Delving into the Latest Updates on Leniolisib phosphate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Leniolisib, CDZ-173, CDZ-173-AZ

+ [2]

Target

PI3Kδ

Action

inhibitors

Mechanism

PI3Kδ inhibitors(Phosphatidylinositol 3 kinase delta inhibitors)

Therapeutic Areas

Immune System DiseasesCongenital DisordersOther Diseases+ [1]

Active Indication

Activated PI3K-delta SyndromeLymphadenopathyCommon Variable Immunodeficiency

Inactive Indication

Primary Sjögren's syndromeSialadenitis

Originator Organization

Novartis Pharma AG

Active Organization

Pharming Technologies BV

Pharming Group NVBallia Holdings Pty. Ltd.

Inactive Organization

Novartis Pharma Services AG

Novartis Pharmaceuticals Corp.Novartis Pharma AG

License Organization

Invitae Corp.

Pharming Group NV

Novartis AG

Drug Highest PhaseApproved

First Approval Date

United States (24 Mar 2023),

Activated PI3K-delta Syndrome

RegulationFast Track (United States), Orphan Drug (United States), Orphan Drug (European Union), Orphan Drug (Japan), Orphan Drug (Australia), Priority Review (Australia), Accelerated assessment (European Union), Promising Innovative Medicine (United Kingdom), Paediatric investigation plan (United Kingdom), Priority Review (United States)

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Structure/Sequence

Molecular FormulaC21H28F3N6O6P

InChIKeyXXEDEGOAYSGNPS-ZOWNYOTGSA-N

CAS Registry1354691-97-6

This is an open-label extension (OLE) study to extend treatment to patients with primary immunodeficiency (PID) disorders linked to phosphoinositide 3-kinase delta signaling who participated in a prior study of leniolisib, LE 7201. The primary objective is to assess long-term safety and tolerability of leniolisib. Secondary and exploratory objectives include various efficacy and immunophenotyping measures for leniolisib.

Start Date29 Apr 2025

Sponsor / Collaborator

Pharming Technologies BV

[+1]

NCT06897358

/ Active, not recruitingPhase 2

A Study to Assess Safety and Tolerability, and Explore Efficacy of Leniolisib for Immune Dysregulation in Common Variable Immunodeficiency (CVID)

In this study, common variable immunodeficiency (CVID) patients will all receive the study drug, leniolisib, for a treatment period of 6 months. Participants will start on a lower dose of leniolisib, followed by a mid and then a higher dose level. The primary goal is to assess the safety and tolerability of leniolisib, and secondary goal is to assess the potential for leniolisib to provide benefits for patients.

Start Date12 Feb 2025

Sponsor / Collaborator

Pharming Technologies BV

[+1]

NCT06549114

/ Active, not recruitingPhase 2

A Study to Assess Safety and Tolerability, and Explore Efficacy of Leniolisib for Immune Dysregulation in Primary Immunodeficiency Disorders

This study is an exploratory, non-randomized, open-label, within-patient dose escalation study. The primary objective is to assess safety and tolerability of leniolisib. Secondary objectives include assessments of PK/PD, and to explore clinical efficacy measures with administration of three different dose levels of leniolisib.

Start Date21 Oct 2024

Sponsor / Collaborator

Pharming Technologies BV

100 Clinical Results associated with Leniolisib phosphate

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100 Translational Medicine associated with Leniolisib phosphate

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100 Patents (Medical) associated with Leniolisib phosphate

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53

Literatures (Medical) associated with Leniolisib phosphate

05 Jan 2026·Journal of Human Immunity

Leniolisib reduced lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome

Article

Author: Hanssen, Robert ; Hassan, Chopie ; Thorneloe, Kevin S. ; Marsh, Rebecca A. ; Rao, V. Koneti ; Ponstein, Yolanda

Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity (IEI) characterized by abnormal FAS-mediated apoptosis of lymphocytes that leads to lymphoproliferation and expansion of CD4−/CD8− double-negative T cells (DNTs). In patients with ALPS-FAS, DNTs have been reported to exhibit increased activity in the phosphoinositide 3-kinase δ (PI3Kδ)/mammalian target of rapamycin (mTOR) pathway. Although mTOR inhibition with sirolimus has improved autoimmune cytopenias and organomegaly in patients with ALPS, it requires monitoring of serum levels, and common adverse events frequently hamper long-term use. As leniolisib, a selective PI3Kδ inhibitor, reduced lymphoproliferation in another IEI known as activated PI3Kδ syndrome, efficacy was examined in a murine model of ALPS. Changes in organ weight and key immune subsets in MRL/lpr−/− mice receiving vehicle or leniolisib (40 or 80 mg/kg/day) by oral gavage were assessed. Leniolisib limited the canonical features of ALPS, including lymphadenopathy, splenomegaly, and elevated DNTs, in a dose-dependent manner. These results support the evaluation of leniolisib in patients with ALPS (NCT06549114).

01 Dec 2025·JOURNAL OF CLINICAL IMMUNOLOGY

Report of the Italian Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome in the Target Therapy Era

Article

Author: Pignata, Claudio ; Marzollo, Antonio ; Ricci, Silvia ; Lodi, Lorenzo ; Marinoni, Maddalena ; Trizzino, Antonino ; Barzaghi, Federica ; Lougaris, Vassilios ; Moratti, Mattia ; Martire, Baldassarre ; Milito, Cinzia ; Tommasini, Alberto ; Costagliola, Giorgio ; Montin, Davide ; Badolato, Raffaele ; Zecca, Marco ; Chinello, Matteo ; Giardino, Giuliana ; De Rosa, Antonio ; Panza, Giuseppina ; Baselli, Lucia Augusta ; Rivalta, Beatrice ; Conti, Francesca ; Cancrini, Caterina

BACKGROUND:

Activated Phosphoinositide 3-Kinase (PI3K) δ Syndrome (APDS), an inborn error of immunity due to upregulation of the PI3K pathway, leads to recurrent infections and immune dysregulation (lymphoproliferation and autoimmunity).

METHODS:

Clinical and genetic data of 28 APDS patients from 25 unrelated families were collected from fifteen Italian centers.

RESULTS:

Patients were genetically confirmed with APDS-1 (n = 20) or APDS-2 (n = 8), with pathogenic mutations in the PIK3CD or PIK3R1 genes. The median age at diagnosis was 15.5 years, with a median follow-up of 74 months (range 6-384). The main presenting symptoms were respiratory tract infections alone (57%) or associated with lymphoproliferation (17%). Later, non-clonal lymphoproliferation was the leading clinical sign (86%), followed by respiratory infections (79%) and gastrointestinal complications (43%). Malignant lymphoproliferative disorders, all EBV-encoding RNA (EBER)-positive at the histological analysis, occurred in 14% of patients aged 17-19 years, highlighting the role of EBV in lymphomagenesis in this disorder. Diffuse large B-cell lymphoma was the most frequent. Immunological work-up revealed combined T/B cell abnormalities in most patients. Treatment strategies included immunosuppression and PI3K/Akt/mTOR inhibitor therapy. Rapamycin, employed in 36% of patients, showed efficacy in controlling lymphoproliferation, while selective PI3Kδ inhibitor leniolisib, administered in 32% of patients, was beneficial on both infections and immune dysregulation. Additionally, three patients underwent successful HSCT due to recurrent infections despite ongoing prophylaxis or lymphoproliferation poorly responsive to Rapamycin.

CONCLUSIONS:

This study underscores the clinical heterogeneity and challenging diagnosis of APDS, highlighting the importance of multidisciplinary management tailored to individual needs and further supporting leniolisib efficacy.

01 Nov 2025·Arthritis & Rheumatology

Precision Medicine in Pediatric Autoimmunity: Leniolisib Treatment of Childhood‐Onset Lupus Nephritis Due to Activated Phosphoinositide 3‐Kinase δ Syndrome

Article

Author: Nicholas Willard ; Angela Minic ; Christian Rickert ; Sara A. Johnson ; Jennifer C. Cooper ; Fuyong Xing ; Hongyu Du ; Melisha Hanna ; Jason P. Weinman ; Tusharkanti Ghosh ; Kimberly R. Jordan ; Mansooreh Ahmadian ; Elena WY Hsieh ; Vijaya Knight ; Clara Lin ; Jonathan P. Lim ; Debashis Ghosh

Objective:

The objective of this study was to investigate the mechanistic underpinnings and treatment response of lupus nephritis (LN) in activated phosphoinositide 3‐kinase δ syndrome type 1 (APDS1) using pathway‐specific therapy and advanced spatial proteomics.

