Member Info for Alquemie

Quick visit to the BB before beer o'clock (more accurately, gin o'clock, as I'm off to a private tasting at one of London's hipster distilleries), some interesting questions and responses today. The Macao submission is most probably at the HK distributor's request. It's a relatively short and straightforward process and can be cheaply extracted from the more comprehensive HK dossier, so no biggie to keep the distributor happy. If a (legal or grey) "backdoor" into China for Rx products exists, the Macao Drug Office would need to put in bigger doors to accommodate the hundreds of Indian companies that have been locked out by the CFDA regulations. Sorry if I've burst any bubbles. As to the "new" drug in the pipeline, the concept is a rework of Invicorp, an ancient injectable ED treatment that Plethora acquired rights to about a decade ago. Invicorp has a somewhat spotty approval history, although a quick Google indicates that it's recently been resurrected by some Swedish company. The FDA had problems over the safety of one of the actives in the product, although I believe that these were resolved to a point where PLE planned (but did not initiate) a US registration study. I'll sidestep the list of regulatory and technical objections and simply offer a considered opinion that topical formulation might be on the fanciful side, as is submission through an 505(b)(2) route. And, to repeat, launch price will be at the highest sustainable price that Recordati believes the product will command, likely benchmarked on dapoxetine. Pricing will be set nationally to take account of the differences in out of pocket cost (pharmacy mark up, private script and consultation contribution cost) and the "North-South" divide. Margins at launch are always much lower than the average across the product lifecycle, presence being more critical the profit in years 1-2 from launch. Gin....is calling....a Siren's call....

Breakdown, based on RP disclosure and the SPA 008 protocol, 8-10 months to PRO clinical validation 12m to final pivotal study report 4-6 months to NDA submission 12 month FDA review (including pre-submission review) Up to another 12m for coding, discount negotiation, PBM review and formulary inclusion (although marketing at free pricing might be possible) The odd month or so might be shaved off, but I'd still plan on 4 years from FDA acceptance of the PRO and study initiation.

No commitment since the Marketing Authorisation will be transferred to Recordati (the amended agreement is essentially a divestment of the product in Europe). As for US marketing, probably another four years or so before you have to worry about it.

For once, I don't believe even RP can eff up the launch. The larger batch size is needed to improve margins over the product life cycle but will not dictate launch price. Product stocks at launch need only cover sampling and requirements can be met by one or at most two of the approved smaller batch size (with plenty left over). If PSNW have worked all of the bugs out, I'd expect a Type IA variation to be granted sometime in April at which point Recordati can commission larger batch/higher margin runs. If the worst comes to the worst and 12 month real time data is necessary to set shelf life, smaller batch runs can easily meet requirements..

Well, I did say March for launch, and I'll stick with my prediction of a Recordati press release to that effect on or close to the 1st to coincide with the ISSM session. Could even be a little lift from the announcement. The change in the HK timeline indicates that the submission will now include the manufacturing data from the larger batch size. No biggie with respect to complicating the process, but HK requires real time stability data (along with six month accelerated data at higher temp and humidity). Assuming all goes to plan with the larger batch size and that HK still keeps to a 5-6 month response from submission, grant could be October 2019 (so 24 months rather than 18).

Pomander, it's also partly timing. I doubt that Recordati have put any effort into launch preparation until very recently, and with blue box issues, collateral preparation and training, launch in five months time is reasonable. Conferences/congresses make good launch platforms as news makes its way into specialist and more general medical communication channels. And since there is no recent clinical data on Fortacin for presentation, association with a general discussion on PE is the next best thing.

Pomander, agreed, 3rd October is the effective date, euros to follow at some point. I think the statement regarding MA transfer is straightforward enough, being unavoidable as a consequence of Brexit, It was the reference to MA transfer being in the original agreement that struck me as a strange thing not to disclose (hence putting it down to yet more sloppy proofreading on RP's part). I was wondering whether anyone would find the hint that March 1st will be the Big Day, but will share and you can leap to your own conclusion: Check the 2-4pm slot. https://issmessm2018.org/thursday-march-1-2018 Recordati are listed as a sponsor/exhibitor, I believe that this is the first ISSM meeting they've sponsored. I could be wrong, but conferences are commonly used as a platform for product announcement and the debate topic strikes me as a bit of a giveaway.

