イボネスシマブの 200 億ドルの疑問: FDA はサミットの特効薬を承認するか?
Welcome to the deep dive. Today we’re really digging into a company that’s well, let’s just say it’s been making waves. Summit Therapeutics. Yeah. And specifically their main drug candidate, Ivanmab. Exactly. So our goal today is to get under the hood, understand the business. What makes this drug ivanessab potentially special? And critically dive into the latest news, especially from the Harmoni trial. What does it all mean particularly for investors? Right. Okay, we’ll look at the positives, the negatives, and what milestones are really key going forward. We’ve sifted through a pile of recent material to pull this together for you. Okay, let’s jump in. All right, so first up, the drug itself. I have an SMAP. You might also see it called SMT12 or AK-112. What exactly is it? So, it’s what’s called a novel bspecific antibbody. Basically, think of one molecule designed to grab onto two different things at the same time, two targets. Yeah. In this case, PD1 and VEGF. Okay, PD1, that rings a bell for many listeners. It’s a target for checkpoint inhibitors trying to get the immune system to fight the cancer and VEGF that’s involved in blood vessel growth for tumors. Right. So, this drug tries to hit both. Precisely. The idea is to uh simultaneously boost the immune response by blocking PD1 and also sort of cut off the tumor’s blood supply and maybe even improve the tumor micro environment by hitting VEGF. Interesting. And it’s not just like mixing two separate drugs together, is it? The sources mentioned some unique design features. Cooperative binding, a tetravalent structure. Yeah, that’s where it gets kind of sophisticated. The cooperative binding means um when it binds to PD1, it actually gets better at binding VEGF and vice versa. More sticky you could say. And tetravalent means it has four binding sites, not the usual two. The whole point of this engineering is apparently to make the drug work much more effectively inside the tumor where both PD1 and VEGF are usually high and hopefully less active elsewhere. Trying to concentrate the firepower. Basically, that’s the idea. Potentially better efficacy, maybe fewer side effects outside the tumor. Got it. And this drug came from Aqueso Inc. originally. Yes. Developed by Aeso in China. Summit has the rights for the big markets outside China, US, Canada, Europe, Japan. So Summit’s driving the bus for development in those key regions, right? Which brings us to the harmonite trial. That’s the big news lately. Definitely global phase three study. And it was looking at a specific group of lung cancer patients, right? EGFR mutant non small cell lung cancer after they’d progressed on drugs like osmmerib. Yeah. a really challenging population. Once those targeted therapies stop working, options are limited. A huge unmet need. So, Harmon and I had two main goals, two primary end points. Progressionfree survival PFS and overall survival OS. Correct. PFS is how long patients live without the cancer getting worse. OS is how long they live overall. Let’s start with the good news. The trial did hit its target for PFS. What did that look like? It looked really quite strong. Adding Ivanessab to chemotherapy showed a statistically significant and clinically meaningful improvement in PFS compared to just chemo alone. Numbers hazard ratio was 0.52 and the p value was tiny less than 0.0000001. Wow. Okay. So 0.52 for our listeners that means almost cutting the risk of progression or death in half a 48% reduction for the ivanessimab group. That sounds pretty significant in this patient group. It really is. And another key point, this benefit was consistent. They saw it in the Asian patients and also in the non-Asian patients, the western group, which made up about 38% of the trial. That consistency is important for global approval, right? It shows it’s not just working in one population. Absolutely. Regulators like the FDA and EMA want to see that. And using chemotherapy alone is the comparison. That was the right benchmark. Yeah. because just adding older PD1 drugs to chemo hadn’t really worked well before in this specific post TKI resistant setting. So chemo is the standard to beat. So achieving that PFS result is definitely noteworthy. No doubt. Okay. But now the other primary endpoint overall survival. This is where the story gets uh more complex. Right. This is the part that’s caused a lot of the discussion. The OS data did not reach statistical significance in this main analysis. What did it show? It showed a positive trend. The hazard ratio was 79. So a 21% reduction in the risk of death, but the p value was 0.057. Just barely over that 05 line typically used for significance. Exactly. So while it’s pointing in the right direction, statistically speaking, you can’t yet rule out that the difference scene was just due to chance. And the sources keep mentioning the OS data is immature. What does that really mean here? It means not enough time has passed and not enough patients unfortunately have passed away yet across the whole study for the statistics to give a really firm answer on long-term survival. Especially it seems for the western patients. Yeah, they had shorter follow-up time compared to how long patients in this group might typically live. So their data is even less mature. So