Good news, bad news

[jayfish101]

This just out today. 7/21/23: Gilead Sciences, Inc. (NASDAQ: GILD) announced that the Phase 3 ENHANCE study in higher-risk myelodysplastic syndromes (MDS) has been discontinued due to futility based on a planned analysis. The safety data seen in this study is consistent with the known magrolimab profile and adverse events that are typical in this patient population. Gilead recommends discontinuing treatment with magrolimab in patients with MDS.

[kmall]

Obviously terrible news for MDS patients.

https://www.gilead.com/news-and-press/p ... r-risk-mds

https://www.reuters.com/business/health ... 023-07-21/

Considering that Gilead shelled out $4.9B for Forty-Seven in 2020 mainly based on the then P2 data of Magrolimab, this shines a light on several areas where Geron has a strategic advantage in both a partnership/BO scenario, and in the future treatment of patients including not only MDS, but several other indications right now. Magrolimab is/was also targeting AML and Lymphoid Malignancies - just as Imetelstat. In February 2022 I posted comparisons between both Magrolimab and Imetelstat, as well as Forty-Seven and Geron titled: "Similarities......"

http://imetelchat.imetelstat.eu/viewtop ... f=1&t=1274


For starters, Geron has successfully finished the P3 IMerge Clinical Trial (MDS), and submitted an NDA to the FDA, which we all anticipate acceptance in the very near future. The cost of a partnership or total BO will only increase with each milestone achieved from this point forward. It would be in Big Pharma's interest to make a move after the acceptance of an NDA, but prior to an FDA approval. This is a fairly small window for negotiations, and one that I think would be considered by any interested parties at this very moment. The Expanded Access Protocol (EAP) granted just last month by the FDA, suggests that approval of Imetelstat is on the horizon.

Second, and only speculation on my part, but I would think that the failure of Magrolimab in the treatment of MDS patients would also cross over into their P2/P3 AML patient group as well. Again, pure speculation, but logic would suggest that since this patient group is difficult to treat, results from the P3 Magrolimab MDS CT would mirror the AML CT. This would be a severe blow to Gilead and Magrolimab moving forward. And again, a terrible circumstance, especially those patients enrolled in the late stage Clinical Trials of Magrolimab.

The removal of Magrolimab from the future potential marketplace for these patient indications should benefit both Imetelstat and Geron, however no one likes a win by default. Today's news could possibly see the FDA expedite the approval process of Imetelstat as another option is suddenly unavailable to patients. -Kmall

[rccola335]

i would think AML would be also be ineffective - hope imetelstat can show use in AML

[biopearl123]

I am a little bit astounded by this announcement, especially since the 1b study showed a 31% CR rate. That preliminary study was not blinded like the PIII magro study. End point OS. As the search for effective heme treatments goes on, the field narrows. Not good news for patients who have so few options but the focus on Imetelstat should sharpen further. Gilead paid top dollar for Forty Seven and still has other ongoing trials so one hopes patients in other areas will benefit.Forty Seven was acquired much earlier in its development. It’s hard not to have a little bit of schadenfreude though, even as hopes strengthen for Imetelstat’s prospects. The value of having a classic PIII study with extremely positive results is apparent. Research is hard and many drugs fall by the wayside. Geron is standing strong.

[kmall]

Bp - A complete head scratcher when you look at the Magrolimab P2 data, which triggered the Gilead BO of Forty-Seven for $4.9B:


"P2 data: In higher-risk MDS, the overall response rate (ORR) was 92%, with 12 patients (50%) achieving a complete response (CR), eight patients (33%) achieving a marrow CR and two patients (8%) achieving hematologic improvement. Additionally, two patients (8%) achieved stable disease.
In untreated AML, the ORR was 64%, with nine patients (41%) achieving a CR, three patients (14%) achieving a CR with complete blood count recovery (CRi) and one patient (5%) achieving a morphologic leukemia-free state (MLFS). Additionally, seven patients (32%) achieved stable disease (SD) and one patient (5%) had progressive disease.

The median time to response among MDS and AML patients treated with the combination was 1.9 months.
No median duration of response or overall survival has been reached for either MDS or AML patients, with a median follow-up of 6.4 months (range 2.0 to 14.4 months) for MDS and 8.8 months (range 1.9 to 16.9 months) for AML."


Obviously a much smaller study group (24 patients) than that of P2 IMerge - but the numbers are extremely impressive none the less. 92% ORR - meaning that only one patient in the entire group had zero response to Magrolimab. 50% CR and 33% or 8 patients achieving marrow CR !!!

