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$TRIL $ALXO -- A Fair Comparison
$TRIL & $ALXO have chosen 2 very different paths to CD47 inhibition & how we evaluate:
- TTI-622/ (621, to come)
- ALX148
Early progress ought be shaped by these respective molecular visions -- the "goalpost" of their own devise.
$TRIL & $ALXO have chosen 2 very different paths to CD47 inhibition & how we evaluate:
- TTI-622/ (621, to come)
- ALX148
Early progress ought be shaped by these respective molecular visions -- the "goalpost" of their own devise.
$TRIL $ALXO
While both companies' CD47 approaches start w/ the same, fusion protein recipe:
SIRPa Decoy Receptor + Fc Region
the path diverges rapidly. Starting w/ ALX148:
. . .
While both companies' CD47 approaches start w/ the same, fusion protein recipe:
SIRPa Decoy Receptor + Fc Region
the path diverges rapidly. Starting w/ ALX148:
. . .
$TRIL $ALXO
ALX148 is "by design" only equipped to do half of the job
--> namely, inhibit the "do not eat" signal propagated by cancer cell by binding to membrane bound CD47.
$ALXO poses this as safety advantage, as RBCs, though bound, are not "eaten"
But, 148 no MONO:
ALX148 is "by design" only equipped to do half of the job
--> namely, inhibit the "do not eat" signal propagated by cancer cell by binding to membrane bound CD47.
$ALXO poses this as safety advantage, as RBCs, though bound, are not "eaten"
But, 148 no MONO:
$TRIL $ALXO
Rather, for ALX148 to "work," it takes two to tango:
- ALX148 to inhibit CD47
- another anti-tumor modality (e.g. mAb) to target tumor and propagate cytotoxic activity:
Rather, for ALX148 to "work," it takes two to tango:
- ALX148 to inhibit CD47
- another anti-tumor modality (e.g. mAb) to target tumor and propagate cytotoxic activity:
$TRIL $ALXO
Before moving to $TRIL, and 622/621 which have each already evinced Monotherapy efficacy, including CRs, let's dwell a bit more on what Mono activity is (and is not) in this context.
Contrary to characterization of some $TRIL hasn't touted monoefficacy unduly..
Before moving to $TRIL, and 622/621 which have each already evinced Monotherapy efficacy, including CRs, let's dwell a bit more on what Mono activity is (and is not) in this context.
Contrary to characterization of some $TRIL hasn't touted monoefficacy unduly..
$TRIL $ALXO
$TRIL CEO Skvarka's own words on the matter during JMP Fireside, below.
622/621 early mono doesn't change combo thesis. Both molecules very likely find mkt in combo (tho, we will revisit 621 in TCL...)
Rather Mono is IMPT as sine qua non of clinical activity:
$TRIL CEO Skvarka's own words on the matter during JMP Fireside, below.
622/621 early mono doesn't change combo thesis. Both molecules very likely find mkt in combo (tho, we will revisit 621 in TCL...)
Rather Mono is IMPT as sine qua non of clinical activity:
$TRIL $ALXO
621 & 622 mono activity are proof positive that the molecules are active, in vivo...
Whereas for solely-combo agents (e.g. Epacadostat, ALX148), whose human studies have no choice but to start in combo, it is hard to separate efficacy of any one element...
621 & 622 mono activity are proof positive that the molecules are active, in vivo...
Whereas for solely-combo agents (e.g. Epacadostat, ALX148), whose human studies have no choice but to start in combo, it is hard to separate efficacy of any one element...
$TRIL $ALXO
See ALX148's promising early data as a combo element in multiple indications, below (these data, why PTI is $ALXO investor).
"Benchmarks" circled in red are matched historicals from prior CTs
Until $ALXO 148 goes H2H in RCT, no Real proof that 148 is active:
.
See ALX148's promising early data as a combo element in multiple indications, below (these data, why PTI is $ALXO investor).
"Benchmarks" circled in red are matched historicals from prior CTs
Until $ALXO 148 goes H2H in RCT, no Real proof that 148 is active:
.
$TRIL $ALXO
The above is why LifeSci Capital, which has vested interest in Alx success as lead IPO manager, conveniently presumes $TRIL Mono data holds promise for "CD47 as a class."
621/622 Mono data provide proof, beyond doubt, of the clinical activity 148 can only surmise.
