Our petition continues to grow every day. We have reached over 135,000 signatures and we’re starting to get the attention of several main stream news outlets. We continue to build a strong team for our campaign that consists of mainly ALS patients and we continue to improve our social media presence. Recently, there have been some groups and individuals out there criticizing our campaign and downplaying the statistical significance of the data from the GM604 Phase IIa trial and the compassionate use trial. In this update we will debunk this criticism. To the set the record straight, Genervon: (1) did not conduct the clinical trials. (2) did not select the trial participants. (3) did not analyze the results. ALL of the patients data collection and analysis were done by clinical sites at Columbia and MGH, independent contract research organizations (CROs) and statistical & biomarker experts. Genervon broke with tradition and released the top line data and analysis to the public and has already filed the extensive "Clinical Trial Report" to the FDA for review. So any accusations saying that Genervon manipulated data and cannot be trusted is pure non-sense. The data speaks for itself. After the ALS Association - National (ALSA) posted their consensus statement on Monday downplaying the statistical significance of the GM604 Phase IIa and the compassionate use trial data, we reached out to Genervon and asked them about the validity of the ALSA’s assertions. Genervon responded with 3 documents. One was a letter from Dr. Paul J. Lupinacci debunking the ALSA’s criticism of small trials and the other is a letter from Dr. Robert Bowser talking about the significance of biomarker data against questions of biomarkers and the high science behind it. They also included 30 points on ensuring Quality Control and maintaining data integrity to counter the allegation of unreliable data. (all included below the links) Biomarker data is the most advanced scientific and sensitive tool confirming the underlying mechanism of ALS disease improvement in multiple targets by GM604. Based on the this biomarker data and the safety data there is no reason why the FDA shouldn’t approve GM604 under the Accelerated Approval Program. There has also been some criticism about our campaign and statements that Genervon is behind our petition. Nothing could be further from the truth. This campaign and petitions were initiated by people with ALS and their families. As needed, we have sought information and data from Genervon to validate the science behind our position and they have been cooperative. Just to be clear, we believe that most of the local ALSA chapters do great work providing needed services to ALS patients. Our disagreement is not with them, we commend their work. Our disagreement is with ALS-National for being unbending and refusing to change with the times to help get promising new drugs to people with terminal diseases before it’s too late for them. ALSA-National has done nothing but try to slow down the release of GM6 which is very unsettling. So the bottom line is GM604 has proven to be safe and the data shows that it’s effective. There’s no reason why the FDA should not grant Approval under the Accelerated Approval Program. It’s for situations like this that the FDA created the AAP. We have a new campaign website to educate our campaigners, and to dispel misinformation and misdirection about the science behind GM604. It's a great resource to learn about the trials and results. https://sites.google.com/site/aap4gm6/home Everyone should also visit Genervon's website, which has a lot of science and trial information. http://www.genervon.com/genervon/medicines_trialdata.php You can keep track of the campaign on Twitter, Facebook and YouTube here: https://twitter.com/gm604als https://www.facebook.com/gm604forals https://www.youtube.com/channel/UCA6BbrjLacyvTzwP9Egp_Vg If you haven't done so already, please email and/or tweet FDA: https://www.change.org/p/janet-woodcock-m-d-fda-accelerated-approval-of-genervon-s-gm604-for-use-in-als/u/9475826 Send a tweet to the two top U.S. Senators on the HELP Committee: http://ctt.ec/j230_ and call/email U.S. HELP Committee Senators: https://www.change.org/p/janet-woodcock-m-d-fda-accelerated-approval-of-genervon-s-gm604-for-use-in-als/u/9425621 Regards, Jehad Majed and Nick Grillo Here is Dr Robert Browers letter, below that Dr. Paul Lupinacci’s letter and the 30 points on QC…. Sorry about the long update but we had to set the record straight. —————————— January 31, 2015 Dorothy Ko Genervon Biopharmaceuticals LLC Pasadena, CA RE: Biomarkers in ALS Dear Dorothy, We examined biofluid samples and identified changes in specific biomarkers during GM6 treatment in ALS patients. These biomarkers included TDP-43, Tau and SOD1. TDP-43 is a pathologic hallmark of ALS and prior studies have shown increased levels of TDP-43 in ALS biofluid samples (1,2,3). A recent in vitro study used patient derived motor neurons generated from iPS cells to screen for drugs that reduce expression levels of TDP-43, and identified compounds that they wish to move to the clinic based on lowering levels of TDP- 43 expression (4). Higher levels of TDP-43 can be neurotoxic and generate cytoplasmic aggregates that impede cellular functions. Collectively, these data indicate that TDP-43 is useful as an ALS biomarker in drug screening and in ALS patients. Therefore this protein should be useful as a biomarker for continued human clinical trials. Tau has been a biomarker of neurodegeneration for many years and is extensively used for Alzheimer’s disease. We have previously used Tau as a biomarker to monitor effects of memantine treatment in ALS patients in a phase 2 clinical trial. We showed that reduction of Tau levels in ALS patients due to drug treatment correlated to reductions of clinical parameters of ALS disease progression (5). Finally, we have also used SOD1 levels in ALS patient biofluids as a biomarker to monitor efficacy of anti-sense oligonucleotide treatment in animal models of ALS and human patients in early clinical trials (6,7). Therefore this protein has also been shown to provide biomarker information within human clinical trials and should not just be considered an exploratory biomarker. Therefore these biomarkers (TDP-43, Tau, SOD1) that each exhibit altered expression levels in response to GM6 within in vitro studies, should be considered useful biomarkers for continued clinical studies of GM6 in the ALS patient population. Sincerely, Robert Bowser, Ph.D. President & CEOIron Horse Diagnostics, Inc. Scottsdale, AZ 85255 REFERENCES: 1. Kasai, T., et al., Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol, 2009. 