"....futility based on a planned analysis."

[kmall]

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

"July 21, 2023 - FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc. (Nasdaq: GILD) today 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."

Anyone have any insight into the above PR from Gilead? It sounds as if safety wasn't an issue moving forward.

"The study enrolled more than 500 patients who were randomized to receive magrolimab in combination with azacitidine or azacitidine monotherapy."

This is a fairly large study group. 520 patients is a rather substantial undertaking. From Clinical Trial Design to initiation of the study, a vast amount of resources were utilized here.

As of now Gilead has "a clinical development program spanning ten potential indications including ongoing trials in solid tumors and two pivotal trials: ENHANCE-2 study in acute myeloid leukemia (AML) with TP53 mutations and ENHANCE-3 in first-line, unfit AML."

Perhaps the answer for their decision for discontinuation lies somewhere in the following statement?

"The health and well-being of patients are our top priorities and while this is disappointing news it confirms the challenges of treating HR-MDS, where no new class of treatments have been approved in nearly 20 years,” said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. “Gilead is deeply grateful to the patients, families, investigators, and the advocacy community who contributed to this research as we learn more about magrolimab and explore its potential in treating other cancers.”

Does this leave Imetelstat as the next new class of treatment to be approved in nearly 20 years for HR-MDS?

Sure seems like it. -Kmall

[biopearl123]

If the Imetelstat high risk MDS/AML studies are fruitful, it’s hard to see where immediate competition comes from. Clearly an area with no recent new therapies. Here is a brief summary of where CAR-t is in MDS and the hurdles presented. Doesn’t look like there is too much there in the immediate future:

https://www.youtube.com/watch?v=SS1EvAP_120&t=159s

This link takes you to the end of the short talk, you have to rewind to the beginning.

[LWS]

"July 21, 2023 - FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc. (Nasdaq: GILD) today 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

."
==========================================
Some thoughts (speculation)--- Perhaps Gilead is conceding the superiority of Imetelstat. Since magrolimab appears to have had some successes, it could possibly reappear in some combination with Imetelstat. There is something that we are missing.

[kmall]

LWS - I was thinking that could be a possibility. If the Imetelstat data poses a threat, then perhaps they see their resources put to better use in other indications?

[Ryan]

I can offer based on experience working with big data that, sometimes it is not even necessary “crunching the numbers “, which requires time and effort of the team members, when specific KPIs (key performance indicators) are clearly negative based ln basic calculations / anecdotal evidence.

In this case, I would presume that patients dropping from the therapy/study in favor of ‘more desperate measures’ and corresponding patient population attrition, which doesn’t require an extensive analysis, that the company saw how this “planned data analysis” was going to go with clear eyes, and recos were probably made to the execs to cut bait.

I’ll further add from experience with close family member who battled blood cancer (CML), when things change for the worse, it is mind numbingly fast, and I would suppose this happened to patients on this therapy despite PR/CRs (as discussed), and the company felt no need to shine a light on this with a more formal data analysis / release.

This is truly a sad outcome for these patients who chose a route with big Pharma (through their acquisition), no fingers being pointed w that straightforward statement.

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

"July 21, 2023 - FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc. (Nasdaq: GILD) today 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."

Anyone have any insight into the above PR from Gilead? It sounds as if safety wasn't an issue moving forward.

"The study enrolled more than 500 patients who were randomized to receive magrolimab in combination with azacitidine or azacitidine monotherapy."

This is a fairly large study group. 500 patients is a rather substantial undertaking. From Clinical Trial Design to initiation of the study, a vast amount of resources were utilized here.

As of now Gilead has "a clinical development program spanning ten potential indications including ongoing trials in solid tumors and two pivotal trials: ENHANCE-2 study in acute myeloid leukemia (AML) with TP53 mutations and ENHANCE-3 in first-line, unfit AML."

Perhaps the answer for their decision for discontinuation lies somewhere in the following statement?

"The health and well-being of patients are our top priorities and while this is disappointing news it confirms the challenges of treating HR-MDS, where no new class of treatments have been approved in nearly 20 years,” said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. “Gilead is deeply grateful to the patients, families, investigators, and the advocacy community who contributed to this research as we learn more about magrolimab and explore its potential in treating other cancers.”

Does this leave Imetelstat as the next new class of treatment to be approved in nearly 20 years for HR-MDS?

Sure seems like it. -Kmall

[kmall]

Ryan - First, condolences for your family member. These hematological disorders as you have pointed out can become quickly unmanageable.

