The following blog was originally posted on Prize4Life's ALS Forum. For more articles on the latest research and drug development news, along with a wide variety of ALS research tools and resources, visit ResearchALS.org.
Amidst the buzz of partnering activity throughout the three day BioPharm America 2011 meeting held in Boston, MA from September 7-9, 2011, there were ample opportunities to hear industry leaders' perspectives on industry trends through workshops and panel discussions. Of particular interest was a session focused on stem cells in regenerative medicine and featured here, given the powerful allure of stem cells to captivate ALS researchers, drug developers, and patients alike. With the generation of ALS patient-derived iPS cell lines and the ground-breaking safety trial of Neuralstem's stem cell therapy in ALS patients, there are high expectations for stem cells to revolutionize ALS drug discovery and therapeutics. Let's hear what industry leaders had to say ...
The session opened with a panel moderated by Brock Reeve, Executive Director of the Harvard Stem Cell Institute. In his introductory comments, Reeve reminded the audience that the first iPS publication came out just five years ago and since then the technology has become almost commonplace in labs across the world. Moreover, the technology has already been improved upon: a subsequent technique was developed to directly induce differentiated fibroblasts into a motor neuron identity, skipping the reprogramming step to the undifferentiated state. These so called induced motor neurons (or iMN) could potentially make it even easier and faster to generate patient specific models of motor neuron disease. [See also related news on recent advances to purify and differentiate stem cells as well as remaining potential pitfalls.]
The "big opportunity" that lay in stem cells was clearly appreciated by the pharma and biotech panel experts who acknowledged the growing trend to incorporate adult, embryonic or induced pluripotent stem cell technologies into a variety of efforts, ranging from drug discovery to development of cell-based therapies. The exciting ferment in the stem cell space has also added to industry's growing interest in and enthusiasm for fostering academic collaborations. While innovation in the stem cell space can come from anywhere, Gary Neil, Corporate VP at J&J, expects most to come from the academic sector.
Both panelists and audience members commented on the more frequent appearances of pharma representative of the likes of Pfizer, J&J, and GSK turning up at regenerative medicine conferences and partnering meetings such as this one as illustrative of pharma's growing interest in regenerative medicine. One explicit example of this interest, Shire's recent acquisition of AdvBioHealing, was taken as a signal that the specialty pharma's intends to build a regenerative medicine franchise around its newly acquired iPS technology.
Reeve asked panelist to offer their perspectives on potential breakthroughs within the proximate five-year horizon for regenerative medicine. Near term success was expected for macular degeneration and other eye diseases as well as for diabetes. Simple models with easy to measure clinical endpoints were perceived as more likely to succeed, whereas diseases with more complex biology (i.e.: stroke and ALS) were perceived as more difficult.
The second panel moderated by John McNeish, Founder of Boston Stem Cell and ex-Pfizer Executive Director of Regenerative Medicine, explored the use of stem cells for drug discovery and translation in greater depth. iPS cells in particular hold great excitement for use in disease modeling, target validation, and drug and biomarker discovery programs. iPS cells also offer a unique opportunity to identify which patients are more likely to respond to a drug by first testing the drug on the patient's own stem cells. In contrast to the relatively young iPS field, panelists noted that the more mature areas of adult and embryonic stem cell biology have yielded several cellular therapies that have moved steadily ahead into a clinical setting, including Advanced Cell Technology's hESC-based Retinal Pigment Epithelial (RPE) therapy for degenerative retinal diseases, Geron's hESC-derived oligodendrocyte progenitor cell therapy for spinal cord injury, Neuralstem's neural stem cell therapy for ALS and major depression, and over 37 ongoing clinical trials using adult stem cell therapeutics.
How close are we to remediating disease in a dish? Very close, according to Leonard Zon, stem cell researcher at HHMI/Children's Hospital Boston and co-founder of Fate Therapeutics, who projects that in three to five years researchers will be able to successfully treat a disease pathology exhibited by the affected cell type derived from patient iPS cells. This is an area of intense investigation, as many groups are actively working to establish disease models in a dish from patient-derived iPS cells and to develop functional assays to enable drug screening, including those studying ALS at The New York Stem Cell Foundation, the California Institute for Regenerative Medicine and elsewhere.