117(1): p. 55-62. 2. Noto, Y., et al., Elevated CSF TDP-43 levels in amyotrophic lateral sclerosis: Specificity, sensitivity, and a possible prognostic value. Amyotroph Lateral Scler, 2011. 12(2): p. 140-143. 3. Steinacker, P., et al., TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol, 2008. 65(11): p. 1481-1487. 4. Egawa, N., et al., Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med, 2012. 4, 145ra104: DOI: 10.1126/scitranslmed.3004052 5. Levine TD, et al., A pilot trial of memantine and riluzole in ALS: correlation to CSF biomarkers. Amyotrophic Lateral Sclerosis, 2010. 11: 514-519. 6. Winer L, et al., SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy. JAMA Neurol, 2013. 70 (2): 201-207. 7. Miller TM, et al., An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomized, first- in-man study. Lancet Neurol, 2013. 12: 435-442. ---------------- Slide show showing the results of TDP 43 in the Genervon GM604 ALS Phase IIa trial. http://youtu.be/uYZFQIrn8A4 ———————— Clinical Trials with Small Sample Sizes Clinical trials with small sample sizes can provide very useful results in the context of drug efficacy. Not all clinical trials can consist of hundreds of patients due to incidence rates of the disease or recruitment issues. These small clinical trials should not be viewed as meaningless simply due to the sample sizes. In fact, these small clinical trials can be very helpful when determining the meaningfulness of the effect size seen in the efficacy measurements. Clinical trials that contain small sample sizes put the active treatment at a distinct disadvantage. These small clinical trials will be underpowered to detect significant differences between the active and placebo groups in almost all, if not all, efficacy endpoints. The statistical hypothesis test starts from assumption that there is no difference between the active treatment and placebo. A p-value of less than 0.05 is typically the threshold to reject that hypothesis and claim that the active treatment is superior in terms that specific efficacy endpoint. However, to achieve that threshold with small samples sizes, there must be complete or near complete separation of the result between the placebo and active treatment groups. For example, in the change from screening in FVC, 3 of the 4 changes from screening in the GM604 group were less than the smallest change from screening in the placebo group, leading to a p-value of 0.0476. There is obvious separation between the treatment and placebo groups in change from screening in FVC. This result should not be mitigated because of the small sample sizes. In fact, this result should be considered quite strong given the lack of power to detect that difference. If there was only one significant result, one could argue that it was spurious and even what you would expect with a Type I error rate of 0.05, regardless of the size of the clinical trial. However, when several endpoints show statistical significance and others are trending that way and have p-values near the 0.05 threshold in the presence of small sample sizes, there is an obvious signal that the active treatment is working. The active treatment is demonstrating an efficacious response that should be heralded, not as a random result found due to the small sample sizes, but as a powerful result found in spite of the small sample sizes. Paul J. Lupinacci, PhD Director of Biostatistics WCCT Global ————————— GALS-001 Data Integrity: 30 steps to ensure QC 1. Submitted application to and obtained IND approval from FDA to start clinical trial 2. Entered clinical trial agreement with trial sites: Massachusetts General Hospital and Columbia University 3. Trial sites approved Informed Consent Form and trial protocol 4. Registered Phase 2A trial of GM604 for ALS treatment on clinicaltrials.gov NCT# 01854294 5. Entered data management, statistical analysis, and clinical study reporting contract with independent Contract Research Organization (CRO) 6. Trial sites recruited and screened ALS patients for eligibility and baseline measurements 7. Held initiation meetings to train sites on protocol and reporting 8. Shipped GM604 to clinical trial sites' research pharmacies 9. CRO independent biostatisticians generated randomization codes for both sites 10. Randomization codes shipped to trial site pharmacist restricted to pharmacist access only 11. All other site personnel blinded to the randomization assignment 12. Clinical assessments and safety lab testings carried out per protocol schedule 13. Trial procedures, evaluations recorded in Case Report Forms (CRFs) 14. Genervon's designated monitor visited trial sites to monitor CRFs and records 15. Biomarker samples processed per protocol and stored at -70C 16. Biomarker samples batch-shipped to CRO for testing 17. Biomarker samples analyzed by CRO 18. Approved and finalized Data Management Plan prepared by independent CRO 19. Case Report Forms scanned into PDF files and sent to CRO Data Management Team for data entry 20. Biomarker data entered into trial database21. Queries and resolution of data with Genervon's site monitor, site PIs, and site trial coordinators 22. Database locked after multiple sign-off by quality control personnel 23. Approved and finalized Statistical Analysis Plan (SAP) 24. CRO biostatisticians prepared statistical analyses per SAP 25. CRO biostatisticians prepared listings, tables, figures and Statistical Report 26. CRO independent medical writer prepared Clinical Study Report (CSR) 27. CRO biostatisticians prepared ad hoc analysis of CSR to capture observed effects not previously reported 28. Genervon submitted CSR and addendum report to FDA 29. CSR and all data, including raw data, under review by FDA 30. FDA and Genervon scheduled End of Phase 2 Meeting to be held in February http://www.every90minutes.org/