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CARA
CARA -
SRPT related predictions:
But first, a note - I am not trying to tweak anyone here. This is just the right board on which to post such things and SRPT has been in the news over the last month or two with significant articles in major newspapers. So it seems timely...
1) I predict that meaningful SAE will show up for Etep or its cousins for other exons. All but one of the oligonucleotides run in big RCTs have shown bad SAE related to oligo technology that was not readily apparent in the smaller, single arm or shorter ph2s. (interesting note - the only oligo that did not show oligo related toxicity in their ph3 RCT was miplomersen. It's interesting because it has really unpleasant SAE of another form - huge injection site reaction - and it has target releated SAE in liver enzymes. Finally note that in the REMs it has apparently shown thrombo, so it is not actually immune to standard oligo SAE.)
2) CG, the ex-CEO under whom most of the really poor science decisions were made, will become CEO of another company (he is now running an incubator) when he finds one that meets 3 of the following 4 conditions: a) treats devestating childhood disease, b) already a very strong/vocal parent advocacy group, c) the 'treatment' has an MOA that sounds, in a soundbite, compellingly like it treats root cause, d) any side effects are minimal or not observable in a small population. (Having these characteristics make for good politics to avoid running a meaningful RCT, but still be able to force approval.)
Random other note on oligo's: I now think it more likely than not that ALNY's TTR drug will show excess bone breaks (due to osteonecrosis - they had two in their fairly small, single arm, ph2).
Entirely new mechanism by which age increases the risk of MI. Completely out of the blue for me, although the original paper was in 2014 (this year's paper provides substantially more foundation).
Dew - I'd love to see your thoughts/possibilities regarding substitutible biogenerics now that Gottlieb is in charge. (if I had to pick one thing Gottlieb has emphasized overwhelmingly, it is the need to enable more generics ASAP. No contest.)
Other than just speeding things up, what else might he lean on? What interim measures might he take?
AMRN
LOXO
LOXO, BPMC and genetically determined cancers.
The conversation on these new TKIs often dances around the difficulties of finding treatable patients so I thought I'd run some numbers. The purpose of running these numbers is to set up a framework for conversation:
LOXO believes that there are 1500 to 5000 new cancer patients a year in the US with NTRK fusions. Call it 3000. And, so far, they have included in their trial 17 different cancer types - some of which are quite large indications. All told the total number of people with cancers of the 17 types (including lung, colon and breast) they have included so far are probably over 500,000 annually in the US. Call it 600,000. So they are predicting 0.5% will test positive for the fusion.
That means that in order to find a single patient they have to give a test to 199 people to find 1 person for whom their treatment will work. And note that they explicitly note that the general tests aren't always reliable. If the test costs $1000 (which is probably a low estimate if their test is a unique test, instead of being part of a single panel for multiple mutations) then that is spending $200k to find a single patient.
By way of contrast, BPMC is talking of finding about 5% of patients with PDGFR mutations - and using the same test costs that translates into 'only' $20k to find a patient.
Note that LOXO, in the past, has talked about attempting to enrich the patient population by finding histologic or origin types that have much higher rates of the fusion - e.g. "7 of 28 younger patients (25%) tested TRK fusion positive [in papillary thyroid cancer]". Obviously this is hugely helpful if it bears out - but this isn't emphasized, and isn't mentioned at all in many of their more recent releases. (Note - following the enrichment strategy significantly shrinks their patient population since, for instance, the indication above is around 1000 patients per year total in the US. Leading to 250 patients treatable by their TKI.). My guess is more than 1/2 of the treatable patients in their estimates are in the most common cancer types at extremely low incidences (e.g. 0.3%) and it isn't clear they will ever be addressable until there is a common panel given routinely like histologies are done today.
Finally, note that both BPMC and LOXO are pursuing RET inhibitors in lung cancer with an incidence rate of around 1 to 2 percent. Call it 1.5%. I'd consider this on the edge of addressable - but would become much more so if it could be combined in a panel with an ALK test.
LOXO
Odd to me that this is treated as such a surprise. Most of this was known, albeit with smaller numbers, last year. The only thing really new is the duration of response which seems pretty impressive, although difficult to gauge because it includes so many cancer types.
And just to cap the thread and reiterate what I've said before, the commercial risk is whether they can actually find patients. By being a very small percentage of the paitients in many many diffent cancer types, the only way they can succeed commercially is if the cancer community starts making it standard practice to test biopsies against an entire panel. And even then, as they note, any one test has substantial failings. Note that Matt Herper's story on this trial is largely about the difficulties of finding patients even for this trial.
Regarding TA -
IONS and platelet issues:
Agree that there is zero question that the current generation of their technology has both platelet and renal issues.
There is also no question that the CEO is delusional about his Adverse Events.
But, that said, for diseases with severe side effects or in orphan diseases the FDA is more lenient. Especially if there is a way to monitor the adverse symptoms and it is reversible (as the thrombo is). The FDA policy in these circumstances is patients choose based upon their personal symptoms.
All told I'd guess 90 percent approval in at least some patient populations. Perhaps 20% chance that approval is in a much larger, pancreatitis population since alleviating severe and frequent pancreatitis could be worth the risk.
Good to have a dialog
This is, I believe, another study about loss of APOC3 being protective. Albeit one of the weaker studies. Once one of the next gen APOC3 RNA drugs gets to market I'd expect it to very significantly impact medicinal use of any EPAs. Of course that is 5 to 10 years away.
