All roads lead to Rome

[biopearl123]

To Ryan’s point, Geron’s MDS study is in R/R ESA patients. What we know about Luspatercept is that it is better than placebo (MEDALIST) and it is better that ESA’s (COMMANDS). But we don’t know if Lus is “better” that Imetelstat. As yet we don’t know total duration of action or what percent of patients are ringed sideroblast patients. We do know the study was not limited to R/S patients as MEDALIST was. We don’t know if it works in R/R patients. And we don’t know if patients refractory to Luspatercept would be candidates for Imetelstat. It certainly seems likely that the COMMANDS study will move Lus into first line therapy. Geron has already pointed out that the control group in the MEDALIST study is not as stringent as that studied in IMerge and the Lus studies include less “sick” patients (very low risk MDS). We don’t know the breakdown of numbers of patients with ringed sideroblasts in the COMMANDS study and if benefit is “across the board”, a point Geron likes to point out. In any case Luspatercept failures may lead to Imetelstat treatment eventually. The benefits of Luspatercept will likely be reaped not only in reduced transfusions but in less iron overload and risk of hemochromatosis. (Also a reasonable expectation from Imetelstat.) This if sustained, would likely result in improved OS. Transformation to AML is correlated to transfusion burden but I don’t know if that is iron overload related or the progression of increasing numbers of mutated malignant cells. Probably the latter. Geron’s approach, by targeting the malignant clone might have a better chance at reducing the risk of disease progression and result in disease modification. That’s just a guess. It seems unlikely given the MOA of Luspatercept that reduction in bone marrow fibrosis, inflammation and control of the malignant clone could be expected. That is speculation on my part. Geron’s studies have included in depth analysis of genetic mutations which appear to be modified by Imetelstat. That may not be the case with drugs that just affect erythrocyte maturation. Confirmation bias possible but there seems to be continued reason for excitement and optimism that should not be “modified” by the Luspatercept studies. There will probably be a place for both but when treatment fails I think at least some roads might actually lead to Imetelstat’s Rome (and Dr. Santini).

[kmall]

Bp - Back in April 2019, Dr. Scarlett did a presentation at the Needham Healthcare Conference where he compared the Luspatercept (pre-approval) study to the P2 IMerge (MDS) data.

I made "short notes" and was able to pull two direct quotes from Dr. Scarlett pertaining to any comparisons of the two. Here's the link:
viewtopic.php?f=1&t=827

Rundown on Luspatercept vs Imetelstat:

"Quotes" are Dr. Scarlett's

Slide 16 – is "most important" -Dr. Scarlett

- Target populations similar

- Biggest change is transfusion burden (4 down) –
- Lusperacept is lower Transfusion burden

- 37% response rate for Imetelstat and 20% for Luspatercept – "Luspatercept doesn’t have the same degree of activity with patients with transfusion burdens" -Dr. Scarlett

- On Luspatercept – "a fine drug and would be shocked if it didn’t get approval” -Dr. Scarlett

**As we all know, Luspatercept did get approved, however, Imetelstat worked MUCH better - 37% vs 20%.....almost double the Response Rate of Luspatercept...... with patients that had a MUCH higher Transfusion Independence (Ti) burden.



In the Q&A that day, Dr. Scarlett also mentioned that:

1 - "they (JNJ) DID NOT HAVE the Luspatercept data BEFORE the Continuation Decision" -Dr. Scarlett

2 - "Doesn’t think any other drugs will reach the relapse refractory numbers that Imetelstat has" -Dr. Scarlett

3 - "Relapse refractory patients are very difficult to treat" -Dr. Scarlett



***Luspatercept doesn't even come close when standing side to side with Imetelstat.

It's like a featherweight ameatuer going up against a Heavyweight champion. Period.

Can't wait for January!!!! -Kmall

[biopearl123]

Kmall, no question Dr. Scarlett anticipated this and positioned Imetelstat appropriately. In both MF and MDS it was always questioned as to why Imetelstat was not positioned for front line therapy. I suspect its because Dr. Scarlett and company know that all roads lead to Rome (eventually).

[biopearl123]

I do think we will see a change in the approval of Luspatercept from just R/S patients (25%) to all subtypes of lower risk MDS. This will change one of Geron’s strongest talking points which emphasized that Luspatercept was approved for only about 25% of the MDS TD population. Now its just a matter of degree, duration and disease modification indicators (bone marrow fibrosis, genetic indicators, OS). Let’s hope Geron comes through on these. bp

[Bridge to Sell]

Biopearl,

Reading the Clinical Trial for COMMANDS I'm struck by the fact that having greater than or equal to 5% blasts was an exclusion criteria. While it's not spelled out more clearly, I believe that this is colloquially referred to as an 'RS Negative' population due to the low threshold. The presence of more blasts would therefore make the patient 'RS Positive'. It would seem to imply that Scarlett's statements that Imetelstat treatment of both subtypes (RS+ and RS-) still holds true and that Luspatercept's potential market size is the same as we have always anticipated.

From Clinicaltrials.gov:

"Documented diagnosis of Myelodysplastic syndromes (MDS) according to WHO 2016 classification that meets revised international prognostic scoring system (IPSS-R) classification of very low, low, or intermediate risk disease, and have < 5% blasts in bone marrow"

https://clinicaltrials.gov/ct2/show/NCT03682536

[Bridge to Sell]

Reading even further, it seems that 15% sideroblasts may be the threshold to be considered RS Positive. If that's true, then Luspatercept's trial seems to have set a very low threshold for RS Negative patients by using the less than 5% number, perhaps stacking the deck towards a positive trial outcome.

"Among the different categories of MDS-RS without excess blasts (< 5%), RARS is generally believed to have the best survival rate with the lowest risk of leukemic transformation."

"Ring sideroblasts (RS) are erythroid precursors with iron laden mitochondria forming a perinuclear ring, and are commonly seen in patients with myelodysplastic syndromes (MDS).1,2 The presence of ≥ 15% RS constitutes the operational diagnosis of MDS-RS."

https://ashpublications.org/blood/artic ... ideroblast

[biopearl123]

Hi Bridge, thanks for posting. Yes, its a little bit apples and oranges. The nomenclature is confusing. R/S is an abbreviation for ringed sideroblasts. This group is presumably “easier to treat” and has a better prognosis especially if the blast level in the bone marrow is low. It is usually associated with a molecular signature of SF3B1. I hope I am posting this correctly. The characterization of very low, low, intermediate and high risk is more correlated in part to the percent of bone marrow blasts present. And yes, the COMMANDS study by including very low risk patients may be a bit skewed toward patients who are “less sick” and have a lower transfusion requirement. It may be that Imetelstat will stand out in patients with the highest transfusion requirements. I think this is a point Kmall has made previously. I am hopeful we will see emerging data to support the notion of actual disease modification with Imetelstat that will set it apart. When Geron expanded the entry criterion (coincident with the QT interval study) it seemed that they might try to have at least some patients that could be more directly compared to the COMMANDS patient population. This remains to be seen.