Pharming announced optimistic numbers at ASH's annual meeting

Pharming Group N.
V.
("Pharming" or the "Company") (Euronext Amsterdam: PHARM) (NASDAQ: PHAR) announces interim analysis data for its Open Label Expansion study.
The study evaluated the investigational drug leniolisib, an orally selective phosphoinositol-3 kinase δ (PI3Kδ) inhibitor, for the treatment of adults and adolescents with phosphoinositol-3 kinase δ hyperactivation syndrome (APDS), a rare primary immunodeficiency disorder
.
New evidence
is included in the announced data.
Principal investigator: V.
V.
Koneti Rao, a physician at the Primary Immunodeficiency Clinic at the National Institutes of Health in Bethesda, Maryland, USA, shared his optimistic findings
in an oral presentation at the 2022 American Society of Hematology (ASH) Annual Meeting.

Dr.
Virgil Dalm, principal investigator and consultant clinical immunology at Erasmus MC in Rotterdam, the Netherlands, commented:

"I am thrilled by the results of Pharming's findings, which further support the use of leniolisib as an investigational treatment that is well tolerated and benefits APDS patients
.
The results showed long-term tolerability of leniolisib, with a median duration of study treatment of just 2 years (102 weeks) and 5 participants receiving 5
years or more.
Patients with APDS often have recurrent infections and require lifelong immunoglobulin replacement therapy (IRT) to reduce this burden
.
It is worth mentioning that leniolisib treatment showed a significant reduction in annualized infection rates, with 37% of study patients treated with IRT able to reduce or completely discontinue their IRT treatment regimen
.
This is a remarkable achievement for any immunogenic birth error study, and through continued research on leniolisib, I look forward to contributing
to the knowledge of better treatment options for patients with APDS.
" "

The ongoing extended study included 37 patients with APDS aged 12 years or older who were treated with the 70 mg selective PI3Kδ inhibitor leniolisib twice daily for up to six years and three months at the data cut-off for interim analysis, with a median duration of study treatment of 102 weeks
.
The primary objective of the study was to evaluate the safety and tolerability of long-term leniolisib treatment in adolescent and adult patients with APDS who had previously participated in the phase II/III leniolisib study
.
The secondary endpoint of the extended study was to evaluate the efficacy and pharmacokinetics
of long-term leniolisib therapeutics in these patients.

The interim analysis found that leniolisib was well
tolerated by this point in the study.
The analysis also demonstrated the durability of efficacy results seen in randomized controlled trials, showing significant improvements
compared to placebo in the common primary endpoint of reduced lymph node size and increased naïve B cells.
Interim results suggest that patients with APDS often see good long-term effects
on immune dysregulation and deficiency (clinical manifestations including infection, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, higher risk of lymphoma, and early mortality).

Most adverse events (AEs) reported in the interim analysis were grade 1 and 2, including upper respiratory tract infections, headache, and fever
.
Grade 1 adverse events were the mildest and grade 5 were the most severe
.
Overall, 13.
5% of adverse events were related to study drugs; These adverse events affected five patients and included weight gain, arthralgia, hyperglycemia, and decreased
neutrophil counts.
For all adverse events assessed in the analysis, 16.
2% were classified as serious, but none were identified as related to
study treatment.
One of the study participants died and was determined not to be related
to the study treatment.

Among the study participants, some experienced a decrease in APDS disease markers, with varying levels of efficacy between individuals
.
Benefits include:

● Decreased lymphadenopathy and splenomegaly and decreased IgM levels

● Improvement or relief of anemia symptoms, thrombocytopenia and lymphopenia; and

● Neutropenia resolution
in all affected patients.

Importantly, 37% of participants who received immunoglobulin replacement therapy (IRT) were able to reduce IRT use
while taking leniolisib.
Six patients were freed from IRT dependence, and four of them had been IRT free for 1 to 2.
5 years
at the time of data cut-off.
As of the data cut-off for interim analysis, none of the three patients with a history of lymphoma prior to the trial had relapsed or new-onset lymphoma
at the time of study.

