PIK3R1

Full year 2023 total revenues increased by 19% to US$245.3 million Record fourth quarter RUCONEST® revenues of US$73.3 million resulted in a 10% increase in full year 2023 RUCONEST® revenues to US$227.1 million Strong start to Joenja® (leniolisib) launch with 81 patients on paid therapy in the U.S. nine months following launch and full year 2023 revenues of US$18.2 million Overall cash and marketable securities increased to US$215.0 million at the end of 2023 from US$208.7 million at the end of 2022 Progressed leniolisib development for APDS in additional geographies and for pediatric patients, and leniolisib indication expansion to primary immunodeficiencies (PIDs) with immune dysregulation linked to PI3Kδ signaling 2024 total revenue guidance of US$280 million – US$295 million (14% – 20% growth) Pharming to host a conference call today at 13:30 CET (8:30 am EDT) Leiden, The Netherlands, March 14, 2024: Pharming Group N.V. (“Pharming” or “the Company”) (Euronext Amsterdam: PHARM / Nasdaq: PHAR) presents its preliminary (unaudited) financial report for the three months and full year ended December 31, 2023. Chief Executive Officer, Sijmen de Vries commented: “We are pleased to have delivered an excellent year in which we transformed Pharming into a multi-product, commercial rare disease biopharmaceutical company. We grew RUCONEST® revenues by 10% in 2023. This demonstrates the continued need for, and importance of, RUCONEST® as a trusted cornerstone of treatment in the competitive HAE market. We launched Joenja® (leniolisib) for APDS in the U.S. in April 2023, shortly after FDA approval, and saw meaningful initial uptake for what is the first and only FDA approved treatment for APDS. We have identified and confirmed over 840 APDS patients in global markets, including over 200 in the U.S. We have started family genetic testing initiatives, important since the majority of APDS patients will have family members also afflicted with the disease. In addition we have commenced studies to determine which of more than 1,100 patients in the U.S., with inconclusive genetic testing results showing a variant of uncertain significance (VUS), have genetic variants that cause hyperactivity in the PI3Kẟ pathway and can, therefore, be classified as APDS disease causing. This allows for an important APDS diagnosis for these patients, who could potentially be eligible for and offered treatment with Joenja®. We also made strong progress preparing for the commercialization of leniolisib in key global markets. We have been receiving requests for individual treatment on a named patient basis, in markets outside of the U.S., and provided the first patients with leniolisib around year-end 2023. Numerous regulatory reviews are ongoing and we are preparing for commercialization in key global markets including Europe, the U.K., Japan, Asia Pacific, Middle East, and Canada. These results reflect Pharming’s dedication to developing and delivering therapies to unserved rare disease patients. Looking to 2024, we remain focused on our goals of identifying additional APDS patients globally, continuing the momentum for Joenja® revenue in the U.S., to obtaining regulatory approvals and bringing leniolisib to APDS patients in need of treatment in additional global markets and to further developing our rare disease pipeline and footprint. We are also seeking to significantly expand the leniolisib market opportunity and revenue growth by pursuing development of leniolisib for additional primary immunodeficiencies (PIDs) beyond APDS, and have advanced plans to start a Phase 2 proof of concept clinical trial in PIDs with immune dysregulation linked to PI3Kẟ signaling.” Fourth quarter and full year 2023 highlights Commercialized assets RUCONEST® marketed for the treatment of acute HAE attacks RUCONEST® performed strongly in the fourth quarter of 2023, with record revenues of US$73.3 million, a 34% increase compared to the fourth quarter of 2022. RUCONEST® revenues for the full year 2023 were US$227.1 million, a 10% increase compared to 2022. The U.S. market contributed 97% of 2023 revenues, while the EU and Rest of World contributed 3%. The RUCONEST® revenue acceleration in the second half of 2023 can be attributed to strong performance in leading key revenue indicators in the U.S. including new physicians prescribing RUCONEST®, new patient enrollments including high frequency attack patients, and the total number of patients. We achieved over 70 RUCONEST® new patient enrollments for four quarters in a row. Total enrollments in 2023 were up 25% vs. 2022 and were a significant driver of the strong RUCONEST® revenue growth. We also increased the RUCONEST® physician prescriber base by 13% during the year, in many cases adding previously unknown HAE prescribers. Joenja® (leniolisib) marketed in the U.S. - the first and only approved disease modifying treatment for APDS Joenja® (leniolisib) received U.S. FDA approval in late March 2023 for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in patients 12 years of age and older, and first commercial shipments to patients took place in April 2023. During the nine months following launch, Pharming made strong and rapid progress transitioning known patients onto commercial therapy. Revenues increased to US$7.9 million in the fourth quarter of 2023, driven by the continued increase in patients on paid therapy, and revenues were US$18.2 million for 2023. As of December 31, 2023, we have 92 APDS patients enrolled in the U.S., of which 81 patients are on paid therapy. APDS patient finding Based on available literature, Pharming estimates APDS prevalence of 1.5 patients per million. Our U.S. and global APDS patient finding efforts progressed during the year and as of December 31, 2023, Pharming has identified over 840 diagnosed APDS patients of all ages in global markets, including over 200 patients in the U.S. Of the identified patients in the U.S., approximately 75% are 12 years of age or older, the majority of whom are currently eligible for treatment with Joenja®. Over 730 patients are in the U.S., Europe, the U.K., Japan, Asia Pacific, Middle East, and Canada, key markets for Pharming with estimated total prevalence of ~2000 APDS patients. Pharming advanced several initiatives during 2023 to diagnose additional APDS patients, including a sponsored genetic testing program in the U.S., partnerships with several genetic testing companies who undertake their own testing efforts and family testing programs. We have initiated a number of programs collaborating with clinicians and patients to aid in reducing the barriers and allowing the appropriate testing in families with APDS, to help identify family members of APDS patients who may also be affected by this disease. APDS is an inherited genetic disease and Pharming believes that many of the over 200 APDS patients already identified in the U.S. are likely to have family members who remain undiagnosed. APDS patient finding - Variant of Uncertain Significance (VUS) resolution APDS is diagnosed based on clinical symptoms, assessment of immune cell function and genetic testing. For a patient to receive a definitive APDS diagnosis, a genetic test revealing a disease-causing (pathogenic or likely pathogenic) variant in either the PIK3CD or PIK3R1 genes is required. Patients with clinical symptoms compatible with APDS frequently receive inconclusive genetic variant test results, i.e. previously unseen variants in the PIK3CD or PIK3R1 genes. It is important to determine if these Variants of Uncertain Significance (VUS) cause APDS. As of December 31, 2023, Pharming has identified more than 1,100 patients in the U.S. with a number of VUSs in the PIK3CD or PIK3R1 genes and is setting up validation studies with various laboratories to confirm which of these variants should be classified as APDS. As results become available, patients with validated variants could be diagnosed with APDS and, therefore, potentially be eligible for Joenja® treatment. Completion of these studies is expected during the fourth quarter of 2024. Leniolisib highlights - regulatory, clinical and commercial strategy updates Leniolisib for APDS Pharming made continued progress in the fourth quarter of 2023 on leniolisib regulatory filings for APDS patients 12 years of age and older in key global markets. In addition, Pharming progressed ongoing clinical trials to support regulatory filings for approval in Japan and pediatric label expansion in key global markets. Pharming’s strategy is to make leniolisib commercially available for APDS patients in additional key markets in Europe, U.K., Japan, Asia Pacific, Middle East, and Canada. Pharming intends to market leniolisib directly in most of these markets following regulatory approval. We currently have 96 patients on leniolisib therapy as part of an Expanded Access Program (compassionate use) or an ongoing clinical study. In addition, Pharming makes leniolisib available on a named patient basis to ensure that physicians can request leniolisib on behalf of individual patients living with APDS, who meet the eligibility criteria and receive local health authority authorization, in certain countries where leniolisib is not commercially available. European Economic Area (EEA) As part of the review process of the Marketing Authorisation Application (MAA) for leniolisib for patients 12 years of age and older, Pharming submitted its response to the European Medicines Agency’s (EMA) Committee for Human Medicinal Products (CHMP) Day 180 list of outstanding issues (LoOI) in October 2023. In November 2023, Pharming received a Day 180 Second LoOI from the CHMP. The CHMP consulted an Ad-Hoc Expert Group (AEG) at a meeting held at the end of November. Pharming is working closely with the CHMP to address the remaining outstanding issues and we are now awaiting CHMP’s opinion on the leniolisib MAA. United Kingdom In November 2023, Pharming announced its intention to MAA with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) through the International Recognition Procedure (IRP) which replaced the European Commission Decision Recognition Procedure (ECDRP) from January 1, 2024. Pharming submitted an MAA for leniolisib on the basis of the US FDA approval on March 12, 2024. Japan clinical trial In May 2023, leniolisib was granted orphan drug designation (ODD) by the Ministry of Health, Labour and Welfare of Japan (MHLW) for the treatment of APDS. In August 2023, Pharming announced that the first patient was enrolled in a Phase III clinical trial in Japan evaluating leniolisib for the treatment of APDS in adult and pediatric patients 12 years of age and older. Patient enrollment in this study is now complete. The single-arm, open-label clinical trial will evaluate the safety, tolerability, and efficacy of leniolisib in three patients, 12 years of age and older, who have a confirmed APDS diagnosis. The study’s primary efficacy endpoints and secondary endpoints mirror those used to evaluate the clinical outcomes of the earlier leniolisib APDS trials. Pharming plans to application for the approval of leniolisib with Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), following completion of the appropriate clinical trials. An approval decision would be expected in nine months based on priority review of the application due to ODD. Eligible patients enrolled in the trial will continue to receive the investigational drug for at least an additional year through an open-label extension trial. Additional markets Pharming filed regulatory submissions in Canada and Australia in the third quarter of 2023, and Israel in the second quarter. These submissions are progressing as expected and we anticipate regulatory action in 2024 for Canada, Australia, and Israel. Pediatric clinical trials In 2023, Pharming initiated two pediatric clinical trials, for children ages 4 to 11 and ages 1 to 6 years old, at sites in the U.S., Japan, and the EU. The single-arm, open-label, multinational clinical trials will evaluate the safety, tolerability, and efficacy of leniolisib in 15 children, per clinical trial, who have a confirmed APDS diagnosis. The primary efficacy endpoints and secondary endpoints of the studies mirror those used to evaluate the clinical outcomes in the previous leniolisib Phase II/III APDS trials for patients aged 12 and older. Pharming is nearing completion of enrollment in the clinical trial for children ages 4 to 11 years old. In November 2023, the first patient was dosed in the clinical trial for children ages 1 to 6 years old. Enrollment in the study is continuing as planned. Leniolisib for additional indications (PI3Kδ platform) - Primary immunodeficiencies (PIDs) beyond APDS As we continue to work towards regulatory approvals of leniolisib for APDS in additional geographies and pediatric label expansion, we have also commenced work to identify and prioritize other indications where leniolisib has the potential to deliver value for patients. PI3Kδ has been identified as an important player in a variety of disease states, and leniolisib has demonstrated an attractive, long-term efficacy, safety and tolerability pro clinical trials conducted in both healthy volunteers and APDS patients. This provides a solid basis for our plans for the investigation and investment in further leniolisib indications. In December 2023, Pharming announced the expansion of its rare disease pipeline with plans to develop leniolisib for additional primary immunodeficiencies (PIDs) with greater prevalence than APDS. Pharming has engaged with and received feedback from the US FDA on its plans to develop leniolisib for PID disorders with immune dysregulation. Primary immunodeficiencies (PIDs) with immune dysregulation Leniolisib, by reducing PI3Kδ activity, could help rebalance immune dysregulation in PIDs, positively impacting clinical manifestations including lymphoproliferation and autoimmunity. Pharming is now in the final stages of preparation for the start of an initial Phase 2, proof of concept, clinical trial in targeted PID genetic disorders with immune dysregulation linked to PI3Kẟ signaling in lymphocytes, with similar clinical phenotypes and unmet medical need to APDS. These PID disorders include ALPS-FAS, CTLA4 haploinsufficiency and PTEN deficiency. The epidemiology of these targeted PID genetic disorders suggests a prevalence of approximately five patients per million. The Phase 2 clinical trial is a single