the trend is positive, but they need more time, more data to potentially cross that statistical significance threshold. That’s the situation. Summit plans to keep following the patients. Let the data mature and see if that OS benefit becomes statistically significant later on. Okay. And what about safety? Adding a new drug usually means more side effects. The safety profile was called acceptable and manageable. No big surprises or new safety issues popped up. But more side effects than chemo alone. Yes, definitely. Severe side effects grade three or higher were seen in about 57% of the ivanessimav group versus 50% in the chemo group. So about a 7% increase. Okay. But there was something favorable about fatal side effects, right? If you exclude deaths caused by the cancer progressing, the rate of fatal side effects from treatment was actually numerically lower in the Ivan Smab arm, 1.8% versus 2.8% for chemo alone. Interesting. So maybe a bit harder to tolerate day-to-day for some, but potentially less risk of fatal treatment complications. That seems to be the pattern observed here. Yeah. A potentially positive point in the overall safety picture. So putting it together, strong PFS win, but OS not significant yet, which leads us straight to the regulators, especially the FDA. This is the absolute crux of the matter right now. Summit’s been talking to the FDA, and the FDA apparently gave them some pretty specific guidance for this particular indication. Yes, the word is the FDA has explicitly stated they need to see a statistically significant OS benefit to approve Ivanab for these EGFR mutant lung cancer patients after TKI failure. Wow. So that 057 P value as it stands isn’t enough for the FDA in this case, that’s a high bar. It is. And it’s interesting because as some sources point out, there’s precedent. The FDA did approve another drug, Amivantamab or Rebravent plus chemo in a similar setting based mainly on PFS data. Right. The Mariposa 2 trial. Their OS data was also immature at the time of that approval. Exactly. So it raises questions about consistency or perhaps evolving standards. But the bottom line seems to be for Ivan Esmab in this trial. The FDA has drawn a line in the sand at statistically significant OS. So, Summits plan to file for approval, the BLA. The timing is now really dependent on whether that OS data matures favorably. That seems logical. They’ve said they intend to file, but they’ll be considering the ongoing FDA discussions and presumably waiting to see if further follow-up pushes that OSP value below. 05. Having fasttrack designation helps keep those conversations going with the FDA, I suppose. For sure. It allows for more frequent interaction, which is crucial when you’re dealing with a complex situation like this. Okay, so that’s Harmoni for post TKI lung cancer, but Ivanmab isn’t just being tested there. Summit’s running a pretty broad program. Oh yeah, it’s quite ambitious. They’re looking at it across multiple cancers and importantly in earlier lines of lung cancer therapy like hormoni 2 that was in China, right? First line lung cancer comparing Ivanmab alone against Kruda. Yeah. Headto-head against Pemmerismab Kitruda in patients whose tumors express PDL1 and Ivanmab actually won on PFS there. Superior PFS against Kitruda monotherapy. Yep. Hazard ratio 51. That strong PFS result led to approval in China by the NMPA earlier this year. But again, the OS data, same story kind of at an interim look requested by the Chinese regulators. The OS trended positive hazard ratio 777, but the P value was 057. Again, not statistically significant at that point. Hm. So, even head-to-head against a major drug like Kituda, hitting that OS significance early is tough and the market noticed that. Oh, yeah. Investors are laser focused on OS, especially when you’re comparing against an established standard. That result definitely caused some jitters. Okay. What about Harmonus 6 also in China? Yes. First line squamus lung cancer. This time, Ivanmab plus chemo versus another checkpoint inhibitor, Tyelismab plus chemo. Yeah, the other PFS win at the primary end point. statistically significant improvement. And interestingly, they reported benefit in both PDL1 positive and negative patients. That’s potentially important, suggesting it might work where PDL1 status is less predictive. Could be. It’s being touted as the first phase 3 win for this type of drug against another PDL1 plus chemo combo. We’re waiting for the full data later this year. And then there’s the big global push into firstline lung cancer, hormone 3. That’s the monster trial. global firstline metastatic NCLC all types all PDL1 levels Ivanessa Mab plus chemo versus kicruda plus chemo the current standard of care for many exactly this targets the biggest market segment success here would be enormous but it’s still enrolling so results are a ways off and harmony 7 is similar also global phase 3 1 lnc but focused on nonquamas type again ivanessab plus chemo versus plus chemo wow okay and beyond lung cancer I saw mention of biliary tract cancer. Yeah, some really interesting phase 2 data there. I have an SMAB plus a chemo regimen called FOXIRI in firstline BTC. What did they see? Pretty high response rates over 53% overall, even higher in gallbladder cancer specifically. Median PFS was 8.5 months and median OS was 16.8 months. 