from yahoo...Imetelstat summary
Imetelstat summary 1
Don't listen to the fearmongers. This late in the game, after so much proof positive data supports Imetelstat's efficacy, fearmongers will say anything to further their position. Here's a brief overview for any new comers.
Cancer treatment is at a crossroads. The traditional way of resection followed by powerful (and toxic) chemo agents is being revolutionized. One of the main arms of research is immunotherapy(IT), which is training the host's cells to identify cancer cells and destroy them. Those cancer cells are identified by antigen markers on the cell surface. Some ITs target a few antigens, some target a few more, but right now I'm not aware of a single IT agent that comes close to curative. The fact that neither many-antigen nor fewer-antigen IT agents have an immediate or drastic effect on the disease says something fundamental about the model. That is to say, IT's approach is like an infantry assault on the front line of another infantry. Infantry is important, but it's not what drives an army, it's the command and control and resources, which you can equate to cancer stem cells, or even further upstream to the very genomic aberration that started it all. So I don't personally believe IT will be a curative approach. I do think it will play a part and it will mature, and there are benefits. IT is extremely safe b/c it's cultured from the host's own cells; but that's a drawback as well, b/c each treatment is individually tailored, so you're talking about an expensive process.
The other approach is small molecule drugs, which isn't anything new as a model. Some chemo agents are small molecule drugs. But the difference is that chemo effects cytotoxicity, basically poisoning the cancer (and the host) with varying degrees of selectivity; whereas the newer generation of these small molecule drugs target cancer's systematic processes selectively and creatively. Imetelstat is one of the latter.
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Imetelstat summary 2
So let's make the comparison between Ruxolitinib and Imetelstat. Ruxolitinib inhibits an enzyme called Janus Kinase(JAK). JAK plays an important role in a signaling pathway called the JAK-STAT pathway which, for people with deletarious types of JAK, ultimately contributes to dysregulation of gene expression, and disease. But JAK-STAT dysreguation isn't the disease itself, its signaling pathway is an artifact of the pathogenesis of the disease, NOT the cause, and NOT a critical pathway, either. So it follows that the efficacy of JAK inhibitors would be poor, and that's exactly what we see. In the best case scenario, Ruxolitinib reduces splenomagaly and eases constitutional symptoms of MF. And even that modicum of benefit is compromised by serious side effects, as the JAK-STAT pathway also regulates the immune system, also liver toxicity. A study by Dr. Tefferi demonstrates a 50% discontinuation of Ruxolitinib by the 2nd year, and 89% discontinuation by the 3rd, due to disease progression or toxicity. There isn't a scientist in the world that thinks JAK inhibitors cure, or will EVER cure MF. Simply put, dysregulation of the JAK-STAT pathway isn't the cause of the disease, nor is it a critical process to pathogenesis. So why target the JAK-STAT pathway? B/c it's one of the pathways we understand, it's low-hanging fruit. And the JAK inhibitor market is about to get fairly crowded, as several companies are developing their own.
A note about how these drugs are discovered. Often times someone will have a hypothesis for what will be an effective drug. Then they'll make a dozen versions of that drug, fairly arbitrarily, rearranging groups of molecules, adding or subtracting things, and then they'll test these dozen drugs and see which one works; then they repeat the cycle, creating dozens of further variants of the ones that work. It's a shotgun approach. And to date, we have Ruxolitinib. Which isn't to say it's worthless, but this is how science progresses... slowly.
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Imetelstat summary 3
Then Imetelstat comes along. Imetelstat is a telomerase inhibitor. This is a categorical shift from JAK inhibition b/c telomerase IS A CRITICAL ENZYME. As a comparison, JAK inhibition is like stopping a bank robber's car by shooting at the tires, and the tires are run-flats; telomerase inhibition is like shooting out the fuel pump and depriving the car of fuel and power, in which case the car will eventually slow to a halt. It is a supremely selective target, one with potential far and away beyond JAK inhibition, as 90% of cancers require telomerase. Unlike JAK, telomerase isn't a part of a complex signaling pathway; instead, it's one of the actual cellular machinery that directly makes DNA. And this is why Imetelstat is so powerful, its target is far far upstream to the JAK-STAT pathway and immunotherapy. Telomerase is a reverse transcriptase; instead of making DNA from DNA copies, it makes DNA from an RNA copy. That RNA copy is embedded in the enzyme, and that's the active site that Imetelstat targets. And the results have been revolutionary. In a disease where the only approach has been symptom management, Imetelstat ENTIRELY cleared high-risk MF patients of fibrosis AND EVEN the molecular signatures of the disease... THIS IS A VIRTUAL CURE for those patients, their actual disease state has been changed, not just symptom relief. For the ones that achieved CR, they live like they don't even have the disease. And for the ones that don't achieve CR, many still receive symptom relief. And this is also how science works, long periods of slow progress, jolted by sudden and drastic progress. Imetelstat is a revolution in treatment for hematologic malignancies; it ACTUALLY MODIFIES THE DISEASE.