arm, open-label, dose range-finding study to be conducted in approximately 12 patients. The objectives for the trial will be to assess safety and tolerability, pharmacokinetics, pharmacodynamics, and explore clinical efficacy of leniolisib in this new PID population. The trial has been designed to inform a subsequent Phase 3 program. Organizational highlights During 2023 our new Chairman, Dr. Richard Peters, was elected, succeeding Paul Sekhri, who came to the end of his maximum term (eight years). Dr. Peters is a highly respected and proven industry leader, who brings extensive medical and commercial acumen for difficult-to-treat and rare diseases, from development stage to large global biopharmaceutical companies, to Pharming. We also strengthened our Executive Committee with the appointment of a Chief Business Officer, Dr. Alexander Breidenbach, who has more than 20 years of partnering, R&D and management experience in biosciences and, in this newly created position, is tasked with the development and execution of Pharming’s growth strategy. Financial Summary Amounts in US$m except per share data 4Q 2023 4Q 2022 2023 2022 Consolidated Statement of Income Revenue - RUCONEST® 73.3 54.6 227.1 205.6 Revenue - Joenja® 7.9 0.0 18.2 0.0 Total Revenues 81.2 54.6 245.3 205.6 Cost of sales (7.1) (6.3) (25.2) (17.6) Gross profit 74.1 48.3 220.1 188.1 Other income 0.5 (1.1) 23.3 14.5 Research and development (11.6) (10.9) (68.9) (52.5) General and administrative (24.0) (17.6) (55.9) (46.0) Marketing and sales (37.9) (29.0) (124.0) (85.8) Operating profit (loss) 1.1 (10.2) (5.4) 18.2 Fair value gain (loss) on revaluation (0.9) (1.2) (0.9) (1.2) Other finance income 1.6 (4.8) 3.7 4.5 Other finance expenses (4.5) (1.5) (9.1) (5.5) Share of net profits in associates using the equity method 0.7 (0.4) (0.3) (1.1) Profit (loss) before tax (2.0) (18.1) (12.0) 15.0 Income tax credit (expense) (0.7) 3.5 1.9 (1.3) Profit (loss) for the period (2.7) (14.6) (10.1) 13.7 Share Information Basic earnings per share (US$) (0.004) (0.022) (0.015) 0.021 Diluted earnings per share (US$) (0.004) (0.022) (0.015) 0.019 Amounts in US$m December 31, 2023 December 31, 2022 Balance Sheet Cash and cash equivalents, restricted cash and marketable securities 215.0 208.7 Current assets 316.3 277.5 Total assets 461.4 425.8 Current liabilities 76.1 59.7 Equity 219.2 204.6 Financial highlights Fourth quarter 2023 Revenues in the fourth quarter of 2023 increased to US$81.2 million compared to US$54.6 million in the fourth quarter of 2022 and US$66.7 million in the third quarter of 2023. This growth was primarily due to a 34% increase in net sales for RUCONEST® compared to the same period last year, as well as an 18% increase compared to the third quarter of 2023. Additionally, Joenja® revenues in the fourth quarter were US$7.9 million, a 21% increase compared to the third quarter. Gross profit in the fourth quarter of 2023 increased by US$25.8 million compared to the fourth quarter of 2022. This growth was driven by higher revenues, although it was partially offset by increased RUCONEST® production costs and royalty payments to Novartis on Joenja® sales. Operating expenses increased by US$16.1 million in the fourth quarter compared to last year. US$8.3 million of this increase is directly related to research and development expenses for leniolisib and marketing and sales expenses for Joenja®. Pharming’s expansion efforts, driven by preparations for the launch and further commercialization of Joenja®, led to a US$7.1 million increase in payroll expenses. In the fourth quarter of 2023, an operating profit of US$1.1 million was realized, in contrast to an operating loss of US$10.2 million in the fourth quarter of 2022. This improvement was primarily driven by the rise in gross profit, partially offset by the increase in operating expenses. Full year 2023 In 2023, Pharming revenues increased by 19% to US$245.3 million. However, operating profit declined to a loss of US$5.4 million, compared to a profit of US$18.2 million in 2022. Similarly, net profit decreased to loss of US$10.1 million, down from a profit of US$13.7 million in 2022. This section will further elaborate on Pharming's financial performance in 2023. Revenues and Gross Profit The 19% increase in revenues was a result of higher unit sales volumes, supported by a price increase below CPI, of RUCONEST® in the U.S. market (US$221.2 million in 2023 compared to US$200.1 million in 2022) and the initial sales of Joenja® (US$18.2 million in 2023) following the launch in April 2023. Revenues in Europe and the rest of the world increased by 12% to US$6.2 million in 2023. Cost of sales increased by 44% from US$17.6 million in 2022 to US$25.2 million in 2023. Cost of sales related to product sales in 2023 amounted to US$23.5 million compared to US$17.4 million in 2022. In addition to the higher unit sales volume, the rise was primarily attributed to rising production costs for RUCONEST® and royalty payments to Novartis on Joenja® sales. The remainder of cost of sales in 2023 (US$1.7 million) stem from impairment charges on inventory (2022: US$0.2 million). Gross profit increased by US$32.0 million, or 17%, to US$220.1 million for the year 2023. The main reasons for this increase were higher sales of RUCONEST® and the launch of Joenja®. Operating Profit (loss) and Other Operating Costs For 2023, operating profit (loss) decreased by US$23.6 million to US$(5.4) million compared with US$18.2 million for the prior year. This decrease was driven by increased operating costs (US$64.5 million) and offset by increased gross profit (US$32.0 million) as mentioned above and increased other income (US$8.8 million). Of the US$64.5 million increase in operating costs, US$10.4 million is attributed to milestone payments for Joenja® following its first commercial sale in the second quarter of 2023. An additional US$25.7 million in expenses is directly related to research and development expenses for leniolisib and marketing and sales expenses for Joenja®. Pharming’s expansion efforts, driven by preparations for the launch and further commercialization of Joenja®, led to a US$24.2 million increase in payroll expenses. Finally, Pharming incurred additional impairment expenses related to our DSP facility at Pivot Park in Oss, the Netherlands, amounting to US$4.7 million in 2023 compared to US$3.9 million in 2022. In 2023, other income increased by US$8.8 million to US$23.3 million as a result of the definitive agreement to sell the Rare Pediatric Disease Priority Review Voucher (PRV) to Novartis for a pre-agreed, one-time payment of US$21.3 million. Pharming was granted the PRV by the FDA in March 2023 in connection with the approval of Joenja®. The amount differs from the previously disclosed US$21.1 million in the press release of the second quarter of 2023 due to currency fluctuations throughout the year. In 2022, Pharming reduced its minority stake in BioConnection from 43.85% to 22.98%. As a result of this one-off transaction, Pharming had recognized a gain of US$12.2 million in 2022. Finance income and expenses Other finance income decreased by US$0.8 million, to US$3.7 million in 2023. This decrease was caused by fluctuations in the exchange rate