Pharming Group N.V. operates as a global biopharmaceutical company.
The company is dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. The company is commercializing and developing an innovative portfolio of protein replacement therapies and precision medicines to serve the unserved rare disease patient.
The company’s first commercialized product, RUCONEST, is the first and only recombinant C1 esterase inhibitor, or rhC1INH, protein replaceme...
Pharming Group N.V. operates as a global biopharmaceutical company.
The company is dedicated to transforming the lives of patients with rare, debilitating, and life-threatening diseases. The company is commercializing and developing an innovative portfolio of protein replacement therapies and precision medicines to serve the unserved rare disease patient.
The company’s first commercialized product, RUCONEST, is the first and only recombinant C1 esterase inhibitor, or rhC1INH, protein replacement therapy. It is approved for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema, or HAE. RUCONEST is commercialized in the United States, the European Economic Area, and the United Kingdom through the company’s own sales and marketing organization, and in the rest of the world through its distribution network.
The company’s second commercialized product, Joenja (leniolisib), is a small molecule kinase inhibitor that was licensed from Novartis International Pharmaceutical AG, or Novartis, in 2019. Joenja received FDA approval on March 24, 2023 for the treatment of activated phosphoinositide 3-kinase delta, or PI3Kd, syndrome, or APDS, in adult and pediatric patients 12 years and older. Joenja is commercialized in the United States through the company’s own sales and marketing organization.
The company has filed for regulatory approval of leniolisib for APDS in additional key markets and have ongoing clinical trials to support regulatory filings for approval in Japan and for pediatric label expansion. In the European Economic Area, it is working closely with the Committee for Human Medicinal Products, or CHMP, to address the remaining outstanding issues and the company is awaiting CHMP's opinion on the leniolisib MAA. In the United Kingdom, the company submitted an MAA for leniolisib for APDS patients ages 12 and older under the International Recognition Procedure, or IRP, on the basis of the FDA approval on March 12, 2024.
The company is also developing leniolisib for additional primary immunodeficiencies, or PIDs, with greater prevalence than APDS.
OTL-105, an investigational gene therapy for the treatment of HAE, is in preclinical development.
Portfolio
RUCONEST approved for the treatment of acute attacks in adult and adolescent patients with Hereditary Angioedema (HAE).
The company’s lead product, RUCONEST is the first and only recombinant C1 inhibitor protein replacement therapy that is approved for the treatment of acute attacks in adult and adolescent patients with HAE.
RUCONEST has been shown to normalize C1INH activity levels to normal and has been shown to be clinically relevant in HAE attack treatment. The standard posology for the treatment of HAE attacks is 50 units per kilogram of the reconstituted product. RUCONEST is administered through a slow intravenous, or IV, injection. One vial contains 2100 U of lyophilized product to be reconstituted with 14ml of water for injection. RUCONEST irreversibly binds to several target molecules, including, importantly the coagulation factor FXII and the protease kallikrein, which (when unbound) cleaves a plasma protein into bradykinin and other products. By binding to and chemically deactivating these molecules, RUCONEST stops the production of bradykinin and all other mediators and thereby stops the HAE attack.
The company markets RUCONEST in the United States, the United Kingdom and the European Economic Area through its own sales force. The company has various access programs designed to ensure that physicians can request RUCONEST on behalf of individual patients, who meet the eligibility criteria and receive local health authority approval, in certain countries where RUCONEST is not commercially available.
Joenja (leniolisib) for the treatment of APDS
The company announced the U.S. Food and Drug Administration (FDA) approval of Joenja (leniolisib) on March 24, 2023 as the first and only treatment indicated for the treatment of adults and adolescents aged 12 years and older with APDS, a rare primary immunodeficiency.