Stem cell transplantation has also cured people, not virtually, but truly cured people. The few who qualify and respond positively to SCT are very lucky. But there are a host of complications with SCT, and it will never be a ubiquitous solution.
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Imetelstat summary 4
Imetelstat has a serious toxicity profile, which is the same as saying Ruxolitinib has a serious toxicity profile, which you can say for all chemo agents too. Getting in a car or an airplane can be deadly too. These are all potentially deadly things when not managed. And yet global transportation is a trillion dollar business, from cars, to planes, tourism, hotels, restaurants, all served by these dangerous, deadly machines. But let's make the comparison between Ruxolitinib and Imetelstat again... both have serious toxicity, but only Imetelstat virtually cures. And the Mayo clinic, Geron, the FDA, and JNJ all agree that Imetelstat's toxicity is completely manageable. The FDA placed a hold b/c they were concerned, and not only did they lift the hold, they also gave the green light for further studies.
The fear mongers pointing at Imetelstat's supposed liver toxicity are MASSIVE IDIOTS, since Ruxolitinib also causes the same liver problems, AND YET WAS APPROVED. These supposed liver toxicities are really just elevated liver enzyme activity, NOT TOXICITY, and these elevated activities resolve to baseline upon discontinuation, which is not to say patients with elevated liver activity can't stay on the drug. They can stay on it. Elevated liver activity in conjunction with other signals would indicate a problem; but in and of themselves, elevated liver activity is a small, small price to pay for someone who has a 1-3 year life expectancy.
Yes, Imetelstat has a toxicity that must be managed. But it has been managed and managed well for nearly 500 patients, WITH THE BENEFIT OF SOME MF PATIENTS BEING VIRTUALLY CURED. Something so simple as dose schedule modification has completely contained any serious toxicity. But how far the dose can be attenuated and still present efficacy is a part of this next study. This is getting really long so I'll try to wrap it up in the next one.
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Imetelstat summary 5 conclusion
The focus has been on Imetelstat as a single agent. But that's not the future. There were a few combo studies for solid tumors that haven't shown results, so from what little info they've released I assume they were lackluster. For MF (and probably MDS), Imetelstat as a single agent causes significant disease modification. This ALREADY is grounds for approval as a single agent, for the serious unmet need in MF and MDS, and probably as a combo treatment for AML.
But solid tumors are the real prize. We know Imetelstat works in hematologic malignancies, so the model for efficacy is there. But getting it to work in solid tumors will be the ultimate goal. Now having this model of efficacy from blood disorders is a major piece of the puzzle for unlocking efficacy in solid tumors. Those previous solid tumor combo studies were conducted years before Dr. Tefferi's unprecedented results. And now ASXL, CALR, JAK mutations and other markers have been identified. What we have is several threads to pull on, and it's only a matter of time and research before we understand the nuances of patient response. Money is no longer an issue, b/c JNJ's coffers are full and always refilling. I don't think solid tumor applications will be approved in the next few years, more like 5-10 optimistically, but JNJ WILL pursue them as a matter of business AND science.
My point is that Imetelstat as a treatment for blood disorders is fait accompli. On that alone, Geron will CONSERVATIVELY be valued at $15 billion. And with JNJ's continued research into solid tumors, Geron will have potential like no other small bio. Once JNJ begins research into solid tumors, Geron will be the most sought after bio acquisition. Imetelstat as a ubiquitous, panacea treatment for all cancers, not as a single agent but as a cocktail, will make Geron into a mid-level pharma player, the likes of REGN or AMGN, or even MRK. This is years ahead, of course. But investors right now have a golden ticket near or long term.
