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ProQR's Genetic Disorder Candidate Gets Orphan Drug Status

Zacks Equity Research
ZacksSeptember 20, 2017Comment
ProQR Therapeutics N.V. PRQR announced that the FDA has granted orphan drug designation to its genetic disorder candidate, QR-313, for the treatment of dystrophic epidermolysis bullosa ("DEB").

ProQR’s share price has increased 2.1% so far this year, underperforming the industry’s rise of 15.3% in the same time frame.

The company has already obtained orphan drug designation for its four other candidates, including its usher syndrome candidate, QRX-421, earlier this month.

We note that orphan drug designation is granted to drugs capable of treating diseases that affect less than 200,000 people in the United States. The status makes QR-313 eligible for seven years of marketing exclusivity in the country, following an approval for DEB. The designation also makes the company eligible for certain other benefits, including tax credits related to clinical trial expenses, exemption from the FDA-user fee and assistance from the FDA in clinical trial design.

QR-313 is a RNA-based therapy for treating DEB, which is caused by mutations in exon 73 of the COL7A1 gene. The mutation result in the loss of functional collagen type VII protein that makes the skin fragile.

ProQR is also engaged in developing RNA-based therapies for other genetic rare diseases including cystic fibrosis (QR-010) and Leber’s congenital amaurosis (QR-110).

In a restructuring move, the company spun off its central nervous system ("CNS") disorders focused company, Amylon Therapeutics, in late August. Amylon will develop RNA-based therapies for the treatment of a rare genetic disease, which leads to strokes in mid-adulthood. ProQR will own majority ownership stake in the newly formed, privately-held company.

ProQR Therapeutics N.V. Price and Consensus

ProQR Therapeutics N.V. Price and Consensus | ProQR Therapeutics N.V. Quote
ProQR Therapeutics N.V.

Visibility on QR-010 in Cystic Fibrosis Just Around the Corner

PRQR: $5.75 | Market Cap: $144M
Market Outperform | Price Target: $14.00
Liisa A. Bayko | +1 312 768-1785 |

Looking for safety and possible efficacy signal in CF data on Monday; we reiterate our Market Outperform rating and $14 risk-adjusted, DCF derived price target on ProQR Therapeutics. Monday is a key inflection point for PRQR as its lead asset QR-010, an inhaled RNA-based, CFTR modulator, will report safety and efficacy data from a small, 28-day, Phase 1b study in cystic fibrosis (CF) patients with F508del homozygous mutations. We look for good safety/tolerability (the earlier single-ascending dose study laid a nice foundation), and we believe some trends in lung function improvement would be a nice to have. In our view, reasons to be optimistic for efficacy trends include evidence of in vivo, on-target activity in the NPD study (see our note from 10/27/16) and strong animal data, offset by an unknown mechanism of action, emerging understanding of the PK/PD as this is the first multi-dose study, a relatively healthy study population with baseline FEV >70%, and unknown ability to cross the mucous layer in CF patients (in vitro experience in non-CF mucous showed good migration). We caution the direct comparison to oral CFTR correctors for these reasons (see Figure 1), but present the data strictly as a reminder of what has been seen in this class in the F508del homozygous population.

As for other exploratory efficacy endpoints, we think the study is too short to expect weight gain and we do not expect improvements in sweat chloride due to the lack of uptake of QR-010 in sweat glands. If all goes well, a larger Phase 2 study in CF will start in 2018. Beyond CF, we see significant potential upside from the company’s broad, RNA-based, early-stage pipeline targeting a number of rare diseases in ophthalmology and dermatology as well as the new Axiomer RNA-editing technology platform (Figure 2). With QR-110 for Leber’s congenital amaurosis Type 10 (LCA 10) and QR-313 for dystrophic epidermolysis bullosa (DEB) both entering the clinic soon, we think these programs are currently under the radar and under-appreciated by the Street. We continue to recommend shares of PRQR ahead of Phase 1b CF data on Monday and we see substantial potential upside long term from the remainder of the company’s expanding pipeline.

