[Music] good morning everyone and it's my pleasure to present a quick summary uh on behalf of my co-investigators and colleagues uh regarding our work with migom combined with dexamethasone and monoclonal antibody therapy for patients with relapse and refractory Myoma and these are preliminary results from the um CC 92480 uh 002 trial um which we presented at this last year's December American Society of hematology in San Diego by way of introduction zide which we formerly called 92480 is a nove
l uh potent oral cereblon E3 ligase inhibitor which um is a so-called cell mod and this has profoundly enhanced um tumorous and immune modulatory effects and these are actually in a different class I would propose than our than the original so-called immunomodulatory drugs or imids and in fact molecularly as a as a chemical structure they are quite distinct but they obviously Target the same thing which is the C3 liaye complex but do so in a much more profound and established way in other words
this binding into this pocket which you can see here in green is that much more uh complete compared to for example pomalidomide um which is an imid uh and obviously engages the same broad Target but does so quite differently and this is reflected by the fact um that if you look at how much closure there is of the cereal ne3 liase complex um with migom this is a striking 100% where is just 20% for pomalidomide now why does this matter because this has a profound effect on how um this target then
modulates antimyeloma effects specific specifically if you close um this pocket as profoundly as Momi does you can see here that there's dramatic killing of amoma cells in preclinical models compared to pomalidomide at the same concentration at the bottom well in fact actually at a higher concentration um than the migom but nonetheless at a concentration that we see uh in patients and the bottom line is migom and a concentration that we also see in patients but at much lower micromolar dosing i
s incredibly active and when you combine mide with monoclonal antibodies in preclinical systems and the effects appear synergistic so with that in mind the um study design that we used for combining Mesi as we affectionally call migd deide with a variety of new drugs um is is summarized here and that basically um as you can see we not only looked at daratumumab and iusab but we also looked at bmib and kilm which we uh reported on previously now I would just simply say for today's discussion we'r
e going to focus on um the DaRuMa M experience and elatab and the objectives were to establish could this be safely combined on the one hand and very importantly was this active um so what did the results show well first and foremost um this shows you the various schedules and to really get to the chase here we looked at a variety of different schedules for the DaRuMa mad migd mind comp just to optimize dose and schedule and we looked at a classical schedule for elab 3 weeks on and one week off
and importantly we looked at two different doses of mamid either 3 or 6 and what we found which was so interesting is if you look at for example in the Dara population of patients the Dara exposed cohort we had a very uh significant triple class refractory highrisk group here compared to the elaab group uh in whom more of them had had prior cd38 exposure if you look at the refractory status as I've mentioned most of these patients were refractory to available therapies and importantly in the ELO
group um at least a third what we call Triple class refractory but I think the most important takeaway from this is all patients that received PRI imids and proteome Inhibitors and most of those patients in the ilusa cohort were actually cd38 refractory now in terms of duration of treatment it's important to sh that the B1 group um were the most um mature in terms of the number of Cycles received um and at the same time the B2 and B3 groups had had less exposure but nonetheless something we cou
ld certainly report on and in the 20 patients who participated in the ilm cohort um we had a decent exposure but the most important point is very few patients had discontinued due to Adverse Events now the the real sort of core of the presentation was here in terms of the side side effect Pro profile which basically shares with you that the um side effect profile when you combine mide with Duma M and as mentioned we looked at two doses. 3 and6 milligrams you can see here um that the side effect
profile um was remarkably good and then when we looked at the actual specifics of the side effect profile neutropenia was the dominant effect as I've mentioned um we saw this at both. 3 and 6 milligrams given according to the respective schedules one was three weeks on and one week off the other was uh two weeks of every uh three weeks and the other one was syncopated where we gave seven days on of uh uh with seven days off and then repeated this and the goal here was really to establish what th
e best and safest dose and schedule was and we were very pleased to see that neutropenia was our dominant side effect but again generally very manageable now in the context of um efficacy these are summarized ized here as you can see for the whole group of patients and remember these are relapse refractory patients and although they were not refractory to cd38 obviously which was key um importantly um obviously therefore we would expect them to be responsive to cd38 targeting but nonetheless wha