Anurag Relan, M.
D.
, Chief Medical Officer of Pharming, commented:

"Pharming is pleased to share the optimistic interim results
regarding the long-term safety and efficacy of leniolisib.
The results announced at the ASH Annual Meeting 2022 build on the results of Phase II/III studies announced earlier this year and published in Blood 1 in November 2022, which highlight the potential
of leniolisib in controlling the emergence of immune-related symptoms of APDS.
We are very proud to have developed a potentially first drug that targets the cause of APDS, helping to fill an unmet need
.
" "

The results of the interim analysis are consistent with data from the Phase II/III clinical trial first reported on February 2, 2022, which investigated leniolisib as a therapeutic agent for adult and adolescent patients with APDS
.
Patients in phase II/III clinical trials achieved a significant reduction in the size of the index lymph nodes and an increase in the percentage of naïve B cells in
peripheral blood compared to placebo.

Based on Phase II/III clinical trial results and long-term, open-label expansion data, the U.
S.
Food and Drug Administration (FDA) is prioritizing new drug applications for Pharming's leniolisib for the treatment of APDS in adolescents and adults, and has designated a March 29, 2023, Prescription Drug User Payments Act (PDUFA) target date
。 In addition, Pharming's marketing authorization application (MAA) for leniolisib for the same patient population has been validated
according to an accelerated evaluation by the European Food and Drug Administration (EMA) Committee for Medicinal Products for Human Use (CHMP).
It is expected to obtain marketing authorization for leniolisib in the EU in the first half of 2023
.

About phosphoinositide 3 kinase δ overactivation syndrome (APDS)

APDS is a rare primary immunodeficiency that infects approximately 1 to 2 people per million people
.
APDS is caused
by mutations in either of two genes that regulate white blood cell maturity (PIK3CD or PIK3R1).
Mutations in these genes result in overactivation
of the PI3Kδ (phosphoinositol 3 kinase δ) pathway.
Balanced signaling in the 2,3PI3Kδ pathway is essential
for physiological immune function.
When this pathway is overactivated, immune cells fail to mature and function properly, leading to immune deficiencies and dysregulation
.
2,4 The main features of APDS are severe recurrent sinus lung infection, lymphocyte proliferation, autoimmune and intestinal lesions
.
5,6 Because these symptoms may be associated with a variety of conditions, including other primary immunodeficiencies, patients with APDS are often misdiagnosed and suffer from a delay
in diagnosis of an average of 7 years.
7 Because APDS is a progressive disease, delayed diagnosis can lead to physical damage accumulating over time, including permanent lung damage and lymphoma
.
5-8 The only way to diagnose the disease is through genetic testing
.

About leniolisib

Leniolisib is a small molecule inhibitor
of the IA PI3K class 110 kDa catalytic subunit δ isomer.
PI3Kδ is mainly expressed in blood cells, and the conversion of phosphoinositol-4-5-triphosphate inositol (PIP2) to phosphoinositol-3-4-5-triphosphate inositol (PIP3) is essential
for normal immune system function.
Leniolisib can inhibit the production
of PIP3.
PIP3 acts as an important cellular messenger that activates AKT via PDK1 while regulating multiple cellular functions such as proliferation, differentiation, cytokine production, cell survival, angiogenesis, and metabolism
.
Unlike the commonly expressed PI3Kα and PI3Kβ, PI3K® and PI3Kγ are mainly expressed
in hematopoietic cells.
The central role of PI3K® is to regulate the cellular functions of the adaptive immune system (B cells and a small number of T cells) and the innate immune system (neutrophils, mast cells, and macrophages), which strongly suggests that PI3K® is a feasible and potentially effective therapeutic target for immune diseases such as APDS
.
To date, Leniolisib has demonstrated good tolerability
in both phase 1 first-in-human trials in healthy subjects and in phase II/III permissible registries in patients with APDS.

References

       1.
Rao VK, et al.
Blood.
2022.
https://doi.
org/10.
1182/blood.
2022018546.

2.
Lucas CL, et al.
Nat Immunol.
2014; 15:88-97.

3.
Elkaim E, et al.
J Allergy Clin Immunol.
2016; 138(1):210-218.

4.
Nunes-Santos C, Uzel G, Rosenzweig SD.
J Allergy Clin Immunol.
2019; 143(5):1676-1687.

5.
Coulter TI, et al.
J Allergy Clin Immunol.
2017; 139(2):597-606.

6.
Maccari ME, et al.
Front Immunol.
2018; 9:543.

7.
Jamee M, et al.
Clin Rev Allergy Immunol.
2019; May 21.

8.
Condliffe AM, Chandra A.
Front Immunol.
2018; 9:338.