And thank you for your insight. Some very interesting and valid points to consider all around. I do find the timing of Gilead's decision questionable as far as Imetelstat is concerned. Perhaps it's completely coincidental, and Geron/Imetelstat doesn't even factor into their equation. Like the JNJ discontinuation, chances are we'll never get a concrete answer and be reduced to reading between the lines. -Kmall

[biopearl123]

Ryan so true. When blast crisis ensues it just a tsunami. As far as timing of the Gilead study cessation I doubt Geron’s LR MDS study has little or no impact since there as yet is virtually no clinical AML or higher risk MDS data with Imetelstat. The magro study failed without any help from Geron. It does however sharpen the focus and hopes for Geron’s nascent HR MDS/AML study. Recall Dr. Wen Ma’s preclinical work in CML blast crisis as well. Regards, bp.

[kmall]

In January 2022 the FDA placed a hold on 5 Clinical Trials with Magrolimab.

"Trials for the CD47-targeting med, magrolimab, were placed on hold due to an “apparent imbalance” in adverse reactions seen in the study arms. The sweeping action covered five trials from early- to late-stage development for the therapy in combination with azacitidine for patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and myeloid malignancies. This included several phase 3 trials called ENHANCE.

The FDA has now wrapped up its review of magrolimab in AML and MDS but will keep the holds on two additional trials in patients with diffuse large B-cell lymphoma and multiple myeloma. Gilead did not elaborate on why the holds were still in place but said it was working with the agency."

https://www.fiercebiotech.com/biotech/f ... d47-trials

https://www.fiercebiotech.com/biotech/g ... trials-and


I don't remember hearing about this last year. Perhaps there is more to the story then "futility based on a planned analysis." ?? -Kmall

[rccola335]

that would explain the PR - they do not want people to think it is unsafe - it probably is ineffective overall for this indication - they have a lot of money invested in this drug and this is why you wait until phase 3 to buy

[biopearl123]

Could also be why Geron slow walking combination AML study

[kmall]

https://www.fiercebiotech.com/biotech/g ... magrolimab

The story continues to unravel.

Looks like Gilead took a $3B+ hit on Wall St. today. The importance of P3 confirmation cannot be understated. -Kmall

[rccola335]

To have such good phase 2 results and bomb on phase three makes you wonder how many phase 2 failures would do better in a larger sample phase three

[kmall]

rccola335 - looks like leapfrogging from 24 patients in P2 to 520 patients in P3 was a nail in the coffin for the MDS CT of Magrolimab. It will be interesting to see if the two P3 Enhance studies for AML suffer the same fate? Gilead has another 8-10 indications ridding on Magrolimab, including solid tumors at the moment. Hopefully the patients enrolled in any of these Clinical Trials have other options available to them. -Kmall

[kmall]

While we're on the topic of current players in the MDS market, this June 6, 2023 Research Report from Delvelnsight mentions Geron and Imetelstat as being one of the key contributors in the next few years, along with Gilead. We all know this list just got a little shorter. -Kmall

https://www.globenewswire.com/en/news-r ... Fibro.html

[biopearl123]

Just a side note. If one looks at the enrollment sizes of various ongoing studies, Geron’s studies are relatively “compact”. It is clear they design studies with an expectation of the kind of strong clinical significance that does not require large numbers of patients to participate. The MF study will likely prove this point again. As we have said many times on this board, disease modification and meaningful life extension are hard to come by and even remissions and symptom improvement may not predict longevity. Kmall thanks as always for these important contributions to our knowledge base. Clearly there are many meds, many companies and many dollars chasing these diseases but until we see true disease modification, there will probably be only a small number of winners. I specifically asked Dr. Scarlett and Dr. Rizo if they saw ANY competitors on the horizon that demonstrated disease modification (exclusive of BMT). And they said no. At the time I took this to include magro which was a leap since of course they would not name names. Regards to all, bp

[biopearl123]

Additionally, as you know I look at Geron’s wording very carefully (see multiple “parsing Scarlett” entries). I believe the legal profession has punished Geron’s good intentions enough. When Geron used the wording “in the clinic or in development” to describe that they were unaware of the progress of other potential agents that might lead to disease modification, I took notice. That had to take some very careful forethought and vetting from Geron’s own legal council. All those meds, all those companies, all those dollars (I only repeat for emphasis), if they can’t prove disease modification, it “coitans” (as they say in Brooklyn), for them. bp