CNST
Constellation Pharmaceuticals, Inc.
stock NASDAQ

Had a ton of requests for this, so going to write up something quick on low sleep
Background on MPN when I wrote up $SRRA before their Buyout by $GSK- https://www.reddit.com/r/Biotechplays/comments/tq8rse/sierra_oncology_srra_myelofibrosis_disease_state/
The FDA has told not just Morphosys $MOR, but also Karyopharm $KPTI, AbbVie $ABBV that in order to get frontline Myelofibrosis approval you need to have both SVR35 and TSS50 reduction at Week 24.
Morphosys just released their phase 3 trial MANIFEST2 - https://www.morphosys.com/en/news/morphosys-phase-3-study-pelabresib-myelofibrosis-demonstrates-statistically-significant
MANIFEST2 which hit on SVR35 at Week 24 - showing 66% for combination pelabresib, a BET inhibitor, and Ruxolitinib vs 35% SVR35 reduction for Ruxolitinib (and placebo) current SOC.
The TSS50 missed, and absolute was 52% vs 46% (aka an absolute symptom benefit in 6% of patients = not great, but still better, but for FDA’s goals a miss nonetheless). They will try to spin this by using another metric they added last minute with FDA (See below) and breaking out intermediate patients.
The remainder of secondary endpoints were good, and the company $MOR doesn’t really have an option but try to force it through the FDA. They have 2 other phase 3 readouts, but near term and for the total value of the company and the result of them buying $CNST they really need this win. Without this they likely drop to the $200MM-$400MM range. With an approval it becomes worth multiple billions… (NFA)
The FDA recently gave a BROAD approval for $SRRA’s momelotinib (owned by $GSK post buyout of DD above).
Timeline: Morphosys has a call November 12th 2023 8 AM EST, they will say totality of data etc. but… the company stated themselves the FDA requires both TSS50 and SVR35…
So where does that leave $MOR? They have multiple agents licensed, Novartis $NVS with Ianalumab and CMK389, Anthos with abelacimab, Mereo $MREO Setrusumab, $LLY Bimagrumab, Hi*Bio with Felzartamab and MOR210…the problem is their burn rate is so high, and if they miss an FDA approval and DON’T make drastic changes, then company is kind of screwed with no money…
Currently they are burning $120MM to comarket a drug with $INCY that is bringing in ~$90MM per year. This drug (Monjuvi aka Tafasitamab) has multiple other phase 3 trials coming up for readout (2024 and 2025). They have another drug (Tulmimetotat EZH1/EZH2 dual inhibitor) in their pipeline but they are YEARS away from possible readout, but did get Accelerated Approval. Still costs and runway have to be front of mind.
Personally I think waiting for Inmind and Frontmind is a losing proposition. You have to fight for approval and safeguard runway.
The company has stated they will not submit to the FDA until mid 2024 (the data was mature August 2023). To me this indicates they will submit with additional data, the MANIFEST2 trial was fully enrolled announced April 4 2023. For RUX in COMFORT1 trial:
The median duration of response was 168 weeks (95% CI, 107.7-NE). Overall survival (OS) at a median follow-up of 268.4 weeks was not reached in the ruxolitinib randomized arm and was 200 weeks in the placebo arm (HR, 0.69; 95%, CI, 0.50—0.96; P =.025).
Two odd things in the press release:
First, the company added a new endpoint September 2023. They did this AFTER meeting with the FDA for a Type C meeting (FDA has 75 days to respond to request for this type of meeting, but likely was much under, so my guess is around August the company requested, this would like up with the data was coming in for all patients).
Secondly, the top KOLs are really really pushing for this:
Myelofibrosis patients experience a severely diminished quality of life due to symptoms such as severe fatigue, night sweats, bone pain and fever – symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment,” said Ruben A. Mesa, M.D., FACP, President and Executive Director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center. “Total symptom score assessment is a validated tool to document the challenges that patients encounter on a daily basis. The symptom reduction shown in MANIFEST-2 is an important result that should be strongly considered when evaluating the efficacy of the pelabresib and ruxolitinib combination therapy for myelofibrosis.”
Ruben, Naveem, and head PI John Macarenhas likely push further, as MPN patients likely would benefit (SVR35 has been correlated with OS).
Next meeting to discuss results is November 21st 2023 8 AM EST.
