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Tex Mex

UniQure N.V. (NASDAQ:QURE) is an end of the week mover in the biotechnology space this week. The company just updated markets as to the progress of one of its lead development assets, a drug called AMT-061, along its pathway towards commercialization.

The situation is a pretty unusual one.

uniQure has been developing a drug called AMT-060 in a target indication of hemophilia and the drug had picked up breakthrough designation in the US as well as a comparable designation in Europe during its early stages of development. However, as per data reported last year, there were some signs that it might not be able to compete with another drug that is being developed in the space, a gene therapy asset that is at pretty much exactly the same stage of development as that of uniQure and is being developed by Spark Therapeutics Inc (NASDAQ:ONCE).

During 2017 to date, therefore, markets have been pretty subdued as relates to uniQure given that it looked as though, even if the company could get AMT-060 to market at the same time as Spark, it wouldn’t be able to compete with the latter based on available efficacy data.

That now looks as though it has all changed, however.

Late this week, uniQure announced that it is ditching AMT-060 in favor of an alternative hemophilia drug, the above-mentioned AMT-061. On a molecular level, the two drugs are pretty much exactly the same, with one exception – two nucleotide substitutions in the coding sequence for factor IX (FIX). In patients with hemophilia, FIX action is key to treatment and, with AMT-061, uniQure thinks that it can go after the same condition, with an almost exactly the same drug, but can dramatically improve on efficacy based on the just mentioned coding sequence alteration.

As per reports, the gene variant, called FIX-Padua, has shown an eight-to-nine-fold increase in FIX activity compared to wild-type FIX protein in preclinical testing.

Of course, in a normal situation, if a company was to drop its lead development asset in favor of an alternative version, however similar, said alternative would have to essentially restart its own pathway towards commercialization. In this instance, however, that’s not the case.

Alongside the company’s reporting of its switching out of its lead candidate, uniQure has also suggested that regulatory agencies in both the US and Europe are willing to accept the switch as part of the same development pathway and, just as importantly, that the program will maintain its breakthrough designation.

What this means, then, is that uniQure has set itself up for an intriguing battle with Spark near term. Both companies are poised to advance their respective assets into a pivotal trial and both companies are doing so under the guise of breakthrough designation.

Whereas once Spark was assumed to be the outright winner if the two assets were put head-to-head, the fact that uniQure’s drug is now (supposedly) dramatically improved over its previous iteration throws a spanner in the works from Spark’s perspective.

What also makes this situation interesting is the fact that uniQure has been able to nail down a pretty favorable trial protocol for the upcoming pivotal investigation. The trial in question will be open-label (meaning the company doesn’t have to compare its drug to a placebo arm) and will evaluate a single dose of AMT-061.

Patients are going to serve as their own baseline in the study, which means each will be evaluated at the start of the trial, then dosed, and then evaluated again once the trial draws to a close, and the primary endpoint of the investigation is a reduction in bleeds.

For those not familiar with hemophilia, it’s an inability to form blood clots correctly and is characterized by excessive bruising and bleeding on the back of small cuts and wounds etc. If uniQure can show that AMT-061 can help patients reduce bleeding from baseline in the upcoming pivotal investigation, the company could be on the fast track for a regulatory green light from both the FDA in the US and the EMA in Europe and, in turn, could grab a fairly decent portion of the available market share ahead of Spark and its own gene therapy asset.

Markets are trading up on the company on the back of the latest news, with uniQure closing out the session on Thursday for a 33% premium to its pre-announcement market capitalization.
Tex Mex
uniQure N.V. (QURE) - Moving Into Pivotal Study

In my last update on uniQure (see here), I noted that the company was benefiting from renewed investor interest in the AAV vector technology, driven largely by a mini-bidding war for tiny Dimension Therapeutics (DMTX) between two larger rare disease players, Regenxbio and Ultragenyx. The larger Utragenyx (RARE) ultimately won the battle for Dimension, paying a 400% premium over the pre-bidding war price. Like uniQure, Dimension has a proprietary AAV gene therapy platform; this is the kind of news that causes me to increase my Charisma and Credibility scores.

Fix-Padua & AMT-061

On October 19, 2017, uniQure announced that following multi-disciplinary meetings with the U.S. FDA and the EMA, the company plans to expeditiously advance AMT-061, which combines an AAV5 vector with the FIX-Padua mutant, into a pivotal study in 2018 for patients with severe and moderately severe hemophilia B.

