FDA Approves Ropeginterferon Alfa-2b-njft for Polycythemia Vera

[JT_Marlin]

The FDA has approved ropeginterferon alfa-2b-njft (Besremi) for use as a treatment in patients with polycythemia vera.1

The regulatory decision was based on safety from the PEGINVERA and PROUD/ CONTINUATION-PV studies and efficacy findings from the PEGINVERA clinical study program.

Results showed that following 7.5 years of treatment with ropeginterferon alfa-2b-njft, 61% of patients achieved a complete hematological response, which was defined as hematocrit less than 45% without phlebotomy for at least 2 months since last phlebotomy, platelet counts of 400 x 109/L or less, leukocytes of 10 x 109/L or less, and normal spleen size.

Notably, 80% of patients experienced a hematological response with the agent; this was based on objective laboratory parameters only, with the exclusion of normal spleen size and thrombosis. These parameters are the most frequently used metrics to make clinical decisions.

In the pooled safety population of patients treated with ropeginterferon alfa-2b-njft , the most common toxicities included influenza-like illness, arthralgia, fatigue, pruritis, nasopharyngitis, and musculoskeletal pain. Serious adverse reactions included urinary tract infection, transient ischemic attack and depression.

“The FDA approval of ropeginterferon alfa-2b-njft (Besremi) for people with polycythemia vera represents the next step in advancing patient care as it provides a critical addition to managing not only symptom burden and near-term complications, but also treating the cancer early, which may help reduce the risk of disease progression over time,” Srdan Verstovsek, MD, PhD, director of the Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms, Department of Leukemia at the University of Texas MD Anderson Cancer Center, stated in a press release. “With the availability of an FDA-approved, next-generation interferon for this indication, it’s time that we focus on preserving the long-term health of patients with polycythemia vera.”

Ropeginterferon alfa-2b is a novel, long-acting, mono-pegylated proline interferon that was designed to have an optimized profile that would allow for improved pharmacokinetic properties. The agent was also developed to have more favorable tolerability and convenience versus conventional interferons. The agent was developed to be given once every 2 weeks or once every 4 weeks during long-term maintenance.3

PROUD-PV, and CONTI-PV, which was the extension study, were open-label, controlled, phase 3 trials that were conducted in 48 clinics in Europe. To be eligible for enrollment, patients had to be 18 years of age or older with an early-stage polycythemia vera diagnosis per the World Health Organization 2008 criteria.

In the trial, participants were randomized 1:1 to either subcutaneous ropeginterferon alfa-2b, which was given biweekly at a starting dose of 100 μg, or oral hydroxyurea at a starting daily dose of 500 mg. At 1 year, patients had the opportunity of enrolling to the extension portion of the research, the CONTI-PV trial.

The primary objective of PROUD-PV was to establish noninferiority of ropeginterferon alfa-2b versus hydroxyurea in terms of complete hematological response with normal spleen size at 12 months. The coprimary end points of CONTI-PV comprised complete hematological response with normalization of spleen size and improved disease burden, with regard to splenomegaly, microvascular disturbances, pruritus, and headache.

A total of 306 participants were enrolled to the trial between September 17, 2013 and March 13, 2015. Of these patients, 257 underwent randomization, with 127 patients treated in each arm; however, 3 patients in the control arm ended up withdrawing consent. A total of 171 patients went on to participate in the CONTI-PV trial. The median follow-up was 182.1 weeks and 164.5 weeks in the investigational and control arms, respectively.

In PROUD-PV, 21% (n = 26) of patients who received ropeginterferon alfa-2b (n = 122) and 28% (n = 34) of those who were given standard treatment (n = 123) met the composite primary end point of complete hematological response. Additionally, improved disease burden was met in 53% (n = 50) of patients in the investigational arm versus 38% (n = 28) of those in the hydroxyurea arm (n = 74) at 36 months (P = .044).

Additional results showed that complete hematological response without the spleen criteria in the investigational and standard arms were 43% (n = 53) of 123 patients compared with 46% (n = 57) of 125 patients, respectively, at 12 months (P = .63; PROUD-PV). At 36 months, these were 71% (n = 67) of 95 patients compared with 51% (n = 38) of 74 patients, respectively (P =.012; CONTI-PV).

“We are incredibly proud to deliver on our goal of bringing treatments like ropeginterferon alfa-2b-njft to the polycythemia vera community where there is clear unmet need for more effective, tolerable and durable treatments to preserve patients’ health and well-being,” Ko-Chung Lin, PhD, co-founder and chief executive officer for PharmaEssentia and inventor of ropeginterferon alfa-2b-njft, stated in a press release. “As we begin working closely with the community to integrate this important treatment into clinical practice, we also continue to expand our scientific efforts to unlock the full potential of our pioneering molecule.”

