Let`s see you poke holes in what is a serious understanding of what the company is really doing if you even understand the science. OBTW- I`m a new investor that's really done some due diligence.
The company announced virtual symposium "VISTA: A New Immune Checkpoint in Cancer, Autoimmunity and Beyond," taking place on June 18th. Discussion will center on VISTA's role in several disease areas and current development programs (led by two key leaders in the space). It is encouraging to see the company lay groundwork ahead of initial clinical data (expected by year end).
As for Jefferies presentation some highlights:
-NHL study BTK combination has readout year end, as does VISTA program.
-IRAK4 works differently for lymphoma versus leukemia. This year everyone has been focusing on AML/MDS study (where IRAK4L is driver of disease). Testing so far shows all comers in AML & MDS seem to benefit on this drug (getting tumor reduction across the spectrum). As combo therapy, they think all comers should be taking the drug (oral, disease modifying, no myelosuppression that's seen with azacitidine or venetoclax).
-Identified opportunity for accelerated approval with FDA for monotherapy. Easy way to identify these patients, preselect, in advance is with one of two spliceosome mutations. There is spectrum of IRAK4L expression, everyone has some. The more IRAK4L you have, the more likely it is to be problematic and a driver of disease. If in general more IRAK4L is potentially problematic, there are two ways to identify them (IRAK4L assay or 1 of those 2 spliceosome mutations). Roughly 20% of patient population within AML and MDS has a spliceosome mutation. That said, they are getting 8 of 9 patients in study showing blast count reductions (clearly don't have to have one of these two mutations to benefit). There are a lot of patients where simply knocking down IRAK4L expression levels will benefit.
-Original theory has panned out in the lab, reinforced by literature in the industry and now they have clinical data (more and more confidence in this consistent line of thinking). In particular, one of things they have not seen in clinic yet but are designing a cohort to examine is FLT3 mutation. All 3 patients with spliceosome mutation have responded (if in post HMA setting, there are NO approved therapies because NOTHING works). 3 of 3 where NOTHING works is pretty compelling. FLT3 drug was designed to hit FLT3, literature outside of Curis seems to point to these two pathways having a connection (IRAK4 is an escape mechanism for FLT3). Stands to reason that should see extra bump in efficacy there as well, so designed a cohort to test that hypothesis and could have a high class headache (two paths to accelerated approval, horse race to see which one wins).
-Talking to KOLs in community, this is the first time a new target has been identified in AML and MDS for years and it just happens to be the single largest target ever identified.
-EHA data confirms hypothesis and learnings from ASH. 8 of 9 patients now showing blast count reductions (can still say this is an all comers drug). 2nd, have been able to identify mutations most likely to respond that allow for monotherapy accelerated path to market. 3rd, seeming hematological recovery in ALL patients that have responses and some of them all the way back up to normal range (any improvement means fewer transfusions and clear clinical benefit). That they are seing that kind of recovery in these patients is exciting at this stage.
-Data cutoff for abstract was February 8th, and patients that came on after is for 500 mg which is above safety cutoff range. What we should expect is richer data set on patients in the original EHA abstract (baseline characteristics, IRAK4 status, genomics, etc). Enriched dataset gives more confidence on where the drug could be able to go.
-For VISTA, event on 18th Curis is sponsor but more an academic forum, led by two major experts in the space, and there will be lot of people and few other companies to push VISTA forward. Share some of what they are learning and make VISTA a bigger topic.
-Assuming they declare phase 2 dose in leukemia study soon, will move into expansion fast (FLT3, combo patients, spliceosome). Lymphoma study is ongoing as well, combination with ibrutinib. BTK downregulate NFkb and so does IRAK4- preclinical data set is really strong, shows combination of two pathways better than either one alone. Last 2 years they showed monotherapy activity, ibrutinib combo study is ongoing and commercial discussion with physicians is that there are a lot of choices for BTK, but here is only one IRAK4.