AMT-061 is a next-generation formulation of AMT-060 that incorporates the FIX-Padua gene R338L mutation. uniQure announced it has acquired a patent family around this technology on October 19th as well (see USPTO 9,249,405). According to the company, FIX-Padua expresses a protein with a single amino acid substitution that has been reported in multiple preclinical and nonclinical studies to provide an approximate 8 to 9-fold increase in FIX activity compared to the wild-type FIX protein (see data below).

All other critical quality attributes of AMT-061 are expected to be comparable to those of AMT-060, including safety, as AMT-061 utilizes the same AAV5 capsid and proprietary insect cell-based manufacturing platform. Importantly, the FDA agreed that AMT-061 will be included under the existing Breakthrough Therapy designation and IND for AMT-060. The EMA also has agreed that AMT-061 will be included under the current PRIME designation. Additionally, the manufacturing processes, controls, and methods are consistent between AMT-060 and AMT-061.

As a reminder, uniQure is currently conducting a Phase 1/2 study (NCT02396342) with AMT-060 in patients with severe hemophilia B and advanced joint disease. This is primarily a safety study, although secondary endpoints including FIX-replacement and FIX-activity, bleeding rate, and other specific analyses such as vector DNA, neutralizing antibodies, and AAV5-capside specific T cells, are also being measured.

uniQure has been reporting data from this study for the past year, with the most recent update coming in July 2017. Data in July at ISTH show all 10 patients (5 in 2 cohorts, a 0.5 x 10¹³ and 2.0 x 10¹³ gc/kg) in the study have demonstrated improvements in their disease state as measured by reduced FIX replacement therapy and bleeding frequency. In the 2.0 x 10¹³ gc/kg dose cohort, no spontaneous bleeds were reported in the last six months of follow-up, with a reduction in the annualized spontaneous bleed rate of 84% compared to the one-year period prior to administration of AMT-060. Total bleeds were reduced by 64%. Eight of the nine patients that required chronic FIX infusions prior to administration of AMT-060 have discontinued prophylaxis after treatment. All eight patients remained prophylaxis-free at the last follow up. This is essentially a "cure".

Across both dose cohorts, cumulative annualized FIX consumption decreased by 79%, from 2.64 million to 544,741 IU. Through up to 12 months of follow-up among the five patients in the second-dose cohort, the mean steady-state FIX activity persisted at approximately 7% of normal. The mean FIX activity at the last follow-up (52 weeks) was 8.82%, ranging from 5.2% to 10.7%. AMT-060 continues to be well-tolerated, and there have been no severe adverse events. As previously announced, three patients experienced mild, asymptomatic elevations of ALT soon after administration. For these patients, ALT levels returned to their baseline readings, no recurrence of ALT elevation has occurred, and no loss of FIX activity was observed. No patients across either cohort have developed inhibitory antibodies against FIX, or demonstrated sustained AAV5 capsid-specific T-cell activation.
Moving Into Pivotal Studies

uniQure expects to move into a pivotal study with AMT-061 in the second half of 2018. The study is expected to be an open-label, single-dose, multi-center, multi-national trial investigating the efficacy and safety of AMT-061 administered to adult patients with severe or moderately severe hemophilia B. The primary objective of the trial is to evaluate AMT-061 for prevention of bleedings. Secondary objectives include additional efficacy and safety aspects. Patients will serve as their own control, with a baseline established during a six-month observational lead-in phase prior to treatment with AMT-061.

Market Opportunity

According to the U.S. CDC, hemophilia occurs in approximately 1 in 5,000 live births. There are about 20,000 people with hemophilia in the U.S. Severe hemophilia B, which is defined as a FIX plasma levels < 1% (normal levels are 50% to 150% of what is needed to form a clot), occurs in about 60% of the cases. Moderate hemophilia B, defined as a FIX plasma level of 1-5%, represents about 15% of the cases. The remaining 25% of hemophilia B patients have mild disease, defined as FIX plasma levels between 6% and 30%. The mainstay treatment is chronic intravenous FIX replacement therapy.

If we assume that only patients with severe hemophilia B will opt for gene therapy, then several companies, including uniQure, Sangamo, and Spark Therapeutics will all battle for around 12,000 patients. I have previous written that Sangamo's data looks superior to both uniQure and Spark, and that Spark actually looks superior to uniQure; however, with the addition of Fix-Padua, it seems as though uniQure has leveled the playing field. For simplicity sake, if we assume each player obtains a third of the market, then uniQure's peak opportunity with AMT-061 is roughly 4,000 patients.