Full ASH meeting December 10th 2023 8:15 PM EST
I HATE to guess near term but if you made me (NFA), I say this trades down and hard. With that being said the company is likely in real trouble if they can’t pull off an FDA approval. With that being said while many are clowning on them I believe the FDA will look at this data and realize that it is pretty solid minus the TSS50. There is a huge gap until that decision is made (read submit mid 2024 = 2025 decision). If the company doesn’t address the runway, they are playing with fire imo. If they can somehow pull a rabbit out of their hat (patient advocacy groups, top KOLs - see above, and maybe additional data) then if the stock is suppressed, could explode. You could make the argument that SVR35 was low for Ruxolitinib compared to historical and apply that to combo arm. You could wait until mid 2024 because you want to know SVR35 and TSS50 *at any time*. Why do I bring this up? In their Phase 2 MANIFEST Arm 3 trial the TSS50 went from 63% up to 80% at any time (not in front of me, someone double check me please). You then sugar it up via Regulatory Affairs. Remember this is only data at W24, and the company is waiting until mid 2024 to submit.
Final Thoughts:
If you can pull all of this off then you can potentially get an approval or can get approval for a sub pop (ASH). This is *not* guaranteed and high risk. I personally do not have a position right now, but did trade in and out during the 2023 run up. If it got substantially cheap, and they make it to potential FDA approval I would re-evaluate, and either play before or after the approval, because *if* approved I believe this company would be worth $3BN in a buyout minimum, and their market cap at that time pending moves by the company will be (likely severely) depressed. The company likely has difficulty with their debt and current burn rate, and so *if* approval is made, they likely are bought out instead of making a go at it. $INCY and $ABBV would be potential acquirers given their investment in Myelofibrosis lately.
So those are my quick thoughts, feel free to give your comments, insights, thoughts below!
Godspeed,
Dr. DD
Free newsletter with DD and misc.
https://docs.google.com/forms/u/1/d/e/1FAIpQLSfaW9CrhylAMyHwsT36VSmEH9cF4cZmnq_wCKkN7stbZxlZKg/viewform?usp=sf_link
No Position, Not Financial Advice, Do your own DD, meme’r / parody, fair use commentary

Had a ton of requests for this, so going to write up something quick on low sleep
Background on MPN when I wrote up $SRRA before their Buyout by $GSK- https://www.reddit.com/r/Biotechplays/comments/tq8rse/sierra_oncology_srra_myelofibrosis_disease_state/
The FDA has told not just Morphosys $MOR, but also Karyopharm $KPTI, AbbVie $ABBV that in order to get frontline Myelofibrosis approval you need to have both SVR35 and TSS50 reduction at Week 24.
Morphosys just released their phase 3 trial MANIFEST2 - https://www.morphosys.com/en/news/morphosys-phase-3-study-pelabresib-myelofibrosis-demonstrates-statistically-significant
MANIFEST2 which hit on SVR35 at Week 24 - showing 66% for combination pelabresib, a BET inhibitor, and Ruxolitinib vs 35% SVR35 reduction for Ruxolitinib (and placebo) current SOC.
The TSS50 missed, and absolute was 52% vs 46% (aka an absolute symptom benefit in 6% of patients = not great, but still better, but for FDA’s goals a miss nonetheless). They will try to spin this by using another metric they added last minute with FDA (See below) and breaking out intermediate patients.
The remainder of secondary endpoints were good, and the company $MOR doesn’t really have an option but try to force it through the FDA. They have 2 other phase 3 readouts, but near term and for the total value of the company and the result of them buying $CNST they really need this win. Without this they likely drop to the $200MM-$400MM range. With an approval it becomes worth multiple billions… (NFA)
The FDA recently gave a BROAD approval for $SRRA’s momelotinib (owned by $GSK post buyout of DD above).
Timeline: Morphosys has a call November 12th 2023 8 AM EST, they will say totality of data etc. but… the company stated themselves the FDA requires both TSS50 and SVR35…
So where does that leave $MOR? They have multiple agents licensed, Novartis $NVS with Ianalumab and CMK389, Anthos with abelacimab, Mereo $MREO Setrusumab, $LLY Bimagrumab, Hi*Bio with Felzartamab and MOR210…the problem is their burn rate is so high, and if they miss an FDA approval and DON’T make drastic changes, then company is kind of screwed with no money…
Currently they are burning $120MM to comarket a drug with $INCY that is bringing in ~$90MM per year. This drug (Monjuvi aka Tafasitamab) has multiple other phase 3 trials coming up for readout (2024 and 2025). They have another drug (Tulmimetotat EZH1/EZH2 dual inhibitor) in their pipeline but they are YEARS away from possible readout, but did get Accelerated Approval. Still costs and runway have to be front of mind.