Updated EHA data:
-300 mg BID chosen as go forward dose into phase 2 studies (no DLTs at this dose, 98% target inhibition, all 4 patients achieved blast reductions including CRi and negative MRD)
-FLT3 patient achieved objective response, after two cycles FLT3 mutation was ¨completely eradicated¨
-Preclinical synergy supports combination trials with venetoclax and azacitidine
-Genomic analysis from multiple patients is quite supportive (DNA sequencing demonstrates disease modficiation with reduction of cancer associated variant allele frequency, RNA sequencing shows disease modification with reduction in long/short ratio of IRAK4 post treatment)
-Individual case studies (AML patient with spliceosome mutation SF3B1, AML patient with FLG3 mutation, AML patient 4 prior lines of chemo obtaining full recovery of hematologic parameters, nice durability on trial)
-On the con side, they did see two more cases of Grade 3 rhabdomyolysis at the 400mg dose (resolved after dose interruption, no renal dysfunction)
As for the KOL call, here are some takeaways:
-2 paths to potential accelerated approval in monotherapy, genomics analysis confirms disease modification in both patient subgroups. Broad registrational pathway in combination with other agents. Blast count reductions in 10 of 12 patients, 5 objective responses including all 3 spliceosome patients and complete erradication of FLT3 mutation in patient unresponsive to leading FDA approved FLT3 inhibitor.
-Patients that had a response was associated with recovery of platelets and neutrophils. They are seeing blast reduction and decrease in molecular tumor burden.
-Bottom line, IRAK4 is fundamental driver of disease across AML and MDS. Case study from patient 3 was quite convincing, complex mutation status, had some blast reduction (not all the way to normal range), been maintained on drug with stable disease, steady improvement in hematologic parameters (strong support of heme improvement and blast reduction to go into combinations, even if there's not a specific marker that indicates regulatory pathway).
-More thoughts on 300mg BID as recommended phase 2 dose. Excellent exposure curve, tight PK (98% target inhibition). Go to 400mg did not add significant additional effect on target versus 300 mg. 300mg is same dose as lymphoma trials as well as low risk MDS study. Had patients on treatment 7 to 8 months without cumulative toxicity, on lymphoma for up to 2 years this dose. Efficacy is maintained over significant periods of time. 4 of 4 patients with blast count reduction, including CRi with negative MRD. Rapidly moving forward with this dose.
-Preclinical data highly supportive of combination with azacitidine and venetoclax. Azacitidine 4948 combo completely eliminates tumor growth THP-1 cell line (has increased levels of IRAK4L), superior to venetoclax azacitidine combo in that model. Triplet combo suggests strong synergy as well. OCI-AML2 cell line 4948 venetoclax combination ¨completely stops¨ growth in tumor cells and triplet causes ¨profound cell killing¨. Both azacitidine and venetoclax are highly myelosuppressive, is a dose limiting issue and we now have a drug showing clear synergy that does not have additive myelotoxicity.
-Q&A: Across both populations majority of patients have excess IRAK4L for variety of reasons, so would suggest this is a broad drug. 3 spliceosome patients had striking responses, but it's early days. Challenge is this is an extremely poor patient population in terms of survival, they don't live long (survival extremely short, prognosis very poor). Durability seen in patients shown so far is quite striking in that context. Survival after first line therapy in patient with HMA failure is 4 to 6 months, patients with AML particularly those treated with HMA + BCL2 inhibitor is few weeks. There is no standard of care here and very unfortunate situation per KOL, swimmer plot quite encouraging in that light.
-Clinical development plan is long term, has activity in majority of AML and MDS patients so will be an ideal combination partner. Broad strategy is adding earlier line across broad spectrum of AML and MDS. Opportunity for rapid registrational approval in genetically defined populations. Studies going on in parallel.
-Investigator initiated study led by leading expert in low risk MDS studying 4948 as monotherapy (wide open for therapies in this population).
-Very safe go forward dose, getting responses and best responses as monotherapy in exactly the setting they hoped to.
-Combo cohorts are kicking off right now, will do doublets first to make sure data consistent before heading into triplet.
-Big caveat here continues to be the small N, number of patients for which we've seen data so far. Devil's advocate is AML patients responding less than MDS, drug has narrower therapeutic index given upper limit is probably 400mg BID.
-Looking to add as many patients as they can now that they've chosen 300mg dose, love to be able to give an update on these patients at ASH. Keep in mind they've dosed at this level along a couple years without any DLTs. Saw some safety signals above this dose, easily identified, easily resolved and there were not many of them (rhabdo in 13% of patients treated at 400mg). Inhibition percentages at 97, 98 98 among 300mg 400mg 500mg levels. Patient case study 3 clearly seeing benefit on drug despite not having spliceosome or FLT3 mutation, example of ideal candidate for someone going on combo therapy in earlier line.
I encourage everyone to do their own due diligence and make a decision on the current facts and what a stock could return as an investment.