References

US FDA approves BESREMI (ropeginterferon alfa-2b-njft) as the only interferon for adults with polycythemia vera. News release. PharmaEssentia Corporation. November 12, 2021. Accessed November 12, 2021. bwnews.pr/3nbXCYO

Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4

US FDA accepts PharmaEssentia’s application for ropeginterferon alfa-2b to treat polycythemia vera. News release. PharmaEssentia Corporation. June 4, 2020. Accessed December 3, 2020. yhoo.it/30fZcxA.

onclive.com/view/fda-approv...

[gvibes]

Good news! Thanks. I guess the question becomes should the people on pegasys (like myself) consider switching to ropeg. There are fewer injections. Are there different side effects? How difficult is switching?

[JT_Marlin in reply to gvibes]

Great question- I actually had an appt w my doc just a day before this news and had asked him about ropeg. His response was that it wasnt yet FDA approved… but that he wasnt so sure he’d want to switch me out.Pegasys has been working quite effectively for me with limited side effects - so hard to make a switch right?

If it aint broke, dont fix it, I guess.

[Snook37 in reply to gvibes]

I think cost will play a big factor. Unless you are at 180 mcg of Pegasys per week, you can get multiple uses out of one vial, and Besremi is indicated every 2 weeks starting off and then every month. I think Besremi is more expensive per vial but you need less vials per month. This is what I will be looking at, but I also don’t have major issues with side effects on Pegasys. I think people with significant side effects on Pegasys could get benefit from Besremi because it will minimize the side effects.

[gvibes in reply to Snook37]

I will have the discussion with my doctor certainly. Pegasys is off spec for p-vera correct? Where ropeg is actually now licensed for p-vera. Does that matter at all?

[Snook37 in reply to gvibes]

I don’t think so, they are basically the same thing but Ropeg is longer acting than Pegasys. May be better just to the extent you keep a more stable amount in your system.

[Snook37 in reply to gvibes]

For whatever reason Pegasys never wanted to sink money into getting approved for MPN. One other benefit to on label approval may be insurance coverage and insurance willingness to cover it for MPN.

[EPguy in reply to gvibes]

Being FDA approved for a specific condition makes more easy or likely to get insurance coverage for that condition. I've read that Cancer drugs in general are also more likely to be covered.

PEG was approved for HepC which is not normally a cancer. So Besremi (Ropeg) has two reasons to be more likely covered, it's specific for the condition and it's for Cancer.

But if you're already covered on PEG the above is less relevant.

[gvibes in reply to Snook37]

So you raise something I have been curious about. I get 180 mcg/vial pegasys. I presently fill the syringe with 90 mcg and throw out the rest. It always seemed crazy to me (especially seeing as how much it cost) but those were the instructions given to me. Should I be rethinking this?

[Snook37 in reply to gvibes]

A lot of money goes down the drain, my doc has no issue with reuse. My wife is a PA and we just wipe the top with an alcohol swab and draw it until every drop is gone. I think many others on here and other forums do the same. Obviously follow your haem’s instructions but it is food for thought. I don’t know of anyone having issues doing it this way. I have a hefty copay and I do not want to waste any of it.

[gvibes in reply to Snook37]

thanks. will look into it.

[EPguy in reply to gvibes]

PharmaEssentia has been claiming, from the press release above,

"Ropeginterferon alfa-2b is a novel, long-acting, mono-pegylated proline interferon that was designed to have an optimized profile that would allow for improved pharmacokinetic properties. The agent was also developed to have more favorable tolerability and convenience versus conventional interferons"

It is supposed to be better tolerated. There is a post on Voice from one member that had trouble with PEG, and was able to tolerate Ropog. Sorry I can't find that post right away.

It uses a different injection system, see picture here, and link

medicines.org.uk/emc/files/...

I've read it's less painful than PEG injection but I have no direct experience with either. As KT_Marlin says, it may be fine to stay with PEG if it's working.

Besremi Pen

[cmc_ufl]

Does anyone know if there are any trials ongoing for approval of Ropeg for ET?

[hunter5582 in reply to cmc_ufl]

This is the one I an aware of. There may be more.

clinicaltrials.gov/ct2/show...

[EPguy in reply to cmc_ufl]

Latest from the mfr:

<<During the meeting (ASH Dec 11-14) , the company will provide an update on SURPASS ET, a Phase 3 pivotal clinical trial of its investigational ropeginterferon alfa-2b (P1101)>>

us.pharmaessentia.com/wp-co...

[jmctrek]

Thank you for sharing the good news! Hoping their phase 3 study of high risk ET patients with HU intolerance/resistance on Ropeg can shed light of its efficacy for ET patients in the future.

[EPguy in reply to jmctrek]

In my opinion there is already some info of interest for at least JAK2 ET. In the report below for Ropeg

firstwordpharma.com/node/18...

