See Part 1.
29 March 2008. This is the second and final part of our coverage of the Drug Discovery for Neurodegeneration meeting, held in Washington, DC, on 4-5 February. To see the slides and hear the complete audio of the meeting, tune into the free webcast. The webcast is organized by session, so to locate a specific talk, consult the meeting program to find the appropriate session. Talks mentioned below include the session number after the speaker’s name for quick reference.
Reuse, Recycle: Repurposing Existing Medicines
Jill Heemskerk (Session III) of the National Institute of Neurological Disorders and Stroke (NINDS) talked about an effort to find new applications to neurodegeneration for existing drugs. The inspiration for such a program comes from repeated instances of crossover drugs: aspirin, originally used for pain but more recently to prevent heart attack, is just one. In repurposing, drugs often hit alternative targets, but come with the advantage that the compounds have already been proven, and approved, for use in humans. Only 3,000 unique compounds have ever been approved by the FDA, so screening 1,000 gives good coverage of the field. At best, such a screen could uncover new indications for old drugs right off the shelf. At worst, the drugs might make good starting points for new compounds.
The NINDS repurposing program began in 2001 and involved a consortium of 27 labs where screens were carried out on the same panel of 1,040 drugs. The compounds were evaluated in 29 different screens covering disease-specific and general neurodegeneration and apoptosis assays in a variety of organisms. Most of the assays (27 out of 29) produced reproducible hits.
As yet, only one of these hits, the antibiotic ceftriaxone, has translated to the clinic, as a potential therapy for ALS. After promising preclinical results in the SOD1 mouse model (see ARF related news story), the antibiotic is now in a pilot study under the direction of Merit Cudkowicz at the Massachusetts General Hospital, Boston. That study will transition into a Phase 3 study this year, Heemskerk said, involving 600 patients at 50 sites.
This drug is good enough that we can put it into ALS in a proof-of-concept trial, Heemskerk said, but there is room for improvement. The antibiotic crosses the blood-brain barrier, but requires chronic intravenous delivery of a high dose to get sufficient brain levels. Heemskerk reports they are now looking for improved compounds with no antibiotic activity.
The fact that there were not more translatable hits is understandable, Heemskerk said, given the requirements for low toxicity, tolerability, and brain penetration. However, as the ceftriaxone experience illustrates, the hits can be a starting point for further chemistry aimed at maintaining neuroactive properties while improving other characteristics. For example, Heemskerk showed the work her group is doing on the cyclooxygenase inhibitor, indoprofen, for spinal muscular atrophy (SMA). SMA is caused by deficient expression of the spinal motor neuron 1 (SMN1) gene. The researchers discovered that indoprofen increased expression of the SMN1 gene and improved in utero survival of SMA mice. However, the compound causes severe gastrointestinal bleeding and is not brain penetrant. In 18 months, through contract work, Heemskerk and NINDS colleague John McCall coordinated the synthesis and testing of more than 1,000 indoprofen analogs to find compounds that reproduce the parent activity and are brain penetrant, orally available, well tolerated, and show no cyclooxygenase inhibition. They currently have two NIH patents and are looking for an industry partner. In the meantime, the group selected a clinical candidate, which is beginning preclinical safety studies. They hope to be in Phase 1 by late this year.
Help Is Available
In the case of SMA, Heemskerk says that means it will have taken just three years from discovering the activity of indoprofen to the clinic. They hope to expand this approach to other diseases. To that end, NINDS is developing a medicinal chemistry service program available for investigators. To use it, researchers will need to have a disease-related assay, active compound(s), and screening resources to improve compounds with iterative medicinal chemistry. Heemskerk also mentioned a new compound screening collection available from the NIH comprising 480 candidates that did not make it to approval, but have been tested in clinical trials.
For people who need help with chemistry and other contract services related to early drug discovery, Duncan Beniston (Session V) of ChemBridge Corporation, San Diego, California, named names in his talk. He offered up impressive resources in the form of extensive lists of commercial sources, and a look through his slides shows the many possibilities open to academic researchers. Of course, buying services takes financial support, and so Neil Buckholtz of the National Institute on Aging and Lorenzo Refolo (Session V) of the NINDS reprised their talk of last year on sources of funding within the NIH for drug discovery and early development (see ARF related live discussion). In general, the NIH programs are unchanged from last year, but some of the program numbers have been altered. Buckholtz recommends referring to the NIH website for the latest information.
Seeing More Clearly
In a session on clinical development, Franz Hefti (Session IV) of Avid Radiopharmaceuticals, Philadelphia, Pennsylvania, gave an update on a new PET reagent for amyloid imaging. Related to the pre-PIB, stilbene SB13 ligand, originally developed by Hank Kung at University of Pennsylvania, Philadelphia, and tested once in humans (Verhoeff et al., 2004), the new ligand is labeled with 18F. While 11C-PIB has provided a proof of concept for PET imaging of amyloidosis, its application will be limited by the short half-life of the 11C isotope. Because the signal decays over minutes, imaging is restricted to a few academic centers with access to a cyclotron where the label can be locally produced for quick use. Replacing 11C with a longer-lived isotope, 18F, would make amyloid imaging more widely available. Christopher Rowe from Austin Hospital, Melbourne, Australia, presented the first data on one of the Avid compounds at the 8th International Conference AD/PD in Salzburg in 2007 (see ARF related news story), which compared favorably to 11C-PIB.
The problem Avid faced with further development was selecting which, among several possible compounds, to go forward with, when only human testing would tell which had the best properties. To make that decision, Avid conducted tests of four tracers under an exploratory investigational new drug application (IND), a mechanism the FDA offers to do limited testing of pharmacokinetics on new compounds in humans. Because the test uses a single, tracer dose, the requirements for animal toxicology testing are not as extensive as for a full IND. Based on the results, Avid selected one compound to move into development under a formal IND. Hefti concluded that exploratory INDs might be helpful to researchers in some situations, where human data are needed to steer compound selection.
In another clinical update, Wayne Rowe (Session IV) of Memory Pharmaceuticals, Montvale, New Jersey, spoke about that company’s α7 nicotinic acetylcholine receptor agonist (MEM 3454), which they are pursuing for improvement of cognitive function in AD and schizophrenia. Preclinical work showed that the compound ameliorated age-related memory decline in rats and primates. In rats, the compound stimulated acetylcholine and dopamine release, and enhanced cognitive function in both young and old rats. Last November, the company completed a Phase 2a trial in people with mild to moderate AD. At lower doses, the compound produced improvement of episodic memory, working memory, and speed of memory. At higher doses, the effects disappear, possibly due to receptor desensitization. Rowe reported the compound will proceed into Phase 2b trials in the next few months. The company has also recently launched an additional Phase 2a trial for the treatment of cognitive deficits in schizophrenia.
For more information on these or any of the other talks, please visit the Web presentations, made available courtesy of the speakers and ADDF. As always, ARF welcomes comments from speakers or participants.—Pat McCaffrey.
This is Part 2 of a two-part story. See Part 1.
To view commentaries, primary articles and linked stories, go to the original posting on Alzforum.org here.
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