The above is why LifeSci Capital, which has vested interest in Alx success as lead IPO manager, conveniently presumes $TRIL Mono data holds promise for "CD47 as a class."
621/622 Mono data provide proof, beyond doubt, of the clinical activity 148 can only surmise.
$TRIL $ALXO
That's all well and good (esp. b/c PTI has vested interest in $ALXO), however--
That in that same note, LifeSci goes on to then criticize 622's Duration of Response as MONO seems a bit rich (if not completely disingenuous).
A very convenient & selective analysis
That's all well and good (esp. b/c PTI has vested interest in $ALXO), however--
That in that same note, LifeSci goes on to then criticize 622's Duration of Response as MONO seems a bit rich (if not completely disingenuous).
A very convenient & selective analysis
$TRIL $ALXO
Well, what's good for the goose is good for the gander:
As of yet, $TRIL 621/622 do not have clear combo efficacy data, whether in heme, or in solid (tho some very early studies under prior co. mgmt).
So, $TRIL can draw some PoC support for early $ALXO, right?
Well, what's good for the goose is good for the gander:
As of yet, $TRIL 621/622 do not have clear combo efficacy data, whether in heme, or in solid (tho some very early studies under prior co. mgmt).
So, $TRIL can draw some PoC support for early $ALXO, right?
$TRIL $ALXO
Here is where $ALXO continues to draw convenient distinctions, then.
While $TRIL monoefficacy is great for CD47 class, nevertheless, there are clear points of distinction betw 148 & 621/622 that ultimately make 148 the best in combo -- & their reasons are legion.
Here is where $ALXO continues to draw convenient distinctions, then.
While $TRIL monoefficacy is great for CD47 class, nevertheless, there are clear points of distinction betw 148 & 621/622 that ultimately make 148 the best in combo -- & their reasons are legion.
$TRIL $ALXO
But first, a quick (re)consideration of $TRIL 621/622 grand design, which allows each molecule to potentially tango all by its lonesome:
But first, a quick (re)consideration of $TRIL 621/622 grand design, which allows each molecule to potentially tango all by its lonesome:
$TRIL $ALXO
621/622, molecules that have some MONO activity --seems like a good recipe for potential combo success as well, right?
Not so fast, says $ALXO.
What about the comparative safety, with 621/622 potentially causing anemia/thrombocytopenia?
Let's compare, then.
621/622, molecules that have some MONO activity --seems like a good recipe for potential combo success as well, right?
Not so fast, says $ALXO.
What about the comparative safety, with 621/622 potentially causing anemia/thrombocytopenia?
Let's compare, then.
$TRIL $ALXO
$TRIL, currently still in mono dose escalation for both 622 & 621, has shown acceptable/good safety profile, w/ no DLTs (w/ clinical sequelae). No RBC-binding, and low thrombo:
How about ALX148 in mono dose escalation?
$TRIL, currently still in mono dose escalation for both 622 & 621, has shown acceptable/good safety profile, w/ no DLTs (w/ clinical sequelae). No RBC-binding, and low thrombo:
How about ALX148 in mono dose escalation?
$TRIL $ALXO
What Alx doesn't bring up, & $TRIL is too classy to,
is that back when ALX148 was in MONO dose escalation, there were 2 DLTs (& one pot'ly unrelated pt death), though $ALXO conveniently words these instances as
"No Evidence of -dose-dependent- cytopenias":
What Alx doesn't bring up, & $TRIL is too classy to,
is that back when ALX148 was in MONO dose escalation, there were 2 DLTs (& one pot'ly unrelated pt death), though $ALXO conveniently words these instances as
"No Evidence of -dose-dependent- cytopenias":
$TRIL $ALXO
So, who's really binding RBCs, then? (And, keep this in mind when we discuss Receptor Occupancy, in just a bit).
$ALXO binds RBCs, by design, and potentially with negative consequences.
$TRIL - no RBC binding to see here
Compare, below:
So, who's really binding RBCs, then? (And, keep this in mind when we discuss Receptor Occupancy, in just a bit).
$ALXO binds RBCs, by design, and potentially with negative consequences.
$TRIL - no RBC binding to see here
Compare, below:
$TRIL $ALXO
As with "Safety" then, so it goes with nearly every "advantage" that $ALXO has claimed for its 148 over other anti-CD47s:
- 148's "smaller molecular weight" for better solid tumor TME penetration.
- 148's higher potency due to better affinity to CD47
etc.
