follow-up ofS Re: follow-up Fernando Martinez [fernando@arc.arizona.edu] Sent:Saturday, June 16, 2007 4:05 PM To: steve.w.yancey@gsk.com Dear Steve, I knew I had signed such agreement in relation to the Asthma in America study, but had forgotten until when it was effective. I am available July 25, but in the afternoon Is PM Otherwise, let me know. June 29 I am in Europe. (clinic in the morning). My idea is to test the hypothesis that these events are associated with very rare polymorphisms in crucial genes. For example: the variant at codon 164 of the BZADR is very rare of chromosomes in Whites) but homozygotes (0.01% of subjects)could be present in excess among subjects with abnormal responses to LABA (I use this as an example, I doubt 164 is involved). If we found it in (say) 0.5% of these subjects, the likelihood of this being by chance is very low. Thus, and for this purpose, 200 random subjects (matched perhaps by ethnicity) could give us an idea if certain variants found in persons with severe events and who are treated with LABA could be causal. If there are enough subjects available, half could serve for screening and half for confirmation. We could discuss this further here. Kind regards Fernando On Jun 15, 2007 11:07 AM, steve.w.yancey@gsk.com wrote: Dear Fernando, I did some checking over the last few days. Turns out that you signed a Confidentially Statement with GSK which remains effective until 07 September 2007. Records show that Robyn Cole in GSK was the originator? In case we move forward concerning protocol development or simply as a consultant, I requested initiation of a Consultant Agreement for your consideration. If later we decide it is not needed, I can terminate the process any time. You asked how seriously GSK would want to pursue additional genetic research projects. That is a complicated question. We are constantly considering data/studies that help inform on the role of LABA and asthma control. For example, if the Michigan researchers have a large number of LABA users, and detailed data concerning the use of LABA leading up to an event, then I imagine that collaborative studies may be possible that help 5/6/2014 8:38 AIV. follow-up :of5 inform on the risk/benefit question, at least relative to genetic variation. But even this source raises many questions. Can controls be found? What local controls should be used? What are they matched against? Could database population controls be used instead? Prospective studies bring their own questions which are far too numerous to list. You mentioned your interest in a meeting to discuss some of these issues and SFA100062. I checked with Dr. Ortega and Dr. Anderson. We could meet with you in Arizona on June 29 or July 25 (morning for 3?4 hours could go longer if needed). Other dates are open but fall later on the calendar. Please advise concerning your interest and availability Kind regards, Steve 919-483?5325 (0) "Fernando Martinez" 11-Jun-2007 10:50 To steve.w.yancey@gsk.com cc Subject Re: follow-up Dear Steve, thank you for writing. What would be truly useful is to have some idea as to how seriously GSK would want to pursue this issue. This mainly has to do with costs: there are different approaches with different budgets and different objectives. Exhausting the Arg/Gly issue is one approach, not expensive but 5/6/2014 8:38 AIV. 1e: follow-up iof5 perhaps at the margins of clinical relevance: I agree that, given what we know today, this SNP is unlikely to yield usable results. A thorough in?depth resequencing of a robust list of candidate genes in search for rare variants BOTH in life-threatening asthma and in lethal asthma (I agree that the Michigan study conclusions are reasonable) is the other extreme: I believe it could really yield usable results and would put GSK at the forefront of severe asthma genetics/pharmacogenetics, but 18 is indeed more expensive and time?consuming and requires a more long-term commitment from the company. I would certainly welcome your visit this summer to discuss these issues and SFA100062. When do you have plans to come west? I am certainly willing to sign reciprocal confidentiality agreements (we do not have one) and some sort of consulting arrangement. Best regards Fernando Fernando D. Martinez, On Jun 11, M.D. 2007 05:43 AM, steve.w.yancey@gsk.com wrote: Dear Fernando, In light of study SFA100062 (GSKs "genetics" study which we showed you at finishing this year, could . inform on the design of future studies (as mentioned below). We have the results from that study, predict asthma control in this (relatively) large prospective study. I not have the haplotype analysis yet. Which leaves me thinking about appropriate next steps or study targets? it became obvious that these results and briefly Arg16Gly does not appear to do There is a recent paper describing all asthma deaths from 2002?2004 in children and young adults in Michigan. In the Discussion section, the authors discuss the pros and cons of investigating near-fatal cases as a surrogate for fatal asthma, and ultimately fall on the side that near-fatal asthma is not an adequate substitute but will complement a 5/6/2014 8:38 AN e: follow-up I 4of5 study of fatal asthma. This conclusion was based primarily on the belief that risk factors are different between these groups. this position? Do you think that a genetics study of near fatal asthma alone would be rejected/seen as incomplete by asthma researchers? Do you support If you are interested, I would like to discuss the results of SFA100062 with you as well as thoughts on next steps. There may not be a convenient meeting location for calendar is amiable, trips to the west coast later this summer? Disclosure Agreement with Until the data are made public, in both our best interest to have an agreement in place if we discuss proprietary information. each or us ATS). If not, and your I may be able to visit you as I have other Do you have a Confidentiality it is Kind regards, Steve Steve Yancey/PharmRD 10-Apr-2007 17:20 Respiratory US CDMA, Steven.W.Yancey@gsk.com 919-483?5325 fax 919-483-4300 To Fernando Marteniz cc Subject follow-up Dear Fernando, Just a brief note to say that we have not forgotten about our discussions at Specifically, we are discussing if there are practical study designs which will identify whether genetic markers are associated with severe asthma exacerbations. have anything to share or query at this point. It is still early days, so I do not If this effort leads to a concept protocol, I hope that you will 5/6/2014 8:38 Al\ e: follow-up consider a development role concerning the full protocol. If you have any questions or comments at any time, please feel free to contact me (see contact information above). Best regards, Steve 3 of5 5/6/2014 8:38 AN