t we were very pleased to see was the obvious Synergy by combining the migom with the DaRuMa M and what you can see here is that in the most mature uh cohort so-called cohort B1 the response rate was 83% uh remarkably in cohort B3 it was approaching 90% And in this less mature group who were on the schedule um that was 14 days on one week off it was 61% but that's probably a function of uh time on treatment as opposed to anything else and what was really interesting was if you look at the group
overall about 80% of patients responded which is again supportive of synergy we would expect migd toide alone to generate a response rate of around 40% and would expect darat Tuma alone to generate a response rate around 30% so to see this 80 to 90% response rate was really very encouraging and I think the real proof of the efficacy of this combination lies in the socalled median durations of response as you can see it has not been reached in terms of cohort B1 or B2 for that matter but if you l
ook at the lower boundary it's 23 months um for the lower boundary of duration of response for cohort B1 which is I think um very encouraging and most importantly if you look at the swimmer spots which are here you can see how well some of the patients on B1 are doing even at the3 milligram dosing compared to0 6 and what you can see here is that we have patients as far out as 41 and now 42 43 and 44 Cycles uh into this experience with the combination and if one thinks of that as a monthly cycle
we're now in in the space of three and a half to four years so this is I think very encouraging um and at the same token if we look at elatab we see here again very well tolerated generally speaking um and very importantly just as we saw with DaRuMa M based therapy no covid related mortality and then excitingly manageable uh um toxicity profile with neutropenia is the issue but again treatable and in this group of patients the response rate was a little lower 45% and this obviously reflects the
fact that the majority almost all of these patients with cd38 antibody refractory and on the other hand I think it also reflects the fact that elatab isn't perhaps as powerful an antibody as DaRuMa maab um but that being said to see in the DaRuMa maab exposed and or refractory population a response rate of around 45% for us was was encouraging it certainly points to this as being a viable option now what about the effects in terms terms of um the pharmaco kinetics and phac dynamics of the treatm
ent and remembering this treatment bomide is designed to modulate te- cell and NK cell responses we affectionally think of Mesi as carti in a pill if you will although I think that's a little bit simplistic but nonetheless it's it's a nice way of thinking about it because it does modulate um te- cells and natural killer cells and what we're pleased to see is that mide was pharmacodynamically active um in and NK cells at all three schedules and at both doses that we tested and very importantly th
ere were some scheduled dependent t- cell effects which suggested this drug really is influencing the behavior of te- cells and then when we looked at the same platform in the elatus patients we showed that migite combined with ELO was actually very active in both the t- cell and NK cell compartment with ELO tuab as well so this was a very consistent signal so what are our conclusions well this is the first analysis of momine combined with monoclonal antibodies and it shows promising efficacy ob
viously with the migd deide combined with the D tumor map we have an overall response rate of around 80% and in one cohort it's approaching 90% with elmab recognizing that there are more refractory population and the vast majority of patients were so-called cd38 refractory we saw a response rate of around 45% so in the context of a well tolerated therapy definitely something worth watching nonetheless the impact in the DaRuMa map cohort was particularly striking with durations of response that a
ppear really very long approaching four years for some of the lead patients so I think what's also terribly important to appreciate is the immune stimulatory effect of migd deide and this I think builds a very exciting rationale for combining mide with our best immune therapies this would include obviously um bcma targeting and gprc 5D approaches in the setting of not only um by specific te- cell engages but also very importantly car car te therapy so a really exciting therapeutic adjunct in the
making in my opinion I want to just close by really acknowledging above all our patients and families who participated in the trial our clinical research teams at each of the perspective sites our our farmer partner in this very uh important work um BMS cell genene and then particularly um the co-investigators that I've listed here um literally from uh both Europe uh and the United States and thank you very much for your kind [Music] attention
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