ProQR Therapeutics N.V. Stock

ProQR Therapeutics N.V. (ProQR) operates as a biotechnology company. The company is dedicated to the creation of transformative RNA therapies to improve the lives of patients and families affected by diseases with high unmet medical need. To achieve this, the company is advancing its proprietary Axiomer RNA-editing platform technology. Using its deep RNA expertise and its strong intellectual property position, the company is advancing a platform to develop these RNA editing therapeutics, which it calls Editing Oligonucleotides, or EONs, for a variety of human diseases.

Since discovering the Axiomer RNA editing technology in 2014, the company has established a leading intellectual property estate in the ADAR editing space, defined the design ground rules, and optimized chemistries for therapeutic use.

The company’s research and development strategy focuses on use of its Axiomer platform to develop novel RNA editing therapeutics to address diseases with high unmet medical need. The company is initially focused on diseases originating in the liver where research into human genetics has shown it that introduction or correction of a mutation may lead to a benefit for patients. The company prioritizes areas with well-established biomarkers for the assessment of early clinical activity and to establish proof of target engagement, established clinically relevant endpoints, and the ability to leverage existing proven delivery technology. The company is advancing AX-0810 for cholestatic diseases targeting Na-taurocholate cotransporting polypeptide, or NTCP, and AX-1412 for cardiovascular disease targeting Beta-1,4-galactosyltransferase 1, or B4GALT1, as its initial pipeline programs.

In addition to advancing its wholly-owned pipeline programs, the company entered into a global licensing and research collaboration with Eli Lilly and Company in 2021 where its Axiomer RNA editing platform is being used to progress new drug targets for disorders toward clinical development and commercialization. Initially focused on five targets, the partnership was expanded to ten targets in December 2022, with an option for further expansion to fifteen targets.

The company has other earlier stage RNA editing platform technologies, including its Trident platform. The company’s Trident RNA pseudouridylation platform is designed to enable the suppression of nonsense mutations and premature stop codons (PTC) that cause 11% of all human genetic diseases. Since all premature stop codons contain uridine, pseudouridylation of that uridine converts those nonsense codons into sense codons. The Trident technology harnesses the endogenously expressed pseudouridylation machinery with guide RNAs to inhibit nonsense messenger RNA (mRNA)-mediated decay (NMD) in a sequence-specific manner and promote PTC readthrough. The Trident technology has the potential to be applied in genetic diseases caused by PTCs.

Both the Axiomer and Trident RNA editing platforms are novel, proprietary RNA technologies invented at ProQR or with the company’s academic collaborators. The company has built a broad intellectual property estate around these technologies and together with the leading academic experts in the RNA field, it continues to advance these technologies.

Strategy

The company is advancing Axiomer as a platform to develop a new class of innovative medicines based on RNA editing, which has the potential to treat a broad range of diseases that lack adequate treatment options. The company’s novel and proprietary RNA editing platform technologies, known as Axiomer and Trident, are new ways to use oligonucleotides to edit single nucleotides in the RNA. The company intends to continue to optimize its platform as it advances to clinical stage and beyond. Key elements of the company’s strategy include:

Pipeline: The company intends to use these platforms to develop novel therapies for targets related to liver-originating diseases and beyond. With its Axiomer RNA-editing technology platform, the company is advancing AX-0810 for Cholestatic Diseases targeting NTCP and AX-1412 for Cardiovascular Disease targeting B4GALT1 as the company’s initial pipeline programs.

Partnerships: The company continues to validate and create value for these platforms by selectively pursuing additional licensing, partnering, and other strategic relationships outside of its core focus area, like its partnership with Lilly.

The company seeks to maximize the value of its pipeline by retaining development and commercialization rights to those product candidates, indications and geographies that can independently develop, seek approval for, and commercialize on its own. Beyond this, for other product candidates, such as those for more prevalent indications, indications and geographies, the company plans to selectively and opportunistically seek potential partnerships following early-stage clinical proof of concept.