16.8 months. How does that stack up? BTC is tough. It compares pretty favorably to historical data and even to some approved regimens like Dervalumab plus chemo which had median OS around say 12 or 13 months in its pivotal trial promising enough that they’re moving forward seems so aeso started a phase three trial in China hormone IGI1 comparing iodess plus chemo against dervalumab plus chemo in firstline BTC okay let’s take a step back the science again why target PD1 and VEGF together especially in that lung cancer group after the EGFR drugs stopped working well The thinking is that the EGFR pathway itself drives up VEGF and when resistance develops the tumor environment often gets really hostile to the immune system very imunosuppressive. VGEF plays a big role in that. So just blocking PD1 doesn’t work well because the immune cells can’t get in or function properly pretty much. VEGF can kind of shield the tumor. So the dual approach hitting both VGF and PD1 aims to like recondition that environment, disrupt the bad stuff VEGF does, make it easier for the immune cells activated by PD1 blockade to actually work. And those unique design features, the cooperative binding and to travel structure are meant to enhance that effect right inside the tumor. That’s the hypothesis. Concentrate the activity where you need it most. This whole PD1 VEGF by specific idea. It seems like big pharma is buying into it looking at the competition. Oh, absolutely. The space is heating up fast. It validates the concept, but it means Summit has serious competition coming like Fizer. Big deal there. Huge deal. Fizer paid $1.25 billion upfront for rights outside China to a competing drug SSGJ7. Total deal value up to $4.8 billion. That drug is going into phase three in China. Wow. and Merc Biotech. Yep. Merc licensed LM299 phase 1 for $588 million upfront, potential $2.7 billion total. Biioentech bought full rights to BNT 327, which is in mid to late stage trials for $800 million. So major players are betting big bucks on this drug class. Good validation for Summit, but but they’ll be up against giants with massive resources and marketing muscle. And Fizer is both a collaborator on some studies and now a future competitor. Yeah, a bit of an interesting dynamic there. Fiser’s funding some combo studies with Summit’s drug and their own ADCs, but now they’ve got their own horse in the PD1 VEGF race, too. Okay, let’s shift gears to Summit itself. The company finances burst. How are they looking based on Q1 2025? Well, they’re still in development stage, so no product revenue yet. They recorded a net loss of about $63 million for the quarter. Cash position pretty solid. Ended March with around $361 million in cash in short-term investments. And importantly, no debt mentioned. Correct. Zero debt. Based on their spending rate, that cash gives them a runway of uh roughly 5 to seven quarters, maybe a bit more. Enough to get them through some of these key data readouts we’ve been talking about. It should cover the near to midterm catalysts. Yeah. Now, leadership, Robert Dugen, Dr. McKisangone, their names come up a lot. And this idea of insider confidence. Yeah. The management team’s a big part of the story. Dugen and Zagayad’s previous success with Pharmacecyc, the company behind In Brua, sold to Abv for $21 billion, carries a lot of weight with investors. People talk about the Dugen effect and the insider ownership is unusual. Extremely high. Dugen himself reportedly owns over 70% of the shares. That’s massive for a public company. And didn’t they just exercise a bunch of warrants? They did. Both Dugen and Zangana bought nearly four million shares each back in April by exercising warrants at a $1.58 per share. Warrants that didn’t expire until 2029. Exactly. Exercising them that early is seen as a huge vote of confidence. It suggests they strongly believe the stock price has significant upside from current levels. So putting it all together, Summit strategy seems pretty aggressive. Go broad, go fast with Ivanessa Mab. Absolutely. multiple big phase three trials running globally at the same time. They’re clearly betting heavily on this one asset and planning to showcase data at all the major cancer meetings. Okay, so given everything, the strong PFS, the OS question mark, the competition, the leadership, the insider buys, how’s investor sentiment looking? Feels kind of polarized. That’s a good word for it. You definitely see significant optimism. People point to the PFS data, the broad potential, the management track record, those insider buys, but there’s also real caution. The Harmon AOS data is a major overhang. Concerns about competition and the valuation of course. Let’s touch on some specific concerns mentioned in the sources. Premature study results. What’s that likely referring to? Almost certainly the Harmony 2 OS data from China. That interim look at 39% maturity showing the positive trend, but P 0.057. It just highlights how sensitive everyone is to OS even when it’s early days or against an actor drug like Kruda can worries about data from China credibility replicability that’s a common theme sometimes with drugs initially developed there but some is counter as these large global trials like harmony and harmonia 3 showing consistency