Ropeg 6 Year Allele Data (apparently) Revealed

[EPguy]

Top point: Data may show an increase in average allele after 5 years on Bes, see orange plot line.

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I've been searching for 6 year update to the familiar plot here, it's not publicly available, and this may be why. The ASH hematology conference is next month and 6 year data is indirectly shown in a preview paper. Some summary papers are available, see links below.

In "Efficacy and Safety of Long-Term Ropeginterferon Alfa-2b Treatment in Patients with Low-Risk and High-Risk Polycythemia Vera (PV)" there is six year allele data. They divide it between 46pts Low Risk(LR) and 49 High Risk(HR). LR is under age 60 without history of thrombosis (clots in arteries or veins). Conveniently 46+49=95 pts which matches earlier docs for the 95 patients in the Conti-PV Ropeg study. So it's very likely the same patients and relevant to this plot.

The LR group was average VAF (allele burden) of 5.6%. HR group was 17.9%. I get a total average of 11.9VAF from that, as seen in this plot. See below how I calculated it.

This is not what we want to see, but I have been expecting it based on earlier PEG data, seen in old posts. Note that the Low risk group would be below this line at 5.6% while high risk is above it at 17.9. But there are no comparable numbers for prior years so we can use only the total average.

I believe a pattern will hold from other reports that those who get the lowest alleles are most likely to maintain it, but the Ropeg studies did not look there so far.

A separate note "LR patients were less likely to harbor additional non-driver mutations (11.4% vs 24.4%)." This may actually be the reverse, non-drivers contribute to risk rather than just incidental to it. This is discussed in detail in other posts including some non-drivers leading to less IFN response. They do continue the familiar relation between CHR (full blood response) and VAF, if indirectly.

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There is a public number the authors have released in a different report, but it is not comparable to the average VAF plot here. "At six years, 20.7% of patients in the ropeginterferon alfa-2b group (n=19) achieved a JAK2V617F allele burden of less than 1%" But it does read nicely hence its easily found result.

ashpublications.org/ashclin...

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We need that IFN + (something) therapy to get more patients in the best place. But we also still don't know how important it is to get to the lowest VAFs.

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My simple calculation: 49ptsx17.9%= 877 (pts%). 46 x 5.6% = 257.

(877+257)/95= 11.9% average. The units work, but I have simplified it greatly. Any stats members are welcome to comment.

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ASH links

The report discussed here: -ash.confex.com/ash/2022/web...

Ropeg related (not sure this link will work) - ash.confex.com/ash/2022/web...

[EPguy]

A good thing to remember, what really matters is this report from the same study (seen in prior posts) which shows out to 7+ years that Ropeg did well keeping "events" down. This matches the idea that even if there is a small VAF rebound the benefits persist. Note the still large difference vs BAT (best available therapy) in the top plot. This good result also matches those from the long term Cornell study (in many prior posts) of earlier IFN therapies.

At the same time we know that BAT is much better than No Therapy if BAT is indicated.

"Event-free survival (risk events: disease progression, death and thromboembolic events) over ≥6 years of treatment was significantly higher among ropeginterferon alfa-2b treated patients than the control group (risk events reported in 5/95 vs. 12/74 patients, respectively"

journals.lww.com/hemasphere...

Event Free Survival

[Paul123456]

Very difficult to draw any meaningful conclusions without knowing more patient data.

For example, how early were interferons started? The earlier the better.

Was this post trying HU? ie a more aggressive disease that HU failed to control?

We have discussed before the research from two years ago that concluded that c. 50% of Pegasys users can achieve remission if they reduce their AB below 10% and keep it under this level for two years?

[EPguy in reply to Paul123456]

You're right how much ambiguity remains. This applies to the entire plot at top here. But I think the year 6 data point at least is comparable in that ambiguous context. All the Bes approvals did not look at VAF, so the regulators didn't need to think about it much.

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I recall some reports have discon limited to <2% VAF. But also seen 10% as you note. Still another report (I think from the Silver group) questioned the whole idea of discon with respect to odds of improving marrow effects.

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It is plenty confusing to really know. In fact the Ropeg study did select more troublesome pts by design from what I can tell. This suggests not too early start.

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For Proud PV (1st 3 years of this study) Pts must meet one or more:

o Age > 60 years at the planned day of the first drug administration;

o At least one previous well documented major cardiovascular polycythemia vera-related event, except bleeding and polycythemia vera-related thromboembolic complications in the abdominal area, see exclusion criterion 7) in the medical history;

o (Failed phlb) - Poor tolerance (defined as a phlebotomy/procedure-related adverse event [AE] causing significant adverse impact on the patient and limiting ability to apply phlebotomy with the intention to keep hematocrit 45%, or if one phlebotomy was not able to reduce hematocrit level to < 45% for the next three months following phlebotomy);

o Progressive splenomegaly (de novo appearance of a palpable spleen, or appearance of the symptoms, related to the enlarged spleen, e.g. pain, early satiety etc., with confirmed size increase);

o Platelet count > 1000 x 109/L (for two measurements within one week);

o Leukocytosis (white blood cell count > 10 x 109/L for two measurements within one week).