The AML data was even more impressive given the disease and dismal treatment prognosis. A 64% ORR is unheard of (I believe), and 41% CR with 3 patients (14%) achieving complete blood count recovery! 7 patients (32%) achieved stable disease (SD), and one patient (5%) achieving a morphologic leukemia-free state (MLFS)......I don't ever recall an AML patient obtaining (MFLS) ?? - although I'm not a physician or clinician, so perhaps that's been achieved before with other treatments?

Magrolimab in my view would be Imetelstats biggest competition in the space at the moment. CAR-T as well poses a potential threat as a marketplace rival, but as of now is a VERY expensive option for patients. If an oral agent of Imetelstat is developed, as planned, it's a total game changer across the board. Yesterday's news may be seeing our underdog surging to the front of the pack in short order. For now I'll reserve any celebration, but Gilead removing Magrolimab as an alternative in MDS is a huge boon for Geron and Imetelstat in the interim. -Kmall

[biopearl123]

Kmall, totally agree. This finding was completely unexpected giving the studies leading up to the PIII. I had an aha moment several years ago when listening to a lecture where an expert made the off hand comment that CRs did not necessarily correspond to improvements in OS. Hence the continued interest in MRD.

[Ryan]

BioPearl, I am certainly further enlightened by your points here. BUT I find it funny you don’t supply the meaning to the German term schadenfreude;). It is a great one. I could think of some Yiddish words to describe the non-stop naysayers and spammers who have joined our journey with this company / drug (like it or not). But I digress.

… in order to point out that you may want to expand of what MRD spells out… molecular residual disease… I think many here may be informed by looking up the definition…

Wow we are finally on the precipice … it feels almost hard to believe. Cheers!

[Ryan]

I re: MRD, here is an article that may be of interest, and is certainly topical:

https://www.fiercebiotech.com/sponsored ... -therapies

[biopearl123]

Hi Ryan, thanks for posting. The M at least in the past was for minimal but maybe the nomenclature has changed. As to schadenfreude, it is a great word with no real translation into english and experiencing it leads to embarrassment and self flagellation. Mea Culpa.

[biopearl123]

Kmall, re CAR-t, I still can’t get a handle on its potential use in MF and MDS. Besides expense and an older target population, it appears that some patients who get CAR-t for other indications actually have some risk of developing myeloproliferative diseases post therapy.

[biopearl123]

Little doubt that Geron’s value did increase by some number with this event.

[Ryan]

Molecular and Minimal are interchangeable:

https://www.bloodpac.org/bloodpac-blog/mrd-solid-tumors

Hi Ryan, thanks for posting. The M at least in the past was for minimal but maybe the nomenclature has changed. As to schadenfreude, it is a great word with no real translation into english and experiencing it leads to embarrassment and self flagellation. Mea Culpa.

[LWS]

schadenfreude

A word that has become timely. It means achieving maximum happiness and joy by seeing maximum pain and misery in others. In the Gilead situation, it does not apply for us, since as much we want Imetelstat to succeed, we do not want Gilead's medicine to fail.

Perhaps, it is time to create a shorter word to express these simultaneous opposite emotions. I will give it a try: Misjoyness.

[kmall]

Bp - Admittedly, I'm not versed it the various treatments for CAR-T, however, it was my understanding that it was effective in several Hematological Disorders. Perhaps this 2023 abstract is what you are referring to?

"High risk-myelodysplastic syndrome following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma: A case report and literature review"

https://pubmed.ncbi.nlm.nih.gov/36741006/


In the meantime, this 2021 article highlights several Hematological Disorders which may benefit from CAR-T treatment, including: AML, CLL, ALL, Multiple Myeloma and B-cell lymphoma, amongst others.

https://stemcellres.biomedcentral.com/a ... 21-02420-8


While the FDA has approved several CAR-T products over the past few years, it seems like the verdict is still out on benefits or side effects for many indications. And like you, I believe that Geron's value has significantly increased with Magrolimab being discontinued for MDS at the moment. -Kmall

[biopearl123]

LWS, your definition is way too extreme. It’s much more subtle then that.

[LWS]

bp --- Schadenfreude is a word that is not so subtle. Perhaps, it applies more properly to various dictators than to anything in the medical world.
==============================

Schadenfreude is a German word that means pleasure derived from the misfortune of others. Some possible synonyms for schadenfreude are:

Gloat
Epicaricacy
Gloating
Sadism
Malevolence
Brutality
Savagery

[biopearl123]

Like I said, it’s difficult to translate just ask a German.