($6.45, Mkt. Cap. $155M)

Nothing to be MAD about, PRQR Ph1b Multiple Ascending Dose Trial a Success

Bottom Line: PRQR announced successful completion of their safety and tolerability placebo-controlled Ph.1b multiple ascending dose (MAD) study evaluating QR-010 in homozygous F508del CFTR mutated cystic fibrosis (CF) patients.
In addition to favorable tolerability across all doses with no drug related adverse events, PRQR reported improvements in exploratory endpoints, most notably, improvements in patient symptoms according to the CFQ-R (12.5mg dose, p=0.0072) and a 10.9% (p=0.0461) improvement in percent predicted forced expiratory volume in 1 second (pp-FEV1) over placebo in a pre-defined subgroup with lower initial lung function at the 12.5mg dose. These data, in combination with previous positive proof-of-concept (PoC) results (LINK) in CF patients provides enthusiasm for development of PRQR’s novel RNA platform. We remain cautiously optimistic, as these are Ph.1b data and the drug development landscape in CF is fiercely competitive. Reiterate OP, PT increased to $12, up from $10.

No adverse events were observed in F508del CFTR gene mutated CF patients exposed to multiple ascending doses of QR-010 via inhalation.
We view these data as positive validation for PRQR’s RNA repair platform as it 1) further validates clinical safety/tolerability and 2) affords PRQR the opportunity to evaluate their RNA platform in a larger and more severe CF population. The current study evaluated four dose levels of QR-010 (6.25, 12, 25, 50mg) in mild CF patients exposed to 12 doses over a 4 week period. Exact plans for future development have not been laid out yet, but the company is notably evaluating collaborations, perhaps as a combo therapy, or as a monotherapy.

Changes in exploratory endpoints encouraging, as study had relative low power and mild CF patients.
QR-010's positive data on measures like nasal potential depolarization (NPD) and CFQ-R respiratory symptom scores are on par with Kalydeco’s (VRTX [OP]) results and suggests PRQR's agent could have clinical merit. Despite a relatively mild CF population, the sub-group of patients with 70-90% ppFEV1 were prespecified wherein QR010 showed a significant increase in ppFEV1 at 4 weeks. Functional read-outs for CFQ-R and pp-FEV1 showed a bell shaped dose response with a suboptimal dose (6.25mg), effective dose (12.5mg), and ineffective high dose (25, 50mg). Other exploratory endpoints were unaffected (i.e., body mass index and sweat chloride), as anticipated since the drug does is not delivered so broadly.

Changes to model, investment thesis, and valuation.
In light of today’s positive results regarding safety and preliminary efficacy, we have updated our model to reflect a 30% probability of success, up from 20%. In addition, we have adjusted peak penetration down to 33% from 45% given the increasingly competitive CF landscape.

PRQR: Price: $6.45; Market Cap (M): $155
Rating: Buy; Price Target: $40.00

Andrew S. Fein
Li Wang Watsek

Believe QR-010 Results Establish POC and Will Likely Trigger Partnership Signing; Reit Buy and $40 PT

Click here for complete report and disclosures

Yesterday, ProQR reported topline data from its Phase 1b study of QR-010. The combination SAD (4 cohorts)/MAD (4 cohorts) trial enrolled 64 homozygous F508del patients. Expectations were appropriately low for observing any efficacy in this safety study in which oligomer delivery was dosed 3x/week for a total of 4 weeks. All patients were either off Orkambi, or had a 12-week washout of Orkambi prior to initiating this study. With respect to safety, QR-010 delivered a very solid and pleasingly unremarkable safety pattern, with no AE’s being attributed to drug treatment and only 3 SAE’s reported from 2 patients (abdominal discomfort and nausea being reported).

Focus on entry criteria give context to the results. Exploratory efficacy endpoints of the CFQR-R (respiratory domain) and improvement in the absolute ppFEV1 from baseline were also measured. It is important at this juncture to point out that the entry criteria did not include a cap on ppFEV1 values so at baseline the mean ppFEV1 was approximately 86% across all groups. Such a high ppFEV1 value suggests that the patient population in this trial is relatively healthy and had little room to demonstrate a ppFEV1 improvement during this short 4-week study. With that in mind, it was reassuring to observe the following increases in the CFQR-R: placebo decreased 6.5 points, the 6.25 mg group improved 13.0 points, the 12.5 mg group improved 19.2 points, the 25 mg group improved 14.3 points and the 50 mg group improved 3.5 points. In the CFQR-R, an increase of 4 points is typically viewed as having a discernible difference on the patient, thus 3 of the 4 doses reached that level of significance, albeit in somewhat of a bell-shaped curve response.