Novel Axiomer RNA Editing Technology Platform

The company’s Axiomer RNA editing technology is based on editing oligonucleotides, or EONs, designed to recruit endogenous ADAR enzymes (Adenosine Deaminases Acting on RNA) to make single adenosine-to-inosine (A-to-I) changes in the RNA in a highly specific and targeted manner.

Across a range of targets, the company has shown both in vitro and in vivo platform proof-of-concept for the company’s Axiomer RNA editing technology platform, including cell models, organoids, and animal models, including relevant higher order species.

Pipeline

The company is advancing Axiomer as a platform to develop a new class of innovative medicines based on RNA editing. The company’s initial pipeline programs include AX-0810 for Cholestatic Diseases targeting NTCP and AX-1412 for Cardiovascular Disease targeting B4GALT1. The company expects to advance these programs to clinical trials in late 2024 / early 2025.

AX-0810, the company’s Axiomer-targeted RNA editing oligonucleotide, aims to reduce the reabsorption of bile acids in the liver by inhibiting NTCP function. AX-1412 represents a potential targeted approach to RNA editing of B4GALT1 that leads to a loss of function is a promising strategy for protecting against cardiovascular disease by simultaneously lowering levels of LDL-c and fibrinogen. B4GALT1 gene is prevalent in the Amish population and associated with lower levels of LDL-c and cardiovascular disease.

The company is developing Axiomer targeted RNA EON AX-1412 to address CVD by editing B4GALT1. RNA editing to a loss of function variant of B4GALT1 can have positive effect on cardiovascular diseases risk factors by leading to hypo-galactosylation of apolipoprotein B100 and fibrinogen. Based on its mechanism of action, AX-1412 is a novel and unique approach to address CVD by lowering LDL-C and fibrinogen levels ultimately leading to a reduced residual risk in cardiovascular diseases. The company intends to advance AX-1412 targeting B4GALT1 to early clinical proof of concept stage, then would seek to partner this program.

Earlier-Stage/Discovery Programs

The company has multiple other early-stage research programs ongoing that target additional diseases with its Axiomer EON approach, including AX-1005 for undisclosed targets in CVD, AX-2911 for nonalcoholic steatohepatitis (NASH), AX-0601 for obesity and Type 2 diabetes, AX-9115 for rare metabolic condition, and AX-2402 for rare neurodegenerative conditions, as well as multiple other targets in its discovery pipeline.

Partnership Strategy

The company’s business strategy is to develop and ultimately commercialize a broad pipeline of RNA therapies based on its Axiomer RNA editing platform technology. The company initially focuses on developing an internal pipeline based on liver-originating diseases, including Cholestatic Diseases and CVD, among others.

Ophthalmology Assets

In August 2022, the company made the decision to exclusively focus its strategy on the advancement of its Axiomer RNA editing technology and to partner its ophthalmology programs. The process to partner these programs is ongoing.

Intellectual Property

Patent Rights

Patent Rights Relating to Axiomer Program

ProQR’s Axiomer RNA editing technology platform uses EONs to recruit and direct endogenously expressed ADARs to edit an A to an I in the RNA, which is then translated as a G, allowing highly specific editing. Since 2014, when the first inventions were conceived at ProQR, the company has been filing patent applications for intellectual property rights related to its Axiomer platform. Many of these claim EONs with specific features that allow them to guide recruitment of endogenous ADAR for the purpose of therapeutic RNA editing, without the need of ADAR overexpression or artificial ADAR recruitment systems. Further to that, the company has grown a strong intellectual property position for EONs that can bring about RNA editing in RNA to yield a gain-of-function alteration or a loss-of-function alteration in a wide variety of therapeutic areas.

With regard to its Axiomer program, the company filed the following international patent applications from 2015 to 2021, several of which were continued in national and regional patent applications after the respective international phases.

PCT/EP2015/080347 – Granted in Canada (CA 2,968,336), China (ZL 201580069286.1), Europe (EP 3234134 B1), Israel (IL 252386), Japan (JP 6718872), New Zealand (NZ 732182), Russia (RU 2711506), South Africa (ZA 2017/03464) and the U.S. (US 10,676,737). Pending in Australia, Brazil, India, and the U.S. (divisional application). The term of any patents resulting from these applications would be expected to extend to at least 2035.