Methods:

We conducted mechanistic investigation of refractory class V LN in an 18‐year‐old female patient with genetically confirmed APDS1 (PIK3CD c.3061G>A, p.E1021K mutation). Response to leniolisib, a selective phosphoinositide 3‐kinase δ (PI3Kδ) inhibitor, was evaluated through clinical parameters and flow cytometry of peripheral blood lymphocytes. Kidney tissue immune architecture was characterized using multiplexed ion beam imaging by time‐of‐flight (MIBI‐TOF) spectrometry, comparing the APDS1‐LN tissue signature with 12 patients with childhood‐onset LN and 5 healthy controls.

Results:

Following three years of unsuccessful treatment with conventional immunosuppressives, leniolisib treatment normalized hyperactive PI3Kδ signaling, resulting in significant improvements in proteinuria, complement levels, and peripheral edema. Multiplexed Ion Beam Imaging (MIBI)‐Time‐of‐Flight (TOF) revealed a distinct tissue‐specific immunopathology with significantly increased proportions of CD8 + T cells (21.6% in APDS1 vs 12.0% in typical LN; P = 0.0410) and M1 macrophages (42.0% in APDS1 vs 9.0% in typical LN; P = 0.1445) clustering around glomeruli with immune complex deposition. This immune signature aligns with the constitutively active PI3Kδ pathway's effect on lymphocyte exhaustion and inflammatory phenotype.

Conclusion:

This investigation advances rheumatology by demonstrating that APDS1‐associated LN displays a specific tissue immune signature and responds to targeted inhibition of the causative molecular pathway. Our findings provide mechanistic insights into genetic drivers of autoimmunity and support pathway‐specific therapeutic approaches for refractory autoimmune manifestations in primary immunodeficiencies.image

81

News (Medical) associated with Leniolisib phosphate

02 Feb 2026

·www.fiercepharma.com

With FDA rejections, Aquestive's shares go up, while Pharming's go down

The FDA issued complete response letters to Aquestive Therapeutics and Pharming in recent days, resulting in vastly different reactions from the market. While Aquestive's share price increased, Pharming's dropped. The FDA issued complete response letters (CRLs) to two companies in recent days, resulting in vastly different reactions from the market.The U.S. regulator rejected Pharming’s bid to gain an expansion for Joenja to treat patients ages 4 to 11 with activated phosphoinositide 3-kinase delta syndrome (APDS), a rare immunodeficiency. With the thumbs down, Pharming’s share price tumbled by 16% on Monday.Meanwhile, the FDA also swatted away Aquestive Therapeutics’ new drug application for Anaphylm sublingual film for the treatment of Type 1 allergic reactions, including anaphylaxis, in patients weighing at least 30 kg (66 pounds). But with the red light, Aquestive’s share price increased by 35%.The reason for the optimism on Anaphylm? The FDA’s concerns with the rescue treatment were limited to its packaging, administration and labeling guidance.“While it is unfortunate to have received a CRL, we believe that, with the clarity we now have from the FDA, we have made significant progress toward approval,” Dan Barber, the CEO of Aquestive, said in a release.The regulator cited difficulties in opening Anaphylm’s pouch and the potential for incorrect film placement, which “the FDA believes could cause significant safety issues in the setting of anaphylaxis,” Aquestive said in a release.“This opening is the one we use with multiple other products that are on the market and one product that’s been on the market for 15 years,” Barber said during a conference call on Monday morning. “It’s a bit of a head scratcher, but we’ll do the work that the FDA has requested.” Aquestive said it has already modified the pouch opening, its instructions for the drug's use and the labeling on its carton. The company will also conduct a new human factors validation study and plans to address potential tolerability issues with its resubmission, which could happen as early as the third quarter, it added.As a needle-free, oral epinephrine option, Anaphylm has been pegged as a potential blockbuster and a game-changer for the New Jersey-based company, which projected in November that its 2025 revenue would come in at between $44 million and $50 million.The CRL does not affect submissions for approval of the treatment in Europe and Canada, which are still on track by the end of this year, Aquestive said. Pharming rejectionIn the CRL the FDA sent to Pharming, the agency cited the potential for “underexposure” in lower-weight patients and has requested additional pediatric pharmacokinetic (PK) data, the company said. The FDA wants to reassess the proposed pediatric doses and confirm that children in the lower-weight dose groups can achieve exposure levels comparable to the approved regimen. The letter also identified an issue with one of the analytical methods used for production batch testing.“While we are disappointed in the FDA’s response, we remain dedicated to making Joenja available to pediatric patients aged 4-11 with APDS,” Fabrice Chouraqui, the CEO of the Netherlands-based company, said in a release. “We are going to work closely with the FDA to provide the necessary information and determine the best and most effective path forward.”The company said it believes it can address the PK and batch testing methodology issues and will request a Type A meeting with the FDA. Analysts from Jefferies noted that “importantly,” the CRL did not reflect any efficacy concerns, indicating that the drug will likely eventually gain approval for the age group. Jefferies added that a third-quarter approval would be a “best-case” scenario at this stage.More information could be available during the company’s investor presentation on Tuesday. Last month, Pharming reported (PDF) preliminary 2025 revenues of $376 million, up 27% from 2024. Through three quarters, Joenja—which was approved in 2023—had produced sales of $38 million, with $15 million coming in the third quarter.The big seller for Pharming is Ruconest, which generated sales of $231 million through the first nine months of 2025. The treatment was approved in 2014 for hereditary angioedema.

