ALS is a disease with poorly understood pathophysiology. In other words, the research world is still struggling to identify the biological hain of events that leads to the emergence of symptoms and disease progression. Furthermore, ALS is not really a singular disease, but a syndrome, a condition defined only by its symptoms and what will probably be identified as several different diseases at some point in the future.
Yet today what we have is a lot of people with savagely progressive neuromuscular degeneration stemming from the mass death of their motor neurons. Each person has his own trajectory of disease progression, with alternating periods of relative stasis and relative acceleration of worsening symptoms.
These facts are important, because they highlight the challenge that drug makers and regulators face when assessing the medical benefit of particular ALS drugs. What seems to work in some patients may not work in others. How do we know when a drug is really benefiting a particular patient, and what percentage of a randomly selected sample of patients must benefit from a product before we recognize that product’s value? These questions constitute huge trial risks for drugs in clinical development for this class of diseases.
This difficulty in determining a drug’s value hurts current ALS sufferers in three ways:
First, good drugs that would save at least some lives if broadly available to patients may fail to show the signals required to proceed toward FDA marketing approval. Because of poor trial design or simply bad luck, the drug’s development will be either slowed or discontinued altogether. Without further clinical trials, no current patients benefit from the drug. None will participate in trial, and none will benefit from eventual FDA approval that never occurs or occurs so far in the future that every current ALS patient dies beforehand.
Second, the experiences of trial participants who do well are routinely ignored if the trial fails to reach its statistical endpoints. Most in the ALS community know at least one patient who, with his doctor, believed his trial drug regimen was having disease-modifying positive effects on his condition before having his drug supply cut off. These patients were told by the drug company in each case that, because the trial failed, the drug must not really be working for ALS patients. The patient is stripped
of a possible lifeline that has been working for him.
Third, the commercial prospects for new drug development in poorly understood
neurodegenerative diseases are bad, due to the great trial risks that come with the space. There are manymore drugs that should be in clinical trial for ALS than the number of drugs that actually are in trial for ALS. A clinical drug candidate must have a special mix of qualities –sometimes arbitrary ones- to draw enough support and funding for clinical trial.
ALS currently has a small number of promising drugs that have been developed through Phase II. Right now, before they are validated in Phase III “confirmatory” studies, these drugs offer special opportunities for current ALS sufferers to access potentially life-saving treatment as an alternative to the almost certain fate of near term death without treatment.
It is our job to enable the drug companies and regulators to make these drugs available without further delay, to as many willing and informed ALS patients as possible.
Potentially effective therapies exist right now, but they’re not accessible.
ALS patients aren’t naïve. They know the difference between anecdotal stories and clinical evidence of safety and efficacy.
They’re also smart enough to deduce that it’s unlikely they’ll live long enough to benefit from a distantly future treatment unless, in the meantime, they somehow gain access to investigational-stage drugs (before waiting for them to be FDA approved).
We believe that when armed with facts, their doctors’ advice, and their own personal preferences for risk and hope, there is no one better to decide the appropriateness of using investigational drugs than the individual dying patients themselves.
ALS Treat Us Now does not promote or recommend any particular investigational drugs. Instead we work to enable patients to access them in cases where those patients and their doctors choose to pursue them. The group directs its access campaigns to drugs that have performed favorably in human safetystudies and have already shown significant signs of efficacy at modifying the disease.
From our research, this category of treatment options would be medically appropriate for a large proportion of ALS patients.
As of April, 2012, there are at least three drugs that fit this category.
1) Dexpramipexole, currently developed by Biogen Idec, is an orally administered small molecule that enhances mitochondrial function and is believed to extend the lives of motor neurons in stress conditions. The drug has proven to be well tolerated in ALS patients and showed reasonably positive dose-dependent efficacy on the
ALSFRS-R endpoint in Phase II. Biogen has in-licensed the program from Knopp Biosciences and has enrolled over 500 patients in a multi-site Phase III trial.
2) NP001, developed by Neuraltus, is an i.v. administered chemical product that regulates the immune system’s inflammatory stress response to suppress the antagonistic properties of glial macrophages. The drug has proven to be well tolerated and is reported to have shown promising efficacy signals in Phase II development.
3) CK-357, developed by Cytokinetics, is an orally administered anabolic agent targeting fast twitchfibers of the patient’s respiratory muscles. The drug’s quick absorption and response times have permitted a short trial duration with crossover between two randomized groups. At ALS symposiums, unofficial discussions about the completed Phase II data suggested a dose dependent positive functional response in ALS patients.
Unless expanded access or accelerated approval programs are explored, all three drugs will remain out of reach to the vast majority of ALS patients for several months or years, due to ineligibility or inability to participate in clinical trials.
REFERENCES:
1. Shuren J. 2009. Final Rules for Expanded Access to Investigational Drugs for Treatment Use and Charging for
Investigational Drugs., U.S. Dept of Health and Human Services / FDA Federal Register.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplic
ations/InvestigationalNewDrugINDApplication/ucm172492.htmpg. 40900
2. Code of Federal Regulations, Title 21, Section 312.305
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.305
3. Code of Federal Regulations, Title 21, Section 312.310
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.310
4. Code of Federal Regulations, Title 21, Section 312.26 (since re-rewritten)
http://edocket.access.gpo.gov/cfr_2003/aprqtr/pdf/21cfr312.36.pdf
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