between the U.S. Dollar and the Euro during 2022 and 2023, which primarily impacts our net cash position. In 2022, the U.S. Dollar strengthened against the Euro, resulting in other finance income of US$4.4 million. However, in 2023, the U.S. Dollar weakened relative to the Euro, leading to other finance expenses of US$3.0 million. This decrease in other finance income was for largely offset by increased interest income from US$0.1 million in 2022 to US$3.7 million in 2023. This was driven by general interest rate hikes as well as investments in short-term readily convertible S&P AAA-rated government treasury certificates using excess cash. Other finance expenses increased by US$3.6 million, from US$5.5 million in, 2022 to US$9.1 million in 2023, mainly caused by foreign currency fluctuations as mentioned earlier. The fair value loss on revaluation (US$0.9 million) relates to fair value adjustments in the BioConnection preference share. This share is included in Pharming's balance sheet as an investment in debt instruments designated at the fair value through the statement of profit and loss (FVTPL). Income tax credit (expense) Income tax credit (expense) shifted from a US$1.3 million expense for the year ending December 31, 2022, to a US$1.9 million credit for the year ending December 31, 2023. This change occurred due to incurring a net loss before tax in 2023, as opposed to a net profit before tax in 2022. Profit (loss) for the year The total net loss in 2023 amounted to US$10.1 million, compared to a total net profit of US$13.7 million in 2022. This decrease was primarily caused by higher operating costs, due to Pharming’s growth trajectory and investments in its product pipeline. In addition, fluctuations in foreign exchange rates adversely impacted the foreign currency results in the statement of income. These increased costs were partially offset by an increase in gross profit and other income. Intangible assets In 2023, intangible assets decreased by US$3.8 million, from US$75.1 million in 2022 to US$71.3 million in 2023. This decrease primarily resulted from regular amortization (amounting to US$5.9 million), partially offset by foreign currency effects (equivalent to US$2.2 million). The amortization relates to regular amortization of software and the existing re-acquired rights related to the acquisition of all North American commercialization rights from Bausch Health in 2016 and the acquisition of all European commercialization and distribution rights from Swedish Orphan International AB (“Sobi”) in 2020. In addition to the aforementioned, the amortization of the Joenja® license commenced, following the FDA approval per March 24, 2023. Amortization is charged based on the economic lifetime of the intangible asset. The economic lifetime of the North American commercialization rights from Bausch Health is 20 years, where the economic lifetime of the European commercialization and distribution rights from Swedish Orphan International AB is 12 years. These estimates did not change compared to the previous year. The economic lifetime of the Joenja® license is established at 14 years. Property, plant and equipment The value of property, plant and equipment decreased from US$10.4 million in 2022 to US$9.7 million in 2023. This decline was primarily driven by regular depreciation (amounting to US$2.4 million), partially offset by capital expenditures (totaling US$1.4 million), which were mainly associated with acquiring new machinery and equipment for Pharming's production process. Right-of-use assets The right-of-use assets decreased from US$28.8 million in 2022 to US$23.8 million in 2023. This decline was primarily driven by regular depreciation (amounting to US$4.2 million) and an additional impairment related to the DSP facility at Pivot Park in Oss, the Netherlands (totaling US$4.7 million). Pharming remains exploring alternative utilization possibilities for this asset. The decrease in the right-to-use assets is partially offset by investments in buildings (US$1.9 million) and cars (US$1.4 million). The 2023 building investments were related to adjustments in the existing right-of-use assets to account for inflation-related higher lease payments. Investments Investments increased by US$0.7 million, reaching US$10.4 million as of December 31, 2023. This growth was primarily driven by a US$1.6 million increase in the equity investment in Orchard, which is designated at fair value through the statement of other comprehensive income (FVTOCI). The rise in value was primarily triggered by the announcement that Orchard had entered into a definitive agreement with Japanese company Kyowa Kirin Co. LTD for the acquisition of Orchard at a premium over the prevailing share price. This transaction was successfully completed on January 24, 2024. Additionally, the overall investments saw a US$0.3 million increase due to favorable currency exchange movements. The increase in investments was partially offset by Pharming’s share of US$0.3 million in the net loss of BioConnection, which is accounted for using the equity method. Furthermore, the investments were impacted by a fair value decrease of US$0.9 million in the preference share in BioConnection, carried at fair value through the statement of profit and loss (FVTPL). Inventories Inventories increased from US$42.3 million for the year ended December 31, 2022 to US$56.8 million for the year ended December 31, 2023. This was largely due to an increase in finished goods and work in progress inventory. Cash and cash equivalents and marketable securities Cash and cash equivalents alone decreased by US$145.8 million to US$61.5 million, as of December 31, 2023. This decline was primarily driven by negative cash flows from operating activities (totaling US$17.5 million) and net-purchases of marketable securities (amounting to US$149.2 million). This decrease was largely offset by the aforementioned PRV sale of US$21.3 million. In 2023, the Company invested in euro-denominated readily convertible S&P AAA-rated government treasury certificates with a maturity of six months or less from the date of acquisition. As of year-end 2023, these marketable securities amount to US$151.7 million. The combined total of cash and cash equivalents, together with restricted cash and marketable securities increased from US$208.7 million at year-end 2022 to US$215.0 million at year-end 2023. In addition to the movements mentioned earlier, this increase is partially attributable to favorable currency exchange fluctuations. Equity The equity position increased by US$14.5 million from US$204.6 million for the year ended December 31, 2022 to US$219.2 million for the year ended December 31, 2023. This increase was primarily driven by transactions recognized directly in equity relating to share based compensation and exercised options (totaling US$17.4 million) as well as other comprehensive income relating to the currency translation reserve (amounting to US$5.9 million) and fair value changes on investments designated as fair value through the statement of other comprehensive income (contributing US$1.2 million). This increase was partially offset by a net loss of US$10.1 million for the year. Convertible bond