We believe the trend is suggestive of effect and warrants further investigation. With respect to ppFEV1, the responses were lower, although a similar bell-shaped response could be observed. Based on both CFQR-R and ppFEV1, a dose of 12.5 mg of QR-010 delivered for 4 weeks duration gave a response that we would interpret as influencing lung function in F508del patients. Although the effect is neither robust nor definitive in this study, it clearly suggests a trend that supports further investigation, especially considering the “uncapped entry criteria.” When the data set was sub-segmented to sort patients with a <90 or >90 ppFEV1 at baseline, an even greater effect was observed. Patients exposed to 12.5 mg QR-010 who had a <90 ppFEV1 at baseline showed a 10.9 ppFEV1 improvement (P value =0.046). Two other exploratory endpoints, sweat chloride levels and weight gain were unchanged in this study. In toto we believe this data continues to support development of QR- 010.
Dennis isn’t the only Rodman that knows how to rebound. Regarding future plans, ProQR has recently added Dr. David Rodman to their management team as the Chief Development Strategy Officer. Dave has a long and prestigious history and is particularly noted, in our opinion, for his ability to design highly informative clinical trials. We expect similar insight and execution for the QR-010 subsequent trials that he will likely design and develop. Dr. Rodman has initially discussed a possible 13-week trial with a 4-week interim analysis that would primarily be used to select 1 or 2 doses that would then be over-enrolled during the final 9 weeks. The reasoning behind this strategy is based on management’s belief that the observed “bell-shaped” curve may be due to accumulation of QR-010 in the lung. We are not entirely convinced that this would explain the decreased response at higher doses. If overexpression of CFTR occurs at higher doses of QR-010, it may not result in increases in functional CFTR activity, or a further effect on mucociliary clearance. But it is not clear how that overexpression would result in a decreased effect on ppFEV1. Moreover, there does not appear to be any significant safety signal associated with the increased dosage. We await a more plausible explanation, which may come from a longer trial, or perhaps as Dr. Rodman indicated, a trial design that uses a higher loading dose followed with a lower maintenance dose. With respect to the “better” (larger magnitude) response in CFQR-R vs ppFEV1, we tend to agree with management that this could be due to CFQR-R displaying a response from the whole lung, large and small airways, whereas ppFEV1 may only be sampling from the large airways, especially in relatively mild patients (>85 ppFEV1). Management is considering inclusion of Lung Clearance Index, LCI, in future studies as that may provide a better perspective on effects in the small airways, especially in milder disease patients. Although FEV1 is still the approvable endpoint for the regulators, we note that more companies have been discussing and including LCI in their trial design, and we expect that trend to continue.

We expect that today’s results are likely to trigger a partnership signing and believe expansion of CFFT partnership should be viewed as validating. Finally, management clearly discussed their ongoing desire to partner QR-010 for future studies, and we believe this may be driven by the exciting advances being made in their other programs including the recently demonstrated in vivo Proof of Concept data for the Axiomer RNA editing platform. Specifically, we can anticipate the ongoing expansion of the ProQR and CFFT partnership to now include targeting of Class I stop mutations. This would satisfy the gap in the CFFT pipeline that occurred following the discontinuation of the PTC Therapeutics' (PTCT; not rated) Ataluren development program. In our assessment, the QR-010 program deserves continued development and could be a salient contributor to what we are now viewing as a broad RNA platform.

Valuation and risks to achievement of target price. Our price target of $40/share is based on a DCF/NPV analysis (discount rate 12.5%, growth rate 2%). Risks to our investment thesis and target price include: (1) failure of QR-010 in clinical studies; (2) failure of QR-010 to secure regulatory approval; (3) failure of QR-010 to achieve peak commercial revenue estimates in our model due to market size, penetration rates, and pricing; and (4) other pipeline failures.