Gene therapy products such as AMT-061 are likely to be extremely expensive. For example, Glybera®, the first approved gene therapy product, cost around $1.4 million. Yes, that's a crazy high number, but considering alternative therapies can cost as much as $300,000 to $500,000 per year (see Soliris® as example), there's potential favorable pharmaco-economics at a one-time payment of $1.4 million. That would put the cumulative potential for AMT-061 at $5.6 billion! If the drug is on the market for eight years, with bell-shaped ramp, peak sales are likely around $1.0 billion. This would be the most aggressive scenario (and I'm uncomfortable with it). Cutting the number in half, to peak sales at around $500 million (due to pricing rebates and lower actual penetration) makes far more sense.

Nevertheless, if we use $500 million as a good peak estimate for AMT-061, with 50% odds of success and an industry-average P/S multiple of 4.5x, with 15% discount rate, I think AMT-061 is worth about $300 million today. UniQure also has AMT-130 nearing clinical trials, and several preclinical candidates, including research with Bristol-Myers and a candidate for hemophilia A, and $104 million in Cash as of June 30, 2017.

As such, the current market value of $385 million ($14.25/sh) looks attractive. Something closer to $500 million - around $18.50/sh - looks reasonable.


Bio5C has no position in any stock mentioned above.
Dr. No
Deze analist heeft het over een potentiële markt van ongeveer 5000 patiënten in de VS.
Wellicht is er ook nog een markt voor patiënten uit de rest van de wereld?
Tex Mex
Even geknipt en geplakt van het HemB draadje. Voor de volledigheid.

Ik vind het toch wel een geniale manoeuvre van het $QURE management om in alle luwte te werken aan AMT061 en dan ineens vriend en vijand te verrassen met deze variant op AMT060, maar wel een variant die in potentie superieur is ten opzichte van ieder ander beschikbaar (gentherapeutisch) (pre)klinisch middel op dit moment voor de behandeling van hemofilie B.
Waarom superieur:
1. In de HemofilieB populatie is de incidentie van antilichamen tegen de door Qure gebruikte vector (AAV5) erg laag, slechts een paar procent, in vergelijking tot bijvoorbeeld de bioengineered vector van Spark Therapeutics (incidentie circa 40%). Deze antilichamen verminderen de effectiviteit van de gentherapie, en dan zou de aanwezigheid van deze antilichamen een argument kunnen zijn om toediening van het (waarschijnlijk zeer dure) AMT061 in deze groep patiënten niet toe te passsen. UniQure heeft echter al aangetoond dat dat in het geval van AMT060/061 (AAV5) vooral een theoretische kwestie is. Kortom op basis hiervan hoeft Qure geen patiënten met hemofilieB uit te sluiten. Dat maakt de markt groter. Voor de andere gentherapieën die van andere vectoren (dan het door QURE voor deze toepassing gepatenteerde AAV5) gebruik maken is dit nog niet bewezen.
2. Weinig/geen aangetoonde immunologische reactie (reactie van het afweersysteem). Kortom de door AMT060/1 getransfecteerde levercellen, die het stollingseiwit waar het lichaam door een genmutatie te weinig van aanmaakte, worden niet aangepakt door het eigen afweersysteem. De studies van Spark laten zien dat dat geen theoretisch risico is: bij 2 van de 9 door Spark behandelde patiënten trad deze reactie wel op, met een vermindering van productie van het stollingseiwit tot gevolg.
3. gebruik van het Padua-gen zou kunnen leiden tot een verhoogd trombose risico bij een te sterke productie van de stollingsfactor IX. De hierboven geposte slideshow laat zien dat op basis van de data in non-humane studies bij de beoogde therapeutische dosis bij mensen verhoging van het trombose risico als 'unlikely' wordt beschouwd.

Kortom qua veiligheidsprofiel lijkt AMT061 hoge ogen te kunnen gooien (zoals dat eigenlijk ook al voor AMT060 gold).

Het gebruik van het Padua gen in AMT061 leidt echter ook tot een hogere factor IX activiteit in vergelijking met de Wild-type variant in 060. En in combinatie met een beter veiligheidsprofiel dan SPK-9001 (dat een veel hogere factor IX activiteit opleverde dan AMT060 door gebruik van het Padua-gen) van Spark leidt dit tot een zeer concurrerend middel. Het moet alleen nog wel even in een fase 3 trial worden waargemaakt...
Maar intussen, daar nog niet teveel op vooruitlopend, is het denk ik erg knap dat uniQure het voor elkaar heeft gekregen bij FDA en EMA dat (waarschijnlijk op basis van het veiligheidsprofiel van AMT060) met AMT061 de fase 1 en 2 studies (inclusief behoud van fast track/BTD) overgeslagen mogen worden. Volgens mij is zoiets niet eerder vertoond.