Drug Approval

02 Feb 2026

·endpoints.news

Pharming’s immunodeficiency drug gets CRL for use in younger patients

The FDA has issued a complete response letter to Pharming, rejecting its attempt to expand the approval of its drug for a rare form of immunodeficiency into younger patients. Joenja was approved in 2023 for a disorder called activated phosphoinositide 3-kinase delta syndrome (APDS) in patients aged 12 and up. On Sunday, the company said the regulator declined to approve the pill’s use in patients aged 4 to 11. Pharming’s Amsterdam-listed shares fell 15% in early trading on Monday. Growing Joenja’s sales is important for Pharming. Analysts expect revenues from its only other product, the hereditary angioedema therapy Ruconest, to fall starting this year, as some patients switch to KalVista’s Ekterly . According to Pharming, the FDA asked for more pediatric pharmacokinetic data due to concerns that lighter patients could be underexposed to the drug. The regulator wants to confirm that children in the lower-weight dose groups can be exposed to similar levels of Joenja as adult and adolescent patients. The approved dose for older patients is two 70 mg pills a day. Patients must weigh at least 45 kg to get the drug. The CRL also identified a problem with one of the methods used to test batches of the drug, and again the FDA requested additional data and clarification on this point. Pharming said it could address the issues raised in the letter and would seek a meeting with the FDA to discuss resubmission. Jefferies analysts wrote in a Monday note that they expect Joenja to be approved in the wider population “eventually,” as the letter did not take issue with the drug’s efficacy. They believe that expanded approval in the third quarter of 2026 could be the best-case scenario, with approval later in the year also a possibility, “assuming it will not take more than a couple of months to generate the required data.” APDS is caused by mutations in one of two genes, known as PIK3CD or PIK3R1, which regulate the maturation of white blood cells, particularly B cells and T cells. These cause hyperactivity of PI3 kinase delta, leading to proliferation of immature B and T cells, which can’t fight infections. Joenja is a small molecule that blocks the production of PI3 kinase delta, allowing immune cells to mature properly. The disorder is ultra-rare, affecting only one or two people in every million. In the US, Joenja costs around $50,000 for a month’s supply. The drug could gain approval in Europe and Japan this year. Phase 2 trials assessing it in patients with other primary immunodeficiencies due to immune dysregulation are also expected to report this year.

