FDA Rejects Ropeginterferon alfa-2b for Polycythemia Vera

[Manouche]

« The drug development process is not always easy or quick. It consists of drug discovery, preclinical and clinical research, and FDA approval. However, sometimes developers are sent back to the drawing board or asked for more information. According to Fierce Pharma, this recently occurred for biopharmaceutical company PharmaEssentia. Although their drug ropeginterferon alfa-2b is sold in the European Union as Besremi, the FDA has rejected the approval request for use in the United States. Before the treatment can become available for patients with polycythemia vera, the FDA has requested additional information. »

patientworthy.com/2021/03/2...

[cmc_ufl]

As someone who works in pre-clinical drug research, I can tell you this kind of thing happens all the time. Since they did not ask for more data, it is likely that this will be a minor hiccup in the approval process, most likely due to the need for some things to be explained a little more by the Pharm company. Hopefully this will not delay its approval for too long!

[hunter5582]

That is certainly disappointing. This comment was noted deeper in the reference.

"Although the FDA rejected the drug’s approval, the organization did not ask for any additional clinical data. However, the FDA did ask PharmaEssentia to provide additional information and instructions around usage: both how patients would be positively impacted and how doctors or other healthcare workers could effectively administer ropeginterferon alfa-2b. Should PharmaEssentia be able to provide this, it may allow for approval at some point in the future."

Hopefully cmc_ufl is right. This is just a minor hiccup and the ball can get rolling again quickly. The last I had heard there was a delay in the FDA being able to visit the factory where the Besremi is made. Hopefully it will get straightened out sooner rather than later,

[Manouche in reply to hunter5582]

For many the fondamental question is : what is the added benefit of Besremi compared to the existing treatments ?

« Results on added benefit

No data are available for the assessment of ropeginterferon alfa-2b for the treatment of adult patients with polycythaemia vera pretreated with hydroxyurea without symptomatic enlargement of the spleen and with resistance or intolerance to hydroxyurea. This resulted in no hint of an added benefit of ropeginterferon alfa-2b in comparison with ruxolitinib. An added benefit is therefore not proven. »

iqwig.de/download/a19-72_ro...

[MPNBlog in reply to Manouche]

Added benefit for me is that I can't take Hydrea, and I have side effects from Pegasys. So I can only consider anagrelide or busulfan, or put up with the Pegasys side-effects. Besremi has much reduced side-effects due to the mono-pegylation. I do hope this can be sorted out with the FDA and is a minor hiccup as cmc-ufl says. Thanks for posting.

[hunter5582 in reply to Manouche]

That commentary is concerning, though I am a bit baffled. With RUX being the only approved PV med and the evidence for ROPEG so clear in the research - not sure why the feedback would be what it is. The benefits of IFN over RUX is pretty well established at this point. Hard to say since we do not see what was submitted to the FDA. Hope it will get sorted out ASAP.

[MPNBlog in reply to Manouche]

I just read this dossier in the link Manouche. It is quite disturbing that the company didn't submit sufficient data to show 'added benefit' of Besremi over HU (which is so much cheaper) or ruxolitinib and therefore no 'added benefit' was found in either group of patients in the trial.

p13 says: 'Based on the available data, an inferiority of ropeginterferon alfa-2b in comparison with HU cannot be excluded with regard to essential treatment goals .' If that's true it will be an impossible battle for approval. If it's not true and requires more data, I do hope the company sorts this out soon so we don't keep dreaming. PharmaEssentia is quite a relatively new medical company and this omission may be explained by their inexperience? I'm not sure about this.

Another issue is that PharmaEssentia lost their legal battle with the Austrian company that they had a licencing agreement with to produce Besremi in Europe, and they now owe a huge debt because of a breach of contract.

nera.com/news-events/press-...

143 million euros in damages ($179mill USD; $124mill GBP) plus legal costs which I understand were very high after 2 1/2 years of litigation.

