ADAR

Adapted from iStock, Drypsiak Vertex may have pivoted away from the space, but candidates in development by Arrowhead/Takeda, Wave, Korro and others could address the damage underlying alpha-1 antitrypsin deficiency and make today’s treatments a thing of the past. Alpha-1 antitrypsin deficiency is a genetic disorder that affects the liver and/or lungs. Approximately 1 in 3,500 people have two abnormal SERPINA1 genes for the alpha-1 antitrypsin (AAT) protein and are at risk of serious organ damage due to AATD. While M-AAT is produced in healthy humans to inhibit neutrophil elastase in the lungs, AATD patients produce Z-AAT, which does not inhibit neutrophil elastase as effectively. If too much neutrophil elastase builds up in the lungs or liver, the result is inflammation which, untreated, can lead to lifelong complications. The only currently approved treatment option for AATD is augmentation therapy , which entails delivering normal alpha-1 antitrypsin collected and purified from blood donors through weekly intravenous administration. But this treatment does not reverse pulmonary damage or stop the progression of liver damage. Multiple companies are developing candidates that would prevent or reverse this damage, and despite some setbacks in the field, in the next 5 to 10 years we could see augmentation therapy become a thing of the past. In August 2024 , Vertex Pharmaceuticals announced that the company would cease research into both of its investigational small molecules for AATD. While Vertex had hoped that VX-634 and VX-668 would treat the disease by correcting the AAT protein, the efficacy was not transformative enough. Along with Vertex’s November 2023 discontinuation of the development of VX-864 for AATD due to reports of rashes and elevated liver enzymes, these setbacks highlight some of the challenges associated with researching new treatments for AATD. Meanwhile, Arrowhead Pharmaceuticals and Takeda are recruiting for three Phase III trials for fazirsiran, an investigational subcutaneous first-in-class investigational RNA interference (RNAi) therapy for AATD-associated liver disease. While Phase II AROAAT-2002 results indicated that fazirsiran led to significant reductions in Z-AAT, the evidence for pulmonary efficacy and improvement is murky because the Phase II trial did not have a placebo arm and the median FEV1 and mean DLCOhbg—markers of pulmonary function—were stable over time in all subjects receiving experimental treatment compared to baseline. While these data do not show any signs of pulmonary decline, there is no sign of overall pulmonary improvement either. In addition, Sanofi is working on SAR447537, an AATD asset acquired from Inhibrx. Formerly known as INBRX-101 , SAR447537 is a fusion protein currently in the recruitment stage for Phase II trials involving AATD emphysema. In Phase I results, safety and pharmacokinetic data supported the intravenous use of SAR447537 every three or four weeks. However, efficacy data related to the liver are not available. In the in vivo base editing space, Beam Therapeutics is investigating the use of BEAM-302 to treat AATD. BEAM-302 is a liver-targeting lipid nanoparticle formulation that is currently undergoing Phase I/II trials and is formulated to be a one-time intravenous injection of an adenine base editor. When tested in rat and mouse models , toxic liver protein levels decreased. Finally, Wave Life Sciences, AIRNA and Korro Bio are competing in the early phases of preclinical/clinical research to develop AATD-targeting subcutaneous RNA-editing oligonucleotides. On Oct. 16, Wave reported positive proof-of-mechanism data from a Phase Ib/IIa trial of WVE-006 in AATD, while Korro Bio released preclinical data this month for its AATD investigational treatment, KRRO-110 . AIRNA had yet to release its adenosine deaminase acting on RNA (ADAR) preclinical data publicly as of July 2024. With all these investigational treatments aiming to transform the way AATD is treated, augmentation therapy could soon be obsolete. If efficacy data for RNA-based oligonucleotides is significant and points to clinical success, RNA-based oligonucleotides could hit the market as soon as four to five years from now. In the meantime, at the current trajectory, fazirsiran could reach the market as early as two to four years from now if all goes well. Given these developments in the AATD space, competition could heat up within the next decade as more efficacy data are released from therapies currently at earlier stages of development.