Drug ApprovalImmunotherapyPhase 2Accelerated Approval

02 Feb 2026

·firstwordpharma.com

FDA knock backs send shares in Pharming down, Aquestive up

Two companies have received complete response letters (CRLs) from the FDA, but the knock backs from the agency have triggered very different reactions from investors.Shares in Pharming fell as much as 16% on Monday, the day after the company disclosed a CRL for its application seeking to expand use of Joenja (leniolisib) into children aged 4 to 11 with activated phosphoinositide 3-kinase delta syndrome (APDS). The phosphoinositide 3-kinase delta (PI3Kδ) inhibitor is already authorised in this indication for adult and paediatric patients 12 years of age and older.Meanwhile, shares in Aquestive Therapeutics jumped nearly 50% on Monday after the company said the FDA issued a CRL for its application seeking approval of Anaphylm (dibutepinephrine) sublingual film for the treatment of Type I allergic reactions, including anaphylaxis, in patients weighing 30kg or more. Devil in the detail…Pharming said that the FDA raised an issue with the potential for underexposure in lower weight paediatric patients and has requested additional pharmacokinetic data to reassess the proposed doses and confirm that these children can achieve exposure levels comparable to the currently approved regimen. The agency also flagged a problem with one of the analytical methods used for production batch testing, and asked for further data and clarification on this point.In its letter, Aquestive noted that the FDA focused on administration and labelling guidance, although it also cited deficiencies in the Anaphylm human factors (HF) validation study. The company said that these included instances of difficulty opening the pouch and incorrect film placement, which could cause significant safety issues in the setting of anaphylaxis. Aquestive had signalled at the start of the year that the FDA identified unspecified deficiencies that prevented labelling discussions at the time, triggering a large drop in the firm's share price. …and the new timelinesPharming said that it believes it can address the clinical pharmacology and batch testing methodology issues outlined in the CRL, but did not provide a potential timeline for a resubmission. "We are going to work closely with the FDA to provide the necessary information and determine the best and most effective path forward," said Pharming CEO Fabrice Chouraqui.Commenting on the news, Jefferies analysts said they expect "approval eventually" for Jojena in younger children, but the "near-term hit to sentiment" comes as paediatric approval was expected to drive a Joenja growth inflection this year.In contrast, Aquestive is targeting a resubmission as early as the third quarter of 2026. "With the clarity we now have from the FDA, we have made significant progress toward approval," remarked chief executive Daniel Barber.The company said that it has already modified the pouch opening, instructions for use, pouch and carton labelling, and plans to "rapidly conduct" a new HF validation study incorporating these changes. While these modifications also require a pharmacokinetics (PK) study to be conducted, Aquestive noted that per the FDA's guidance, the HF and PK trials can be conducted in parallel.

100 Deals associated with Leniolisib phosphate

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External Link

KEGG	Wiki	ATC	Drug Bank
D11158 D11159	-	-	DB16217

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Activated PI3K-delta Syndrome	United States	Pharming Technologies BV	24 Mar 2023

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Lymphadenopathy	Phase 3	United States	Novartis Pharmaceuticals Corp.	24 Aug 2015
Lymphadenopathy	Phase 3	Belarus	Novartis Pharmaceuticals Corp.	24 Aug 2015
Lymphadenopathy	Phase 3	Czechia	Novartis Pharmaceuticals Corp.	24 Aug 2015
Lymphadenopathy	Phase 3	Germany	Novartis Pharmaceuticals Corp.	24 Aug 2015
Lymphadenopathy	Phase 3	Ireland	Novartis Pharmaceuticals Corp.	24 Aug 2015
Lymphadenopathy	Phase 3	Netherlands	Novartis Pharmaceuticals Corp.	24 Aug 2015
Lymphadenopathy	Phase 3	Russia	Novartis Pharmaceuticals Corp.	24 Aug 2015
Lymphadenopathy	Phase 3	United Kingdom	Novartis Pharmaceuticals Corp.	24 Aug 2015
Common Variable Immunodeficiency	Phase 2	United States	Pharming Technologies BV	12 Feb 2025
Common Variable Immunodeficiency	Phase 2	Spain	Pharming Technologies BV	12 Feb 2025