Joenja (leniolisib) is an oral small molecule PI3KDelta inhibitor approved in the U.S. Joenja inhibits the production of phosphatidylinositol-3-4-5-trisphosphate, which serves as an important cellular messenger and regulates a multitude of cell functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism. Results from a randomized, placebo-controlled Phase II/III clinical trial demonstrated clinical efficacy of Joenja in the coprimary endpoints; demonstrating statistically significant impact on immune dysregulation and normalization of immunophenotype within these patients, and interim open label extension data has supported the safety and tolerability of long-term Joenja administration. Leniolisib is also being evaluated in two Phase III clinical trials in children with APDS and a Phase III clinical trial is ongoing in Japan in adult and pediatric patients 12 years of age and older with APDS.
In partnership with Novartis, the company studied leniolisib to assess the efficacy and safety of leniolisib in patients with APDS. The study, a Phase II/III potentially registration enabling study was composed of two sequential parts. The first part included six patients in an open-label dose escalation study designed to assess the safety, tolerability, pharmacodynamics and pharmacokinetics of leniolisib.
The first part of the study showed that oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex-vivo and improved immune dysregulation.
The second part was a randomized, blinded, placebo-controlled study, which enrolled 31 patients with APDS who were 12 years of age or older. Patients were randomized 2:1 to receive either leniolisib 70 mg twice daily or placebo for 12 weeks.
In the study, leniolisib was generally well-tolerated.
On March 2, 2021, the company announced the launch of a sponsored genetic testing program, ‘navigateAPDS’, designed to assist clinicians in identifying patients and their family members with APDS, which may lead to earlier diagnosis.
In Europe, the company is intensifying its patient identification efforts together with leading immunology centers of excellence treating patients with APDS and other rare immune deficiencies.
The company advanced several initiatives during 2023 to assist in the diagnosis of additional APDS patients, including its sponsored genetic testing program in the U.S. and Canada, partnerships with several genetic testing companies who undertake their own testing efforts and family testing programs. The company has 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.
As of December 31, 2023, the company 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. The company expects completion of these studies during the fourth quarter of 2024.
Regulatory Status
The United States
On March 24, 2023, the FDA approved the company’s New Drug Application, or NDA, of Joenja (leniolisib) for the treatment of patients ages 12 and older with APDS. The FDA evaluated the Joenja application for APDS under Priority Review, which is granted to therapies that have the potential to provide significant improvements in the treatment, diagnosis or prevention of serious conditions. Joenja launched in the U.S. in early April 2023.
European Economic Area
In October 2020, the company announced that the European Commission had granted orphan drug designation for leniolisib for the treatment of APDS, based on a positive opinion from the Committee for Orphan Medicinal Products, or COMP, of the European Medicines Agency, or EMA.
In January 2022, a positive decision was made by the EMA on the Pediatric Investigation Plan, or PIP, for leniolisib. For the registration of new medicines in Europe, biopharmaceutical companies are required to provide a PIP which outlines the strategy for investigation of a new medicinal product in the pediatric population. The positive PIP opinion from the Pediatric Committee, or the PDCO, is an endorsement of the clinical program to evaluate the safety and efficacy of leniolisib in patients from 1 year of age to less than 18 years of age with APDS.
In August 2022, the company announced the leniolisib MAA was granted accelerated assessment by EMA’s CHMP. The accelerated assessment reduces the review timeframe from 210 days to 150 days. Upon request, EMA will grant an accelerated assessment of an MAA if they decide the product is of major interest for public health, and in particular, from the viewpoint of therapeutic innovation.
In October 2022, the company submitted an MAA to EMA for leniolisib as a treatment for APDS in adults and adolescents 12 years or older.
The MAA was supported by positive data from a Phase II/III study of leniolisib, announced on February 2, 2022, which met its co-primary endpoints of reduction in lymph node size and increase in percentage of naïve B cells in patients with APDS. Furthermore, safety data from the study showed that leniolisib was well tolerated by participants. Also submitted as part of the MAA were data from a long-term OLE study in patients with APDS treated with leniolisib.