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But on the other end, ContiPV (the -after three year portion-) accepted only pts that were already promising:

"(blood count responses) and...Otherwise a clear, medically verified benefit from treatment with ropeginterferon alfa-2b (e.g. normalization of disease-related micro-vasculatory symptoms, substantial decrease of JAK2V617F allelic burden).

In the Bes approval in Germany they excluded the ContiPV portion bec of this selectivity.

But the best allele reductions were up to M36 in the top plot, these being just the troublesome pts.

[ainslie]

interesting info, is the control group on meds, I see the Bes group AB Reduced from 38 to 12 and the control group went fro 37 to 44 , I wonder if either of these fairly modest changes are going to make much difference to prognosis bearing in mind Dr Spivak view that those with AB under 50 are in for a easier ride. I still think it’s strange they chose patients with quite lo AB to begin with ie 38. Either way if I could reduce my AB even from 38 to 12 I would take it even if we don’t really know what it means yet. Quote Dr V.

[EPguy in reply to ainslie]

The control is largely or entirely on HU. I agree it's strange how low the avg AB was for a group with PV.

I agree on going for lower allele, I'd rather try for lowest allele now and find out later how much it mattered.

[kristinmarie]

For your information, this drug is not generally available in UK, as ropeginterferon alfa-2b (Besremi®) is not recommended for use within NHSScotland.

Here is the website link, scottishmedicines.org.uk/me...

Indication under review: as monotherapy in adults for the treatment of polycythaemia vera without symptomatic splenomegaly.

In a phase III study, ropeginterferon alfa-2b failed to demonstrate non-inferiority to hydroxycarbamide in treatment-naïve patients who required cytoreductive therapy and in patients who had a partial response to hydroxycarbamide.

The submitting company did not present a sufficiently robust clinical and economic analysis to gain acceptance by SMC.

This advice takes account of the views from a Patient and Clinician Engagement (PACE) meeting.

[EPguy in reply to kristinmarie]

I recall this rejection. Is the Scottish (SMC) report binding on Britain? It says "is not recommended for use within NHSScotland"

It seems this submission used VAF reduction as an endpoint, see quote here, and the well timed question from mhos61 here is on this point, SMC is not convinced VAF and their use of it is valid. In the US they used CHR as the comparison. CHR is more accepted as important so this could be one difference.

"There are also major concerns regarding the model response parameter included in the indirect comparison. This was a laboratory type outcome (JAK2 level) that was translated into final outcomes (progression events) in the model. This resulted in layers of assumptions which adds a substantial amount of uncertainty to the cost-effectiveness results"

[kristinmarie in reply to EPguy]

The Scottish SMC report says, "ropeginterferon alfa-2b failed to demonstrate non-inferiority to hydroxycarbamide", concisely, ropeginterferon alfa-2b is inferior to hydroxycarbamide.

It should also be noted that the FDA approval of ropeginterferon alfa-2b was based on the single-arm phase II efficacy results, but rather than the head-to-head effectiveness comparison of ropeginterferon alfa-2b vs hydroxycarbamide in phase III study. That is, FDA appears to agree with the Scottish SMC report on the inferiority of ropeginterferon alfa-2b.

This drug, once taunted as a game-changer, is rarely prescribed, maybe due to its price or the lack of superior efficacy or whatever. The company that sells it also knows about the drug's deficiencies. They are planning to conduct yet another single-arm study to optimize its dose regimens. Here is the weblink: ash.confex.com/ash/2022/web...

[EPguy in reply to kristinmarie]

The CHR results were not as impressive as the allele on Ropeg, but still better than HU:

"After 5 years’ treatment, ...55.8% in the ropeginterferon alfa-2b arm and ...44.0% in the control arm achieved complete hematologic response (CHR) according to modified European LeukemiaNet (ELN) criteria"

nature.com/articles/s41375-...

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I see the same, that FDA approval of efficacy was based on only Ph 2 Peginvera study. But FDA did include the Proud/Conti/PV trial for safety:

"The pooled safety population described in the Warnings and Precautions section reflects exposure to BESREMi as monotherapy for the treatment of polycythemia vera dosed every two to four weeks in 178 patients in two open-label trials [PEGINVERA, PROUD/CONTINUATION PV]"

accessdata.fda.gov/drugsatf...

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There is this intriguing note in FDA label, the formula changed, I presume between Peginvera and Proud PV:

"Because of formulation changes, the recommended starting dose, titration amounts, and maximum dose of BESREMi differ slightly from those used in the trial"

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Has there been a conclusion that Bes is inferior to HU? By the numbers it seems to tilt the other way.

The two plots at top of this thread are compelling for superiority but are not part of any drug approvals. If Bes is a game changer it is via these less time tested advantages. IFN in general is well demonstrated in MPN treatment.

In my case I am more satisfied with Bes over HU, having been on both. I am pleased with my allele reduction (of uncertain benefit).