For ALS, progress has been slowed by an unanticipated finding. Unlike motor neurons derived from ALS mouse ESCs, which exhibit a characteristic disease pathology, motor neurons generated from both familial and sporadic ALS patient iPS cell lines lack an obvious disease phenotype even after extended periods in culture. The apparently healthy nature of these cells may bode well for transplantation back into the patient for use as a cellular therapy. However, the difficulty in detecting a disease phenotype necessitates the development of sensitive assays to identify a disease signature, a necessary step before these cells can be used to screen drugs.
While progress is being made on several fronts to advance stem cell-based drug discovery and therapies, the field continues to wrestle with the hype surrounding stem cells - a double edged sword for the field. While a certain amount of hype attracts investment money, it also preys on the vulnerabilities of patient communities, desperate for treatment. As ACT's Business Development Director Matthew Vincent noted, regenerative medicine's snake oil practitioners will hamper legitimate scientific efforts and slow the entire field. He cautioned against getting caught up in the hype and hubris over the revolutionary nature of stem cells when it comes to managing the associated risks, which range from regulatory to manufacturing to reimbursement. Goeff MacKay, President and CEO of Organogenesis, further emphasized the importance of assessing reimbursement very early in the process, calling it an early go/no-go decision point.
As part of our continuing series featuring interviews with some of the leading players in the field of ALS research, drug development, and treatment, Prize4Life spoke with Dr. Ed Kaye, currently the Chief Medical Officer at AVI BioPharma and the former Group Vice President and Therapeutic Head for Lysosomal Storage Disorders and Neurodegenerative Diseases at Genzyme Corporation. Dr. Kaye serves on Prize4Life's Scientific Advisory Board. In this video, he shares his thoughts on the recent $1M ALS Biomarker Prize award, the importance of private funding to complement public funding of ALS research, and the potential of the incentive prize model in biomedical research.
You can watch all of the extended interviews by subscribing to our YouTube channel here. You can also view the original video these interviews were collected for, 'Driving Breakthroughs in ALS Research: Prize4Life and the $1M ALS Biomarker Prize,' below.
Earlier this year, Prize4Life interviewed some of the top minds in the ALS research, clinical, and industry communities asking for their thoughts on ALS, the drug development landscape, and the potential of the incentive prize model in spurring biomedical innovation.These interviews were compiled into a short video that was screened at a gala in New York City celebrating the awarding of the $1M ALS Biomarker Prize to Dr. Seward Rutkove.
We are sharing the extended versions of these interviews on our website. The first video featured Dr. Vicki Sato, a professor at Harvard Business School and former president of Vertex Pharmaceuticals. You can view that video here.
The following is an interview with Dr. Robert Horvitz, a Professor of Biology at the Massachusetts Institute of Technology, an investigator with the Howard Hughes Medical Institute, and winner of the 2002 Nobel Prize in Physiology for discovering and characterizing the genes controlling cell death in the nematode worm Caenorhabditis elegans. Dr. Horvitz discusses his personal connection with ALS, the need for increased funding in the field, and how his work advances ALS research.
You can also view the original video, 'Driving Breakthroughs in ALS Research: Prize4Life and the $1M ALS Biomarker Prize,' below.
The Third Annual 5K4Life, benefiting Prize4Life, is almost upon us!
Our founder and CEO, Avi Kremer, will be in attendance for the race this year. Avi was diagnosed with ALS in 2006 and launched Prize4Life to rapidly accelerate the discovery of a cure for the disease.
Members of Team Ashley helped make last year's 5K4Life a tremendous success...
ALS is a devastating neurodegenerative disease that afflicts more than 600,000 people around the world, robbing them of the ability to move, speak, and ultimately to breathe. Most patients will die within 2 to 5 years.