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05438407 (GlobeNewswire) Manual	Phase 3	Activated PI3K-delta Syndrome	21	leniolisib	dfykswikda(bhzrkadhev) = The improvement in lymphoproliferation and immunophenotype correction were seen across the four dose levels being investigated and were consistent with the improvements previously reported in adolescent and adult patients. ltcpcwywjy (kleqrhrpqv ) View more	Positive	11 Dec 2024
NCT02859727 (Pubmed) Manual	Phase 3	Activated PI3K-delta Syndrome PI3K Mutation	6	Leniolisib	svxzeswlwy(grjrzbexeu) = Of 83 adverse events through year 5, 90.36% were grade 1; none were grade 4-5 nor deemed leniolisib-related hekqozlqrc (fnlxrakikq )	Positive	09 Apr 2024
NCT02435173 (FDA) Manual	Phase 2/3	Activated PI3K-delta Syndrome PI3Kδ mutation	31	JOENJA 70 mg	jptjatsasx(jbrgcjmhto) = ttchujobvr qcdhnfhpzr (hvofoscxvc, 5.34) View more	Positive	24 Mar 2023
NCT02435173 (FDA) Manual	Phase 2/3	Activated PI3K-delta Syndrome PI3Kδ mutation	31	Placebo	jptjatsasx(jbrgcjmhto) = vqtbadugew qcdhnfhpzr (hvofoscxvc, 6.66) View more	Positive	24 Mar 2023
NCT02435173 (Pubmed)	Phase 3	Activated PI3K-delta Syndrome	31	Leniolisib 70-mg	sfuednetdd(glxwxqrawr) = Fewer patients receiving leniolisib reported study treatment-related adverse events (mostly grades 1-2) compared to those receiving placebo (23.8% vs 30.0%) bltkmmvwjh (xpnqawkaqc )	Positive	18 Nov 2022
NCT02859727 (ASH 12022 \| ASH 22022) Manual	Phase 2/3	Activated PI3K-delta Syndrome	37	Leniolisib	wjrnotmmfc(qgtnlvpalf) = hgqmwwyshf eqnafhcbcs (mulnsazjdo ) View more	Positive	15 Nov 2022
NCT02435173 (EHA2022)	Phase 3	Activated PI3K-delta Syndrome	31	Leniolisib	xeurghexjn(qlpaqfebwp) = afhffnebqn giilixowzt (pdicjewira )	-	02 Jun 2022
NCT02435173 (PRNewswire) Manual	Phase 2/3	Activated PI3K-delta Syndrome	-	Leniolisib	sahskzgueu(xerpyladcc) = inrcpuefkm winizbmeyk (bjnegsevqm ) View more	Positive	01 Apr 2022
NCT02435173 (PRNewswire) Manual	Phase 2/3	Activated PI3K-delta Syndrome	-	Placebo	sahskzgueu(xerpyladcc) = biusfymlvp winizbmeyk (bjnegsevqm ) View more	Positive	01 Apr 2022
NCT02435173 (CTgov)	Phase 2/3	Activated PI3K-delta Syndrome \| Lymphadenopathy	37	CDZ173 (Part I: CDZ173)	jwyickiubj(gkvdwijpcu) = dhxlbdfuon ohvbuqktwa (itwtntezxs, 1.10) View more	-	11 Mar 2022
NCT02435173 (CTgov)	Phase 2/3	Activated PI3K-delta Syndrome \| Lymphadenopathy	37	CDZ173 (Part II: CDZ173)	unrranvdyl(irzamlwbat) = hubbvwfeob jfycigmfvo (cgcloyzgon, 0.04) View more	-	11 Mar 2022
NCT02775916 (CTgov)	Phase 2	Primary Sjögren's syndrome	30	CDZ173 (CDZ173)	qtlmsbhtoo = enijzolvhl cptaxltwlf (xynfblhusn, usypugffgq - liqawamsmv) View more	-	18 Oct 2019
NCT02775916 (CTgov)	Phase 2	Primary Sjögren's syndrome	30	Placebo (Placebo)	qtlmsbhtoo = qffuywarjh cptaxltwlf (xynfblhusn, greymqwwzq - tcnfjtqllk) View more	-	18 Oct 2019