Member Info for Alquemie

Monty, I agree that the article does contain inaccuracies.

Mr Gibson somewhat inopportunely states that 23,500 prescriptions have been filled, where this is actually sales to wholesalers since, as an non-reimbursed product, it's not possible to determine the actual number of filled scripts.

That sales to wholesalers were given as 20,975 units for the "first half" (end June, possibly July), indicates that only 2,535 units have been purchased in the past six months or so. I do wonder how much of the first tranche of purchased units is still sitting on warehouse pallets and heading towards expiry.

Wholesalers are clearly not buying into the story, which is turn indicates that demand from retail pharmacies is barely registering in what is the world's most developed market for PE treatment. This clarifies why Recordati is not expanding marketing to other territories even at low incremental cost.

At a blended wholesale price of Euro 23.8 per unit and assuming no rebates or chargebacks, I make RP's take just under Euro 84,000.

So that's the next office party covered then.

Monty, not sure how I can make this any clearer

The EMA accepted that the patient benefit measures were appropriate and demonstrated that increased IELT correlated with overall benefit. The FDA does not accept that the same measures are sufficiently validated to support a label claim, hence the need for validation of a new concept of benefit.

The complexity is in establishing that the concept is appropriate to the condition/patient group and can be reliably measured, and not in the mechanics of measurement per se (the measures included in the EMA submission evolved over years, with dapoxetine studies supplying much of the data).

There's no question that a relationship between increase in IELT and benefit has not been established, but my point was that the delta over baseline is not critical, providing it's sufficient to result in significant improvement in the domain under consideration. In short, in the context of validation, the FDA will not give a flying one over how many minutes on the stopwatch providing there's a measurable reduction in distress.

To repeat, the risk is not in achieving the same levels in IELT improvement observed in other studies but in the COA office's interpretation of "bother" related data. History suggests that the ongoing Phase II might best be considered a pilot study and that another crank of the handle will be needed. Roll on Q2 2020.

The Italian, I'm sure that they are planning for success. My back of envelope stats are certainly not predictive of failure, but do indicate that bigger numbers would improve the odds, as would a longer treatment period.

But, while you can maximise the chance of generating desired objective endpoint data, the big unknown is always how subjects will individually perceive and quantify improvement in their condition, whether your PRO instrument is adequate in the artificial situation of a clinical study or indeed whether the concepts you are attempting to define and measure are relevant to the "patient experience".

The other unknown is how the FDA will consider the data within the context of the revamped COA qualification programme (and what the timeline might be).

Monty, it's not a question of "not working" but of satisfying a different set of regulatory criteria to support a label claim.

Mere demonstration of an increase in IELT is insufficient for approval, unless it can be linked to measurable patient benefit ("pleasure" is not a concept that regulators recognise). In the US, over the counter delay sprays can legally sport a "helps in the prevention of premature ejaculation" label claim, hence the need for differentiation through an approvable "reduces the distress caused by PE" claim.

The EMA was happy to accept that the methodology used to collect and quantify subjective benefit was adequate: the FDA is of a different opinion, hence the requirement for a validated patient reported outcome which links IELT with a statistically significant reduction in "bother", along with definition of what patients and partners feel contributes to "bother". The quantum of improvement in IELT is not in itself critical, providing the difference over placebo is sufficient to ring all the bells with respect to subjective reduction in distress.

You are missing a piece of history. When PLE kicked off PSD502 development, there was no accepted definition of PE. PLE, along with J&J, sponsored development of the now accepted ISSM definition of almost always a minute or under. The pivotal studies were undertaken in men with an under a minute baseline with the hope that the FDA would accept the ISSM definition in an NDA submission.

The gamble in the US is not that PSD502 will not show a significant treatment effect with respect to IELT, but that a relationship between improvement and reduction in distress cannot be satisfactorily established. That the reduction in distress over placebo observed in both pivotal studies was modest but still statistically significant is of some comfort, albeit after a much longer treatment period.

Since the FDA have never approved a PE treatment or even accepted a means of measuring distress, it's not easy to estimate the odds of success, although first time failure would not automatically rule out another attempt. But you can count on an outbreak of squeaky bum syndrome around the middle of 2020 as the FDA COA boys and girls dissect the data.