On October 28, 2022, the company announced that its Marketing Authorization Application (MAA) for leniolisib had been validated for scientific evaluation under an accelerated assessment by EMA's Committee for Human Medicinal Products (CHMP).
In February 2023, the company announced that the CHMP decided to shift its assessment of the MAA for leniolisib to a standard review timetable. The list of questions it received from the EMA included a request to submit updated data from the ongoing open-label extension (OLE) study collected after the interim analysis included in the original MAA.
In May 2023, the company submitted its response to the CHMP Day 120 list of questions. Subsequently, as part of the MAA review procedure timetable, the company received the CHMP Day 180 list of outstanding issues in July 2023. In August 2023, the company announced that considering the rarity of the disease and the unmet need for the treatment of APDS patients, the EMA's CHMP would consult an Ad-hoc Expert Group, or AEG, at a closed meeting also involving the company’s representatives including leniolisib investigators and APDS patients.
The company submitted its response to the CHMP Day 180 list of outstanding issues, or LoOI, in October 2023. In November 2023, the company received a Day 180 Second LoOI from the CHMP. The CHMP consulted the AEG at a meeting held at the end of November 2023.
The company is working closely with the CHMP to address the remaining outstanding issues and we are now awaiting the CHMP's opinion on the leniolisib MAA.
The United Kingdom
In February 2022, the MHRA granted Promising Innovative Medicine, or PIM, designation to leniolisib for the treatment of APDS. A PIM designation is an early indication that leniolisib is a candidate for the MHRA’s Early Access to Medicines Scheme. This scheme provides an opportunity for treatment options to be used in clinical practice in parallel with the later stages of the regulatory process.
In November 2023, the company announced its intention to file an MAA with the MHRA for APDS patients ages 12 and older, through the IRP which replaced the European Commission Decision Recognition Procedure, or ECDRP, beginning January 1, 2024. The IRP allows a company to submit an MAA for a product on an abbreviated review timeline if the same product has already received a marketing authorization from one of the MHRA’s specified reference regulators, or RRs, including the EMA and the FDA.
The company submitted an MAA for leniolisib under the IRP on the basis of the FDA approval on March 12, 2024. The MHRA has 110 days with an option to enforce a 60 day clock stop, if needed, from the date the IRP submission is validated, to review and issue its decision.
Canada, Australia, and Israel
The company filed regulatory submissions for APDS patients ages 12 and older in Canada and Australia in the third quarter of 2023, and Israel in the second quarter. These submissions are progressing as expected and it anticipates regulatory action in 2024 for Canada, Australia, and Israel.
Market access
The company markets Joenja (leniolisib) for the treatment of APDS in adults and adolescents 12 years of age and older in the United States. The company has named patient and expanded access programs designed 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 approval, in certain countries where leniolisib is not commercially available.
Pipeline development
Japan Clinical Trial
In May 2023, the Ministry of Health, Labour and Welfare of Japan, or MHLW, granted leniolisib orphan drug designation, or ODD, for the treatment of APDS. In August 2023, 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 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. Each patient will receive weight-based dosing up to 70 mg of leniolisib twice daily for 12 weeks. The study’s primary efficacy endpoints and secondary endpoints mirror those used to evaluate the clinical outcomes in each of the earlier leniolisib APDS trials.
The company plans to file an application for the approval of leniolisib with Japan’s Pharmaceuticals and Medical Devices Agency, or 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.
Pediatric Clinical Trials
The company has developed a clinical plan to include children as young as one year of age. During the first half of 2022, the company received positive decisions from the EMA and MHRA on the PIP for leniolisib as a treatment for APDS in children. The leniolisib PIP includes two planned, global clinical trials in pediatric patients with APDS aged 4 to 11 years old and aged 1 to 6 years old. These two studies were initiated in 2023 and will support regulatory filings worldwide for pediatric label expansion.