The convertible bond has increased by US$5.0 million to US$138.4 million at year-end 2023, moving from US$133.4 million as of December 31, 2022. This increase was mainly driven by foreign currency effects. During 2023, a total of US$4.0 million of interest was paid on the bond. Lease liabilities Lease liabilities decreased by US$0.2 million, moving from US$33.3 million as of December 31, 2022 to US$33.1 million as of December 31, 2023. This decrease was primarily driven by monthly or quarterly lease payments of US$5.1 million. However, it was partially offset by new leases (amounting to US$3.2 million), regularly accrued interest expenses (equivalent to US$1.2 million) and foreign exchange effects (totaling US$0.8 million). Outlook/Summary For 2024, the Company anticipates: Total revenues between US$280 million and US$295 million (14% to 20% growth), with quarterly fluctuations expected. Continued progress finding additional APDS patients in the U.S., supported by family testing and VUS validation efforts, and subsequently converting patients to paid Joenja® (leniolisib) therapy. Increasing ex-U.S. revenues leniolisib - from commercial availability or through our Named Patient Program and other funded early access programs in key global markets. Completion of leniolisib clinical trials to support regulatory filings for approval in Japan and pediatric label expansion in key global markets. Progress towards regulatory approvals for leniolisib in the EEA, the U.K., Canada, Australia, and Israel. Initiate and advance a Phase 2 clinical trial for leniolisib in PIDs with immune dysregulation linked to PI3Kδ signaling to significantly expand the long-term commercial potential of leniolisib. Continued operating cost investments to accelerate future revenue growth. Our current cash on hand and the continued cash flow from product revenues are expected to be sufficient to fund these investments. No material cash burn is expected prior to the impact of potential acquisition or in-licensing transactions. Continued focus on potential acquisitions and in-licensing of clinical stage opportunities in rare diseases. Financing, if required, would come via a combination of our strong balance sheet and access to capital markets. No further specific financial guidance for 2024 is provided. Additional information Presentation The conference call presentation is available on the Pharming.com website from 07:30 CET today. Conference Call The conference call will begin at 13:30 CET/08:30 am EDT on Thursday, March 14. A transcript will be made available on the Pharming.com website in the days following the call. Please note, the Company will only take questions from dial-in attendees. Webcast Link: Conference call dial-in details: Additional information on how to register for the conference call/webcast can be found on the Pharming.com website. Financial Calendar 2024 Annual Report and 20-F 2023 April 4 1Q 2024 financial results May 8 Annual General Meeting of Shareholders May 21 2Q/1H 2024 financial results August 1 3Q 2024 financial results October 24 For further public information, contact: Pharming Group N.V., Leiden, The Netherlands Michael Levitan, VP Investor Relations & Corporate Communications T: +1 (908) 705 1696 E: investor@pharming.com FTI Consulting, London, UK Victoria Foster Mitchell/Alex Shaw T: +44 203 727 1000 LifeSpring Life Sciences Communication, Amsterdam, The Netherlands Leon Melens T: +31 6 53 81 64 27 E: pharming@lifespring.nl About Pharming Group N.V. Pharming Group N.V. (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) is a global biopharmaceutical company dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. Pharming is commercializing and developing an innovative portfolio of protein replacement therapies and precision medicines, including small molecules, biologics, and gene therapies that are in early to late-stage development. Pharming is headquartered in Leiden, Netherlands, and has employees around the globe who serve patients in over 30 markets in North America, Europe, the Middle East, Africa, and Asia-Pacific. For more information, visit and find us on LinkedIn. Risk profile We continue to closely monitor and manage the key risks and opportunities, and will respond appropriately to any emerging risk. We will issue a full overview of our risk pro our Annual report 2023 to be published on April 4, 2024. Related party transactions There are no material changes in the nature, scope, and (relative) scale in this reporting period compared to last year. Auditor’s involvement The Condensed Consolidated Interim Financial Statements have not been audited by the Company’s statutory auditor. Forward-looking Statements This press release may contain forward-looking statements. Forward-looking statements are statements of future expectations that are based on management’s current expectations and assumptions and involve known and unknown risks and uncertainties that could cause actual results, performance, or events to differ materially from those expressed or implied in these statements. These forward-looking statements are identified by their use of terms and phrases such as “aim”, “ambition”, ‘‘anticipate’’, ‘‘believe’’, ‘‘could’’, ‘‘estimate’’, ‘‘expect’’, ‘‘goals’’, ‘‘intend’’, ‘‘may’’, “milestones”, ‘‘objectives’’, ‘‘outlook’’, ‘‘plan’’, ‘‘probably’’, ‘‘project’’, ‘‘risks’’, “schedule”, ‘‘seek’’, ‘‘should’’, ‘‘target’’, ‘‘will’’ and similar terms and phrases. Examples of forward-looking statements may include statements with respect to timing and progress of Pharming's preclinical studies and clinical trials of its product candidates, Pharming's clinical and commercial prospects, and Pharming's expectations regarding its projected working capital requirements and cash resources, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the scope, progress and expansion of Pharming's clinical trials and ramifications for the cost thereof; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in Pharming's 2022 Annual Report and the Annual Report on Form 20-F for the year ended December 31, 2022, filed with the U.S. Securities and Exchange Commission, the events and circumstances discussed in such forward-looking statements may not occur, and Pharming's actual results could differ materially and adversely from those anticipated or implied thereby. All forward-looking statements contained in this press release are expressly qualified in their entirety by the cautionary statements contained or referred to in this section. Readers should not place undue reliance on forward-looking statements. Any forward-looking statements speak only as of the date of this press release and are based on information available to Pharming as of the date of this release. Pharming does not undertake any obligation to publicly update or revise any forward-looking statement as a result of new information, future events or other information. Inside Information This press release relates to the disclosure of information that qualifies, or may have qualified, as inside information within the meaning of Article 7(1) of the EU Market Abuse Regulation. Pharming Group N.V. Condensed Consolidated Financial Statements in U.S. Dollars (unaudited) For the year