They will need to recoup those funds from somewhere, meaning that Besremi will probably remain very very expensive. It will therefore be a challenge for national agencies to approve it for expenditure of public funds. Hence the need to prove benefit over other cheaper alternative medications. I am somewhat concerned about this development. Fingers crossed it gets sorted out.

[Manouche in reply to MPNBlog]

What I also find disturbing with this report -written by the German Institute for Quality and Efficiency in Healthcare (IQWiG) - is that IQWiG regularly communicates with similar organisations in other countries, such as with the National Institute for Health and Clinical Excellence (NICE) in the UK and the Haute Autorité de Santé (HAS) in France. Unfortunately, France also rejected Besremi three months ago...

has-sante.fr/upload/docs/ev...

[MPNBlog in reply to Manouche]

Hi Manouche, thanks for getting back. I didn't know France had rejected it. My school French isn't sufficient to read this, and google translate isn't coming up. I'll keep trying to translate it. Best wishes.

[jmctrek]

Will keep hoping for progress, despite this setback. Thanks for the update.

[dhenry]

The criteria for deciding "non-inferiority" of Besremi vs. HU seems to be different in France vs. the data points evaluated by the FDA. The French agency based their decision on comparative data at 12 months which was virtually the same for both drugs. At 36 months, Besremi shows better results than HU. So, I guess the decision rests on how the data is evaluated.

[Manouche in reply to dhenry]

Same story with the German agency:

“Based on the incomplete data presented by the company, an added benefit of ropeginterferon alfa-2b versus the ACT “HU” has not been proven in treatment-naive patients or in patients pretreated with HU with polycythaemia vera without symptomatic enlargement of the spleen and without resistance or intolerance to HU.”

iqwig.de/download/a19-72_ro...

[EPguy in reply to Manouche]

If France or Germany used only 12 months, most IFN therapies won't look so good vs HU tolerant patients. The EU approved it in 2019 as 1st line for PV based on the 3 year Proud-PV study, and the 5 year Continuation PV study is very compelling. I don't know how Europe works, I would think EU approval should be enough.

For the US I posted recently about the progress. FDA's March rejection was over details in the use instructions, and more substantially bec FDA could not get to Taiwan for factory inspection. They accepted a 2nd submission from the company and 2 FDA guys are there right now in quarantine for a very rare covid era overseas inspection. (based on a Chinese language discussion site in Taiwan)

They said any bad results should be known next few weeks, if any. There's also two retired FDA agents working for the company over there to advise and be sure the factory operations are in order. It's supposed to have FDA action Nov 13.

Most of us are quite clear on benefits of INF. See the new thread "Long term INF results"

Incidentally on the PharmaEssentia site they recently added a pre-clinical "Next Generation P1101 (Ropeg) for MPN. Quite curious what's new.

[Manouche in reply to EPguy]

P1101 is another designation for ropeginterferon alpha 2b.

clinicaltrials.gov/ct2/show...

[EPguy in reply to Manouche]

The "Next Generations of P1101" (RopegInterforen) is listed their web site as if it is an all new drug vs regular P1101 (RopegInterferon). See image here, the short green line. Must be something good. It might be possible to find out on the Taiwan web sites I've been checking.

PharmEss

[Manouche in reply to EPguy]

It would be great. Do you have any link to share?

[EPguy in reply to Manouche]

The chart above is from PharmaEssentia US site

pharmaessentia.com/focus-mp...

The absolute latest stuff is in Taiwan.

It's a real rabbit hole of mystery getting into the Taiwan sites. I select Chinese

language in Google, I have a rudimentary understanding of a very few words, and start at it.

If there are any readers here of traditional Chinese that would be great.

Here is a link to the company's Taiwan site

pharmaessentia-tpe.com/tw/p...

Buried in there is the item in quotes below, the line re 09/20 is of our interest. I added the *** But its link is dead.

I can't find the original article I posted here nor in Taiwan, it's in MPN voice somewhere, reproduced at bottom here for background on this 09/20 announcement. This was from udn.com, but no luck there today.

If you want to go at it, they often use the number 6446 to describe the company in Taiwan.