Andrew S. Fein

Li Wang Watsek

ProQR Therapeutics N.V.
First Cystic Fibrosis Patient Data for QR-010 Delivers

PRQR: $6.45 | Market Cap: $162M
Market Outperform | Price Target: $20.00
Liisa A. Bayko | +1 312 768-1785 |

Efficacy and safety set foundation for Phase 2b study to follow next year; we reiterate our Market Outperform rating and raise our risk-adjusted, DCF derived price target price target to $20 from $14 on ProQR Therapeutics after raising our probability of success for the program. PRQR delivered encouraging efficacy data for its potential new CF medicine QR-010, measured for the first time in patients with both improvements in lung function (FEV1) and CF respiratory symptom scores (Figures 1 and 2), both within group and compared to placebo. The data were even more profound in the pre-specified subgroup of patients where it may be anticipated to discern an effect (i.e., those with lower lung function with 70-90% FEV1 at baseline), and in the mid-dose (12.5mg) cohort where lung improvement after 28 days was superior to CFTR correctors from Vertex (VRTX, MO, $200 PT); however, we caution against drawing conclusions on relative efficacy given the early stage of this program with small patient numbers and different study designs (Figure 3).

While the bell-shaped dose response curve requires some contemplation, at this early stage and with so few patients in each cohort, we feel good about the signal reported and point out that similar patterns have been observed for other successful drugs— a relevant example is an early study of VRTX's CFTR potentiator Kalydeco (Figure 4). The safety profile looks clean with no SAEs that stand out and discontinuation rates were balanced (two on drug vs. one on placebo) and within normal range.

Next steps include a detailed presentation of data at the upcoming NAFC meeting in November, after which the company will meet with regulators to discuss the design of a larger Phase 2b study, which is expected to begin next year. As a result of these data, we increase our assumption for the success of eventual approval to 20% from 5%, raise our target to $20 from $14, and we strongly recommend owning shares of PRQR as we think the stock is significantly undervalued relative to the opportunity at hand in CF, not to mention the rest of the emerging rare disease pipeline which could begin to bear fruit over the next couple years (Figure 5).

Gisteren heb ik naar de webcast geluisterd. Deze verhoging van de price target had ik niet verwacht.
Pricetargets zijn natuurlijk vrij interpretabel...belangrijker is te kijken naar de opbouw van hun betoog hoe ze tot een outperform-advies e.d. zijn gekomen.
Analisten hobbelen meestal achter de feiten aan...met de kennis van nu makkelijker dan vooraf te voorspellen dat iets al dan niet goed zal verlopen.

Een manier om een bedrijf een bepaalde waarde toe te kennen kan zijn door te kijken naar de waardering (marktcap) van peers die op andere vlakken al wat verder zijn en waaraan een bepaalde marktcap gehangen kan worden.
Op het moment dat PRQR de markt weet te overtuigen van een serieuze kans van slagen, dan kan het miljard gepasseerd worden. Daarvoor is het nu nog wat vroeg, maar ik vertrouw erop dat die dag wel gaat komen...ProQR heeft inmiddels een paar potjes op het vuur staan en kan er gewed worden op meerdere paarden in de PRQR-stal.
Dank ivet voor het plaatsen van de rapporten. Hierbij de volledige versie van Leerink
wat leren kersverse analistenrapporten met verhoogde koersdoelen ons bij deze handel?
20% verhoging van koersdoel leidt tot 20% lagere koers? zijn blijkbaar 2 werkelijkheden die door elkaar lopen? De markt heeft altijd gelijk...analisten (bijna) altijd ongelijk?
Dr. Bob
Analistenrapporten beginnen een verschil te maken als die door de grote(re) namen worden opgesteld.
• Bottom Line: Today PRQR announced dosing of the first patient
in its ph.1/2 program for QR-110 in Leber’s congenital amaurosis
10 (LCA 10), a rare genetic disorder resulting in blindness. Though
it has taken longer to launch than we expected, PRQR is still
positioned ahead of its closest LCA 10 competitor, Editas, who
anticipates an IND-filing in mid-2018. Based on its early Ph.1/2
status, we do not yet include any probability adjusted QR-110
revenue in our model, but we are encouraged by the in vitro work
done and we are optimistic about QR-110 moving forward into what
we predict to be a $500MM market oppt'y.
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