ended 31 December 2023 Condensed consolidated statement of income Condensed consolidated statement of comprehensive income Condensed consolidated balance sheet Condensed consolidated statement of changes in equity Condensed consolidated statement of cash flow CONDENSED CONSOLIDATED STATEMENT OF INCOME For the year ended 31 December Amounts in US$ ‘000 2023 2022 Revenues 245,316 205,622 Costs of sales (25,212) (17,562) Gross profit 220,104 188,060 Other income 23,349 14,523 Research and development (68,914) (52,531) General and administrative (55,877) (46,016) Marketing and sales (124,049) (85,803) Other Operating Costs (248,840) (184,350) Operating profit (loss) (5,387) 18,233 Fair value gain (loss) on revaluation (930) (1,185) Other finance income 3,663 4,485 Other finance expenses (9,069) (5,463) Finance result, net (6,336) (2,163) Share of net profits (loss) in associates using the equity method (289) (1,083) Profit (loss) before tax (12,012) 14,987 Income tax expense 1,893 (1,313) Profit (loss) for the year (10,119) 13,674 Basic earnings per share (US$) (0.015) 0.021 Diluted earnings per share (US$) (0.015) 0.019 CONDENSED CONSOLIDATED STATEMENT OF COMPREHENSIVE INCOME For the year ended 31 December Amounts in US$ ‘000 2023 2022 Profit (loss) for the year (10,119) 13,674 Currency translation differences 5,913 (10,349) Items that may be subsequently reclassified to profit or loss 5,913 (10,349) Fair value remeasurement investments 1,167 (705) Items that shall not be subsequently reclassified to profit or loss 1,167 (705) Other comprehensive income (loss), net of tax 7,080 (11,054) Total comprehensive income (loss) for the year (3,039) 2,620 CONDENSED CONSOLIDATED BALANCE SHEET As at 31 December Amounts in US$ ‘000 2023 2022 Non-current assets Intangible assets 71,267 75,121 Property, plant and equipment 9,689 10,392 Right-of-use assets 23,777 28,753 Long-term prepayments 92 228 Deferred tax assets 28,332 22,973 Investment accounted for using the equity method 2,285 2,501 Investments in equity instruments designated as at FVTOCI 2,020 403 Investment in debt instruments designated as at FVTPL 6,093 6,827 Restricted cash 1,528 1,099 Total non-current assets 145,083 148,297 Current assets Inventories 56,760 42,326 Trade and other receivables 46,157 27,619 Restricted cash 222 213 Marketable securities 151,683 — Cash and cash equivalents 61,519 207,342 Total current assets 316,341 277,500 Total assets 461,424 425,797 Share capital 7,669 7,509 Share premium 478,431 462,297 Other reserves (2,080) (8,737) Accumulated deficit (264,834) (256,431) Shareholders’ equity 219,186 204,638 Non-current liabilities Convertible bonds 136,598 131,618 Lease liabilities 29,507 29,843 Total non-current liabilities 166,105 161,461 Current liabilities Convertible bonds 1,824 1,768 Trade and other payables 70,693 54,465 Lease liabilities 3,616 3,465 Total current liabilities 76,133 59,698 Total equity and liabilities 461,424 425,797 CONDENSED CONSOLIDATED STATEMENT CHANGES IN EQUITY For the period ended 31 December Attributable to owners of the parent Amounts in US$ ‘000 Share capital Share premium Other reserves Accumulated deficit Total equity Balance at January 1, 2022 7,429 455,254 3,400 (273,167) 192,916 Profit (loss) for the year — — — 13,674 13,674 Other comprehensive income (loss) for the year — — (11,054) — (11,054) Total comprehensive income (loss) for the year — — (11,054) 13,674 2,620 Other reserves — — (1,083) 1,083 — Income tax benefit from excess tax deductions related to share-based payments — — — 430 430 Share-based compensation — — — 6,392 6,392 Options exercised / LTIP shares issued 80 7,043 — (4,843) 2,280 Total transactions with owners, recognized directly in equity 80 7,043 (1,083) 3,062 9,102 Balance at December 31, 2022 7,509 462,297 (8,737) (256,431) 204,638 Profit (loss) for the year — — — (10,119) (10,119) Other comprehensive income (loss) for the year — — 7,080 — 7,080 Total comprehensive income (loss) for the year — — 7,080 (10,119) (3,039) Other reserves — — (423) 423 — Income tax benefit from excess tax deductions related to share-based payments — — — 203 203 Share-based compensation — — — 9,251 9,251 Options exercised / LTIP shares issued 160 16,134 — (8,161) 8,133 Total transactions with owners, recognized directly in equity 160 16,134 (423) 1,716 17,587 Balance at December 31, 2023 7,669 478,431 (2,080) (264,834) 219,186 CONDENSED CONSOLIDATED STATEMENT OF CASH FLOWS For the year ended 31 December Amounts in $’000 2023 2022 Profit (loss) before tax (12,012) 14,987 Adjustments to reconcile net profit (loss) to net cash used in operating activities: Depreciation, amortization, impairment of non-current assets 15,925 13,188 Equity settled share based payments 9,251 6,392 Gain on disposal of investment in associate 0 (12,242) Fair value gain (loss) on revaluation 930 1,185 Gain on disposal from PRV sale (21,279) 0 Other finance income (3,663) (4,485) Other finance expenses 9,069 5,463 Share of net profits in associates using the equity method 289 1,083 Other (1,080) (1,576) Operating cash flows before changes in working capital (2,570) 23,995 Changes in working capital: Inventories (14,434) (15,016) Trade and other receivables (18,538) 2,364 Payables and other current liabilities 16,228 11,992 Restricted cash (438) 273 Total changes in working capital (17,182) (387) Interest received (paid) 2,883 85 Income taxes received (paid) (655) (1,235) Net cash flows generated from (used in) operating activities (17,524) 22,458 Capital expenditure for property, plant and equipment (1,437) (1,376) Proceeds on PRV sale 21,279 0 Investment intangible assets (27) (601) Proceed from sale of Investment associate 0 7,300 Purchases of marketable securities (382,014) 0 Proceeds from sale of marketable securities 232,811 0 Net cash flows generated from (used in) investing activities (129,388) 5,323 Payment of lease liabilities (5,126) (3,311) Interests on loans and leases (4,046) (3,952) Settlement of share based compensation awards 8,133 2,281 Net cash flows generated from (used in) financing activities (1,039) (4,982) Increase (decrease) of cash (147,951) 22,799 Exchange rate effects 2,128 (7,381) Cash and cash equivalents at January 1 207,342 191,924 Total cash and cash equivalents at December 31 61,519 207,342 ---ENDS---