Personally I think waiting for Inmind and Frontmind is a losing proposition. You have to fight for approval and safeguard runway.
The company has stated they will not submit to the FDA until mid 2024 (the data was mature August 2023). To me this indicates they will submit with additional data, the MANIFEST2 trial was fully enrolled announced April 4 2023. For RUX in COMFORT1 trial:
The median duration of response was 168 weeks (95% CI, 107.7-NE). Overall survival (OS) at a median follow-up of 268.4 weeks was not reached in the ruxolitinib randomized arm and was 200 weeks in the placebo arm (HR, 0.69; 95%, CI, 0.50—0.96; P =.025).
Two odd things in the press release:
First, the company added a new endpoint September 2023. They did this AFTER meeting with the FDA for a Type C meeting (FDA has 75 days to respond to request for this type of meeting, but likely was much under, so my guess is around August the company requested, this would like up with the data was coming in for all patients).
Secondly, the top KOLs are really really pushing for this:
Myelofibrosis patients experience a severely diminished quality of life due to symptoms such as severe fatigue, night sweats, bone pain and fever – symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment,” said Ruben A. Mesa, M.D., FACP, President and Executive Director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center. “Total symptom score assessment is a validated tool to document the challenges that patients encounter on a daily basis. The symptom reduction shown in MANIFEST-2 is an important result that should be strongly considered when evaluating the efficacy of the pelabresib and ruxolitinib combination therapy for myelofibrosis.”
Ruben, Naveem, and head PI John Macarenhas likely push further, as MPN patients likely would benefit (SVR35 has been correlated with OS).
Next meeting to discuss results is November 21st 2023 8 AM EST.
Full ASH meeting December 10th 2023 8:15 PM EST
I HATE to guess near term but if you made me (NFA), I say this trades down and hard. With that being said the company is likely in real trouble if they can’t pull off an FDA approval. With that being said while many are clowning on them I believe the FDA will look at this data and realize that it is pretty solid minus the TSS50. There is a huge gap until that decision is made (read submit mid 2024 = 2025 decision). If the company doesn’t address the runway, they are playing with fire imo. If they can somehow pull a rabbit out of their hat (patient advocacy groups, top KOLs - see above, and maybe additional data) then if the stock is suppressed, could explode. You could make the argument that SVR35 was low for Ruxolitinib compared to historical and apply that to combo arm. You could wait until mid 2024 because you want to know SVR35 and TSS50 *at any time*. Why do I bring this up? In their Phase 2 MANIFEST Arm 3 trial the TSS50 went from 63% up to 80% at any time (not in front of me, someone double check me please). You then sugar it up via Regulatory Affairs. Remember this is only data at W24, and the company is waiting until mid 2024 to submit.
Final Thoughts:
If you can pull all of this off then you can potentially get an approval or can get approval for a sub pop (ASH). This is *not* guaranteed and high risk. I personally do not have a position right now, but did trade in and out during the 2023 run up. If it got substantially cheap, and they make it to potential FDA approval I would re-evaluate, and either play before or after the approval, because *if* approved I believe this company would be worth $3BN in a buyout minimum, and their market cap at that time pending moves by the company will be (likely severely) depressed. The company likely has difficulty with their debt and current burn rate, and so *if* approval is made, they likely are bought out instead of making a go at it. $INCY and $ABBV would be potential acquirers given their investment in Myelofibrosis lately.
So those are my quick thoughts, feel free to give your comments, insights, thoughts below!
Godspeed,
Dr. DD
Free newsletter with DD and misc.
https://docs.google.com/forms/u/1/d/e/1FAIpQLSfaW9CrhylAMyHwsT36VSmEH9cF4cZmnq_wCKkN7stbZxlZKg/viewform?usp=sf_link
No Position, Not Financial Advice, Do your own DD, meme’r / parody, fair use commentary