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I have seen that dosing study. I think this is a bad idea to start higher than current practice as we've seen right here on the forum. Slow careful titration is the best.

[kristinmarie in reply to EPguy]

Congratulations! You are one of the lucky patients on Besremi who achieve quick and sustained response in terms of HCT. There are others in this forum who claimed their HCT numbers are creeping up despite using this drug.

This expensive medication is not generally available in the UK, unless the patient is willing to shell out 1,800 pounds per dose with his own money. I believe that in Germany and France, their healthcare systems do not pay for this drug neither. One may purchase it online for about 2,000 euros, if he is willingly to pay out of his own pocket (everyone.org/besremi-ropegi.... Yet, in the US, the price is >$7,000 for one single use. Yikes!

For such a high price, one may expect Besremi to be super effective, or not? Should the drug be effective immediately or should the PV patient have to wait for years to see results? This is no miracle drug, but is it even better than Pegasys? For your reference, Pegasys has an annual cost of ~5,000 pounds via NHS. Yes, the entire year of Pegasys costs about 5,000 pounds, while that same amount of money will get you ONE dose of Besremi in the US .

In the newly proposed phase 3b study, the maker of Besremi is going with 250-350-500 three dose levels, trying to elevate the efficacy of the drug. Only time will tell whether this is the right approach.

[EPguy in reply to kristinmarie]

I've been fortunate to respond well to HU and IFN. But I know that can change any time.

I agree if one is paying these prices out of pocket, it's an easy choice of PEG over Bes. I don't think they are different enough in performance to justify the price diff. But the big thing Bes has is specific approval for MPN use (PV). This is to extent just a bureaucratic distinction but with the cost of these approvals it's why they get the big $.

If one is paying directly there is huge incentive to multi dose the syringe.

I don't agree with that more aggressive titration in the 3b study as I noted, we just can read the forum to know that.

This is a point plot of some members' doses on Bes and CHR response, I've posted a while ago. (as of last summer) It does contra indicate the high starting doses they are proposing.

healthunlocked.com/mpnvoice...

Point Plot

[mhos61]

Are the MPN experts any closer to knowing the prognostic significance of maintaining a low allele burden. I’m aware it possibly reflects milder disease, less inflammation etc, which is obviously a good thing.

I found out my allele burden percentage for the first time this week, it’s only 3.6! I was diagnosed with ET six years ago, and have been on low dose hydrea all that time! Shame I don’t know what the percentage was at diagnosis.

Any thoughts?

[EPguy in reply to mhos61]

As in many posts and reports, the signif of allele (VAF) remains under debate. I think all agree less is better, but at what cutoffs and what other factors?

My Dr agreed that getting a low VAF even lower via IFN is harder than reducing a very high allele. But it does happen as in posts here and my own 14-10% reduction at 6 months of IFN.

3.6 is a quite low number, and after 6 years that is great to be there. But as you say what was it 6 years ago, it was rarely checked back then. I think it needs to be well below 1% to approach a "cure" from various reports. And non-driver mutations also are a factor, these can be harder to reduce.

[Manouche in reply to mhos61]

Hi mhos61,

« I found out my allele burden percentage for the first time this week, it’s only 3.6! I was diagnosed with ET six years ago, and have been on low dose hydrea all that time!« 

It’s been reported that HU can sometimes induce a deep molecular response and a remission. You seem to be one of those 👍🏻

[mhos61]

Oh wow, thank you!

That would be some good news for hydrea...👍 Can you recommend any articles on this finding?

I must admit I am totally surprised by the results. I thought I’d be lowish due to stable counts, low symptom burden etc, but never for one moment thought single figures!

It did cross my mind that hydrea may have halted what was already ‘early disease’. Obviously because I didn’t have allele burden percentage at diagnosis I can’t make any comparisons. It would be nice to know though.

Thanks again!

[EPguy in reply to mhos61]

A main trial that compared HU directly to IFN is the familiar Ropeg, which has this familiar plot. HU (the gray line labeled control) showed good allele reductions early.

More on the point here :

"..in the control arm, (HU) only 1 patient (1.4%) achieved an allele burden <1% at 60 months " (Bes gave 21% this result at 6 years)

nature.com/articles/s41375-...

So HU can provide excellent reductions, but it is not common.

There should be other studies, while this is the most recent.

In general HU is a good therapy for many from various info we've seen. Could be at the lower alleles it is esp effective but I know of no specific data on this.

Ropeg HU

[mhos61]

It’s quite possible the hydrea has reduced my allele burden; however, it’s also possible it was even lower at diagnosis and has increased very slowly.

We hear all the time about the interferons effect on allele burden reduction, so I find it amazing that even one hydrea patient achieved an allele percentage of less than <1% after 60 months.

Thanks for your input!

[EPguy in reply to mhos61]

I think the lower initial VAF is quite plausible. HU also can revert marrow as in recent posts, but this data goes only to 12 months. My Dr agrees it's not long enough to judge that benefit.