Expect 10% growth in RUCONEST® revenue, significantly exceeding prior guidance Expect Joenja® revenues of approximately US$18 million with 81 patients on paid therapy at year end Leiden, The Netherlands, January 8, 2024: Pharming Group N.V. (“Pharming” or “the Company”) (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) announces today updated full year 2023 guidance, including RUCONEST® and Joenja® revenues, and a progress update on the U.S. launch of Joenja® (leniolisib) for APDS. For the full year 2023, total revenues are expected to increase by 19% to approximately US$245 million (preliminary and unaudited*). Sijmen de Vries, Chief Executive Officer, commented: “We are pleased to have concluded an excellent year in which we transformed Pharming into a multi-product, commercial rare disease biopharmaceutical company. We expect 10% growth in RUCONEST® revenues, significantly exceeding our previous guidance for low single digit annual revenue growth. We launched Joenja® (leniolisib) for APDS in the U.S. in April, shortly after FDA approval, and saw fast uptake from patients for the first and only FDA approved treatment for APDS. These results reflect the dedication of Pharming employees to develop and deliver therapies to otherwise unserved rare disease patients. Looking towards 2024, we remain focused on our goals to obtain regulatory approvals and commercialize leniolisib for APDS in additional global markets, and to further develop our rare disease pipeline and footprint. We seek to significantly expand the leniolisib market opportunity by pursuing development of leniolisib for additional primary immunodeficiencies (PIDs) beyond APDS, including a Phase 2 proof of concept clinical trial protocol in PIDs with immune dysregulation linked to PI3Kẟ signaling planned to start in 2Q 2024.” Updated 2023 guidance (preliminary and unaudited*) RUCONEST® for HAE For the full year 2023, we expect RUCONEST® revenues to increase by 10% to approximately US$227 million, significantly exceeding our previous low single digit growth guidance.New patient enrollments in 2023 were up 25% vs. the prior year and were a significant driver of the strong RUCONEST® revenue growth achieved throughout 2023.In 2023, Pharming saw the first full-year, post-pandemic benefit of its first quarter 2020 restructuring and expansion of its U.S. salesforce. The Company achieved record numbers in leading metrics including increasing the RUCONEST® physician prescriber base by 13% during the year, in many cases adding previously unknown HAE prescribers. Joenja® (leniolisib) for APDS For the full year 2023, we expect Joenja® revenues of approximately US$18 million driven by the continued increase during the fourth quarter in patients on paid therapy. First commercial shipments of Joenja® to patients took place in April 2023.As of December 31, 2023 we have 92 APDS patients enrolled in the U.S., of which 81 patients are on paid therapy.Our U.S. and global APDS patient finding efforts progressed during the year. As of December 31, 2023, Pharming has identified over 840 diagnosed APDS patients in global markets targeted for commercialization, including over 200 patients in the United States. In addition, we have identified more than 1,100 patients in the U.S. with a number of variants of uncertain significance (VUS) in the PIK3CD or PIK3R1 genes and are setting up validation studies with various laboratories to confirm which of these variants should be classified as APDS. As results become available, patients with validated variants could be diagnosed with APDS and be eligible for Joenja® treatment. Completion of these studies is expected during 4Q 2024. Overall cash and marketable securities Preliminary, unaudited cash and cash equivalents, together with restricted cash and marketable securities, are expected to total US$215.0 million at the end of 2023, compared to US$199.2 million at the end of the third quarter 2023 and US$208.7 million at the end of 2022. *Updated guidance based on preliminary selected financial results that are unaudited and subject to adjustment. Pharming expects to issue full financial results for the fourth quarter and full year 2023 in March 2024. The Company has not completed its financial closing procedures for the quarter or year ended December 31, 2023 and actual results could differ from these preliminary financial results. About Pharming Group N.V. Pharming Group N.V. (EURONEXT Amsterdam: PHARM/Nasdaq: PHAR) is a global biopharmaceutical company dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. Pharming is commercializing and developing an innovative portfolio of protein replacement therapies and precision medicines, including small molecules, biologics, and gene therapies that are in early to late-stage development. Pharming is headquartered in Leiden, Netherlands, and has employees around the globe who serve patients in over 30 markets in North America, Europe, the Middle East, Africa, and Asia-Pacific. For more information, visit www.pharming.com and find us on LinkedIn. Forward-looking Statements This press release may contain forward-looking statements. Forward-looking statements are statements of future expectations that are based on management’s current expectations and assumptions and involve known and unknown risks and uncertainties that could cause actual results, performance, or events to differ materially from those expressed or implied in these statements. These forward-looking statements are identified by their use of terms and phrases such as “aim”, “ambition”, ‘‘anticipate’’, ‘‘believe’’, ‘‘could’’, ‘‘estimate’’, ‘‘expect’’, ‘‘goals’’, ‘‘intend’’, ‘‘may’’, “milestones”, ‘‘objectives’’, ‘‘outlook’’, ‘‘plan’’, ‘‘probably’’, ‘‘project’’, ‘‘risks’’, “schedule”, ‘‘seek’’, ‘‘should’’, ‘‘target’’, ‘‘will’’ and similar terms and phrases. Examples of forward-looking statements may include statements with respect to timing and progress of Pharming's preclinical studies and clinical trials of its product candidates, Pharming's clinical and commercial prospects, and Pharming's expectations regarding its projected working capital requirements and cash resources, which statements are subject to a number of risks, uncertainties and assumptions, including, but not limited to the scope, progress and expansion of Pharming's clinical trials and ramifications for the cost thereof; and clinical, scientific, regulatory and technical developments. In light of these risks and uncertainties, and other risks and uncertainties that are described in Pharming's 2022 Annual Report and the Annual Report on Form 20-F for the year ended December 31, 2022, filed with the U.S. Securities and Exchange Commission, the events and circumstances discussed in such forward-looking statements may not occur, and Pharming's actual results could differ materially and adversely from those anticipated or implied thereby. All forward-looking statements contained in this press release are expressly qualified in their entirety by the cautionary statements contained or referred to in this section. Readers should not place undue reliance on forward-looking statements. Any forward-looking statements speak only as of the date of this press release and are based on information available to Pharming as of the date of this release. Pharming does not undertake any obligation to publicly update or revise any. Inside Information This press release relates to the disclosure of information that qualifies, or may have qualified, as inside information within the meaning of Article 7(1) of the EU Market Abuse Regulation. For further public information, contact: Pharming Group, Leiden, The NetherlandsMichael Levitan, VP Investor Relations & Corporate CommunicationsT: +1 (908) 705 1696 Heather Robertson, Investor Relations & Corporate Communications ManagerE: investor@pharming.com FTI Consulting, London, UKVictoria Foster Mitchell/Alex Shaw/Amy ByrneT: +44 203 727 1000 LifeSpring Life Sciences Communication, Amsterdam, The NetherlandsLeon MelensT: +31 6 53 81 64 27E: pharming@lifespring.nl