Patients aged 4 to 11 years
This Phase III clinical trial is evaluating the investigational drug leniolisib in children with APDS at sites in the United States, Japan, and the EU.
The single-arm, open-label, multinational clinical trial will evaluate the safety, tolerability, and efficacy of leniolisib in 15 children aged 4 to 11 years who have a confirmed APDS diagnosis. The study's primary efficacy endpoints and secondary endpoints mirror those used to evaluate the clinical outcomes in the previous leniolisib Phase II/III APDS trials for patients aged 12 and older.
The first patient was enrolled in February 2023 and the company is nearing completion of enrollment in the clinical trial.
Patients aged 1 to 6 years
This Phase III pediatric clinical trial is evaluating a new pediatric formulation of the investigational drug leniolisib in children with APDS at sites in the United States, Japan, and the EU.
The single-arm, open-label, multinational clinical trial will evaluate the safety, tolerability, and efficacy of leniolisib in 15 children aged 1 to 6 years of age who have a confirmed APDS diagnosis. These patients will receive a specific, pediatric granulated formulation of leniolisib. The study’s primary efficacy endpoints and secondary endpoints mirror those used to evaluate the clinical outcomes in the previous leniolisib Phase II/III APDS trials for patients aged 12 and older.
The first patient was dosed in November 2023 and enrollment in the study is continuing as planned.
Additional indications (PI3Kd platform)
PIDs beyond APDS
As the company continues to work towards regulatory approvals of leniolisib for APDS in additional geographies and pediatric label expansion, it has also commenced work to identify and prioritize other indications where leniolisib has the potential to deliver value for patients. PI3Kd 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 profile in clinical trials conducted in both healthy volunteers and APDS patients. This provides a solid basis for the company’s plans for the investigation and investment in further leniolisib indications.
PIDs with immune dysregulation
In December 2023, the company announced the expansion of its rare disease pipeline with plans to develop leniolisib for additional PIDs with greater prevalence than APDS. The company has engaged with and received feedback from the FDA on its plans to develop leniolisib for PID disorders with immune dysregulation.
Leniolisib, by reducing PI3Kd activity, could help rebalance immune dysregulation in PIDs, positively impacting clinical manifestations including lymphoproliferation and autoimmunity. Based on the company’s APDS experience, leniolisib has potential to be an effective and tolerable chronic treatment approach for PIDs with immune dysregulation linked to PI3Kd signaling.
The company is in the final stages of preparation for the start of an initial Phase II, proof of concept, clinical trial in targeted PID genetic disorders with immune dysregulation linked to PI3KDelta 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 II 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 III program.
The Phase II clinical trial will be conducted at the National Institute of Allergy and Infectious Diseases, NIAID – part of the National Institutes of Health, or NIH – with lead investigator Gulbu Uzel, M.D., Senior Research Physician, and co-investigator V. Koneti Rao, M.D., FRCPA, Senior Research Physician, Primary Immune Deficiency Clinic (ALPS Clinic).
Pre-clinical pipeline
OTL-105
In 2021, the company entered into a license agreement with Orchard to research, develop, manufacture and commercialize OTL-105, an ex-vivo autologous gene therapy for the treatment of patients with HAE due to a deficiency of C1INH. This novel approach has the potential of being curative, allowing HAE patients to live a normal life, without being dependent on acute or prophylactic use of HAE medication.
OTL-105 is based on Orchard’s ex-vivo autologous gene therapy platform approach which is designed to use the HAE patients’ own blood stem cells and insert those cells into a working copy of the gene that is reduced in HAE. In pre-clinical proof of concept studies, gene-corrected stem cells produced relevant active C1-esterase inhibitor.
Preclinical development of OTL-105 continued during 2023 including work towards the preparation of preclinical proof of concept studies.
On January 24, 2024, Kyowa Kirin Co., Ltd., a Japan-based global specialty pharmaceutical company, completed an acquisition of Orchard. The company is responsible for funding of the OTL-105 program and do not anticipate any negative impact of the acquisition on OTL-105.
