In June 2021, I covered ProQR (NASDAQ:PRQR) when it was about to publish pivotal information from lead candidate Sepofarsen (QR-110), an RNA remedy focusing on Leber congenital amaurosis 10 (LCA10) because of the most typical p.Cys998X mutation within the CEP290 gene. That trial didn’t meet its major endpoint, as was revealed in February subsequent yr. This decimated the inventory, and though there was some slight restoration, the inventory is again to the place it was buying and selling after February 2022.

PRQR is a Dutch firm that makes use of antisense RNA know-how to focus on inherited retinal illnesses. Their core merchandise are antisense oligonucleotides [ASOs] which may modify protein expression via altering RNA. While that is much like gene therapies, the distinction is that since ASOs goal RNAs and never DNA, their impact is reversible and never inherited. On the con aspect, they’ve a poor toxicity profile as a result of oligonucleotides are inherently unstable and vulnerable to enzymatic degradation, and efforts to stabilize them end in toxicities. However, quite a lot of progress has been made within the final decade, and quite a few ASOs at the moment are authorized.

In 2021, Sepofarsen was conducting a part 2/3 trial referred to as ILLUMINATE in 36 adults and kids the place an intravitreal injection was given both with sepofarsen or with a sham process. An earlier part 1/2 trial confirmed that the drug was protected, and in addition confirmed early indicators of efficacy with clinically significant enhancements in BCVA, so it was transformed right into a pivotal trial.

In Feb 2022, this trial toplined, and failed to fulfill the first endpoint of Best Corrected Visual Acuity (BCVA). Key data:

According to the topline evaluation at 12 months, the imply BCVA change within the 160/80 μg dose group and 80/40 μg group dose teams stood at -0.11 logMAR (p=0.96) and -0.13 logMAR (p=0.97), respectively, in comparison with -0.12 logMAR within the sham group. Therefore, no profit was present in both remedy arm vs. sham.

There was additionally no distinction between the handled and sham teams when it comes to secondary endpoints of full-field stimulus take a look at and mobility.

These outcomes led to a shutting down of its whole pipeline after the inventory crashed greater than 75% in a single day. Their second program, QR-421a for Usher Syndrome, was additionally shut down. However, QR-421a has had unhealthy historical past, after it missed the FDA-approved BCVA rely of a three-line acquire, and in addition when its imply enchancment of 5 retinal areas within the handled eyes by a minimum of 7dB got here out solely as equal to sham. Thus, its shutting down was no shock.

This leaves PRQR with a very preclinical or discovery stage pipeline now, one that’s not value contemplating. Lead packages within the lab are AX-0810 for Cholestatic Diseases focusing on: NTCP, and AX-1412 for Cardiovascular Disease focusing on: B4GALT1. So the corporate has moved away from eye illnesses and gone into liver and different illnesses.

Such shifts should not new for this firm. Before eye, PRQR used to do cystic fibrosis. The firm produced early constructive outcomes for that program in 2017, however then fizzled out, fairly prefer it did with eye illnesses. So far, then, we have now three packages they’ve run utilizing their ASO know-how, and every has failed after producing preliminary constructive information. This report just isn’t good, and speaks to one thing essentially incorrect with their science, or a minimum of their trial execution.

Interestingly, they’ve a big legacy partnership with Eli Lilly for his or her antisense know-how. The partnership started in 2021, and much more surprisingly, Eli Lilly expanded the partnership with a contemporary $75mn infusion in December final yr, although PRQR halted its eye packages and principally went again to the drafting board. So what precisely did Lilly see in PRQR’s Axiomer know-how? According to Andrew C. Adams, Ph.D., Lilly senior vice chairman of genetic drugs and co-director of the Institute for Genetic Medicine:

We have been impressed with the progress thus far with our companions at ProQR and have conviction that RNA enhancing might be an vital different to different extra everlasting therapies.

The two corporations will collaborate in undisclosed targets within the central nervous system and peripheral nervous system. Lilly has been actively wooing corporations within the RNA house, and it additionally tentatively agreed “to provide ProQR with access to the company’s proprietary delivery technology for its wholly owned pipeline.” Their due diligence should have discovered one thing helpful in PRQR’s core know-how even when the latter has constantly didn’t show it in trials.

Financials

PRQR now has a market cap of $136mn and a money stability of €139 M, in money and money equivalents. Last yr, they reduce their workforce by 30% and in addition stopped all their packages. Right now they solely have early packages, so bills can be low. Research and improvement (R&D) prices had been €6.1 million for the quarter ended March 31, 2023 whereas basic and administrative prices had been €4.0 million. At that price, they do certainly have sufficient money till 2026, as they declare.

Risks

PRQR is an nearly destroyed firm making a gallant effort to recuperate from its varied debacles. While Eli Lilly nonetheless sees residual worth (value $75mn in money and fairness) within the Axiomer know-how, it has repeatedly didn’t show itself. As such, investing in such an unproven know-how is inherently dangerous.

PRQR has a low money stability, which, with their decreased bills, will assist them survive, nevertheless it is not going to be sufficient to assist them do a lot of anything. If they attempt to purchase belongings or enterprise into later stage medical trials, this small amount of money will fizzle out.

Bottom line

There is nothing fascinating right here save the Eli Lilly deal. However, that deal itself – with its undisclosed targets and undisclosed trial progress – has little to supply. I’ll keep away from.