Some 35 leading international ALS clinicians, academicians and
representatives from industry, NIH and FDA came together on April 1 at The
ALS Association's Drug Company Working Group Meeting, held as an affiliate
meeting of the American Academy of Neurology annual meeting in Honolulu.
Participants from The ALS Association (ALSA) were Dr. Lucie Bruijn, Mary
Lyon, MSN, RN, Vice President, Patient Services and Ellyn Phillips,
National Trustee and Chair of ALSA's Advocacy Committee.
Begun in 1995 by ALSA to stimulate and accelerate treatment development
for ALS, the Drug Company Working Group is a forum for important, ongoing
dialogue among leaders in the field of ALS treatment development focused
on the status of basic science in ALS and the opportunities and challenges
in translating laboratory findings to treatments for patients. Goals for
this Spring 2003 meeting were to:
-- Develop and build on existing interest of pharmaceutical and biotech
companies to conduct work that will lead to therapies for ALS
-- Explore current federal incentives for ALS research and therapy
development
-- Update industry representatives, scientists and clinicians about ALSA's
new programs
Don Cleveland, PhD, of The Ludwig Institute at the University of
California, San Diego, spoke on "Current Research Efforts in ALS: Towards
Therapeutic Approaches." Dr. Cleveland's presentation formed the backdrop
for a review of the opportunities available in the field of ALS therapy
discovery.
-- Dr. Cleveland provided an overview of the status of ALS research with
particular emphasis on viewing ALS not as a disease of the motor neurons
only, but implicating the likely pathological interactions among several
different cell types surrounding the motor nerves
-- The concept of ALS as a disease involving multiple types of cells was
demonstrated in Dr. Cleveland's research approach in mice
-- He went on to discuss very exciting ALSA-sponsored work in process that
takes the approach that by lowering the mutant SOD1 protein, survival
might be increased in response to the reduction of the toxic properties of
the mutant SOD1 (for more on this work, see
http://alsa.org/research/awardlgc_cleveland.cfm)
Lucie Bruijn, PhD, ALSA's Science Director and Vice President, Research,
summarized information from an ALSA meeting in September, 2002 with the
FDA and NIH directed toward a number of existing programs in these
agencies that offer opportunities for orphan disease treatment development
research and clinical trials. In her comments titled "ALS as an Orphan
Disease," Dr. Bruijn presented potential funding avenues and financial
incentives for drug and biotechnology companies to develop and test
treatments for ALS. She reviewed the opportunities of the Orphan Drug Act
and other incentives from NIH and FDA to encourage investigators and
companies to invest in ALS drug discovery. Through ALSA's and others'
advocacy efforts, Department of Defense funding as well as the recently
announced request for applications from the Office of Rare Disease
Research provide potential additional resources for ALS research.
Dr. Bruijn pointed out the "strengths" in the ALS field, noting in
particular the development and availability of ALS animal models for
research - unlike a number of other diseases such as Alzheimer's. Also,
investigators have identified a number of possible disease mechanisms -
all of which are potential targets for drug therapy either as monotherapy
or they set the stage for combination therapies. Said Dr. Bruijn, "Another
strength of the ALS field, as well as an attractive incentive for industry
to develop ALS therapies, is the tremendous unmet need for therapies in
this devastating disease, numbers of clinicians experienced in clinical
trials and a very motivated patient population."
Moderator, Hiroshi Mitsumoto, MD, Columbia University, New York, led the
group discussion portion of the meeting that included panelists Jeffrey
Rothstein, MD, PhD, Johns Hopkins University, Baltimore, and Jeffrey
Rosenfeld, MD, PhD, Carolinas Medical Center, Charlotte. There was
spirited discussion and debate of different points of view among the
participants. Key talking points included:
-- Challenges of clinical trials: Absence of surrogate markers for ALS;
what are the most valuable and appropriate end points?
-- Combination drug therapies and trials: Lack of industry interest in
combination trials unless all therapies are owned by the company; lack of
clarity of which of the drugs in a combination are having what, if any,
effects on their own before combining multiple drugs
-- The pros and cons of conducting clinical trials versus off label use of
currently available drugs that have shown benefit in mice
-- Current status of stem cell research and as a possible treatment: The
last several years of experience in laboratory research with stem cells
for ALS suggests that more laboratory research is needed. More information
is necessary about the number and type of stem cells required, determining
how they act, what they will do, if they will perform as motor nerve
replacement or as support cells for dying motor neurons, and a number of
other questions. Although very promising, scientists are unable to predict
how rapidly the research field can be translated into significant clinical
benefit as there are still too many unanswered questions and significant
hurdles to be addressed in the laboratory:
-- What are the limitations of animal models in predicting outcomes for
human trials? Many promising compounds from animal models are not
successful in the clinic. This emphasizes the need for careful
standardized animal testing. More work is needed to establish appropriate
dosage in clinical trials
Summing up, after the meeting, Dr. Bruijn said, "The real value to
workshops like these is the dynamic interaction and differing points of
view among investigators from so many different disciplines."
All participants agreed that the value of such opportunities is to share
what incremental knowledge has been gained and to stimulate new research
and therapy ideas. Industry representatives also spoke of their commitment
to ALS work. The participants recognized that more debate and discussion
is needed between the academic scientists and the ALS clinicians.
ALSA's Drug Company Working Group continues to be an important forum for
such dialogue and the "launching pad" for follow-up, targeted meetings.
ALSA is already planning the next steps that include the annual meeting of
the Drug Company Working Group in Spring 2004 in San Francisco.
June conference to focus on challenges of clinical trials
Clinical investigators are working on the concepts and challenges of
clinical trials. Dr. Mitsumoto announced an upcoming June conference on
challenges of ALS clinical trials. This is a forum for furthering the
discussions of many of the topics covered in the last several ALSA Drug
Company Working Group meetings. The importance of bringing new, young
scientists and clinicians into the ALS field was stressed as a method to
increase new ideas, energy and investigations.
Many of the concepts introduced and discussed at ALSA's September 2002
meeting with the FDA and NIH, along with this April 2003 meeting of the
Drug Company Working Group, are a prelude to the June clinical trials
conference. For the June conference ALSA is funding the attendance of each
of the medical directors from its 18 certified ALSA Centers.
In addition to stressing the importance of clinical treatment trials, ALSA
also funds, and emphasizes the need for, clinical management research. On
the day prior to the June clinical trials conference, Dr. Bruijn, Mary
Lyon and the medical directors from the 18 certified ALSA Centers will
meet to finalize a multi-center research protocol that will investigate
the clinical benefits and outcomes patients and families experience.
through the multidisciplinary approach to clinical care. In addition to
stressing the importance of clinical treatment trials, ALSA also funds,
and emphasizes the need for, clinical management research.