<<Achieving deep molecular response correlated statistically significant with lower age and lower allele burden at the start of treatment.>>

Jak2 ET tends to have a lower allele than PV so it is reasonable that starting Ropeg early as possible in our age and allele journey is a good thing. I hope we will see this in the SURPASS ET data to come next month. Maybe some info for CALR and MPL also, I don't know if these are included.

My specialist says ET and PV are really on a continuum ( I take it to refer to JAK2) and the distinction is becoming out of date. He describes my condition as "MPN" without this distinction, not withstanding my username. This is his opinion.

But remember INF needs years to show good allele reductions.

I have posted this table elsewhere showing allele reduction to 8.5 on Ropeg. The very latest update from the link above shows even further allele reduction to 7.3 and even worse outcome for HU (control is mostly HU) :

allele burden decreased from median 37.3% at baseline to 7.3%, while it increased from 38.1% to 42.6% in the control group (p<0.0001).

Assuming this trend holds in the SURPASS update I think insurance co's may be convince- able to cover at least JAK2 ET.

Update Nov 15: see my reply in the post from Manouche below for more comments on the allele data.

healthunlocked.com/mpnvoice...

ContiPV

[jmctrek in reply to EPguy]

Thank you for highlighting the allele burden reduction on PV patients in the Ropeg study. My hematologist has suggested that the JAK2 mutation will always have an advantage, which I interpret to mean that my allele burden will increase with age.

I’m curious to understand, if ET and PV are on a continuum, where does post-ET MF fit on the continuum? Also interested to know why the SURPASS-ET study recruits high risk ET patients who didn’t respond well to HU vs being all inclusive, with invitations to ET patients who are treatment naive.

Regardless, it gives me hope and certainly incentivizes me to consider treatment over observation at an earlier age.

[EPguy in reply to jmctrek]

From the reference below your idea is on the point:

<<A sizable proportion of patients with PV achieved operational cure after 5 years’ ropeginterferon alfa-2b treatment. Lower age and lower allele burden at baseline predicted allele burden <10% at 5 years, suggesting that ropeginterferon alfa-2b should be initiated early in PV to achieve the greatest long-term benefit.>>

library.ehaweb.org/eha/2021...

The graphical chart referenced in my MPN Voice Nov 15 edit is striking to me. (reproduced here for convenience) This chart is from real data but not in any actual study as noted in that post.

I had one specialist that stated INF cannot stop allele progression. That is now provably false in my opinion based on these studies.

For ET and PV my understanding is both can progress to MF, with PV and its higher allele possibly having higher risk of such progression. But there is a category of PreMF that blends to ET, I don't have knowledge to figure that one.

Ropeg vs allele

[EPguy in reply to jmctrek]

Here is another quote on the point of not waiting:

<<Tenthly, the notion of treating these diseases only when far advanced is antithetical to treating other forms of cancer>>

ncbi.nlm.nih.gov/pmc/articl...

[jmctrek in reply to EPguy]

Highly insightful article about the sequelae of chronic inflammation in MPN patients. The arguments are strong for early treatment, though I noted the authors disclosed fundings from Novartis Oncology, which may put certain medications in a more favorable light.

[EPguy in reply to jmctrek]

Regarding inflammation the supplement N-AC is also being studied. Dr. Angela Fleischman is specialized in MPN and inflammation.

You're right about Novartis, they make Jakavi, and that is featured in the article. My Dr suggested I try it, I might, but if I would want it only at low dose with INF.

One line I found in the article I've not seen before.

<<The role of smoking in MPNs pathogenesis is further supported by a most recent study showing that a high proportion of MPNs patients actually have a smoking history>>

I don't fit that history, but it is not surprising to see.

[william-Indo]

Just keep it as another bullet in your pocket to fight this blood disorder.Use it when your treqtmwnt not working as well

[EPguy in reply to william-Indo]

Traditionally therapy has been considered to be working when blood counts are controlled. But in there is a recent focus in MPN field on reducing allele along with blood counts, partly because it is only recently well known to be possible. (see chart above Ropeg vs allele) But some specialists in the field have not joined this thinking so far, including my first Hem.

I have focused since my Dx last year on asking my Drs to consider allele counts as a therapy goal. My view is once the old HU or Phleb isn't working anymore our disease is likely already progressing, and maybe INF can proactively stop that.

[william-Indo in reply to EPguy]

I agree.

In my case, I also consider to change to INF since my HU has increase to 2000mg per day.

It is too risky

[Manouche]

« The green light will allow PharmaEssentia to venture into the United States market, and the company is preparing to make Besremi available to distributors in the U.S. in the coming 3-4 weeks, it said at an investor conference in Taipei on Monday.« focustaiwan.tw/sci-tech/202...

[EPguy in reply to Manouche]

I would guess one can ask about insurance coverage only once it's actually available to buy.