As with "Safety" then, so it goes with nearly every "advantage" that $ALXO has claimed for its 148 over other anti-CD47s:
- 148's "smaller molecular weight" for better solid tumor TME penetration.
- 148's higher potency due to better affinity to CD47
etc.
$TRIL $ALXO
Again, all of this is not to say that 148 is not meritorious, or that 621/622 don't have some questions to answer--
Recall that PTI is long shares of both.
Rather, it's to say -- more than one can (and imo) will succeed, a la PD-(L)1 ICIs.
Now, back 2 present.
Again, all of this is not to say that 148 is not meritorious, or that 621/622 don't have some questions to answer--
Recall that PTI is long shares of both.
Rather, it's to say -- more than one can (and imo) will succeed, a la PD-(L)1 ICIs.
Now, back 2 present.
$TRIL $ALXO
$TRIL 622 ASH Update, while largely incremental, holds positives, and some questions for the discerning investor.
On the positive side of the column:
- Safety good, now dosing at 18mg (over apples to apples range of ALX148!)
- Durable CR
$TRIL 622 ASH Update, while largely incremental, holds positives, and some questions for the discerning investor.
On the positive side of the column:
- Safety good, now dosing at 18mg (over apples to apples range of ALX148!)
- Durable CR
$TRIL $ALXO
And now to the potential negatives, questions:
- Where is the missing N, from dosing at or above 0.8mg?
Went from 6/18 ORR, to 6/17 ORR at ASH...
- Dose dependent RO increase & durability...
- Those "ephemeral" PRs...
Let's consider, fairly...
And now to the potential negatives, questions:
- Where is the missing N, from dosing at or above 0.8mg?
Went from 6/18 ORR, to 6/17 ORR at ASH...
- Dose dependent RO increase & durability...
- Those "ephemeral" PRs...
Let's consider, fairly...
$TRIL $ALXO
With a large caveat that 622 MONO efficacy stands very much on its own terms as clear signal of activity & that that should be clear takeaway,
We can consider the perceived lack of durability of responses:
With a large caveat that 622 MONO efficacy stands very much on its own terms as clear signal of activity & that that should be clear takeaway,
We can consider the perceived lack of durability of responses:
$TRIL $ALXO
And when considering durability of response, I think it only fair to start by noting that the deepest response, CR, has thus far been quite durable, at 289 days and counting.
As to PRs -- please note the "red", both pts where response may have been foreshortened.
And when considering durability of response, I think it only fair to start by noting that the deepest response, CR, has thus far been quite durable, at 289 days and counting.
As to PRs -- please note the "red", both pts where response may have been foreshortened.
$TRIL $ALXO
As to Receptor Occupancy and durability upon 622 dosing increase, it seems fair to say that 622 RO may be nearing its peak (and 18mg/kg might be RP2D, no bad thing).
However, let's reconsider what RO says, and doesn't say.
As to Receptor Occupancy and durability upon 622 dosing increase, it seems fair to say that 622 RO may be nearing its peak (and 18mg/kg might be RP2D, no bad thing).
However, let's reconsider what RO says, and doesn't say.
$TRIL $ALXO
Receptor Occupancy is at best a "surrogate" for target engagement, and moreover, long-term saturation in RO may be a bad thing.
Why deal with a surrogate, when you have the "real thing" of monoefficacy?
Receptor Occupancy is at best a "surrogate" for target engagement, and moreover, long-term saturation in RO may be a bad thing.
Why deal with a surrogate, when you have the "real thing" of monoefficacy?
$TRIL $ALXO
And note in particular that this "excessive" saturation and binding RO may have led to the severe side effects and toxicity previously noted for ALX148 in mono dose escalation:
And note in particular that this "excessive" saturation and binding RO may have led to the severe side effects and toxicity previously noted for ALX148 in mono dose escalation:
$TRIL $ALXO
Now, let's imagine for a moment, what tmrw might bring -- beyond the 621 update, to the content of the CC:
1st thought: additional 622 response data at 12mg/kg.
In "blue", three pts at 12mg w/o response assess. to date & beyond avg time of other PR onset:
Now, let's imagine for a moment, what tmrw might bring -- beyond the 621 update, to the content of the CC:
1st thought: additional 622 response data at 12mg/kg.
In "blue", three pts at 12mg w/o response assess. to date & beyond avg time of other PR onset:
