TMPRSS6

Agios focuses on developing groundbreaking therapies for patients with rare diseases. Credit: kiehlord/Shutterstock. Agios Pharmaceuticals has announced that the US Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to tebapivat (AG-946) to treat myelodysplastic syndromes (MDS). The development comes after the company completed a Phase IIa trial of tebapivat in lower-risk MDS in 2023 and is now initiating a Phase IIb study of the asset for the same indication. The FDA’s Office of Orphan Drug Products awards ODD to aid the development of treatments for rare diseases affecting fewer than 200,000 people in the US. The designation offers several benefits to Agios, including tax credits, FDA fee exemptions and the potential for seven years of market exclusivity post-approval. Agios Pharmaceuticals research and development chief medical officer and head Sarah Gheuens stated: “Receiving orphan drug designation for tebapivat in MDS underscores the importance of bringing new oral treatment options to patients suffering from this rare disease. See Also: FDA grants breakthrough therapy designation to Neuraptive’s NTX-001 FDA grants breakthrough therapy status to Arrowhead’s plozasiran “We aim to deliver the first oral therapy that addresses anaemia due to ineffective erythropoiesis in lower-risk MDS, which affects approximately 75,000 to 80,000 patients in France, Germany, Italy, Spain, the UK and the US, and accounts for approximately 70% of MDS cases.” Agios focuses on developing groundbreaking therapies for patients with rare diseases. Its lead asset is mitapivat, a PK [pyruvate kinase] activator. This asset previously received ODD for PK deficiency, thalassaemia and sickle cell disease. In the US, Agios markets a first-in-class PK activator for adults with PK deficiency, offering a novel disease-modifying therapy for this rare and chronic haemolytic anaemia. Agios’ clinical pipeline also includes treatments for alpha and beta-thalassemia, sickle cell disease, paediatric PK deficiency, MDS-associated anaemia, and phenylketonuria. Agios is developing a preclinical TMPRSS6 siRNA as a potential treatment for polycythemia vera. In May 2024, Agios agreed to sell its stake in vorasidenib to Royalty Pharma for $905m. The company, which owns the royalties on the drug’s US sales, receives a 15% royalty on annual US net sales of vorasidenib up to $1bn.

– Reported Positive Topline Data from Phase 3 ENERGIZE-T Study; Expect to File sNDA Based on ENERGIZE and ENERGIZE-T Studies Encompassing All Thalassemia Subtypes by End of 2024 – – Announced $905 Million Purchase Agreement for Vorasidenib Royalty with Royalty Pharma; Agios to Receive a Total of $1.1 Billion in Payments Upon FDA Approval of Vorasidenib – – Reported Results from Phase 3 ACTIVATE-KidsT Study of Mitapivat in Children with Pyruvate Kinase (PK) Deficiency Who are Regularly Transfused – – PYRUKYND® (Mitapivat) Net Revenue of $8.6 Million in Q2; Cash, Cash Equivalents and Marketable Securities of $645.3 Million as of June 30, 2024 – CAMBRIDGE, Mass., Aug. 01, 2024 (GLOBE NEWSWIRE) -- Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, today reported business highlights and financial results for the second quarter ended June 30, 2024. “Based on the positive data generated in the Phase 3 ENERGIZE and ENERGIZE-T studies, mitapivat is the first therapy to demonstrate efficacy in all subtypes of thalassemia, and we look forward to filing for FDA review by the end of the year,” said Brian Goff, chief executive officer at Agios. “This morning, we were pleased to report topline data in the Phase 3 ACTIVATE-KidsT study of mitapivat, which is the first study to report safety and efficacy data in children with PK deficiency. We continue to make significant progress toward our vision of becoming a leading rare disease company with a potential multi-billion-dollar franchise in PK activation. Finally, we were pleased to bolster our cash position through a purchase agreement with Royalty Pharma for our vorasidenib royalty, with Agios now positioned to receive a total of $1.1 billion in payments upon FDA approval of vorasidenib.” Second Quarter 2024 and Recent Highlights PYRUKYND® Revenues: Generated $8.6 million in net revenue for the second quarter of 2024, a 5 percent sequential increase from the first quarter of 2024, primarily driven by increased patient demand. A total of 201 unique patients have completed prescription enrollment forms, representing an increase of 7 percent over the first quarter of 2024. A total of 128 patients are on PYRUKYND® therapy, a 7 percent increase from the first quarter of 2024.Thalassemia: Met the primary and all key secondary endpoints in the Phase 3 ENERGIZE-T study of mitapivat in adults with transfusion-dependent alpha- or beta-thalassemia.Presented positive results from the Phase 3 ENERGIZE study of mitapivat in adults with non-transfusion-dependent thalassemia in a plenary session at the European Hematology Association 2024 (EHA2024) Hybrid Congress. Pediatric PK Deficiency: Announced topline data from the Phase 3 ACTIVATE-KidsT study of mitapivat in children with PK deficiency who are regularly transfused. Agios plans to present a more detailed