But you can be a part of the cure! Support Prize4Life's efforts to drive breakthroughs in research at the 5K4Life!
4. Fundraise for the 5K4Life to help bring us closer to a world free of ALS
Fundraising for Prize4Life is a way to honor someone you know living with ALS, to remember someone who has passed away from the disease, or to deliver hope to the thousands of ALS patients and their families battling it. Join Prize4Life's efforts, and the next ALS breakthrough could be yours...
In April of 2009, a group of filmmakers came together to create "Trapped," a short film meant to raise awareness of ALS and marshal support for efforts to discover a cure. Director/Producer James Takata, Writers/Producers Zach Lewis and Jim Mahoney, and Producer Jhennifer Webberley worked with Amy Yamner Jenkins, the Chair of Prize4Life's Board of Directors, on the project. The film tells the story of Stephen, a talented young composer and pianist who discovers he has ALS after an eerie progression of symptoms. And though he begins to lose his ability to physically write music and play the piano, his spirit and genius cannot be taken by the disease. As Director Takata describes, though is body is deteriorating, "his ability is still there."
"Trapped" has been shown at numerous festivals, including the California Independent Film Festival, Methodfest, and the Neuro Film Festival sponsored by the American Academy of Neurology Foundation. The film won a bronze medal at the New York-based Telly Awards.
In 2009, Prize4Life had the opportunity to sit down with some of the creators of the film. You can read a transcript of that interview on our blog here.
For more information on the film's cast and crew, visit the IMDB profile page here.
On July 21, 2011, the American space shuttle program came to an official end when shuttle Atlantis rolled to a stop at NASA’s KennedySpaceCenter on Merritt Island in Florida. For 30 years, the shuttle program ferried astronauts into Earth’s orbit to launch, repair, and recover satellites, construct the International Space station, and conduct countless experiments and invaluable scientific research.
One such experiment, undertaken during the final shuttle mission, studied the loss of bone and muscle mass in a micro-gravity environment as well as a therapy that might be able to arrest that degeneration. Mary Bouxsein, PhD, a scientist in Beth Israel Deaconess Medical Center’s (BIDMC) department of Advanced Orthopedic Studies and Assistant Professor of Orthopedic Surgery at Harvard Medical School, served as the co-principal investigator of the study, leading a team of researchers from BIDMC, Amgen, BioServe Space Technologies, and the University of North Carolina. The study was funded by NASA’s Ames Research Center.
The research will not only yield insights into how astronauts can address a fundamental problem of long space flights, it could also lead to a greater understanding and potential prevention of bone loss for aging or diseased individuals here on Earth.
“Mechanical loading is required to maintain musculoskeletal health,” explains Dr. Bouxsein. “On earth, our bones experience mechanical forces from being pushed and pulled by muscles that work against gravity to keep us upright and moving around, as well as from the impact of our body weight against the ground. These forces are much lower in micro-gravity environments and, as a result, the rate of bone loss among astronauts is about 10 times greater than that seen in postmenopausal women. So, while this research is designed to better understand and prevent skeletal fragility among astronauts, it may also tell us a great deal about the future potential of this novel therapy to improve bone strength here on earth, in both older persons and in individuals with reduced physical activity due to various clinical conditions, such as stroke, spinal cord injury or cerebral palsy.”
You can watch Dr. Bouxsein explain her team’s work leading up to the shuttle launch in the video below.
Thirty mice (affectionately dubbed ‘mousetronauts’) were launched into space as a part of mission STS-135, the final shuttle flight. Dr. Bouxsein’s rather enthusiastic blog details the mission from soup to nuts (or launch to post-touchdown beach party after all of the equipment, supplies, and specimens had been collected at the KennedySpaceCenter). You can read her blog here.
One of Dr. Bouxsein’s collaborators was Dr. Seward Rutkove, also of BethIsraelDeaconessMedicalCenter. Dr. Rutkove is the Chief of the Division of Neuromuscular Diseases at BIDMC as well as the recipient of Prize4Life’s $1M ALS Biomarker Prize.