Certainly nothing obvious in the 3rd October announcement with respect to conditions, so perhaps for once the cheque truly is in the post. There's some strangeness in the second para on page 5 in that it's stated that the Previous Agreement provided for transfer of the MA to Recordati on payment of the �6m variation milestone Since this has never been disclosed before, I'm assuming it's a drafting error. Transfer of the MA as provided in the Restated Agreement is inevitable due to Brexit (the MA holder needs to be located in a member state), although being picky, it's no longer a licence agreement but a divestment. There's some modest financial benefit to RP in that they will no longer be responsible for PV and risk management and other MA maintenance costs. On the other hand, RP no longer have automatic right of return should Recordati decide that Fortacin is not worth the effort, nor access to study data developed by Recordati and the right to exploit such data. But, given their complete dependence on Recordati and limited control as licensor, I'd say that they are no worse of. I'm not a betting man, but I'd risk a modest wager that announcement of the European launch will be made by Recordati on, or close to, 1st March 2018, based on public domain disclosure (from a fairly obvious source).

Dougie999, the shouty NIGELFOREST makes a valid point in that, given RP's history, an absence of information is in itself unremarkable, although why a company would not disclose that the most single most important element of a US pivotal study has received the nod from the FDA beggars belief. You might try emailing the following question to Mr Gibson: Could you please confirm that the PEBQ is acceptable to the FDA as a valid and appropriate means of capturing subjective endpoints under SPA PE-008? You could push your luck by also enquiring as to when first dosing might be expected.

Dougie999, the interim report states "Q3 2017" so the meeting should have already taken place. I'm assuming by "new entity" you mean as in "new to the FDA"- hardly the case, since PLE ,then Shionogi and now RP would have been in discussion with the FDA since long before the US pivotal study (so for at least a decade). As a fixed dose formulation of two long approved (and generic) actives, you can reasonably assume that Fortacin is "low risk", although regulators take a conceptually different view on the risk presented by a pharmaceutical product, with the onus being on the developer to establish absence of risk, no matter how theoretical that risk might be. In the case of Fortacin, there is the complication that there is potential for transfer to the partner, so the level of risk presented, no matter how small, needs to be established. Opinion only, but the likeliest cause for FDA concern is that there is no chronic use safety data. They may also require strong justification for the inclusion of prilocaine, specifically its contribution as an active. That the EMA took a pragmatic view to the risk presented by Fortacin is encouraging, but it's certainly not predictive of the FDA view. As to "beneficial" treatment, the FDA does not exist to actively prevent drug approval but assists to the limits allowed by law. The difficulty in the case of Fortacin (or whatever the US name will be) is that there is no established measure of "distress" or regulatory agreement on the "symptoms" of PE. The FDA have advised RP that if they develop a validated means of establishing symptomatic relief in PE, then the product is potentially approvable with "relief of PE symptoms" as a label claim. The catch is that RP needs to develop, test and then convince the FDA that the selected means of measurement is valid, something that has not been done to date. That's not to say it's impossible, but neither should it be viewed as a slam-dunk.

Pomander, my estimate was 8 months to Part 1 read out, then 13 months to Part 2 read out (RP's estimate), then 14 months for filing, acceptance and approval, making 35 months from initiation. However, I was assuming the PRO validation study would involve 50-80 subjects, but, as a newly minted and untested PRO, the statistics would really have to shine, possibly meaning more subjects and a longer time to Part 1 read out. The non-dosing PRO study was listed on Centrewatch (a clinical trials database) in November 2015 with recruitment at a single centre in South Florida (South Florida Medical Research, Aventura Study, FL) and is no longer listed (so either completed or terminated). The Part 1 dosing PRO validation study is part of the 008 SPA study and, if registered,would appear on the NIH Clinical Trials database or the WHO ICTRP database (just looked- nada). As to the FDA meeting, yes, it's by no means a negative in the context of moving the 008 study forward. However, given that the SPA study was claimed to have been accepted at the end of 2014, that the PRO submission was eventually made five months after the initial RP estimate, that no announcement regarding PRO acceptance by the FDA has been made (by no means a minor achievement), that there was a radical change in study design sometime after March 2016, and that the study still remains to be registered, the need for a face to face at this point suggests to me that there are still real issues to be resolved. I've commented on this before, but the EMA and FDA perspective on PE drug approval is very different. I can address the specifics at length, but it's well to remember that the FDA has never approved a PE drug and even 13 years after the last PE NDA submission, has never developed a framework to expedite approval. The FDA is, from personal experience, generally more accommodating than inflexible, but is still on the learning curve when it comes to matching PE study outcomes with label claims.

Dougie999, there would have been a clinical, but non-dosing study to develop the PRO questionnaire ahead of submission to the FDA in March 2016. The next step is validation in treated subjects, but no corresponding clinical study has been registered, so safe to say that no study is yet underway.