analyses of the results at an upcoming medical meeting.Completed enrollment of the Phase 3 ACTIVATE-Kids study of mitapivat in children with PK deficiency who are not regularly transfused. Topline data from this study are expected in 2025. Corporate Development: Announced a $905 million purchase agreement with Royalty Pharma for Agios’ rights to its vorasidenib royalty. Under the agreement, Agios will receive a payment of $905 million upon approval of vorasidenib by the FDA and Royalty Pharma will receive the entirety of the 15% royalty on annual U.S. net sales of vorasidenib up to $1 billion, and a 12% royalty on annual U.S. net sales greater than $1 billion. Agios retains a 3% royalty on annual U.S. net sales greater than $1 billion. Agios retains rights to a $200 million milestone payment from Servier upon FDA approval of vorasidenib.Entered into a distribution agreement with NewBridge Pharmaceuticals to advance commercialization of PYRUKYND® in the Gulf Cooperation Council (GCC) region. NewBridge, a leading specialty company headquartered in Dubai, will commercialize PYRUKYND® in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates. Key Upcoming Milestones & Priorities Agios expects to execute on the following additional key milestones and priorities by the end of 2024: Thalassemia: File sNDA for mitapivat in thalassemia based on the positive results from the Phase 3 ENERGIZE and ENERGIZE-T trials (year-end).Sickle Cell Disease: Complete enrollment in the Phase 3 portion of the RISE UP study of mitapivat (year-end).Lower-risk Myelodysplastic Syndromes: Dose first patient in Phase 2b study of tebapivat (AG-946) (mid-year).Other: Potential approval of Servier’s vorasidenib for the treatment of IDH-mutant diffuse glioma. The FDA has assigned a PDUFA action date of August 20, 2024. Second Quarter 2024 Financial Results Revenue: Net product revenue from sales of PYRUKYND® for the second quarter of 2024 was $8.6 million, compared to $6.7 million for the second quarter of 2023. Cost of Sales: Cost of sales for the second quarter of 2024 was $1.5 million. Research and Development (R&D) Expenses: R&D expenses were $77.4 million for the second quarter of 2024, compared to $68.9 million for the second quarter of 2023. The year-over-year increase was primarily attributable to an increase in costs associated with the in-licensed siRNA TMPRSS6 program for polycythemia vera. Selling, General and Administrative (SG&A) Expenses: SG&A expenses were $35.5 million for the second quarter of 2024 compared to $30.4 million for the second quarter of 2023. The year-over-year increase was primarily attributable to an increase in commercial-related activities as we prepare for the potential approval of PYRUKYND® in thalassemia. Net Loss: Net loss was $96.1 million for the second quarter of 2024 compared to $83.8 million for the second quarter of 2023. Cash Position and Guidance: Cash, cash equivalents and marketable securities as of June 30, 2024, were $645.3 million compared to $806.4 million as of December 31, 2023. Agios expects that its cash, cash equivalents and marketable securities together with anticipated product revenue, interest income and payments upon FDA approval of vorasidenib, will provide the financial independence to prepare for potential PYRUKYND® launches in thalassemia and sickle cell disease, and to opportunistically expand our pipeline through both internally and externally discovered assets. Conference Call Information Agios will host a conference call and live webcast with slides today at 8:00 a.m. ET to discuss second quarter 2024 financial results and recent business highlights. The live webcast can be accessed under “Events & Presentations” in the Investors section of the company’s website at www.agios.com. The archived webcast will be available on the company's website beginning approximately two hours after the event. About Agios Agios is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases. In the U.S., Agios markets a first-in-class pyruvate kinase (PK) activator for adults with PK deficiency, the first disease-modifying therapy for this rare, lifelong, debilitating hemolytic anemia. Building on the company's deep scientific expertise in classical hematology and leadership in the field of cellular metabolism and rare hematologic diseases, Agios is advancing a robust clinical pipeline of investigational medicines with programs in alpha- and beta-thalassemia, sickle cell disease, pediatric PK deficiency, MDS-associated anemia and phenylketonuria (PKU). In addition to its clinical pipeline, Agios is advancing a preclinical TMPRSS6 siRNA as a potential treatment for polycythemia vera. For more information, please visit the company’s website at www.agios.com. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential benefits of PYRUKYND® (mitapivat), tebapivat (AG-946), TMPRSS6 siRNA and AG-181, Agios’ PAH stabilizer; Agios’ plans, strategies and expectations for its preclinical, clinical and commercial advancement of its drug development, including PYRUKYND®, AG-946 (tebapivat) and AG-181; the potential FDA approval of vorasidenib; Agios’ use of proceeds from the transaction with Royalty Pharma; potential U.S. net sales of vorasidenib and potential future royalty payments; Agios’ strategic vision and goals, including its key milestones for 2024; and the potential benefits of Agios’ strategic plans and focus. The words “anticipate,” “expect,” “goal,” “hope,” “milestone,” “plan,” “potential,” “possible,” “strategy,” “will,” “vision,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this press release could also be affected by risks and uncertainties relating to a number of other important factors, including, without limitation: risks and uncertainties related to the impact of pandemics or other public health emergencies to Agios’ business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios’ results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA, the EMA or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios’ ability to obtain and maintain requisite regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; competitive factors; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios’ ability to establish and maintain key collaborations; uncertainty regarding any milestone or royalty payments related to the sale of its oncology business or its in-licensing of TMPRSS6 siRNA, and the uncertainty of the timing of any such payments; uncertainty of the results and effectiveness of the use of Agios’ cash and cash equivalents; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios’ public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this press release speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Consolidated Balance Sheet Data(in thousands)(Unaudited) June 30, 2024 December 31, 2023Cash, cash equivalents, and marketable securities $645,296 $806,363Accounts receivable, net 3,762 2,810Inventory 23,937 19,076Total assets 773,063 937,118Stockholders' equity 660,510 811,019 Consolidated Statements of Operations Data(in thousands, except share and per share data)(Unaudited) Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 Revenues: Product revenue, net$8,615 $6,712 $16,804 $12,321 Total revenue 8,615 6,712 16,804 12,321 Operating expenses: Cost of sales$1,495 $1,108 $2,122 $1,662 Research and development 77,401 68,895 146,021 136,196 Selling, general and administrative 35,536 30,409 66,550 58,776 Total operating expenses 114,432 100,412 214,693 196,634 Loss from operations (105,817) (93,700) (197,889) (184,313)Interest income, net 8,120 8,254 17,009 16,345 Other income, net 1,579 1,640 3,213 3,144 Net loss$(96,118) $(83,806) $(177,667) $(164,824)Net loss per share - basic and diluted$(1.69) $(1.51) $(3.14) $(2.97)Weighted-average number of common shares used in computing net loss per share – basic and diluted 56,802,546 55,604,330 56,593,011 55,435,796 Contacts: Investor ContactChris Taylor, VP Investor Relations and Corporate CommunicationsAgios PharmaceuticalsIR@agios.com Media ContactDan Budwick1ABdan@1abmedia.com

Divesiran eliminated the need for phlebotomy in all well-controlled patients following infrequent dosing and was well tolerated Data support advancing divesiran into Phase 2 LONDON, UK I June 27, 2024 I Silence Therapeutics plc (“Silence” or the “Company”), (Nasdaq: SLN), an experienced and innovative biotechnology company committed to transforming people’s lives by silencing diseases through precision engineered medicines, today announced positive results from the ongoing SANRECO Phase 1 repeat dose study of divesiran (SLN124), a siRNA (short interfering RNA) targeting TMPRSS6 , in patients with polycythemia vera (PV). “With today’s very exciting PV data, Silence is continuing to emerge as a true platform company. Both of our lead proprietary programs are now generating excellent clinical results,” said Craig Tooman, President and CEO at Silence. “Divesiran is poised to be the first siRNA for PV, and we look forward to advancing development with a phase 2 start planned by year-end.” The 34-week, open-label Phase 1 study is evaluating divesiran (3 mg/kg, 6 mg/kg and 9 mg/kg) administered subcutaneously every 6 weeks for four doses, with a 16-week follow-up period following the date of the last administered dose in up to 24 PV patients. Key inclusion criteria include a PV diagnosis and a history of requiring at least three phlebotomies in the last six months or five in the last year prior to screening. Patients are allowed to be on stable doses of cytoreductive agents. Given the exploratory nature of this Phase 1 study, both well-controlled patients – defined as those with hematocrit (HCT) levels at 45% or less – as well as those with HCT levels greater than 45% at baseline on current standard of care treatment were enrolled. The data being presented today are based on a data cut-off date of March 29, 2024, and include analysis of 16 patients over a time range of approximately 4 to 34 weeks of study involvement. Of the 16 patients, 8 patients are considered well-controlled and 8 patients have HCT levels over 45% at baseline. To date, divesiran has been observed to be well tolerated with no major safety issues. None of the 8 patients entering the trial with well-controlled HCT levels required a phlebotomy during the divesiran treatment period, which was defined in the study as the period up to 6 weeks after