I'm not suggesting that RP are flying blind on this, but the purpose of study is not to determine drug efficacy as such, but to establish that treatment results in a measurable improvement in a novel measure of distress ("bother") over placebo, and equally importantly, that the questionnaire is appropriate and robust in the population under test.

We know that the FDA took over 15 months to agree that the questionnaire was suitable for clinical validation and the protocol does read as though there have been FDA-suggested add-ins (the inclusion of psychometric testing, for example).

However, validation of a novel study concept is much more touchy-feely than simply hitting the primary outcome and, since the whole clinical outcomes assessment process is itself a work in progress, it's reasonable to suppose that the FDA may not be satisfied with all of the data generated from this relatively small study or that it's not sufficient to support a label claim.

Also worth remembering that the FDA did not accept the endpoints/methodology used in the PSD502 studies all those years ago nor has any other company successfully secured FDA agreement with respect to establishing label claims. Not an issue in China or other Asian territories as most have already approved dapoxetine with established measures of distress.

@The Italian,

Let me qualify the "shoestring" comment, which was made in reference to the study size and design (not budget).

Bear in mind that the objective is to validate an untested measure of effect (reduction of degree of "bother") and to establish that the questionnaire can reliably capture this subjective measure. Such instruments are normally validated through an iterative process, starting with a relatively large number of subjects, not necessarily in the context of a clinical study.

Extrapolating from historical improvement rates from both treatment and placebo, 50 subjects per group (with only a one month baseline and treatment period) strikes me as being underpowered, particularly as the outcome is critical for progress. The safety shot would have been to have undertaken validation in stages and across two or more studies, or otherwise up the numbers and double the treatment period to two months.

That said, the primary outcome is only a single uptick in improvement in the treatment over placebo group. Whether this will be enough to satisfy the FDA COA office is anybody's guess.

Multiple trial sites are the norm in clinical studies and essential when, as in PE, patient presentation and referral rates are minuscule, and you need to secure both subject and partner sign up. A UK company which is trialing a novel PE drug used ten sites for a similarly sized Phase II study (and over 25 recruitment sites in the US for a 220 subject dose response study).

Quantum reflects OEP's limited reach outside of Taiwan (and Taiwan itself being awash with over the counter delay sprays and "performance enhancing" traditional Chinese medicines, but the deal is indeed heavily risk averse.

Royalty reduction on generic entry is standard in licensing agreements (other triggers being term, end of market exclusivity or patent expiry). Degree of royalty reduction can be tied to actual impact on originator product sales or number of generic competitors.

Monty, more than happy to congratulate RP- the last couple of decades have taught me that there's no such thing as an easy licensing transaction.

I've have dealings with Orient Europharma in several projects areas (mainly oncology) and still in touch with their old BD team. Business model is to acquire rights to end of life/ minor Western products from companies with no presence in Taiwan and the smaller Asian countries.

Plus point is that they are experienced in imported drug registration. Unless the regs have changed recently, I'd expect the bridging study to be no more than a small Pk and metabolite study, so 2020-2021 local approval entirely possible. On the negative side, ex-Taiwan pharma presence is weak (largely distribution operation, not marketing).

Deal structure is what I would expect from OEP: heavily backloaded and minimal upfront and milestones (since they carry all regulatory costs). Having said that, a potential sub $1m in commercial milestones, with annual net sales triggers (not aggregate sales) triggers suggests a very modest expectation. The China deal is similarly risk-averse/low expectation, having annual net sales triggers rather than aggregates.

But fair play, getting anything out of an antique data package, with no patent protection or market exclusivity is a result.

Hmm.... what happened to the hard returns in my post?