across regions like they did with PFS and harmony helps address that then there’s the valuation sources mention a market cap anywhere from $13 billion up to over $20 billion recently for a company with no sales yet. Yeah, that’s steep. It clearly implies the market is already pricing in a lot of future success for Ivanessa Map. It makes the stock inherently high risk, high reward. Any news, good or bad, could move it significantly. And the comparator in harmony chemo alone, some might still question that. Well, as we discussed, given that standard IO plus chemo failed previously in this specific post TKI setting, chemo was the relevant standard and the trial for the approved competitor Ammy Vantab also used chemo alone. So it seems appropriate contextually. So looking ahead, boiling it all down, what are the absolute mustwatch catalysts? Number one, without a doubt, is the mature OS data from the global harmony trial. Given the FDA’s specific requirement, that result is make or break for US approval in that post TKI setting. Okay, what else? More mature OS from Harmony 2 in China versus the full data reveal from Harmoni 6 that head-to-head win in Squamus NSLC. And longer term, the really big ones, Harmony 3 and Harmony 7, those global firstline NSLC trials against Kitruda plus chemo, they target the biggest prize. Results are further out, but they are absolutely critical for the long-term story. Plus progress in other areas like that billiary tract cancer phase three, right? Keep an eye on the whole pipeline, Brett. Okay, so let’s wrap this deep dive. We’ve seen the real promise with ivanessab. Impressive PFS data. this unique dual targeting design potential across many cancers backed by experienced leaders with huge personal stakes. But we’ve also got the significant hurdles. Top of the list is getting that statistically significant OS data from Harmoni to satisfy the FDA for that first potential US approval. Plus, fierce competition is coming. The valuation is already high and just executing on all these massive trials is a challenge in itself. So, here’s a final thought for you listening. Ivanessab has this unique design. Summit has this aggressive strategy. Can that overcome the specific OS hurdle set by the FDA, especially in that post TKI group, and beat back the competition? Or will the OS data challenges and the high valuation prove too much? Thinking about everything we discussed, what single piece of data in the future do you think will be the most decisive for Summit’s path forward? Definitely a lot writing in the next few data points. Indeed. Thanks for joining us for this deep dive. My pleasure. And for everyone listening, remember to subscribe to The Deep Dive, give us a like if you found this useful, and hit that notification bell so you don’t miss our next exploration. Stay informed.
Ivonescimab’s $20 BILLION Question: Will the FDA Greenlight Summit’s Wonder Drug?
Is Summit Therapeutics’ ($SMMT) Ivonescimab the breakthrough lung cancer drug investors and patients have been waiting for? Join us on “The Deep Dive” as we dissect this promising bispecific antibody targeting PD-1 and VEGF.
We unpack the groundbreaking science behind Ivonescimab (SMT112 / AK112), its unique cooperative binding, and tetravalent structure. Critically, we analyze the latest results from the pivotal HARMONi trial in EGFR-mutant non-small cell lung cancer (NSCLC) patients post-TKI failure.
In this episode, you’ll learn:
HARMONi Trial Breakdown: Strong Progression-Free Survival (PFS) data (HR 0.52) – what does it mean?
The Overall Survival (OS) Dilemma: Why the p=0.057 OS result has the FDA (and investors) on edge.
FDA’s Explicit Guidance: The high bar Summit must clear for US approval.
Comparing Apples to Apples? How Ivonescimab stacks up against competitors like Amivantamab (Rybrevant).
Beyond HARMONi: Updates on HARMONi-2 (vs. Keytruda in China), HARMONi-6, and the massive global HARMONi-3 & HARMONi-7 trials.
New Frontiers: Promising data in Biliary Tract Cancer (BTC).
The Competition Heats Up: How Pfizer, Merck, and BioNTech are entering the PD-1/VEGF bispecific space.
Summit’s Financial Health: Cash runway, debt, and the implications of their Q1 2025 report.
Insider Confidence: Why Robert Duggan & Dr. Maky Zanganeh’s massive warrant exercises are turning heads.
Investor Sentiment: The bull vs. bear case for Summit Therapeutics.
Key Catalysts: What upcoming data points could make or break $SMMT stock.
We sift through the data, the financials, the competition, and the regulatory landscape to give you a comprehensive understanding of Summit Therapeutics and the future of Ivonescimab. What single piece of data will be most decisive?
Tune in for our in-depth analysis! Don’t forget to LIKE, SUBSCRIBE, and hit the NOTIFICATION BELL for more deep dives into the world of biotech and investing!
#SummitTherapeutics
#Ivonescimab
#SMMT
#BiotechInvesting
#StockMarket
#CancerResearch
#LungCancer
#NSCLC
#FDA
#ClinicalTrials
#HARMONiTrial
#PD1
#VEGF
#BiotechStocks
#Oncology
#DrugDevelopment
#Pharmaceuticals
#Investing
#HealthcareStocks
Disclaimer: The content of this podcast is for informational purposes only and should not be considered financial or investment advice. Always conduct your own research and consult with a financial advisor before making any investment decisions.