Pompe Disease program – Discontinued
As announced in its first quarter 2023 results, the company decided that, based on its preclinical investigations and evaluations for potential differentiating features of Alpha-Glucosidase, for the treatment of Pompe Disease, it would discontinue further development of this asset.
Manufacturing
RUCONEST
The company has developed a unique, scalable, reproducible, current Good Manufacturing Practices, or cGMP, validated methodology for the production of high-quality recombinant human proteins.
The company has entered into manufacturing and supply agreements for RUCONEST with, among others, Sanofi S.A., or Sanofi, and BioConnection Investments B.V., or BioConnection, for these downstream processes, as it does not have a GMP-certified lab capable of performing the quality control procedures necessary for the release of product.
Joenja
Pursuant to its agreement with Novartis relating to Joenja, the company has agreed to manufacture both the drug substance, as well as the drug product via its own Contract Manufacturing Organizations, or CMOs. For the drug substance, Ardena Holding N.V., or Ardena, has been chosen as the CMO. For the film coated tablets, Skyepharma Production SAS, or Skyepharma, has been chosen as the CMO. The 70 mg film coated tablet manufactured by Skyspharma have been launched for patients 12 years of age and older. In addition, two pediatric formulations are also being developed; the first, lower strengths tablets that also will be manufactured at Skyepharma, and the second, film coated granules that are being developed by Almac Group.
Strategy
For leniolisib, the company’s strategy is to make the drug available in key markets including the United States, Europe, the U.K., Japan, the Asia Pacific, the Middle East and Canada.
Intellectual Property
RUCONEST has patent protection in the U.S. and EU until October 7, 2026, as well as biologics reference product exclusivity in the United States expiring July 16, 2026.
As of December 31, 2023, the company solely owned 110 granted patents, of which 8 are U.S.-issued, and 12 pending patent applications, of which 2 are U.S. pending patent applications. Commercially or strategically important non-U.S. jurisdictions in which the company holds issued or pending patent applications include (in addition to Europe): the United Kingdom, China, Japan, Canada, Israel, Australia and New Zealand. The company also has exclusive license to 161 patents and patent applications from Novartis related to leniolisib.
The company’s granted patents and pending patent applications include the making of C1INH in the milk of transgenic mammals. In addition, the company’s pending patent applications also include claims for the use of C1INH in PE.
The company expects to have patent protection for leniolisib in APDS under the Novartis composition of matter patent (U.S. Patent No. 8,653,092, EU patent EP259094B1) through July 2036 in the U.S. and EU, which the company anticipates may be extended to January 2037 if it obtains a pediatric extension. The USPTO adjusted the expiration when the patent was granted to account for delays in the approval of the patent, and an extension was applied for shortly after the FDA approved Joenja (leniolisib). Similarly, in the E.U., a supplemental protection certificate will be applied for shortly after approval in the E.U. It is these extensions which we anticipate will result in the 2036 expiration.
In the European Economic Area, upon successful completion of the agreed PIP, leniolisib would be eligible for up to an additional two years of marketing exclusivity in the EU, on top of the ten-year EU market exclusivity after market approval as result of its EU Orphan Drug Designation. Thus, the company anticipates that the patent protection will extend beyond the marketing exclusivity.
Trademarks
The company has registered trademarks in the European Union (EU), the United States and key international markets it intends to focus on for its company name ‘Pharming’ with the associated logo, ‘RUCONEST’ with its associated logo, as well as for Joenja and its associated logo.
Research and Development
The company's research and development expenses included $68.9 million for the year ended December 31, 2023.
Government Regulation and Product Approval
The company’s operations are also subject to non-U.S. anti-corruption laws, such as Dutch anti-bribery laws as contained in the Dutch Criminal Code (Wetboek van Strafrecht).
History
Pharming Group N.V. was incorporated in 1988.
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