Curiouser and curiouser....Uptake must be very low indeed if Plan B is to launch in a country with no established sales operation, a blanket lack of prescriber endorsement and a presumed reliance on distance prescribing.I wouldn't describe the UK a being a "mature market" with respect to PE (ED, yes, PE no), with dapoxetine not being marketed here until five years after Germany and Italy. While it doesn't capture off label or private prescribing, the lack of NHS interest in PE treatment is illustrated by dapoxetine expenditure, totalling £192,000 in 2017 (England only, never endorsed in Scotland and Wales). Fortacin NHS expenditure in the same period was on 3 cans to a total of £135. From past conversations with two of the largest online pharmacies, I estimate annual dapoxetine distance prescribing to be worth less than £100,000 (caveat- I've never been able to verify this). The UK male population has been studied to death with regards to PE prevalence and treatment-seeking, both being similar to figures for he major European countries. With 20.5m men (18-64) in the UK, I make that 172,000 men on any Rx, say 26,000 at a peak Fortacin uptake of 15%. . At a generous average of 3 units per punter per year, outsourcing (£20 wholesale, 60% margin) yields net revenue of £0.93m, while owning the distance selling channel (£50 retail, 60% margin) might yield a tastier £2.3m. But still small beer unless you can capture all of the treatment-seeking population, or double treatment-seeking or develop the fabled (imaginary?) "lifestyle" market. And five, maybe ten years to peak?There may be a rationale for aiming for launch before Brexit. I can't see how this would complicate launch per se, but might reflect the possibility that UK manufactured products may no be longer be accepted in Europe without revalidation (many pharmas which manufacture in the UK have secured testing facilities in mainland Europe), and/or that PSNW will require recertification at some point as an EU acceptable manufacturer, with distribution being at least temporarily restricted to the UK. Certainly interesting to see whether Recordati keep up their urologist-focused promotion in the core European territories or whether this is the marks start of walking backwards from Fortacin (and perhaps the urology franchise in general).

All very curious....

Fortacin has been listed in the Greek and Romanian national formularies for months, and, as in the other territories, with a urology sales force already in place, it could have been launched at very modest cost. Minuscule sales have never prevented the promotion of other portfolio products (Vitaros, Kentera, Urispas and other "for show" details).

And for a promotion sensitive product such as Fortacin, postponing launch in countries with a field force in place while perhaps launching in the the hardest market of all (no sales presence, no urology portfolio, NHS blacklisting, lowest per capita specialist representation), with the only viable option being remote prescribing and supply either directly or through a third-party), marks a strange shift in strategy.

Complete speculation on my part, but I'm aware that Recordati have recently received approval for a Urorec generic in the EU and while they have indicated an expectation of continued modest growth (largely in ex-core territories), I'm wondering whether they are looking to close out the urology franchise (at least in developed markets) early to focus on higher margin specialities.

Might be more than three years, as I've assumed an almost immediate turnaround from the COA division, no Type C meeting request and minimal delay in pivotal study site set-up. Possibly safer to add another 6-12 months.

I've assumed a single pivotal study, although as a new indication, the FDA might require two studies. Back of envelope stats calculation gives a minimum of 250-300 subject (couples) recruitment, but could be greater depending on the robustness of the PEBEQ instrument. I'd also expect a Type B meeting before NDA submission, which might add on another three months, and I've made no allowance for further clinical input (combination justification, any additional extended dosing tox,or for bridging studies if change in manufacture).

As to the BOD report card, since they are incapable of making a credible estimate of the PDUFA date, negligence and incompetence are reasonable accusations, as is "misleading", whether by design or not.

Looking back through my diligence notes, since end 2014, the anticipated US PDUFA date/launch has been variously stated as Q1 2017, Q2 2018, Q1 2019, Q4 2019, the last from the October 2017 company presentation. Approval timelines do change, but it takes talent to be so consistently wrong.

I've been transparent in my timeline estimate- why not ask the BOD to share their own assumptions?

I'm stating that a PDUFA date in 2021 is a nonsense and not assigning a reason or motive.

As for " a little tight", given timeline allows only 12 months for the pivotal study and NDA submission, potential for a spot in the Guinness Book of Records.

And speaking of the black stuff, it's well past beer o'clock.

Unfortunately not. As a Class 5 imported drug never previously trialled in China, local clinical evaluation is mandatory.

The unknown is whether the NMPA will accept that the existing clinical study dossier is sufficient for IND registration and CTA acceptance for at least one Pk study and subsequent pivotal study, or whether an additional study(ies) are required for IND and CTA acceptance.

I'd expect any additional IND-enabling study to be modest, possibly only a repeat of the extended dosing and drug metabolite studies in healthy Chinese subjects.

2021? Only if time travel is involved....