Dr. Rutkove’s lab will be conducting studies over the next six months on the two specimens they received from the experiment in order to learn more about the progression of muscle atrophy that accompanies disuse. Rutkove is the developer of electrical impedance myography (the work for which he won our million-dollar prize), a process which compares the flow of an electrical current through healthy muscle and muscle that has degenerated as ALS progresses. You can read more about EIM technology in an earlier blog post here.
There is currently no reliable diagnostic test for ALS. However, by making a distinction between the muscle degeneration that occurs due to illness or lack of use (accentuated in this experiment by the micro-gravity of a low Earth orbit) and atrophy that stems from a neurogenic disorder, electrodiagnostic tests might be able to tell scientists more about the nature of ALS in a given patient sooner which could improve the impact of potential therapies.
"One of the things you learn from years of dealing with drug people, is that you can turn your back on a person, but never turn your back on a drug."
- Raoul Duke, Fear and Loathing in Las Vegas
"In the field of observation, chance favors only the prepared mind."
- Louis Pasteur
The above quotes allude to the growing realization that new opportunities exist for many "old" drugs, but sophisticated knowledge management platforms will be needed to properly identify these drug repositioning opportunities.
Amid the "fear and loathing" accompanying the numerous reports of the drug development pipeline drying-up, the biopharmaceutical industry is warmly embracing the drug repositioning model as an efficient and expedited mechanism to fuel their clinical development programs with "old" drugs that have newly appreciated indications. At the recent Drug Repositioning Conference held in San Francisco, CA on July 13-14, 2011, industry experts convened to share their insights from their own drug repositioning experiences, to discuss the impact drug repositioning has had on the drug development landscape, and to assess new directions for the field.
The concept of drug repositioning (or repurposing) is not new. In the past, serendipitous observations played a principle role in identifying novel uses for approved drugs already on the market for other indications, noted Pankaj Agarwal, Director of Computational Biology, Molecular Discovery & Development at GlaxoSmithKline. Aspirin serves as a classic example.
What is new however is that biopharmas, including Merck Serono, AstraZeneca and GSK, all of whom were represented at this conference, are now placing a premium on leveraging their prior research and development (R&D) investments to rescue stalled clinical-stage compounds by re-investigating their efficacy for treating alternative new indications.
Given the high attrition rate of experimental drugs, drug repositioning offers a "solution for speedy re-introduction of compounds back into the pipeline," commented Natalia Novac, Associate Manager, R&D Knowledge Management Operational Excellence at Merck Serono. While Novac commented that Serono's original repurposing business model had focused on Phase 3 clinical compounds, they now realize that they need to start earlier, after a drug passes Phase I safety and toxicity testing, to plan for secondary indications. Others in the audience advocated preparing even earlier, at the preclinical stage in the product lifecycle, a practice adopted at Pfizer, to identify potential alternative indications that could be used either as a back-up, if efficacy testing for the primary indication fails, or as a repositioning strategy.
Some in the audience challenged the notion that only drugs that have passed Phase I harbor future value for repurposed use, indicating that a drug that failed its initial Phase I study when delivered at a high dose could be safely delivered at a much lower dose that fell within the therapeutic window for the treatment of an alternative indication. Taken together, these divergent criteria argue the utility of broadening eligibility to include all clinical compounds (and perhaps even preclinical compounds) under consideration for repositioning.
Knowledge Management: Pillar of the Drug Repurposing Approach
Nowadays, biopharma is not leaving these hidden, yet potentially golden, repositioning opportunities up to chance alone. There is a concerted effort within biopharma to capture and organize the vast amounts of existing public and proprietary data into rich knowledge networks of biological pathways and disease targets.