the last dose. All patients in the well-controlled group maintained adequate control of HCT levels as per treatment guidelines. Of the 8 patients entering the trial with HCT levels above 45%, 2 patients each required one phlebotomy. The baseline HCTs of these 2 patients were 56% and 53%. None of the 6 other patients in this group required a phlebotomy. Notably, none of the 13 patients entering the trial with HCT levels of 50% or below – 8 well-controlled patients and 5 patients with HCT levels of 46-50% – have required a phlebotomy to date. In all dose groups, there was a sustained reduction in hematocrit during the treatment period and favorable effects on indices of iron metabolism. Hepcidin levels increased and were sustained within physiological levels in all dose groups, demonstrating target engagement. “Divesiran treatment in PV patients results in sustained increases in hepcidin, reflecting crucial target engagement,” said Professor Tomas Ganz, MD, PhD, Distinguished Professor of Medicine and Pathology Department of Medicine, UCLA. “Divesiran exerts a beneficial effect on hematological parameters and significantly reduces phlebotomies. These exciting data suggest that divesiran has the potential to produce clinically meaningful outcomes in this patient population.” “Based on these early results, divesiran appears to meaningfully impact key hematological parameters in this rare myeloproliferative neoplasm,” said Steven Romano, MD, Silence’s Head of Research and Development. “We are particularly encouraged by the safety profile and the potential for divesiran to be administered infrequently to PV patients requiring pharmacological intervention to manage their disease.” As of today, Silence has enrolled 21 patients in the SANRECO study and the Company anticipates closing enrollment at the end of this month. Full results are expected to be presented at a scientific meeting later this year. Divesiran has received FDA Fast Track designation and FDA Orphan Drug Designation for PV. Conference Call and Webcast Details Management will host a conference call and webcast today, June 27, 2024, at 8:30 am ET to discuss results from the ongoing SANRECO phase 1 study. To access the call, please register online at https://register.vevent.com/register/BI33ea9b075fa841ea9597cc915562e79c . Participants are requested to register at a minimum of 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same web page for six months. A live webcast will also be available on the Investors section of the Company’s website at www.silence-therapeutics.com . An archived webcast will be available on the Company’s website approximately two hours after the event. About PV PV is a rare, myeloproliferative neoplasm – a type of blood cancer – characterized by the excessive production of red blood cells, often resulting in elevated hematocrit levels. Elevated hematocrit above 45-percent is associated with a four-times higher rate of death from cardiovascular or thrombotic events. PV is associated with a range of burdensome symptoms including fatigue, cognitive disturbance and pruritis and additionally, longer term can transform to myelofibrosis and Acute Myeloid Leukemia. The aim of treatment is to maintain hematocrit less than 45%, a level that is associated with a reduced incidence of thrombosis and CV-associated death. The current standard of care includes repeated phlebotomies to reduce hematocrit and/or cytoreductive agents to reduce red blood cell production. There are currently no approved therapies that specifically target red blood cells and hematocrit. About Divesiran Divesiran is Silence’s wholly owned siRNA developed from its proprietary mRNAi GOLD™ platform that “silences” TMPRSS6 expressed almost exclusively in the liver. TMPRSS6 is a negative regulator of hepcidin, the body’s master regulator of iron metabolism including its absorption, distribution, and storage. By silencing TMPRSS6 in PV patients, divesiran aims to increase hepcidin production and release by liver hepatocytes, leading to the restriction of iron to the bone marrow and, thus, reducing the excessive production of red blood cells, a process dependent on availability of iron. About Silence Therapeutics Silence Therapeutics is developing a new generation of medicines by harnessing the body’s natural mechanism of RNA interference, or RNAi, to inhibit the expression of specific target genes thought to play a role in the pathology of diseases with significant unmet need. Silence’s proprietary mRNAi GOLD™ platform can be used to create siRNAs (short interfering RNAs) that precisely target and silence disease-associated genes in the liver, which represents a substantial opportunity. Silence’s wholly owned product candidates include zerlasiran designed to address the high and prevalent unmet medical need in reducing cardiovascular risk in people born with high levels of lipoprotein(a) and divesiran designed to address hematological diseases, including polycythemia vera. Silence also maintains ongoing research and development collaborations with AstraZeneca and Hansoh Pharma, among others. For more information, please visit https://www.silence-therapeutics.com/ . SOURCE: Silence Therapeutics