LEIDEN, the Netherlands and CAMBRIDGE, Mass., Oct. 25, 2024 (GLOBE NEWSWIRE) -- ProQR Therapeutics N.V. (Nasdaq: PRQR) (“ProQR”), a company dedicated to changing lives through transformative RNA therapies based on its proprietary Axiomer™ RNA editing technology platform, today announced the closing of its previously announced underwritten public offering of 18,000,000 ordinary shares (the “Offering”) at a public offering price of $3.50 per share, for total gross proceeds of $63.0 million, before deducting underwriting discounts and commissions and other offering expenses payable by ProQR. All of the shares in the Offering were sold by ProQR. In addition, ProQR today announced the closing of its previously announced concurrent private placement of 3,523,538 ordinary shares to Eli Lilly and Company, in a separately negotiated transaction, at a price per share equal to the public offering price (the “Private Placement”). The total gross proceeds of the Private Placement were approximately $12.3 million. The ordinary shares sold in the Private Placement were not subject to any underwriting discounts or commissions. Evercore ISI, Cantor, Raymond James and Oppenheimer & Co. acted as joint lead bookrunning managers for the Offering. A shelf registration statement on Form F-3 relating to the Offering (including the accompanying prospectus) was filed with the Securities and Exchange Commission (the “SEC”) on September 30, 2024 and was declared effective on October 10, 2024. The Offering was made only by means of a prospectus and prospectus supplement that form a part of the registration statement. A final prospectus supplement relating to and describing the terms of the Offering has been filed with the SEC and may be obtained for free by visiting the SEC’s website at www.sec.gov. Copies of the final prospectus supplement and the accompanying prospectus relating to the Offering may be obtained from: Evercore Group L.L.C., Attention: Equity Capital Markets, 55 East 52nd Street, 35th Floor, New York, New York 10055, by telephone at (888) 474-0200 or by email at ecm.prospectus@evercore.com; or Cantor Fitzgerald & Co., Attention: Capital Markets, 110 East 59th Street, 6th Floor, New York, New York 10022 or by email at prospectus@cantor.com. You may also obtain these documents free of charge by visiting the SEC’s website at www.sec.gov. The ordinary shares sold in the Private Placement have not been registered under the Securities Act of 1933, as amended (the “Securities Act”), or any state or other applicable jurisdiction’s securities laws, and may not be offered or sold in the United States absent registration or an applicable exemption from the registration requirements of the Securities Act and applicable state or other jurisdictions’ securities laws. This press release shall not constitute an offer to sell, or a solicitation of an offer to buy these securities, nor shall there be any sale of, these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. About ProQR ProQR Therapeutics is dedicated to changing lives through the creation of transformative RNA therapies. ProQR is pioneering a next-generation RNA technology called Axiomer™, which uses a cell’s own editing machinery called ADAR to make specific single nucleotide edits in RNA to reverse a mutation or modulate protein expression and could potentially yield a new class of medicines for both rare and prevalent diseases with unmet need. Based on its unique proprietary RNA repair platform technologies ProQR is growing its pipeline with patients and loved ones in mind. ProQR Therapeutics N.V. Investor Contact:Sarah KielyProQR Therapeutics N.V.T: +1 617 599 6228skiely@proqr.comor Peter KelleherLifeSci AdvisorsT: +1 617 430 7579pkelleher@lifesciadvisors.com Media Contact:Robert StanislaroFTI ConsultingT: +1 212 850 5657robert.stanislaro@fticonsulting.com

LEIDEN, Netherlands and CAMBRIDGE, Mass., Oct. 22, 2024 (GLOBE NEWSWIRE) -- ProQR Therapeutics N.V. (Nasdaq: PRQR) (“ProQR”), a company dedicated to changing lives through transformative RNA therapies based on its proprietary Axiomer™ RNA editing technology platform, today announced the pricing of its previously announced underwritten public offering of 18,000,000 ordinary shares (the “Offering”) at a public offering price of $3.50 per share, for total gross proceeds of $63.0 million, before deducting underwriting discounts and commissions and other offering expenses payable by ProQR. All of the shares are being offered by ProQR. In addition, ProQR has granted the underwriters a 30-day option to purchase up to 2,700,000 additional ordinary shares at the public offering price, less underwriting discounts and commissions. Concurrently with the Offering, ProQR has entered into a share purchase agreement with Eli Lilly and Company (“Lilly”), one of its existing shareholders and a strategic partner of ProQR, in a separately negotiated transaction pursuant to which ProQR agreed to offer and sell, and Lilly agreed to purchase, 3,523,538 ordinary shares to permit Lilly to maintain its current pro rata beneficial ownership (16.4%) of the number of the ordinary shares to be outstanding immediately following the closing of the Offering and the concurrent private placement (without giving effect to any exercise by the underwriters of the option to purchase additional shares), at a price per share equal to the public offering price for total gross proceeds of approximately $12.3 million, subject to a purchase price cap of $15.0 million, the consummation of the Offering and the satisfaction of other customary closing conditions. The sale of the ordinary shares to Lilly in the concurrent private placement will not be registered as part of the