PCT/EP2017/065467 – Granted in Japan (JP 7074345), South Korea (KR 10-2418185) and the U.S. (US 10,988,763). Pending in Australia, Canada, China, Eurasia, Europe, Israel, New Zealand, and the U.S. (continuation application). The term of any patents resulting from these applications would be expected to extend to at least between 2037.

PCT/EP2017/071912 – Granted in Europe (EP 3507366 B1), Japan (JP 2019-511856), New Zealand (NZ 751483), South Korea (KR 10-2501980), South Africa (ZA 2019/01016) and the U.S. (US 10,941,402). Pending in Australia, Canada, China, India, and the U.S. (continuation applications). The term of any patents resulting from these applications would be expected to extend to at least between 2037.

PCT/EP2018/051202 – Granted in the U.S. (US 11,274,300). Pending in Europe. The term of a patent resulting from this application would be expected to extend to at least between 2038.

PCT/EP2019/062163 – Pending in Australia, Canada, Europe, Japan, New Zealand, and the U.S. The term of any patents resulting from these applications, if issued, would be expected to extend to at least 2039.

PCT/EP2020/053283 – Pending in Australia, Canada, Europe, Israel, New Zealand, and the U.S. The term of any patents resulting from these applications, if issued, would be expected to extend to at least 2040.

PCT/EP2020/059369 – Pending in Australia, Canada, China, Europe, Israel, Japan, New Zealand, and the U.S. The term of any patents resulting from these applications, if issued, would be expected to extend to at least 2040.

PCT/EP2020/060291 – Pending in Australia, Canada, Europe, Israel, New Zealand, and the U.S. The term of any patents resulting from these applications, if issued, would be expected to extend to at least 2040.

PCT/US2020/037580 – Granted in South Africa (ZA 2021/09497). Pending in Australia, Canada, China, Europe, Israel, India, Japan, New Zealand, and the U.S. The company filed this application together with The Regents of the University of California as a co-applicant. In the Axiomer program the company is working together with Dr. Peter Beal of the University of California, Davis, CA, USA. The term of any patents resulting from these applications, if issued, would be expected to extend to at least 2040.

PCT/EP2021/070535 – Pending in Australia, Canada, Europe, Japan, and the U.S. The term of any patents resulting from these applications, if issued, would be expected to extend to at least 2041.

Patent Rights Relating to TRIDENT Program

With regard to its TRIDENT program, the company filed an international patent application (PCT/US2019/024282) in 2019 directed to antisense oligonucleotides that are applicable for nucleotide-specific pseudouridylation. A patent was granted in South Africa (ZA 2020/05217) and applications are pending in Australia, Canada, China, Europe, Israel, India, Japan, New Zealand, and the U.S. In the TRIDENT program the company is working together with Prof. Yi-Tao Yu at the University of Rochester, New York (NY), the U.S.A. The term of any patents resulting from these applications would be expected to extend to at least 2039.

License Agreements

In February 2019, the company entered into an agreement with the University of Rochester, New York, which gives it a world-wide, exclusive, royalty-bearing, sublicensable license in the field of antisense oligonucleotides for use in nucleotide specific RNA editing through pseudouridylation, under certain patent rights of University of Rochester. This license agreement contains certain diligence obligations for the company coupled to milestone payments and complements the company’s intellectual property relating to the Trident program. The royalties payable under this license agreement are in the low single digits.

Trademarks

The company uses various trademarks and tradenames, including without limitation ‘ProQR’, ‘Axiomer’, ‘Trident’, and the company’s corporate logo, which it uses in connection with the operation of its business.

Research and Development

For the year ended December 31, 2022, the company incurred expenses of € 50,867,000on research and development.

Regulatory Matters

Any products for which the company receives FDA approval are subject to continuing regulation by the FDA, including among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, complying with certain electronic records and signature requirements and complying with FDA promotion and advertising requirements.

History

ProQR Therapeutics N.V. was founded in 2012. The company was incorporated in the Netherlands in 2012.