2023年，美国FDA共批准55款新药上市，仅次于2018年的59款。其中新分子实体达37种，小分子居多，占比约达55%（30款）。从疾病领域来看，小分子新药多集中在肿瘤和罕见病领域，其次为免疫炎症、感染、神经系统、心血管及代谢类疾病。综合来看，2023年FDA批准的小分子新药一大亮点在于，具有创新机制的疗法占比延续了近年来不断攀升的大趋势。本文总结了2023年具有代表性和突破性的小分子新药，以期希望通过这些小分子新药的结构、作用机制和临床数据，对未来国内的小分子药物研发有所启发。2023年FDA批准的小分子药物一览来源：药渡数据FDA批准的首款非共价BTK抑制剂药品名称：Jayprica(Pirtobrutinib)获批时间：2023年1月27日适应症：复发或难治性套细胞淋巴瘤（MCL）Pirtobrutinib目前为礼来所有，是一款非共价BTK激酶抑制剂，用于治疗至少二线全身治疗后复发或难治性套细胞淋巴瘤（MCL）的成年患者。在B细胞中，BTK信号导致B细胞增殖、运输、趋化性和粘附所必需的通路激活。Pirtobrutinib与BTK野生型和C481突变体结合，从而抑制BTK激酶活性。临床表现：FDA的批准基于单臂的BRUIN试验中部分患者的数据：在120名MCL患者中，93%的患者接受过2次或以上治疗，所有患者均接受过一种或多种共价BTK抑制剂的既往治疗，接受Pirtobrutinib治疗的MCL患者的总体缓解率（ORR）为50%，缓解持续时间（DOR）中位数为8.3个月。Pirtobrutinib结构式来源：药渡数据FDA批准的首款口服SERD药品名称：Orserdu(Elacestrant)获批时间：2023年1月27日适应症：乳腺癌Elacestrant是由Stemline Therapeutics开发的口服雌激素受体拮抗剂（SERD），用于治疗在至少一种内分泌治疗后疾病进展的，ER+/HER2-、ESR1突变的晚期或转移性乳腺癌的绝经后女性或成年男性。在ER+/HER2-乳腺癌细胞中，Elacestrant在诱导通过蛋白酶体途径介导的ERα蛋白降解的浓度下抑制17β-雌二醇介导的细胞增殖。Elacestrant在体外和体内均表现出抗肿瘤活性，包括对氟维司群、CDK4/6抑制剂耐药的ER+/HER2-乳腺癌模型以及具有雌激素受体1基因（ESR1）突变的模型。此前，SERD只有氟维司群于2002年上市，且需要肌肉注射给药。临床表现：FDA的批准基于在EMERALD III期临床试验的疗效：478名ER+/HER2-晚期或转移性乳腺癌的绝经后女性和男性。在228名（48%）有ESR1突变的患者中，Elacestrant组的PFS中位数为3.8个月，氟维司群或芳香酶抑制剂组为1.9个月。Elacestrant结构式来源：药渡数据FDA批准的首款口服治疗慢性肾病引起的贫血药物药品名称：Jesduvroq(Daprodustat)获批时间：2023年2月1日适应症：成人因慢性肾病（CKD）引起的贫血Daprodustat是由GSK开发的口服HIF-PHI（缺氧诱导因子-脯氨酰羟化酶）抑制剂，用于每日一次治疗接受透析至少四个月的成人因慢性肾病（CKD）引起的贫血。CKD是一个日益增加的全球健康负担，影响着全世界7亿患者，据估计，1/7的CKD患者还患有贫血。抑制HIF-PHI可以稳定缺氧诱导因子，从而导致促红细胞生成素和其他参与纠正贫血的基因转录，类似于人体在高海拔地区发生的生理效应。临床表现：FDA的批准基于ASCEND-D试验的结果：8000多名接受长达4.26年治疗的患者中，与标准护理促红细胞生成素刺激剂（ESA）相比，Daprodustat可改善和/或维持血红蛋白（Hb）在目标水平（10-11.5g/dL）内，而不会增加意向治疗（ITT）人群的主要不良心血管事件。Daprodustat结构式来源：药渡数据FDA批准的首款治疗FA的药物药品名称：Skyclarys(Omaveloxolone)获批时间：2023年2月28日适应症：弗里德赖希共济失调Omaveloxolone是由Reata Pharmaceuticals开发的first-in-class口服药物，用于每天一次治疗16岁及以上的弗里德赖希共济失调（Friedreich’s ataxia）。Friedreich’s ataxia是由编码线粒体蛋白frataxin的基因突变引起的，功能性frataxin的丧失会破坏铁硫簇的生物合成，诱导线粒体功能障碍并增加对氧化应激的敏感性。该疾病会对脊髓、周围神经和大脑造成进行性损伤，导致肌肉运动不协调、平衡不良、行走困难、言语和吞咽能力改变以及寿命缩短。Omaveloxolone的治疗机制尚不清楚，一般认为Omaveloxolone属于NRF2激活剂（五环三萜类），通过激活抗氧化转录因子NRF2起作用。临床表现：FDA的批准基于II期MOXIe试验的结果：在第48周时，与安慰剂相比，Omaveloxolone治疗组具有统计学意义的较低mFARS评分（损伤较小），治疗差异为-2.4分。Omaveloxolone结构式来源：药渡数据全球首款用于治疗Rett综合征药物药品名称：Daybue(Trofinetide)获批时间：2023年3月10日适应症：Rett综合征Trofinetide是由Acadia Pharmaceuticals公司开发的第一个用于治疗2岁及以上的Rett综合征患者的药物。Rett综合征是一种复杂、罕见的神经发育障碍，通常由MECP2基因的基因突变引起，该基因的缺陷已被证明会导致突触通讯受损，特点是在6-18个月之前有一段正常发育期，随后出现显著的发育倒退。具体表现为失去获得的沟通技巧，其它症状还可能包括出现手部刻板行为（如拧手和拍手）以及步态异常。Trofinetide是IGF-1（胰岛素样生长因子1）的氨基末端三肽（甘氨酸-脯氨酸-谷氨酸，GPE）的合成类似物，对Rett综合征患者发挥治疗作用的机制尚不清楚。临床表现：FDA的批准基于Trofinetide在两个主要疗效终点：Rett综合症行为问卷（RSBQ）总分和临床总体印象-第12周时的改善（CGI-I）量表得分，与安慰剂相比具有统计学意义的显著改善。Trofinetide结构式来源：药渡数据FDA批准的首款针对APDS的疗法药品名称：Joenja(Leniolisib)获批时间：2023年3月24日适应症：PI3Kδ过度活化综合征（APDS）Leniolisib是由Pharming开发的口服PI3K-δ（活化磷酸肌醇3-激酶-δ）激酶抑制剂，用于治疗12岁及以上患者的PI3K-δ综合征（APDS）。APDS是一种罕见的原发性免疫缺陷病，由PIK3CD或PIK3R1基因（编码PI3K-δ蛋白）中的遗传变异引起，每百万人中有1-2人患病。APDS患者会出现反复感染，尤其是鼻窦、耳朵和呼吸道，还会出现淋巴结、扁桃体和其他器官肿大，这些器官会导致气道和胃肠道阻塞。此外，APDS患者更容易患上淋巴瘤等血细胞癌。临床表现：FDA的批准基于一项为期12周的双盲、随机、安慰剂对照研究：纳入的31名12岁及以上APDS患者中，21名患者接受了70mg的Leniolisib，10名患者接受了安慰剂，每天两次，持续12周。到研究的第85天，与安慰剂相比，服用Leniolisib的患者淋巴结大小减少，幼稚B细胞计数增加37%，这表明潜在的免疫缺陷得到了纠正。Leniolisib结构式来源：药渡数据FDA批准的首个直接针对泪液蒸发的干眼症治疗药物药品名称：Miebo(Perfluorohexyloctane)获批时间：2023年5月18日适应症：干眼症Miebo是由Bausch+Lomb（博士伦）和Novaliq共同研发的一种半氟化烷烃，用于治疗干眼症（DED）的体征和症状，是FDA批准的第一款用于治疗干眼症的处方滴眼液。干眼症影响数百万美国人，是最常见的眼表疾病之一。Miebo旨在减少眼表泪液蒸发。全氟己基辛烷是一种半氟化烷烃，含有6个全氟化碳原子和8个氢化碳原子，可在泪膜的气液界面形成单层，减少蒸发。临床表现：在GOBI和MOJAVE的III期关键研究中，Miebo达到了主要体征和症状疗效终点：早在第15天和第57天，患者就经历了症状缓解，在这两项研究中观察到Miebo治疗组相对于对照组（盐水）的tCFS和VAS评分都显著降低。Perfluorohexyloctane结构式来源：药渡数据FDA批准的首款专门用于治疗FLT3-ITD阳性AML的FLT3抑制剂药品名称：Vanflyta(Quizartinib)获批时间：2023年7月20日适应症：急性髓系白血病（AML）Quizartinib是由第一三共开发的第二代FLT3激酶小分子抑制剂，可与标准阿糖胞苷和蒽环类药物等化疗药物联合使用，或作为化疗后的维持单药治疗，用于治疗FLT3-ITD突变的急性髓系白血病（AML）成人患者。Quizartinib及其主要活性代谢物AC886以相当的亲和力与FLT3的ATP口袋结合，两者对FLT3-ITD突变的结合亲和力比FLT3低10倍。临床表现：QuANTUM-First是一项随机、双盲、安慰剂对照的全球III期研究，结果显示：与单独使用标准化疗相比，经Quizartinib治疗后死亡风险降低了22%，接受Quizartinib治疗的患者的CR中位持续时间延长了三倍多，为38.6个月。Quizartinib结构式来源：药渡数据FDA批准的首款专门针对蠕形螨的根治疗法药品名称：Xdemvy(Lotilaner)获批时间：2023年7月25日适应症：蠕形螨睑缘炎Xdemvy是由Tarsus Pharma开发的一种外寄生虫杀剂（抗寄生虫药）滴眼液，用于治疗蠕形螨睑缘炎。Xdemvy是一种对螨虫具有高度选择性的γ-氨基丁酸（GABA）门控氯离子通道抑制剂，抑制这些GABA氯离子通道会导致目标生物体产生麻痹作用，导致其死亡。在美国，蠕形螨性睑缘炎影响着大约2500万眼科患者，这是一种常见但经常被误诊或诊断不足的眼睑疾病，由蠕形螨感染引起，蠕形螨是人体皮肤上最常见的体外寄生虫。蠕形螨性睑缘炎的特征是发红、炎症、睫毛缺失或错位、沿眼睑基部水平瘙痒。临床表现：FDA的批准基于两项随机、多中心、双盲、空白对照研究（Saturn-1和Saturn-2）的结果，旨在评估Xdemvy在833名患者中的安全性和有效性。患有蠕形螨性睑缘炎的患者以1:1的比例随机分配到Xdemvy治疗组或对照组，并在6周内每天每只眼睛给药两次，试验结果表明Xdemvy治疗组达到了显著改善。Lotilaner结构式来源：药渡数据FDA批准的首个治疗FOP药物药品名称：Sohonos(Palovarotene)获批时间：2023年8月16日适应症：减少FOP患者的新异位骨化体积Sohonos是由Ipsen开发的一种口服生物可利用的视黄酸受体激动剂（类维生素A），用于减少FOP（进行性骨化性纤维发育不良，俗称“石头人症”）患者的新异位骨化体积Sohonos对RAR的γ亚型具有特殊选择性，通过与RARγ结合，Sohonos抑制SMAD1/5/8的磷酸化来减少BMP/ALK2下游信号通路，从而减少ALK2/SMAD依赖性软骨形成和骨细胞分化。进行性骨化性纤维发育不良是一种罕见的常染色体显性遗传疾病，全球只有约900名患者。临床表现：FDA的批准基于III期MOVE试验的关键疗效和安全性数据，研究结果表明，与不进行超出标准护理的治疗相比，Sohonos可有效减少年度异位骨化体积。Palovarotene结构式来源：药渡数据FDA批准的首个用于治疗MDD的口服选择性5-HT1A受体激动剂药品名称：Exxua(Gepirone)获批时间：2023年9月22日适应症：重度抑郁症（MDD）Gepirone是由Fabre-Kramer公司开发的first-in-class每日一次的口服5HT1A受体的选择性激动剂，用于治疗成人重度抑郁症（MDD）。Gepirone的抗抑郁机制被认为与其5HT1A受体选择性激动剂活性有关。临床表现：Gepirone的批准基于两项为期8周的成人（18-69岁）随机、双盲、安慰剂对照临床试验，主要疗效指标是第8周时汉密尔顿抑郁量表（HAMD-17）总分相对于基线的变化。在这两项研究中，Gepirone治疗组的患者在主要疗效相比安慰剂组有统计上显著的改善。Gepirone结构式来源：药渡数据首创AKT抑制剂、口服选择性三磷酸腺苷（ATP）竞争性抑制剂药品名称：Truqap(Capivasertib)获批时间：2023年11月16日适应症：乳腺癌Capivasertib是由阿斯利康开发的丝氨酸/苏氨酸激酶AKT所有3种亚型（AKT1-3）的抑制剂，与氟维司群联合用于治疗患有激素受体（HR）阳性、HER2阴性、患有一种或多种PIK3CA/AKT1/PTEN改变的局部晚期或转移性乳腺癌成年患者。肿瘤中AKT激活是上游信号通路激活、AKT1突变、磷酸酶和张力蛋白同源物（PTEN）功能丧失以及磷脂酰肌醇3-激酶（PIK3CA）催化亚基α突变的结果。临床表现：FDA的批准基于一项III期、双盲、随机试验CAPtello-291，该试验评估Capivasertib联合氟维司群与安慰剂加氟维司群治疗局部晚期HR阳性、HER2低或阴性乳腺癌。全球试验招募了708名HR阳性、HER2低或阴性乳腺癌患者，这些患者在芳香酶抑制剂治疗以及最多一线化疗期间或之后复发或进展。Capivasertib联合氟维司群与单用氟维司群相比，可将疾病进展或死亡风险降低50%，中位无进展生存期（PFS）分别为7.3个月与3.1个月。Capivasertib结构式来源：药渡数据中国药企“出海”典范药品名称：Fruzaqla(Fruquintinib)获批时间：2023年11月8日适应症：结直肠癌Fruquintinib（呋喹替尼）是由和黄医药开发的一款口服的高选择性、强效的VEGFR-1/2/3抑制剂，用于治疗既往接受过氟嘧啶、奥沙利铂和伊立替康治疗的转移性结直肠癌患者，包括既往接受过抗VEGF治疗和/或抗EGFR治疗（RAS野生型）的患者。在美国，2023年将诊断出约153000例新发结直肠癌病例，占所有新发癌症病例的7.8%。大约70%的结直肠癌患者无论是在诊断时还是治疗后都会出现转移性疾病。临床表现：FDA的批准基于两项大型III期试验的数据FRESCO和FRESCO-2的结果，两项研究均达到了主要和关键次要疗效终点：呋喹替尼治疗组（461名）的中位OS为7.4个月，而安慰剂组（230名）为4.8个月；呋喹替尼治疗组的中位PFS为3.7个月，而安慰剂组为1.8个月；呋喹替尼组的疾病控制率（DCR）为55.5%，而安慰剂组为16.1%。Fruquintinib结构式来源：药渡数据FDA批准的首个硬纤维瘤疗法药品名称：Ogsiveo(Nirogacestat)获批时间：2023年11月27日适应症：进展性硬纤维瘤Nirogacestat是由SpringWorks Therapeutics开发的口服γ分泌酶抑制剂，用于治疗需要全身治疗的进展性硬纤维瘤成年患者。硬纤维瘤是局部侵袭性和侵袭性软组织肿瘤，可导致严重的发病率。此外，当重要结构受到影响时，硬纤维瘤可能会危及生命。虽然硬纤维瘤不会转移，但现有的超适应症全身治疗通常难以治愈，并且手术切除后复发率高达77%。临床表现：Nirogacestat的有效性在一项国际、多中心、随机、双盲、安慰剂对照试验中进行了评估：与安慰剂相比，Nnirogacestat治疗组的PFS具有统计显著性改善，疾病进展风险降低了71%；Nirogacestat治疗组的缓解率为41%，而安慰剂组只有8%。Nirogacestat结构式来源：药渡数据首款口服单药PNH疗法药品名称：Fabhalta(Iptacopan)获批时间：2023年12月5日适应症：阵发性睡眠性血红蛋白尿症（PNH）Iptacopan是由诺华研发的补体因子B抑制剂，用于治疗成人阵发性睡眠性血红蛋白尿症（PNH）。Iptacopan与补体旁路途径的因子B结合，调节C3的裂解、下游效应子的产生以及末端途径的扩增，在补体级联的替代途径中发挥近端作用，控制C3b介导的EVH和末端补体介导的IVH。PNH患者具有获得性突变，使红细胞容易被补体系统过早破坏，特点是溶血、骨髓衰竭和血栓形成，其组合和严重程度各不相同。现有的C5抑制剂治疗（以输注形式给药）可能会使PNH症状不受控制。高达88%接受抗C5治疗的患者可能患有持续性贫血，其中超过三分之一的患者每年至少需要输血一次。临床表现：FDA的批准基于III期APPLY-PNH试验，该试验针对的是尽管先前接受过抗C5治疗但仍存在残余贫血（血红蛋白<10g/dL）的患者，这些患者转而使用Iptacopan，该试验证明在不输注RBC的情况下，该药物在改善血红蛋白方面具有显著获益，与继续接受抗C5治疗的患者相比，显著减少了输血率。Iptacopan结构式来源：药渡数据结语通过一览2023年FDA批准的小分子新药概况，我们发现，这些小分子新药中有相当大的比例为“first-in-class”，或是针对特定疾病的首款疗法，或是针对特定疾病的首款具有全新机制的疗法。这对我国医药研发领域具有较大启发意义，医药研发真正的意义并非一味地追求“ME-too”或者“Me-better”等能够快速变现的同质化产品，而是在不断追求解决人类实际疾病的过程中收获成功。在原始驱动力上，国内药企还有很多需要学习的地方。后续发展如何，药渡还将持续关注。参考资料FDA官方药物说明书各大药企官网、公告、年报等维基百科