Offering. The Offering is not contingent upon the completion of the concurrent private placement. The ordinary shares purchased in the concurrent private placement will not be subject to any underwriting discounts or commissions. The ordinary shares to be sold in the concurrent private placement are being issued pursuant to the exemptions provided by Section 4(a)(2) of the Securities Act of 1933, as amended (the “Securities Act”). These shares have not been registered under the Securities Act, or any state or other applicable jurisdiction’s securities laws, and may not be offered or sold in the United States absent registration or an applicable exemption from the registration requirements of the Securities Act and applicable state or other jurisdiction’s securities laws. ProQR currently intends to use the net proceeds from the Offering and the concurrent private placement, together with its existing cash and cash equivalents, to primarily fund research and development and clinical development to support the advancement of its current or future product candidates and the expansion of its research and development programs, and the remainder for working capital, capital expenditures and other general corporate purposes. Evercore ISI, Cantor, Raymond James and Oppenheimer & Co. are acting as joint lead bookrunning managers for the Offering. The Offering and concurrent private placement are expected to close on October 24, 2024, subject to the satisfaction of customary closing conditions. A shelf registration statement on Form F-3 relating to the Offering (including the accompanying prospectus) was filed with the Securities and Exchange Commission (the “SEC”) on September 30, 2024 and was declared effective on October 10, 2024. The Offering is being made only by means of a prospectus and prospectus supplement that form a part of the registration statement. A preliminary prospectus supplement relating to and describing the terms of the Offering has been filed with the SEC and may be obtained for free by visiting the SEC’s website at www.sec.gov. A final prospectus supplement relating to the Offering will be filed with the SEC. When available, copies of the final prospectus supplement and the accompanying prospectus relating to the Offering may be obtained from: Evercore Group L.L.C., Attention: Equity Capital Markets, 55 East 52nd Street, 35th Floor, New York, New York 10055, by telephone at (888) 474-0200 or by email at ecm.prospectus@evercore.com; or Cantor Fitzgerald & Co., Attention: Capital Markets, 110 East 59th Street, 6th Floor, New York, New York 10022 or by email at prospectus@cantor.com. You may also obtain these documents free of charge by visiting the SEC’s website at www.sec.gov. The ordinary shares to be sold in the concurrent private placement have not been registered under the Securities Act, or any state or other applicable jurisdiction’s securities laws, and may not be offered or sold in the United States absent registration or an applicable exemption from the registration requirements of the Securities Act and applicable state or other jurisdictions’ securities laws. This press release shall not constitute an offer to sell, or a solicitation of an offer to buy these securities, nor shall there be any sale of, these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. About ProQR ProQR Therapeutics is dedicated to changing lives through the creation of transformative RNA therapies. ProQR is pioneering a next-generation RNA technology called Axiomer™, which uses a cell’s own editing machinery called ADAR to make specific single nucleotide edits in RNA to reverse a mutation or modulate protein expression and could potentially yield a new class of medicines for both rare and prevalent diseases with unmet need. Based on its unique proprietary RNA repair platform technologies ProQR is growing its pipeline with patients and loved ones in mind. Forward-Looking Statements This press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “goal,” “intend,” “look forward to,” “may,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would” and similar expressions. Forward-looking statements are based on management’s beliefs and assumptions and on information available to management only as of the date of this press release. These forward-looking statements include, but are not limited to, statements about the expected timing and completion of the Offering and concurrent private placement. Such forward-looking statements involve risks and uncertainties, many of which are beyond ProQR’s control, including risks and uncertainties related to market conditions and satisfaction of customary closing conditions related to the Offering and the concurrent private placement. There can be no assurance that ProQR will be able to complete the Offering and the concurrent private placement on the anticipated terms, or at all. Applicable risks also include those that are included in ProQR’s prospectus supplement and accompanying prospectus filed with the SEC for the Offering, including the documents incorporated by reference therein, which include ProQR’s Annual Report on Form 20-F for the year ended December 31, 2023, and any subsequent SEC filings. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and ProQR assumes no obligation to update these forward-looking statements, even if new information becomes available in the future, except as required by law. ProQR Therapeutics N.V.Investor Contact:Sarah KielyProQR Therapeutics N.V.T: +1 617 599 6228skiely@proqr.comor Peter KelleherLifeSci AdvisorsT: +1 617 430 7579pkelleher@lifesciadvisors.com Media Contact:Robert StanislaroFTI ConsultingT: +1 212 850 5657robert.stanislaro@fticonsulting.com