Waar ik zelf nog nieuwsgierig naar ben is in hoeverre het feit dat QURE een exclusieve licentie voor het gebruik van het Padua-gen heeft verkregen dit ook gevolgen heeft voor het genproduct van Spark. De koers van het aandeel Spark Therapeutics ($ONCE) lijkt onaangedaan door het goede nieuws dat $QURE vorige week naar buiten bracht, ondanks het feit dat SPK-9001 van $ONCE gebruik maakt van deze zelfde (gepatenteerde) genetische variatie.
Wie zou daar op dit forum iets meer over kunnen zeggen?

Tot slot maakt de aap die QURE vorige week even uit de mouw liet komen mij nieuwsgierig naar de toekomst. Ik ben benieuwd naar wat de disclosure van de tot dusverre undisclosed targets nog gaat brengen. En of AMT061 tot nieuwe, deals met aansprekende partners gaat leiden.
Tex Mex

One stock that bucked this negative sentiment on the biotech sector last week was UniQure (QURE). The stock nearly doubled in five trading sessions which made many members in the Biotech Forum community quite happy as this small cap name was one of the half dozen positions in our "Holding Pen" and was included there on July 20th within a detailed investment analysis.

We posted that research a month later on our sister thread "The Busted IPO Forum" as we believed there was a good chance this Busted IPO would eventually make good. Let's revisit this name quickly in today's Spotlight feature.

Analyst Commentary and Balance Sheet
This news triggered the first analyst commentary on this name in some three months. Oppenheimer chimed in Thursday to reissued its Buy rating and $17 price target (already exceeded). Its analyst noted:

While we have been waiting for an update to the clinical trial plan for the first hemophilia B product candidate AMT-060, QURE has astutely-and stealthily-brought another product candidate (AMT-061) into the clinic. This product has potentially 6x to 7x the well-known FIX expression levels of AMT-060 and may lead to mean FIX activity of approximately 30% to 50% of normal; a potentially significant benefit to moderate to severe hemophilia B patients. While we await further visibility on the pivotal Phase 3 design, we reiterate our bullish stance.
Chardan Capital followed with a more optimistic Buy rating raising its price target to $35 that same day. Chardan's analyst provided this color for his optimistic view:

We now believe that uniQure can achieve hemophilia B segment leadership in vector gene therapy (GT). Our assumptions for hemophilia B vector GT leadership for uniQure do not rely on the view that uniQure's IP on the FIX-Padua mutant is blocking IP for Spark Therapeutics (Buy) or that the patents discussed above are blocking. The view is based on the utilization of Padua and the AAV5 capsid, which to us are uncontroversial: uniQure's product likely enables broader use in hemophilia B than other vector gene therapy. uniQure utilizes AAV5 which seems to have the lowest prevalence of preexisting neutralizing antibodies (NAb) of tested AAV vectors, meaning that AMT-061 has the potential to be administered to nearly all hemophilia B patients. By comparison, for SPK-9001, roughly 40% of patients have NAbs against SPK-9001's capsid.
uniQure ended the first quarter of 2017 with some $120 million in cash and marketable securities on the balance sheet.

As always, one should cull some profits on this types of biotech rockets using the "Jensen Rules" or something similar. I would not chasing uniQure after its big rally as it is quite possible some profit taking happens in the weeks ahead given the size and speed of the huge rise. That said, I plan to retain the majority of my shares in this name as further appreciation could be ahead as uniQure advances its pipeline and garners increasingly positive analyst support.

Disclosure: I am/we are long AMGN,CELG,GBT,QURE,TSRO,VYGR.
Tex Mex

Dr. No schreef op 29 okt 2017 om 17:40:

Deze analist heeft het over een potentiële markt van ongeveer 5000 patiënten in de VS.
Wellicht is er ook nog een markt voor patiënten uit de rest van de wereld?

Wereldwijd waren er in 2015 zo'n 40.000 patiënten met gediagnosticeerde Hemofilie B. 75% hiervan is naar schatting 'severe' of 'moderate' aangedaan.
Dan zit je wereldwijd dus op een potentieel van 30.000 patiënten, afhankelijk van hun mogelijkheden om toegang tot prijzige gezondheidszorg te krijgen.
~ New Nonclinical Data on AMT-061 to be Presented Saturday, December 9, 2017 ~

uniQure Announces Presentations at the 59th American Society of Hematology (ASH) Annual Meeting
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