AveXis reported data from a Phase 2 trial on 15 patients who were still alive after two years, without the need for a ventilator. Patients who had received a low dose of AVXS-101 are now at a median age of 27.8 months and those who had received a high dose, are at a median age of 30.7 months; typically only 8% of untreated patients with SMA Type 1 are event-free after 20 months of age. Clearly, the data to date on AVXS-101 excited Novartis too, which announced last month it is acquiring AveXis for $8.7 billion.
Biogen also reported data related to SMA on its antisense RNA drug nusinersen (SPINRAZA®), which was in-licensed from Ionis Pharmaceuticals in 2016 prior to the drug’s approval by FDA in December 2016. The first approved therapy for this condition, the drug is administered via intrathecal infusion a few times per year to slow the progression of the disease. Data continues to show long-term treatment benefits for patients in both motor function and survival. However, the therapy is very expensive — $750,000 in the first year of therapy and $350,000 per year thereafter — and it must be taken for life.
Antisense oligonucleotide approaches to the treatment of other neurological diseases were also highlighted at AAN this year, with reports on early-phase clinical trials in Huntington’s disease, hereditary ATTR amyloidosis, and even Alzheimer’s disease. We will keep watching for results from these trials to better understand the potential for this new class of drugs in neurological conditions.
The big question for both gene therapy and antisense approaches is when should therapy start for a progressive neurological disease? When the disease manifests or even before symptoms appear? In the case of a genetic disease like SMA, one probably wants to treat patients as early as possible given the predictability of the course of the illness and its impacts. For other conditions, the answer may not be as clear, especially given the high cost of therapy. And the considerations for a one-time treatment will likely be different from those for therapies that require repeated administration for the reminder of a patient’s life.