Pomander,the timeframe and structure is RP's own for a two parter registration study, I've only added 8 months for setup, recruitment and review and assuming the study gets under way early next year. According to RP, 13 months to Part 2 readout from Part 1, then further 14 months to approval (27 months from first read out). I'm saying closer to 35 months from a standing start. RP's "Q4 2019" approval estimate was predicated on a start by mid-2017. It's the scheduled Q4 FDA meeting that's making me think that there are still regulatory issues to be resolved, although RP might also have had to drag their feet on study initiation due to a shortage of readies.

Pomander, I'm factoring in the delay in study initiation. Assuming that there are no outstanding FDA issues around PRO content or validation or the combination product rule, and study initiation very early 2018, 21 months takes us to Q4 2019, data packaging and pre-submission review would start the PDUFA clock early 2020, with approval before year end. Allowing for coding, payer discount negotiation and PBM formulary inclusion, could be up to another year before sales begin.

Dougie999, the differences between the March 2016 and April 2017 US study and submission timelines suggests to me that, contrary to RP�s expectation, the FDA indicated that validation of the PRO instrument in a dosing study is necessary. I believe that the proposed 008 study is a two-parter, with the Part 1 read-out relating to PRO validation and Part 2 providing the subjective endpoint data necessary for registration. The April 2017 presentation states 13 months between read-outs, which seems reasonable, and allowing for setup and recruitment, I�d say at least 21 months all in. Assuming kick off in early 2018, FDA submission might be possible around end 2019, with approval late 2020, perhaps add on an extra quarter for submission delay.

Pomander- check the registration date, coming up for a decade ago. This was the US arm of the pivotal study completed in 2009.

Aaah, now I can see where the confusion arises! By "study registration", I was referring to clinical study registration, which would indicate that all is good with the PRO instrument. Apologies for that. As to abandoning the US submission, it's not inevitable providing appropriate endpoints and the means of capturing them can be agreed with the US. Difficult yes, but certainly not impossible. However, there is precedent for throwing in the towel with regard to US pivotal PE studies- J&J, Furieux, Menarini and Vyrix come to mind, and of course Sciele.

More than welcome, but sadly, while there are expedited routes for drugs intended for cancer and rare diseases, knob sprays and other lifestyle products have to get in line. The US registration study timeline might become clearer following the next FDA meeting, but even with a green light, I'd still estimate mid-2020 for approval.

Sorry, Pomander...now you are confusing me, as I could not recall making reference to registration nor case number! To repeat, development of a PRO or other COA measure is not fixed with respect to timeline or as to what might satisfy the FDA. The last agreed study design hinges on demonstration of the PEBQ as an appropriate measure of subjective change. Without a nod from the FDA's COA office that the PEBQ constitutes a robust and acceptable instrument, there is no point in commencing the study. True, shortage of cash and manufacturing issues might have forced RP to soft pedal on progressing the US, but given how important securing agreement that a PRO is indeed a valid means of measuring outcome in PE, where only one, long defunct,company has ever claimed to make the FDA smile, and absence of acceptable outcomes and a means of capturing them scuppered J&J/Furieux's pursuit of dapoxetine approval in the US, it's straining credulity to think that they would not shout the news out loud. The PEBQ exists in so much as, being copyrighted, it's claimed as part of PLE's intellectual property, but having asked around, to the best of my knowledge it has yet to be used as part of any academic or commercially sponsored study. As to the problem, no PRO, no registration study. Options are to either go around the houses again with an amended PRO (adding 1 or 2 years?) or abandon US submission. Overview of the COA process at link below: https://www.fda.gov/drugs/developmentapprovalprocess/drugdevelopmenttoolsqualificationprogram/ucm284077.htm

Pomander, happy to recap on what's in the public domain. The PRO (premature ejaculation bothersomeness questionnairre- PEBQ) was developed by PLE to meet the essential FDA requirement for a validated measure of subjective benefit. A (non-publicised) clinical, but non-dosing study with the objective of fine-tuning the PEBQ. was initiated at a single US centre (South Florida) in November 2015. PLE have stated that the PEBQ was submitted to the FDA in March 2016. PROs are evaluated under the Clinical Outcome Assessment Qualification Program (COA), which is a dialog/advocacy based process and as such,there in no registration or case number (as is assigned with IND or NDA applications). Companies may, or may not, elect to disclose that some form of COA measure is under discussion. We know that the FDA have agreed that a study using a validated PRO is sufficient for grant of marketing authorisation: the big unknown is whether the FDA agree that the PEBQ is sufficiently robust to capture the data across all of the subjective measures required to support labelling claims and hence to proceed to clinical validation of the PEBQ. Again, I'm assuming that this is the main topic of conversation at the next FDA meeting, along with meeting fixed-dose combination product requirements.