Merck Serono, AstraZeneca, and GSK are all heavily investing in various Knowledge Management platforms. Speakers mentioned a host of existing automated technology platforms that review texts (i.e.: publications, abstracts, clinical case reports, etc.), extract entities (i.e.: proteins X and Y) and build relationships between entities (i.e.: protein X activates protein Y) to create biological knowledge networks. These networks could be overlaid onto disease specific network maps to facilitate identification of key, possibly novel, disease targets. This type of approach could also be used to identify the relevant indication(s) based on their drug's established mechanism of action.
In addition to fully automated platforms, organizations such as Thomas Reuters offer MetaMiner Partnerships to "bring the highly specialized expertise in manual curation and disease map development to create new pathways quickly" for its clients. In a collaborative move, Reuters launched a new consortium in July 2011 to map the bioprocesses for all FDA drugs approved in the last three years.
Spotlight on AstraZeneca's High-Investment Foray into Drug Repurposing
AstraZeneca's aptly named New Opportunities group has been tasked with finding new opportunities for existing compounds in areas that the company is currently not working in. Regenerative medicine is one such new area, remarked Nick Brown, Associate Director of Informatics for AstraZeneca's New Opportunities group. Orphan diseases were also considered attractive gateway indications, suggesting that ALS could be within AstraZeneca's sights if the right opportunity were to be identified.
AstraZeneca is going further than most when building their Knowledge Management Platforms. As Brown explained, his group is in the process of bringing together over 2000 proprietary internal databases from across AstraZeneca's global reach. He admittedly faces a huge standardization challenge, but makes the point that these disparate databases contain tons of valuable proprietary information about their own drugs that remain relatively inaccessible. Brown strongly believes that re-capturing this propriety information "hidden away" will reveal novel and lucrative repurposing opportunities for AstraZeneca. Brown has also developed a rich Asset Repositioning Matrix that has already led to the identification of new disease targets and indications, as well as, potential collaborators and key opinion leaders.
The 20-member group functions as a virtual R&D with a budget comparable to one of AstraZeneca's therapeutic areas, underscoring their confidence in and commitment to the repurposing strategy. Formation and funding of this group also emphasizes AstraZeneca's belief, also expressed frequently by other conference attendees, that factoring human data into the knowledge maps is "huge". Given the size of AstraZeneca's investment and commitment it was interesting that the primary focus to date for this group had been on late stage Phase II or III compounds in clinical development, suggesting that a considerable amount of Phase I and pre-clinical information still remained untapped.
The value proposition behind the drug repositioning approach is obvious: generate new revenue streams by leveraging prior capital- and resource-intensive investments and in so doing offer patients better treatments. While the opportunities are vast, there are several important limitations, including issues of commercialization, patentability, freedom of use, and the regulatory path to approval, to name just a few. Not to fear - speakers including commercialization expert David Cavalla, regulatory expert Ken Phelps, and patent attorney Kevin McLaren, discussed a slew of strategies to work through these vital issues. Further discussion of these issues can be found here and here.
So given the buzz generated at this conference, my question is: can ALS drug development benefit from a drug repositioning approach?
One way I thought about this was in terms of speed. The critical need for expedited drug development for ALS is underscored by the aggressive and merciless progression of disease resulting in death typically within three years after diagnosis. Clinical development of a repurposed drug could significantly shorten the traditional drug development timeline and bring an efficacious drug to patients faster and, in so doing, offer access to more ALS patients.
Ok, so yes, repositioning saves time, but is it relevant to ALS? As noted by speaker Chris Lipinski, Scientific Advisor at Melior Discovery, 30% of clinical compounds have new uses and (strikingly) 90% of these new uses are on-target. These findings indicate that rather than finding new molecular targets for old drugs, we are discovering the relevance of these druggable targets in new indications, implying that there are major gaps and flaws in our fundamental understanding of disease biology.
Final thought: As our understanding of ALS biology deepens and disease targets are further validated, a drug repurposing approach could be a valuable complement to traditional ALS drug discovery efforts.
So who's with me?
- Sheila Menzies, Scientific Program Officer at Prize4Life
This blog post was originally published on the ALS Forum at www.researchALS.org.
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