The validation study completion date is March 2020. COA review is open-ended, but assuming a quick turnaround, the pivotal study would not commence until start of 2021. Statistics dictate minimum recruitment of 200-300 couples (2:1 randomisation, one month baseline assessment, three months on treatment, one to three month follow-up) and benchmarking against the previous pivotal studies, let's say 30 months to dossier completion.

NDA submission Q3 2023, acceptance and PDUFA date before year end, earliest approval Q3/Q4 2024.

@MattD78, experience has taught me to be wary of "industry averages" with respect to approval/registration timelines, but I will volunteer qualified estimates.

The Latin American countries do not require local clinical trial data for registration, at least for products previously approved in the EU and US. Assuming no issues over dossier content, GMP manufacture (Brazil and Mexico may undertake site inspection), time from dossier acceptance to authorisation could be: Brazil (24 to 30 months); Mexico (12 to 18 months), and Argentina (12-18 months, possibly closer to 12 months).

Saudi Arabia- 12-18 months, possibly closer to 12 months.

Countries other than China which require local clinical trial data (unless previously included in a multinational study, or where ethnicity was sufficiently represented in registration studies) include Russia (mandatory Phase III); South Korea, and Taiwan (pharmacokinetic and other bridging studies).

Taiwan does accept data from other Asian study populations and registration might be possible off the back of Chinese study data (although that's several years away); South Korea requires ethnic population study data, study size on a case by case basis. I'd estimate 36 months for both from dossier submission with local bridging studies.

Russia has a glacial review process, and including the mandatory clinical study, you could be looking at 4-5 years.

Above estimates come with a strong health warning in that they assume smooth sailing, with no extensive questions from regulatory authorities or GMP certification issues. Dossier requirements are increasingly more similar than different between jurisdictions, but allowing for translation and pre-submission review, I'd add six months to each timeline from the date of local distributor/agent appointment.

Thanks- didn't thing I'd imagined it. Not like JG to get something wrong...

In fairness, he may have assumed that the study being listed on the centre website indicated "recruitment". Protocol change is minor, so only consequence is delay, although December in New York State is not the best of times to begin a clinical study.

Apologies if I have this wrong, but I recall someone (possibly The Italian) posting a response from JG a few weeks back to the effect that study recruitment had commenced.

As of the last update of 30th November, status remains as "not yet recruiting", with a revised start in December 2018 and anticipated completion in March 2020 (previously October 2019). There's a change in the secondary study outcomes so the delay may have been due to no more than protocol revision.

http://tinyurl.com/yd5e9snv

Prof- I did a double take on reading that as well: "net receipts" and "net sales" are one and the same thing. And while it's a highly backloaded agreement, a base royalty of 37.5% is hardly credible.

The "Exclusivity" section mentions sub-licensees and I suspect that there is a line missing after "25% net receipts" to the effect that this applies to sub-licensees/affiliate companies within the WB or Fosun group (hence the use of "receipts" rather than "sales").

First, all credit to RP.

Concluding a marketing agreement (particularly for China) is never a walkover, and while the headline value is modest, there are no regulatory and development costs to impact on cash flow.

Difficult to benchmark the approval timeline since imported drug approvals under more recent regulation have been confined to fast-tracked essential drugs (cancer, orphan, antiviral). That WB have included upfront and milestone refunds dependent on the NMPA decision and subsequent clinical development requirements indicates that even the Chinese are unsure as to how this is going to play.

My estimate would be allow nine months for translation, submission preparation, local analysis of three GMP batches (finished product) until the IND/CTA decision, then a pharmacokinetic study (less than 20 subjects), with possibly a repeat of the extended exposure studies (in Chinese subjects, again small numbers), then onto a pivotal study (200-300 couples). With the approval of dapoxetine in China a few years back, there's already an established regulatory path and accepted study endpoints which should simplify the process. The Fortacin preclinical work is a bit whiskery, but any repeat/updated work could be completed in parallel with clinical development.

On paper, 36 months looks to be a push, but on the assumption that WB can expedite analysis and clinical trial set up through their existing network , it's not inconceivable that approval could be obtained well within 60 months. If I was building a valuation model for this, I'd use 48 months as my base case for now.