AKBA
FGEN AKBA
IONS
AKBA FGEN GSK and PHD Inhibitors:
The cite you indirectly gave ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497972/ ) is a perfect example of the fact that we really don't know much about the target differences between Roxadustat and Vadadustat. For instance it says:
Roxadustat:
"FG-4592 inhibits all three HIF-PHDs" (no comparative IC50s)
Vadadustat:
"AKB-6548 stabilizes HIF2a to a greater extent than HIF1a" (no comment on relative PHD inhibition)
In contrast the paper provides much more information about the GSK and Bayer compounds (it gives IC50s for all 3 PHDs for Bayer, and for 2 IC50s for GSK). But for AKBA and FGEN... pretty much squat.
That said, even if we knew the relative IC50s for each PHD I don't think it would tell us much because PHD/HIF system is at the nexus of a very very complex set of control loops - most of which we know little to nothing about. The best characterization I can cite is the one that JQ pointed out - that Roxa seems to have liver effects that Vada doesn't. (Random note: GSK, like Roxa, shows lipid lowering
AKBA and FGEN
LOXO
LOXO BPMC RXDX Dicephera – survey of modern kinase inhibitors (i.e. over the last 3 years):
I’ve argued for a while that the kinase inhibitors were generally pretty unpredictable drugs – because they were too unspecific (e.g. #msg-96549701 ). But over the last 2 or 3 years this has started to change dramatically and there is *starting* to be a lot more data on what matters and what doesn’t.
The intent of this post is to put forth a working set of hypotheses on this topic – although because it is still early days with this level of specificity I fully expect to modify some portions of these hypotheses.
Factors that matter?
1) Generally, targeting Wild Type enablers of a cancer, even with a very specific kinase inhibitor, is not, by itself, very productive. Lots of tox, mild efficacy. See, for instance, BLU-554, a highly selective inhibitor of FGF4 in hepatocellular cancer. Note that this is not to say that it has no utility or no possibility of success – just that highly specific TKIs do not, by themselves, seem to be a game changer from the older, less specific TKIs.
2) Upregulation of the target via extra gene copies doesn’t seem to be particularly productive? See above example – and the high rate of failures of the earlier generation of (non-specific) TKIs in general upregulation. (In contrast, even though Gleevec, the early ALK inhibitors and RET inhibitors were fairly non-specific, they still result in dramatic effects in ALK fusion and RET mutation – albeit with significant side effects.)
3) In contrast, targeting genes that are either mutated or fused in cancer seems to be very reliable. See Gleevec, LOXO’s Larotrectinib (a TRK inhibitor target that hits WT TRK – but they are targeting patients with TRK fusion (I suspect they have other data in other forms of TRK upreg that show it doesn’t work well since they have made verbal passing reference to it?)) and BPMC’s BLU-285 (inhibitor of either a mutant form of KIT or a mutant form PDGFRa – although I still haven’t figured out how that was accomplished)
4) Obviously, targeting a mutant form of the kinase with a high specificity TKI will have very low side effects – see BLU-285 data in Aggressive Systemic Mastositosis. Less obviously (even surprisingly), even a drug that targets WT kinase very specifically can also have very low side effects when used against the mutations I referenced in #3 above. See Larotrectinib data – where they appear to have long duration efficacy and virtually no side effects.
So, where does this lead?
Factors that would potentially influence future uptake?
a) What are all the TKI fusions in cancer? This is still very much an area of discovery – and a sector growth rate driver.
b) What are all the TKI activating mutations in cancer? (I suspect this is harder to determine than fusions?)
c) Some of these driving mutations seem to be low rate in many different cancer types – e.g. see LOXO’s Larotrectinib, in which they claim to have FDA buy-in on an approval pathway that specifically does not mention any particular traditional cancer type – only TRK-fusion. Ultimately this will require a whole new assay system that tests any given biopsy for 100’s of fusions/mutations at once – because it is the mutation that will matter, not the organ of origin. (Note that this is a potential difference of approach for BPMC and LOXO – with BPMC trying to target small patient populations of traditionally diagnosed cancer that almost always has the mutation, but LOXO is, for Larotrectinib, trying to target a larger population that is spread across many traditional cancer types.)
Random other notes:
a) Several of the above companies appear to make claims to have highly specific TKIs that inhibit both WT and the expected mutations. I don’t yet have a good handle on how much to believe of this.
b) I don’t know much, yet, about RXDX – but in my brief perusal they don’t seem to be as focused on high specificity. I listed them only because they show up in some of the same conversations.
c) And, finally, to repeat. The above notes are a set of working hypotheses. I fully expect them to change as more data comes in. I documented them as a way of gathering my thoughts, and creating a way to think about incoming data. And, of course, to gather critique.
FGEN
FGEN random doodle caused by revisiting old notes.
TRVN - Notes from the telecon and slides:
a) The composite respiratory endpoint ("Respiratory Safety Burden" = incidence of respiratory depression x average duration) was very well behaved wrt dose. For one of the trials they actually noted that p=0.07 for the 0.35 dose (they noted it because there is something odd in the bar chart in that the error bars for 0.35 and morphine do not overlap - begging the question as to why it isn't stat sig. My *guess* is that this is an artifact of some odd statistical gatekeeping methodology (i.e. controlling for multiple endpoints)?)
b) For Upper GI issues (anti-emetic use, vomiting, nausea) one of the trials was stat sig better vomiting for 0.35 (while still using less anti-emetic) and the other was vice versa. So there is a good case that the rate of upper GI issues is around 1/2 the morphine rate at dose of 0.35mg.
c) They noted that they intend to use the results to determine cost - but guessed it to be in the range of $60-$140 per day. (My comment is that is, to my surprise, not all that different from PCA morphine costs, which is, per the following cite, around $40 to $60 per day - see https://www.dovepress.com/cost-of-opioid-intravenous-patient-controlled-analgesia-results-from-a-peer-reviewed-fulltext-article-CEOR. Further, interestingly, the paper gives an added cost of an additional $400 for PCA errors and AE.)