-Focus solely on oncology, main asset is ME-401 PI3 delta kinase selective inhibitor (oral agent) currently in registration directed trial for 3L Follicular LymphomaAnother exciting asset is voruciclib CDK inhibitor (4/6), most activity against CDK9 (MYC transcription, MCL1 transcription)
-Cash ended March $192M pro forma post Kyowa Kirin deal
-ME-401, delta selective inhibitors receive much attention because important for Bcell malignancy survival. There are several approved (2 as oral, 1 as injectable) so is validated target but issue with the class is toxicity which has plagued widespread utility of drug. Toxicity of class is early hepatitic toxicity (could be off target, occurred typically at 5 weeks) and others are later in use (consensus is dependent on inhibitions of Tregs, continuous over time). One differentiating feature of ME-401 is different chemical chasis, has very extensive volume distribution gets out of blood into tissue very well, penetrates cells extremely well and doesnt like to come out (tends to bind to delta in irreversible fashion). Drug gets to target more efficiently. Other agents have to be dosed in a way to get maximal clinical efficacy, as they try to get up on dose curve to get maximum clinical efficacy they bump into these toxicities so they have to come back down. We are the only drug able to be used up on the plataeu at the maximum clinical efficacious dose and not sacrifice efficacy. We have a very differentiated drug in regards to pharmaceutical properties, allows us to do things these other companies cannot.
-Dosing strategy is different as well using intermittent schedule. Reasoned if we changed schedule rather than dose, allowing drug to concentrate in tumors, we can maintain efficacy while dropping effective peripheral dose in plasma and marrow where Tregs are generated. Tested this first in patients experiencing toxicity, put them on drug holiday and put them on intermittent schedule. Intermittent schedule is dose for 7 days, give 21 day holiday. Based on calculation and animal data, we predicted our drug is on target in tumor for minimum 14 to 16 days above EC90. During drug holiday period drug drops significantly in periphery and allows refunction or repopulation of Tregs. Standard paradigm now is to give drug for 2 months continuous (induction), move to intermittent schedule at month 3. They are seeing no more onset of these immune toxicities as a result. Clinically they believe there is a good likelihood that their hypothesis is somewhat accurate.
-Devil's advocate, why can other companies not do this? Answer, they are not working on plateau, working on linear portion of curve. As they back down, they will see breakthrough in progression in tumor growth re competition.-How flexible is this regimen? Can you switch patients back to continuous dosing if they start progressing on treatment? So far, data suggests once patient undergoes clinical response they tend to stay (fairly durable). This is possible and is being tested in registration study (available to patients should they choose).
-This profile also gives flexibility to combine with other drugs. Data with Rituxan suggests can use same schedule (very nice effect with Rituxan, high response rates). Could use with chemo. Etc. There are plans to test all these possibilities and hypothesis with other agents to see how much utility there is.-As for Kyowa Kirin partnership, started with Japanese only license a couple years ago, Great partners to work with. 2 years ago started talking about extending partnership, culminated in license and co development agreement (codevelopment co marketing in US, 50/50 share, development costs split equally). Outside US, gave them license where smaller company receives royalties and milestone payments. Deal involved $100 million upfront and half billion $$ in milestones. Kyowa Kirin in process of building worldwide oncology franchise. Gave MEI resources to explore different studies and indications. Agreed contractually on certain studies that will be done (an important point).-As for data, ASCO/EHA update and key takeaways, focus was on intermittent schedule. Showed response rates very good, in FL observation times are well past a year so starting to get good sense of durability of response (havent reached) and tolerability (not seeing toxicities seen with Gilead's idealisib). Not much difference if patients had 1 or multiple prior therapies, nor did size of tumors.
-TIDAL pivotal study, in same population as received accelerated approval for other PI3 deltas, patients who are relapsed or refractory to 2 prior therapies (includes 1 chemo and 1 CD20), essentially 3rd line or greater. Accelerated approval targeted, therefore endpoint is response. FDA made it clear that durability of response is criticial for any oncology indication, safety important as well obviously. Enrollment had expected to complete in August, but has been impacted by COVID-19 pandemic, sites screening now at pre Covid levels. 120 patients is goal and won't be completed until end of year or Q1 2021. They are in 100 clinical sites around world, so good screens observed in countries where Covid under control.
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