-------------------------

" Newspaper dynamics

latest news

Related reports

Event message

09/21 The company's first phase clinical trial plan of KX01 for solar keratosis (AK) in Japan has been approved by Japan PMDA

***09/20 US Drug Certificate-FDA will conduct factory inspections this week***

09/06 Yaohua Pharmaceutical's August 2021 Revenue Report

09/01 U.S. Medicinal Products-FDA notified the timeline of coming to Taiwan for factory inspection

08/29 Yaohua Pharmaceutical Co., Ltd. statement"

--------------------

---------------------

Sept 08 2021

Since the outbreak of the epidemic, the US Food and Drug Administration (FDA) has greatly reduced the number of overseas factory inspections. On the 25th of last month, it reiterated that it would not go abroad unless it is mission critical, which caused delays in the listing of many pharmaceutical companies around the world in the United States. Yaohuayao (6446) has recently broken the convention. Two FDA officials arrived in Taiwan last Saturday (4th) and are expected to conduct factory inspections on Yaohuayao at the end of September. The company aims to obtain US marketing approval for the new drug in November.

FDA officials said last month that from March 2020 to March this year after the outbreak, the FDA conducted a total of 821 mission-critical inspections, of which only 29 were overseas. According to official data, before the outbreak, the FDA conducted annual inspections at home and abroad. The number of factory inspections is more than 1,600.

Huang Zhenggu, general manager of Yaohua Pharmaceutical, confirmed yesterday (7) that after the two FDA officials arrived in Taiwan last Saturday, they are currently under quarantine at an epidemic prevention hotel. Two weeks later, they will go to Yaohua Yao’s Taichung factory to inspect the factory. The entire inspection process is estimated to be one week. Time, the results will be notified on the last day of the factory inspection. If it goes well, Yaohuayao will be able to announce on the same day whether there are no major defects.

Huayao has developed a new type of interferon P1101. In recent years, it has actively applied for marketing authorization in the United States for polycythemia vera. However, in March this year, it received an FDA request for a supplement, suggesting to modify the "Patient Use and Operation Instructions" for the syringe in the imitation list. Test; until June 4, when the FDA notified again, the review can be completed on November 13 this year.

Huang Zhenggu stated that the treatment project PV of the new drug that Huayao applied for listing is a rare disease, which belongs to the unmet medical need (Unmet Medical Need) and meets the FDA's "critical mission" qualification. Therefore, the FDA sent special personnel to Taiwan to inspect the factory.

Huang Zhenggu explained that the Taichung plant of Yaohua Pharmaceutical is a P1101 API manufacturer. In the past, it has passed the EU EMA twice and the Taiwan Food and Drug Administration conducted two factory inspections before listing. In order to apply for the listing of P1101 in the United States, the FDA has completed the inspection of the P1101 filling foundry. The US subsidiary of Yaohuayao has also passed the FDA’s GLP certification. This time FDA officials came to Taiwan to inspect the factory, which can be said to have obtained the US drug certificate. For the last hurdle, Yaohuayao also hired two retired former FDA officials to come to Taiwan to perform the exercise at the Taichung factory.

[EPguy in reply to Manouche]

I just got the Taiwan site link to work, see below. I'd guess "sand table" is a simulation.

pharmaessentia--tpe-com.tra...

---------------

US Drug Certificate-FDA will conduct factory inspections this week

2021.09.20

Back to the previous page

FDA officials have completed the 14-day quarantine of the epidemic prevention hotel, and the body is healthy and everything is normal. The PCR test on the 12th day was negative.

The officials have already stayed in the Taichung Hotel according to the original planned schedule, and their actions will be in accordance with the regulations of the command center and comply with the 7-day self-management.

As usual, officials have previously provided a list of key documents required for factory inspections, so that we have time to make complete preparations.

A factory inspection will be carried out this week.

The company has been fully prepared, and has previously arranged for former FDA officials and consultants to visit the Taichung factory for guidance and conduct multiple sand table deductions, and everything is ready.